MANAGEMENT GUIDELINES FOR ANXIETY

DISORDERS IN CHILDREN AND ADOLESCENTS

Prabhat Sitholey1 , Anil Nischal2

Anxiety disorders represent one of the most common categories of psychopathology in children and
adolescents. Apart from separation anxiety disorder, a well recognized problem of childhood, it is now
widely accepted that generalized anxiety disorder, social phobia, specific phobia, posttraumatic
stress disorder, obsessive compulsive disorder and panic disorder all occur during the childhood and
adolescent years. Numerous studies examining the nature and treatment of anxiety disorders have
appeared during the recent years. Significant advances in this area include the investigation of
pharmacological agents and development of effective psychosocial interventions. Prevalence rates
for having at least one childhood anxiety disorder vary from 6% to 20% over several large
epidemiological studies (Costello et. al., 2004). Co-morbidity is extremely common among children
and adolescent suffering from anxiety disorders. A recent study of children aged 8 - 13 years, having
a primary diagnosis of anxiety disorder revealed that 79% of the sample also had another co-morbid
anxiety disorder, mood disorder or behavior disorder (Kendall et. al., 2001). In view of such findings,
consideration needs to be given to co-morbidities as their presence will guide selection of specific
treatments.

The objective of these guidelines is to provide up-to-date information about management of anxiety
disorders. Literature was reviewed by a computerized search in the month of June 2007 using the
keywords child, adolescent, anxiety disorder, treatment, and management. The search covered a
period of 10 years (1997 through 2007).Articles retrieved and their relevant references were reviewed
for the purpose of framing these guidelines. The information has been presented in two sections -
Assessment and Treatment. Certain statements in this guideline are followed by abbreviations MS or
CG. MS stands for minimal standards and reflects that the statement is based on rigorous empirical
evidence while CG stands for clinical guidelines indicating that the statement is based on empirical
evidence and/or strong clinical consensus.

ASSESSMENT
Defining the boundary between extremes of normalcy and psychopathology is a dilemma that
pervades all psychiatry. In many cases of childhood anxiety disorder this dilemma is at its zenith. The
defining point for caseness is often ambiguous as many childhood anxieties are not only common but
also have an adaptive role in human development. It is strongly recommended that psychiatric
assessment of children and adolescents should routinely include screening questions about anxiety
symptoms [MS]. If the screening indicates significant anxiety, then the clinician should do a formal
evaluation to determine subtype of anxiety disorder, the severity of anxiety symptoms and functional

1. MD Professor and Head, 2. MD Assistant Professor, Department of Psychiatry, CSM Medical

University UP, Lucknow, India

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impairment [MS] (Connolly et. al., 2007). Anxiety may be considered symptomatic when it is impairing
and prevents / limits developmentally appropriate adaptive behavior. A useful rule for determining
diagnostic threshold is the child's ability to recover from anxiety and to remain anxiety-free when the
provoking situation is absent. The child's lack of flexibility in affective adaptation is an important
pathological indicator. In addition, the degree of distress and dysfunction associated with anxiety also
help in reaching a diagnosis. Anxiety disorders impair emotional, cognitive, physical and behavioral
functioning in multiple areas and are usually chronic in nature. Hence, the child needs to be evaluated
in context of his family, school, community, and culture. Important areas of assessment include
history of onset and development of anxiety symptoms, associated stressors, medical history, school
history, family psychiatric history and mental status examination. The psychiatric assessment should
always consider differential diagnosis of physical conditions & psychiatric disorders that may mimic
anxiety disorders [MS]. Early detection and effective treatment may reduce the impact of anxiety on
academic and social functioning in youth and may reduce the persistence of anxiety into adulthood.

INSTRUMENTS FOR ASSESSMENT

Earlier, determination of childhood anxiety largely relied on rating scales or interviews inquiring about
multiple unrelated fears and worries generating a count without a clear clinical meaning (Lapouse &
Monk, 1958). The emphasis has now shifted to the study of diagnostic groups that reflect explicit
clinical criteria. A comprehensive evaluation should include a detailed structured or semi structured
psychiatric interview to establish the anxiety disorder diagnosis and detect co-morbid psychiatric
disorders. In addition, clinical rating scales, self report scales and parent report instruments may be
used to determine the type and severity of anxiety symptomatology. This practice also allows for
monitoring of these symptoms over time.

Over the last two decades there has been a proliferation of instruments to determine the presence of
anxiety disorders in children or quantify levels of anxiety. Assessment instruments include paper-
and-pencil scales for children, parents and teachers, as well as child and parent interviews.
Interested readers are referred to a review of commonly used instruments by Brooks & Kutcher, 2003.
An overview is provided below.

Rating scales:
Rating scales serve diverse purposes. They are used to screen large groups, to examine the relative
contribution of genetics and environment, to assess severity and as outcome measures of treatment
efficacy. Rating scales that anteceded the present nosology of anxiety disorders were designed to
assess a plethora of factors such as worry, physiological anxiety, fear of bodily harm, etc. rather than
anxiety syndromes. These include the Revised Children's Manifest Anxiety Scale (RCMA; Reynolds
&Richmond, 1985), the State Trait Anxiety Inventory for Children (STAIC; Spielberger, 1973) and the
Revised Fear Survey Schedule for Children (FSSC-R; Scherer and Nakamura 1968; Ollendick 1983).
In addition, the Child Behavior Checklist (CBCL; Achenback 1991) which generates a non specific
factor of emotional disturbance, called the internalizing factor" may be used as a rating scale.

The limitations of the older rating scales and increasing interest in childhood anxiety disorders has
led to development of more sensitive and diagnostically relevant measures of childhood anxiety.
Recent efforts reflect the classification of anxiety disorders and a move towards specificity of content,
with relevance to diagnostic grouping. Newer scales devised with these considerations include the
Social Anxiety Scale for Children (La Greca et.al., 1988; La Greca & Stone, 1993) and for
Adolescents( La Greca & Lopez, 1998), the Multidimensional Anxiety Scale for Children (MASC;
March et. al., 1997; March & Albano,1998) and the Screen for Child Anxiety Related Emotional
Disorders (SCARED), which has a parent version also (Birmaher et. al.,1997; Monga et. al., 2000).
The MASC and SCARED appear to be promising for clinical purpose according to Research Unit on

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Pediatric Psychopharmacology Anxiety group study, 2001.

A major clinical challenge is to differentiate between anxiety and depression. Anxiety scales do not
adequately distinguish between children with anxiety disorders and those with other diagnosis (Klein,
1994). Therefore, though anxiety scales may provide an overall estimate of anxiety levels, they
cannot be viewed as contributing to the diagnosis of anxiety disorders, and clinicians would be
unwise to rely on them only for differential diagnostic decisions.

Diagnostic Interviews:
Several systematic diagnostic interviews for children and for parents as informants have been
devised to meet different purposes and vary accordingly. The Diagnostic Interview Schedule for
Children (DISC; Shaffer et. al, 1996) was developed for use in epidemiological studies. It is highly
structured and can be used even by individuals who have no clinical training. A computer based
version is also available. The Diagnostic Interview for Children and Adolescents (DICA; Herjanic &
Reich, 1982; Reich et. al., 1991) is another highly structured instrument. The Child and Adolescent
Psychiatric Assessment (CAPA; Angold & Costello, 1995) also devised for epidemiological studies,
requires adequate training as it is less structured than DISC. The CAPA, in comparison to other
instruments, additionally covers assessment of functioning in school, social relationship, etc. along
with specific symptoms, allows for clarification of questions and more closely resembles usual clinical
interview. The Kiddie Schedule for Affective Disorder and Schizophrenia (K-SADS) has been
developed from a clinical perspective. Its present and lifetime version allows full latitude of inquiry.
(Chambers et. al. 1985, Kaufmen et al, 1997). The Anxiety Disorder Interview Schedule for Children
(ADIS) originally prepared to assess anxiety disorders has been expanded to provide diagnosis for
other major disorders. This can be employed to collect detailed information in a flexible clinical fashion
(Silverman & Albano 1996).

All the instruments described above have demonstrated modest to adequate test-retest reliability
with anxiety disorders faring no better or worse than most other diagnosis. There is little to guide
selection of instruments in terms of better reliability or validity but the DISC is the most widely used
worldwide.In Lucknow K-SADS-PL (Kaufmen et al, 1997) is the preferred tool. We understand that
many of the above mentioned tools not be available easily, others might not be suitable for use in
Indian population due to variety of reasons. The authors recommend use of K-SADS for diagnostic
assessment, CGI for severity evaluation and CGAS (Shaffer et al, 1983) for global assessment of
functioning as a minimal standard. Additionally, DOTES may be used for monitoring medication side-
effects (Campbell et al, 1985). Although conceived for research purposes, diagnostic interviews may
be useful to clinicians as they provide a comprehensive coverage of symptomatic status, are
excellent teaching tools and allow comparisons. In the end it needs to be said the though many
instruments are available all of them have not been conclusively shown to distinguish between
various anxiety disorders or anxiety disorders and other child psychiatric disorders. As such, a
sufficient level of precision for diagnostic classification has not been reached. Available evidence
only supports the diagnostic validity of social phobia but not other disorders.

OUTLINE OF DIAGNOSTIC ASSESSMENT

A. Obtain history from parents, patient, and other pertinent informants.

1. Note onset and development of symptoms and the context in which symptoms occur and are
maintained.
a. DSM - IV target symptoms, with particular attention to the following:
i. Determination of whether anxiety is stimulus specific, spontaneous, or anticipatory.
ii. Evaluation for avoidant behavior (degree of constriction of daily life).

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 b. Biopsychosocial stressors.
c. Co morbid psychopathological symptoms, maladaptive personality traits, and internal
conflicts.
d. Impact of symptoms on the daily life of the patient and family.
e. Social and familial reinforcers of symptoms.
2. Emphasize developmental history with special consideration of the following:
a. Temperament
b. Ability to sooth self or be soothed.
c. Quality of attachment.
d. Adaptability.
e. Stranger and separation responses.
f. Childhood fears.
3. Obtain medical history, especially noting the following:
a. Numbers of visits to physician or emergency room for these or other symptoms.
b. Medications taken by the patient that could produce anxiety symptoms.
c. Medical disorders
4. Obtain school history.
a. Academic, athletic, social and behavioral functioning.
b. Disparity between potential and actual achievement.
c. Patterns of attendance.
5. Obtain social history.
a. Environmental stressors such as disorganized home, presence of child abuse
(physical, emotional or sexual) or neglect, mental or physical illness or death in family
members, or exposure to danger or violence.
b. History of separations and losses.
c. Degree of involvement with peer group and social competence.
6. Obtain family history with particular attention to the following:
a. Patient's past and present role in the context of family functioning.
b. Family stresses, resources, and coping style.
c. Family psychiatric history with emphasis on the following:
i. Anxiety disorders (including obsessive compulsive disorders).
ii. Mood disorders.
iii. ADHD.
iv. Psychoactive substance use disorders.
v. Tic disorders.
vi. Psychotic disorders.
vii. Suicidal behavior.

B. Interview the patient, including a mental status examination with special note of the
following:
1. Patient's reports of symptoms, including self-assessment of impairment.
2. Objective signs of anxiety, including motor tension, autonomic hyperactivity, vigilance and
scanning, variations in speech patterns and production and separation difficulty.
3. When developmentally appropriate, communication of anxiety through play and drawings.
Play techniques can be used to understand a child fears and reasons for anxiety.

C. Conduct family assessment.

1. Evaluation of family interactions and dynamics.
2. Assessment of parent -child relationship.

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D. Administer structured or semi structured interview for anxiety and comorbid diagnosis.

E. Administer clinical, self-report, and parent-report instruments for severity of anxiety

symptoms.

F. Refer for IQ and psychological testing if indicated clinically and for learning disability,
and speech and language testing if required and facilities are available.

G. Conduct physical evaluation of the child or adolescent.

1. Physical examination.
2. Consultation and collaboration with family practitioner, pediatrician or other specialties
as per need.
3. Evaluation of medical and neurological conditions as indicated. (See sec II.A below)

DIFFERENTIAL DIAGNOSIS

A. Consider physical conditions that may mimic anxiety disorders.

1. Documented hypoglycemic episodes.
2. Hyperthyroidism.
3. Cardiac arrhythmias
4. Caffeinism.
5. Pheochromocytoma.
6. Seizure disorders.
7. Migraine.
8. Central nervous system disorders (e.g., delirium or brain tumors).
9. Medication reactions: antihistamines, antiasthmatics, sympathomimetics, steroids,
SSRIs, anti-psychotics (akathisia), and nonprescription preparations, including diet pills
and cold medicines.

B. Screen for psychiatric disorders that may be comorbid with or misdiagnosed as anxiety
disorders.
1. Mood disorders.
2. ADHD.
3. Adjustment disorder.
4. Substance use disorders, including alcohol, nicotine, marijuana, cocaine, stimulants,
inhalants, and hallucinogens.
5. Borderline or other personality disorders.
6. Eating disorders.
7. Somatoform disorders.
8. Tic disorders.
9. Trichotillomania.
10. Reactive attachment disorder.
11. Pervasive developmental disorders.
12. Schizophrenia.
13. Sleep Terror Disorder.

C. Establish diagnosis of specific type of anxiety disorder. More than one may be present.

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 1. Anxiety disorder beginning in childhood and adolescence: separation anxiety disorder.
2. Anxiety disorders affecting children, adolescents and adults.
a. Generalized anxiety disorder (inclusive over-anxious disorder of childhood).
b. Specific phobia.
c. Social phobia.
d. Panic disorder.
e. Obsessive - compulsive disorder.
f. Posttraumatic stress disorder.

Treatment
The evidence that childhood anxiety disorders cause suffering and impairment and may entail long
term liability highlight the need for effective treatments. Some interventions, such as CBT, are based
on theoretical models of anxiety while others such as medication, follow demonstrated efficacy in
adult anxiety disorders. Child and adolescent psychiatrists usually employ an integration of several
approaches in treating patients with anxiety disorders. In general, treatment planning should
consider severity of and impairment produced by the anxiety disorder. A multimodal approach is
advisable and psychotherapy should be considered an integral part of the management of childhood
anxiety disorder [CG] (Connolly et. al., 2007). Literature is replete with case reports and studies
evaluating various approaches. Wherever controlled studies are available, case reports have not
been considered in framing the recommendations. We initially brief the different approaches followed
by disorder-specific recommendations.

BEHAVIOR THERAPY:
Behavior therapy targets the patient's overt behavior and emphasizes treatment in context of family
and school instead of focusing on intrapsychic conflicts. (Bernstein et. al., 1997). Etiology is not the
focus of attention (Kazdin, 1991).Two comparative studies demonstrate efficacy of behavior therapy
(systematic desensitization) in treatment of children with school refusal. (Miller, 1972; Blagg and Yule,
1984).

CONGNITIVE BEHAVIOUR THERAPY:

CBT is the most well studied intervention. It integrates the behavioral approach with an emphasis on
changing the cognitions associated with the patient's anxiety. The basic notion is that distorted
cognitions about the dangerousness of the environment underlie anxiety symptoms. The aim is to
replace negative beliefs with more neutral realistic ones. The technique encourages the patients to
restructure their thoughts into a more positive framework resulting in more assertive and adaptive
behavior (Bernstein et. al., 1997). Cognitive interventions include identifying anxious feelings and
thoughts, recognizing somatic responses to anxiety, and devising a plan to deal with these
symptoms. Behavioral interventions include modeling, role-playing, relaxation techniques, exposure
and rewards. CBT has been used for a variety of childhood anxiety disorders and is said to be
effective (Roblek & Piacentini ,2005; Cartwright-Hatton et. al., 2004). Another major advantage of
CBT is availability of treatment manuals that allow comparison across studies. The controlled studies
of CBT may be divided into those that have used a no-treatment waiting list control group, and those
that have compared CBT to a non-specific control intervention. Early trials often used waiting list
controls. The problem with this methodology was that this confirms to patients that they require
treatment, but withholds it. Another limitation is that this control does not reveal the specific
usefulness of an intervention, because there is no way of determining whether treatment was
effective because of its particular nature, or because of non-specific factors such as therapist's
interest and concern, or the family mobilizing itself to bring the child for treatment. Even if control
psychotherapy is used, it should be equivalently appreciated by recipients, so that treatment effects

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are not due to difference in treatment credibility. The most informative studies are those which rely on
a comparison treatment that is reasonable and credible i.e. use attention controls. CBT was
examined in two systematic studies by Kendall (Kendall 1994, Kendall et al. 1997) and he reported
that the group receiving CBT had significantly better outcome. However, two other studies of CBT
using attention controls reported no difference in efficacy (Last 1998; Silverman et. al., 1999). Other
studies have examined parental involvement (Bernstein et. al.,2005, Spence et. al., 2000,
Mendlowitz et. al. 1999) and report benefits of the same. In a study on family cognitive behavioral
therapy for childhood anxiety disorders Wood et. al., 2006 report that family CBT may provide
additional benefit over and above child-focused CBT. These findings provide preliminary support and
encourage further research in parental participation in treatment for childhood anxiety. Many other
studies are available, most of them suffer from methodological limitations, but there is evidence of
improvement which is sustained over time (Kendall et al. 1996, Barrett et al.2001, Kendall et al. 2004).
A recent review of CBT studies concluded that cognitive behavioral therapy appears an effective
treatment for childhood and adolescent anxiety disorders in comparison to waiting list or attention
control. There was no evidence for a difference between an individual, group or parental/family
format. CBT can be recommended for the treatment of childhood and anxiety disorders, although with
only just over half improving, there is a need for further therapeutic developments (James et. al.,
2005).

PSYCHOANALYSIS AND PSYCHODYNAMIC PSYCHOTHERAPY:

Clinical data on psychoanalysis consists largely of case reports and most accounts report favorable
results. Systematic studies of psychoanalysis (Heinicke and Ramsey-Klee, 1986; Target and
Fonagy,1994) relevant to childhood anxiety disorders report improved capacity for relationships,
frustration tolerance, balanced use of defenses and improvement in adaptation.

Psychodynamic psychotherapy is a derivative of psychoanalysis with modifications such as less

frequent appointments, greater participation of parents in treatment, and more explicit use of active
support, practical guidance and environmental interventions (Bemporad, 1991). Anxious children
generally benefit from mastering themes of separation, autonomy, self-esteem, and age appropriate
behavior (Bernstein et al., 1997). Studies documenting efficacy in children are available (Muratori et.
al.2003, Barett et. al., 1998, Hampe et al 1973, Miller et al, 1972). Overall, it is an effective but time
consuming approach. Until recently this approach was widely practiced and accepted but has been
overtaken by CBT now.

PARENT CHILD INTERVENTIONS AND FAMILY THERAPY:

Early temperamental traits of passivity, shyness, behavioral inhibition, fear & withdrawal in unfamiliar
situations and insecure mother-child relation have been associated with increased risk of developing
anxiety disorders during childhood (Capsi et al, 1995; Kagan et al 1988; Biederman et al, 1993;
Warren et al, 1997; Prior et.al. 2000; Williams et. al. 1990). Therefore, attention to temperament and
parent- child relationship is vital. Parent child interventions include helping parents encourage the
child to face new situations, refraining from excessive criticism and intrusiveness, responding to
child's emotional needs and encouraging child to engage in activities despite anxiety (Ginsburg et.
al.,2002; Barrett P M, 1996; Crawford et. al. 2001).
Family theory views anxiety symptoms in interpersonal terms and postulates that anxiety
symptoms reflect problems in the family system (Last et. al. 1991). Bernstein et al .1990 in a study of
76 families identified family difficulties in areas of role performance, values and norms. It has been
suggested that working with the family is a key to decrease anxiety symptoms experienced by the
child. The aim of the therapy is to disrupt the dysfunctional family interactions that promote insecurity
and to support areas of family competence (McDermott et. al. 1989).

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PHARMACOLOGICAL TREATMENT:
Pharmacotherapy should preferably be used as adjunct to behavioral or psychotherapeutic
interventions rather than as a sole intervention. This approach is important to prevent symptom return
after discontinuation of medications. SSRI's have been extensively used for adult anxiety disorders
and have documented safety and efficacy. Although several open trials of SSRI's in children have
appeared, the most important study till date is a large multicentric, placebo controlled study
(Research Unit on Pediatric Pharmacology Anxiety Group, 2001) documenting efficacy of
fluvoxamine in children with mixed anxiety disorders (Social phobia, separation anxiety and
generalized anxiety disorder), without major depression. 79% of the children on medication
improved, as compared to 28% on placebo over a period of 8 weeks. Williams & Miller, 2003 after
reviewing evidence state that the serotonin selective reuptake inhibitors should be considered first-
line pharmacological treatment for anxiety disorders in children and adolescents [CG]. However,
medications other than SSRIs may also be considered for treatment of anxiety disorders in children
and adolescents [CG]. Klein, 1994 in his review of literature on TCAs states that the support for the
efficacy of TCAs in children with separation anxiety is inconsistent. Bernstein el. at., 2000 reported
efficacy of imipramine compared to placebo in adolescents with school refusal and anxiety disorders.
Although there are reports supporting efficacy of benzodiazepines in childhood anxiety disorders,
the safely profile of SSRIs and evidence of their recent usefulness weaken consideration of
benzodiazepines. However, they may be used on short term basis for immediate respite from anxiety
symptoms. Less commonly buspirone and -blockers may be employed if required. At this time, there
are no specific dosing guidelines for children and adolescents with anxiety disorder. Experts
recommend starting at low doses, monitoring side effects closely, and then increasing the dose
slowly on the basis of treatment response and tolerability. Clinicians need to appreciate that anxious
child and anxious parents may be especially sensitive to any worsening in the child's somatic
symptoms or emergence of even transient side effects of medications. Selection of medication is
guided by several factors, primarily co morbidity and side effect profile (Connolly et. al., 2007).

DISORDER SPECIFIC RECOMMENDATIONS

Separation Anxiety Disorder, Generalized Anxiety Disorder and other Anxiety Disorders:
Majority of pharmacological studies of children and adolescents with anxiety disorders enroll a mixed
diagnostic group including with SAD, GAD and/or Social phobia. Several trials support efficacy of
SSRIs in treatment of anxiety disorders in children. Efficacy and safety of fluovoxamine & Paroxetine
in children and adolescent with SAD, GAD and/or social phobia, of sertraline for youth with GAD, and
of fluoxetine for youth with SAD, GAD and/or social phobia has been documented in well designed
trials (Reinblatt et.al.,2007; Seidel et.al.,2006; Muller et. al., 2005; Wagner et.al.,2004; Birmaher et. al.
2003; Brent D A, 2003; Pine DS, 2002; RUPP study, 2001; Rynn et. al. 2001). The most common side
effects reported were abdominal discomfort and headache. No major problems were reported.
Currently, an SSRI is the first line choice medication for children and adolescent with anxiety
disorders, including those with SAD. Fluoxetine has also been reported to be clinically effective as
maintenance treatment of anxiety disorders in children and adolescents (Clark et. al., 2005).
Preliminary findings from controlled trials of extended release venlafaxine in treatment of youths with
generalized anxiety disorder (Rynn et. al.2002, Rynn et. al.2007) and social phobia (Tourian
et.al.2004) suggest it may be well tolerated and effective. Tricycles antidepressants are an alternative
choice. However, scientific data for this group is much less convincing than that for SSRI's. Controlled
studies for TCA's in SAD and/or school refusal report contrasting findings (Bernstein et. al. 1996). A
study comparing CBT + Imipramine and CBT + placebo for adolescent school refusal with co-morbid
anxiety and depression reported response rate of 70% and 28% respectively after 8 weeks of
treatment. The point to be noted is that these patients did not suffer from pure anxiety problems
(Bernstein et. al. 2000). Use of BZD's in treatment of youth with anxiety disorders is backed by limited

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data. Due to dependence potential this class of medications is reserved for short term use, typically in
combination with an SSRI's or TCA while waiting for the onset of therapeutic effect of SSRI / TCA. It
has been recommended that the SSRI should be continued for approximately one year after
remission of target symptoms. Subsequently, during a low stress period a watchful medication free
trial may be given. If relapse occurs SSRI should be immediately reinstated (Pine D S, 2002).

In terms of psychotherapeutic interventions, CBT has the greatest empirical support (Albano et. al.,
2002; Bernstein et. al., 2000; Dadds et. al. 2001; Velting et. al. 2004; Barrett PM, 1998; Kendall et. al.
1996; Last, 1998). The common components are 1. Education about nature of anxiety. 2. Activities to
increase recognition of anxious thoughts and feelings. 3. Coping strategies such as adaptive self talk
(cognitive-modification), progressive muscular relaxation and diaphragmatic breathing, and 4.
Exposure to anxiety-provoking stimuli. The role of family therapy as a positive addition has also been
documented along with efficacy in group format for SAD, GAD and social phobia (Barrett et. al. 1996;
Dadds et. al. 2001; Kearney et. al. 2003). Data strongly supports short term efficacy of group/
individual CBT and SSRI's for youth with anxiety disorders. In anxiety disorders of mild severity, CBT
should be initiated first, followed by SSRI in case of non-response. In practice, the two approaches
are often combined for severe, impairing anxiety disorders. In cases of Generalized Anxiety Disorder
CBT or CBT plus medication both are appropriate approaches based on severity of the case.
Medication alone is not recommended. In mild to moderate cases CBT alone usually suffices
(Connolly et. al., 2007).

Social Phobia:
CBT and SSRIs are the first line treatments. To our knowledge there is no published study examining
efficacy of SSRIs in a sample of pure social phobia. However, studies of CBT in such samples are
available and report CBT to be effective (Dadds et. al. 2001; Velting et. al. 2004; Beidal et. al. 2000).
Depending on presentation, treatment may begin with CBT alone or CBT plus an SSRI (Mancini C. et.
al., 2005). CBT here consists of social skills training, increased social opportunities, relaxation
techniques, adaptive self-talk (cognitive restructuring), exposure and response prevention.
Individual, group and school-based all interventions have found to be effective (Albano et. al. 1999;
Masia et. al. 2001; Baer et. al. 2005)

Specific Phobia:
Treatment for specific phobias differs from CBT of SAD, GAD and social phobia. It primarily involves
graded exposure to the feared stimuli, imaginary or actual, according to hierarchy constructed by the
child progressing gradually from mild to most significant fears (Velting et. al. 2004). When exposure is
paired with relaxation the technique is referred to as systematic desensitization. Other treatments
include modeling, and cognitive exercises to facilitate adaptive thoughts. These also can be paired
with graded exposure. Outcome studies report significant and sustained improvement with these
approaches (Muris et. al. 1999; Bernstein et. al. 2005; Silvermann et. al. 1999; Berman et. al. 2000).

Panic Disorder:
CBT again is the first line of treatment. Components include 1. Education about the physical
experience associated with panic attacks. 2. Breathing and relaxation exercises. 3. Interceptive
exposure (i.e. exposure to cues associated with panic). 4. In vivo exposure. 5. Cognitive modification
to reduce catastrophic misinterpretation. Ollendick, 1995 reported efficacy of this approach in a
multiple-baseline design analysis. In practice an SSRI may be added to CBT (Masi et. al. 2001). Masi
et. al. 2006 after reviewing the empirical evidence of pharmacotherapy in early-onset panic disorder,
including selective serotonin re-uptake inhibitors, benzodiazepines and tricyclics conclude that the
data supporting efficacy are still limited, and no controlled studies are available. Research in this area
is wanting.

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Posttraumatic Stress Disorder
Although only some of the children and adolescents exposed to traumatic life events develop full-
blown posttraumatic stress disorder, many others experience some PTSD symptoms and associated
functional impairments. A variety of psychopharmacological and psychosocial treatments are
currently available for this group of anxiety disorders but the effectiveness of most of those
interventions has not been adequately evaluated. Only trauma-focused cognitive behavioral
interventions and SSRIs enjoy empirical evidence of efficacy.

Psychotherapeutic treatments:
Trauma-Focused CBT: Widely regarded as the first line treatment for PTSD. Several RCTs proving
trauma focused CBT to be superior to other treatment are available. It decreases PTSD, depressive
and behavioural symptoms, and /or functional impairment in traumatized children. Majority of
research has been done on sexually abused children (Cohan et al, 2004). Typically 10-16 treatment
sessions are given. The major components of this treatment are
- Psycho education about traumatic reactions and PTSD
- Stress-inoculation- including affective modulation, muscle relaxation, focused
breathing, thought stopping, and cognitive coping techniques.
- Gradual exposure- consisting of carefully calibrated efforts to encourage the child to
recall and describe increasing details about the traumatic events as well as thoughts,
feelings and physical sensations experienced at the time of the original trauma as well
as during retelling.
- Cognitive processing
- Parental treatment component
Eye Movement Desensitization And Reprocessing (EMDR): Variant of trauma focused CBT, in
which exposure and cognitive reprocessing interventions are paired with directed eye movements;
fewer sessions are required.
Crisis Intervention: Consist of one to three sessions provided in the immediate aftermath of a
traumatic event. It is often provided in a community setting and includes encouragement to discuss
feelings, provision of emotional support and psycho education about common reaction to stress and
advice about managing these reactions.
Play Therapy: Therapists do not direct the form or content of child's play but rather interpret
themes in it thought to be representative of certain inner conflicts.
Other Techniques
Psychodynamic & psychoanalytical technique
Parent-child interaction therapy
Dialectical behaviour therapy
Relationship based conjoint parent-child treatment

Pharmacological treatment:
The data supporting efficacy of pharmacotherapy in early-onset panic disorder, including selective
serotonin re-uptake inhibitors, benzodiazepines & tricyclics is limited (Masi et. al.,2006). Only one
randomized trial has been conducted. This study evaluated the comparative impact of imipramine vs
chloral hydrade on development of PTSD in acutely burnt children and demonstrated the efficacy of
imipramine (Robert et. al, 1999). Several open trials have demonstrated clinical improvement with
adrenergic blockers (PPNL), clonidine, dopamine antagonists (risperidone) and opiates. In practice
SSRI's, TCA's, venlafaxine, bupropion or any of the above mentioned medications may be used. No
information is available with regard to optimal length of treatment, need for maintenance treatment or
use of multiple medications in treatment of childhood PTSD.

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Obsessive Compulsive Disorder:
It is now being increasingly appreciated that although OCD in children is often chronic and can be
severe, the outlook for patients receiving prompt diagnosis and appropriate treatment is quite
positive. Considerable progress has been made in testing and refinement of both pharmacological
and psychosocial treatments. Both forms of treatment are very effective in symptom relief and
produce improvements in functioning, Clinical consensus suggests that combined treatment has
added benefits. Treatments should begin with educating the family of the child about how to handle
their child's behavior, which may be disrupting family life. On the internet www.ocdresource is a useful
source of information about the disorder. If the disorder is hampering school performance, teachers
need to be told about the child's problem and if possible be involved in the child's behavioral program.
Choice of first line therapy depends on the symptom pattern, severity, and the patient's and family's
preference. Whatever is used, it is important to urge flexibility, as combination therapy may be
eventually required.

Cognitive-Behavior Therapy:
The technique of CBT needs to be modified in accordance with the developmental age of the child.
CBT for pediatric OCD basically encompasses three techniques
1. Exposure and Response prevention
2. Cognitive therapy and
3. Relaxation training.

ERP is the most recommended and effective approach. Cognitive therapy, which involves changing
false beliefs, challenging reality of obsessions and necessity of compulsions, is usually ineffective as
a sole treatment for OCD. However, it is a useful complement in most cases. Relaxation therapy is
primarily used to manage anxiety produced by exposure but has no direct affect on O.C. Symptoms.
Older children and adolescents respond well to CBT modeled on approaches used for adult OCD.
However, younger children require a number of modifications. These include additional efforts to
educate child and family about the nature of excessive anxiety and the role of treatment, sensitizing
the child to the impact of OCD on his/her life and fostering motivation for change through his/her co-
operation and perseverance in treatment, building a shared language to better communicate the
nature of associated feelings or cognitions, and including behavioral rewards for maintaining
engagement in treatment. Manuals for modified CBT for OCD suitable for children are available.
Methodology, though undergoing continued refinement currently involves.
1. Daily exposure to cues avoided because of associated discomfort and rituals, and
2. Maintaining exposure and not ritualizing for at least an hour or until discomfort subsides.

Developmentally modified forms of CBT for children appear to confer similar benefits in children as
observed for adult population (O'Kearney et. al., 2006). Uncontrolled trials of CBT appear highly
promising, with excellent response in up to 75% of the patients. Although, gains from ERP persist
beyond discontinuation, booster treatment may help long term progress, and additional treatment
may be needed for relapses brought on by stress. O'Kearney et. al., 2007 after reviewing evidence on
benefits of cognitive-behavioural therapy for children and youth with obsessive-compulsive disorder
report that CBT should be regarded as a first line equivalent to anti-OCD medication with the potential
to lead to better outcomes when combined with medication than medication alone can provide.
Additional studies are needed to further clarify CBT's benefits and to investigate how it can be made
more available as a treatment option for children and youth who suffer from OCD.

Pharmacological Treatment:
Although pediatric trials of SSRIs have lagged behind those in adults, there is now extensive
substantiation of the utility of pharmacotherapy in pediatric OCD. An initial trial of Serotonin Reuptake

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Inhibitor (SRI), most often an SSRI is the treatment of choice. If there is inadequate response at 10-12
weeks, another SSRI may be tried.

Serotonergic Agents:
Clomipramine was the first agent shown to be effective in O.C.D. A meta-analysis suggested that it
may possess greater efficiency for pediatric OCD than the SSRIs (Allen, 1994; Practice Parameters
for OCD, 1998). De Veaugh-Geis et.al, 1992 documented the efficacy of clomipramine in pediatric
O.C.D in randomized controlled trial. However, being a tricyclic, it is associated with significantly
greater risk of side effects and therefore is relegated to a second or third line treatment choice in
children and adolescent with OCD. The evidence base supporting the efficacy and safely of SSRIs
has considerably strengthened over the last few years (Geller et. al. 2004; Geller et. al. 2003; Practice
Parameters for OCD, 1998). Anti-obsessive efficacy of fluoxetine, fluvoxamine and sertraline has
been reported by controlled trials (March et.al.1998 Geller et. al. 2002; Liebowitz et. al. 2002, Riddle
et. al. 2001). Similar benefits have been reported for Paroxetine (Geller et. al. 2003) and for
Citalopram (Mukkades et. al. 2003). Low initial doses, with slow upward titration, are the rule.
Patients should be told trials of more than one agent may be required, at times with augumenting
agents. In controlled trials reduction in baseline symptom rating with treatment of upto 16 weeks has
been relatively consistent, although modest, ranging from 18 to 44 percent (Geller et. al. 2003; Geller
et. al. 2002; Liebowitz et. al. 2002; Riddle et. al. 2001). Studies including long term observation report
continued symptom reduction upto one year. Data suggests that treatment benefits with SSRIs are
stable and can be expected to strengthen in many with continued treatment. Overall, SSRIs have
been found to be well tolerated by child and adolescent patients with OCD. However, almost 50% of
the children and adolescents treated with an SSRI continue to have interfering symptoms and may
require trials of alternative SSRIs, combined pharmacotherapy and addition of psychotherapeutic
interventions.

Augmenting Strategies and Adjunctive agents:

Up to 50% childhood OCD cases show no or partial response to SRI treatment, even if two different
SRIs are used (Geller et.al ,2003). Hence, augmentation strategies may be required. There are no
randomized controlled trials of the utility of augmentation strategies in Pediatric OCD. However,
based on experiences in adult patients, augmentation of an SRI might be considered for pediatric
patients with a partial response or intolerance to higher doses. In adults, three agents, Clonazepam,
Haloperidol, and Risperidone (Mc Dougle et.al., 1995; Pigott et.al.,1992) have been shown to be
effective in controlled trials. These agents are worth a try. Another strategy, addition of a second
concurrent SRI, has been used to a limited extent in children. An open table trial of six adolescents
(Simeon et.al. 1990) combined fluoxetine and clomipramine and reported decreased doses
requirement for both medications and fewer side effect. Figueroa et.al., 1998 described an open
series of seven patients given clomipramine and SSRI (fluoxetine, sertraline or paroxetine) and
followed through 5-22 months. Combination therapy appeared to be more effective than
monotherapy for all cases. Adjunctive treatment may be indicated for children and adolescent with
OCD with comorbidities. The comorbidity of tic disorders may require the addition of a-agonists or
neuroleptics. Co-morbid anxiety symptoms are benefited by addition of BZDs or Buspirone.
Depressive Symptoms may improve with lithium addition.

Treatment Planning:
Many experts and consensus guidelines recommend CBT as the first line approach for the majority of
children and adolescents with OCD. However, more severe symptoms, comorbid depression or
limited cooperation may prompt the clinician to consider medication alone or in combination with CBT.
One half or more of the young patients with OCD usually require combined therapy at some point of

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time to achieve complete remission. OCD is often chronic and long-term medication treatment is
often required to maintain symptom control (Leonard et.al. 1991). Whenever discontinuation is
attempted, tapering should be gradual usually over several weeks. Long term (indefinite) drug
maintenance is suggested after 2-4 relapses. Concomitant CBT has been observed to assist
medication discontinuation in some patients (Stanley & Turner 1995; Wever & Rey 1997). Periodic
resumption of CBT may be necessary to combat symptom exacerbation in response to stress or
development transitions. In general, OCD in children & adolescent is very responsive to treatment.
Majority of patients should experience significant relief and return to functioning. Reducing delays in
diagnosis and aggressive treatment, often with combined approaches goes a long way in minimizing
impact of the disorder on children development.

Selective Mutism:
Data on treatment of selective mutism is mostly limited to single case studies. Controlled trials are
lacking. In spite of this, the conviction that behavioral techniques are an essential component of
management of selective mutism is widespread. Reports describe successful use of techniques such
as contingency management, stimulus fading, systematic desensitization, negative reinforcement
and shaping. A combination of behavioral techniques is probably the most common and successful
treatment approach (Anstending K, 1998; Dow et. al. 1995; Holmbeck et. al. 1992; Watson et. al.
1992). A hierarchy of situations in which the child has difficulty speaking is prepared. Then, the child is
guided to systematically engage in speaking- related behaviors (e.g. mouthing speech, making
sounds , whispering and so on.) in increasingly more difficult situations. With repeated attempts,
associated anxiety dissipates through autonomic habituation. When the feared consequences of
speaking fail to occur anxiety is further reduced. Typically, child is given rewards after attempts to
engage in desired behaviors. The young age of most children with selective mutism and the fact that
most of these children initially do not speak to the therapist necessitates parental involvement in
treatment. Traditional anxiety-reducing behavioral techniques like shaping, gradual exposure and
reinforcement are often used in initial sessions. Involvement of school personnel for providing regular
communication and support in school is also highly recommended.

Other Psychosocial therapies:

Although behavior therapy is most commonly employed, accounts of successful treatment of
selective mutism with use of play therapy, family therapy, psychodynamic therapy, and group therapy
are also available (Watson et.al. 1992; Tatem et.al. 1995; Dow et. al.; Bozigar & Hansen, 1984;
Anstendig et. al. 1998). These strategies may be used as per need. It is common for children with
selective mutism to have some degree of speech or language difficulties which exacerbate speech-
related anxiety. In such cases speech therapy should be considered as an adjunct to other
interventions.

Pharmacological Treatments:
SSRI medications appear to be effective. A double-blind, placebo controlled trial of fluoxetine in
children with selective mutism indicated significant benefit (Black & Uhde, 1995). In addition,
fluvoxamine was also found to be efficacious in a large multicentric study of anxiety disorders (RUPP
Anxiety Group Study, 2001). Several open trials and case reports also support the use of SSRIs for
selective mutism (Cartson et.al. 1999; Dow et. al. 1995). As of now, behavior therapy when available
and practical should be considered the initial intervention strategy. In resistant cases, a combination
treatment may be used.

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REVIEW Open Access

Canadian clinical practice guidelines for the

management of anxiety, posttraumatic stress and
obsessive-compulsive disorders
Martin A Katzman1*, Pierre Bleau2, Pierre Blier3, Pratap Chokka4, Kevin Kjernisted5, Michael Van Ameringen6,
the Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/
Association Canadienne des troubles anxieux and McGill University

Abstract
Background: Anxiety and related disorders are among the most common mental disorders, with lifetime
prevalence reportedly as high as 31%. Unfortunately, anxiety disorders are under-diagnosed and under-treated.
Methods: These guidelines were developed by Canadian experts in anxiety and related disorders through a
consensus process. Data on the epidemiology, diagnosis, and treatment (psychological and pharmacological) were
obtained through MEDLINE, PsycINFO, and manual searches (19802012). Treatment strategies were rated on
strength of evidence, and a clinical recommendation for each intervention was made, based on global impression
of efficacy, effectiveness, and side effects, using a modified version of the periodic health examination guidelines.
Results: These guidelines are presented in 10 sections, including an introduction, principles of diagnosis and
management, six sections (Sections 3 through 8) on the specific anxiety-related disorders (panic disorder,
agoraphobia, specific phobia, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder,
and posttraumatic stress disorder), and two additional sections on special populations (children/adolescents,
pregnant/lactating women, and the elderly) and clinical issues in patients with comorbid conditions.
Conclusions: Anxiety and related disorders are very common in clinical practice, and frequently comorbid with
other psychiatric and medical conditions. Optimal management requires a good understanding of the efficacy and
side effect profiles of pharmacological and psychological treatments.

Introduction evidence-based recommendations. This guideline docu-

Anxiety and related disorders are among the most com- ment is not focused on any individual type of clinician
mon of mental disorders. Lifetime prevalence of anxiety but rather on assessing the data and making recommen-
disorders is reportedly as high as 31%; higher than the dations. Subsequent user friendly tools and other
lifetime prevalence of mood disorders and substance use initiatives are planned.
disorders (SUDs) [1-5]. Unfortunately, anxiety disorders The guidelines include panic disorder, agoraphobia,
are under-diagnosed [6] and under-treated [5,7,8]. specific phobia, social anxiety disorder (SAD), generalized
These guidelines were developed to assist clinicians, anxiety disorder (GAD), as well as obsessive-compulsive
including primary care physicians and psychiatrists, as disorder (OCD), and posttraumatic stress disorder
well as psychologists, social workers, occupational thera- (PTSD). Also included are brief discussions of clinically
pists, and nurses with the diagnosis and treatment of relevant issues in the management of anxiety and related
anxiety and related disorders by providing practical, disorders in children and adolescents, women who are
pregnant or lactating, and elderly patients, and patients
with comorbid conditions.
* Correspondence: mkatzman@startclinic.ca
1
Department of Psychiatry, University of Toronto, Toronto, ON, M5S 1A1,
Canada
Full list of author information is available at the end of the article
2014 Katzman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
http://www.biomedcentral.com/1471-244X/14/S1/S1
Methods
These guidelines are based on a thorough review of
the current literature and were developed by a panel of
Canadian experts in anxiety and related disorders
through a consensus process. Data on the epidemiology,
diagnosis, and treatment (psychological and pharmacolo-
gical) were obtained through MEDLINE searches of
English language citations (19802012), using search
terms encompassing the specific treatments and specific
anxiety and related disorders. These searches were supple-
mented with data from PsycINFO and manual searches of
the bibliographies of efficacy studies, meta-analyses, and
review articles. Treatment strategies were rated on
strength of evidence for the intervention (Table 1). A clini-
cal recommendation for each intervention was then made,
based on global impression of efficacy in clinical trials,
effectiveness in clinical practice, and side effects, using a
modified version of the periodic health examination guide-
lines (Table 2).
The guidelines were initiated prior to the introduction
of the American Psychiatric Associations (APA) fifth edi-
tion of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-5) and the committee was sensitive to
potential changes to the nosology of anxiety and related
disorders and its impact on the guidelines. However, it
was agreed that, since the evidence for treatment is based
on studies using DSM-IV criteria (or earlier), the intro-
duction of the DSM-5 would not fundamentally alter the
evidence and recommendations at this time. Whether
using DSM-5 diagnostic criteria for the inclusion patients
in clinical trials in the future will have an impact on out-
comes, remains to be seen.
The panel of Canadian experts in anxiety and related
disorders responsible for the development of these
guidelines via consensus process included 10 psychia-
trists and seven psychologists who were organized into
subpanels based on their expertise in particular anxiety
or related disorders as well as in treating specific patient
populations. Preliminary treatment recommendations
Table 1 Levels of evidence
1 Meta-analysis or at least 2 randomized controlled trials (RCTs) that
included a placebo condition
2 At least 1 RCT with placebo or active comparison condition
3 Uncontrolled trial with at least 10 subjects
4 Anecdotal reports or expert opinion
Levels of evidence do not assume positive or negative or equivocal results,
they merely represent the quality and nature of the studies that have been
conducted.
Level 1 and Level 2 evidence refer to treatment studies in which randomized
comparisons are available. Recommendations involving epidemiological or risk
factors primarily arise from observational studies, hence the highest level of
evidence for these is usually Level 3. Recommendations, such as principles of
care, reflect consensus opinion based on evidence from various data sources,
and therefore are primarily Level 4 evidence.
Page 2 of 83
Table 2 Treatment recommendation summary
First-line Level 1 or Level 2 evidence plus clinical support for
efficacy and safety
Second-line Level 3 evidence or higher plus clinical support for
efficacy and safety
Third-line Level 4 evidence or higher plus clinical support for
efficacy and safety
Not Level 1 or Level 2 evidence for lack of efficacy
recommended
and the evidence upon which they had been based were
reviewed at a meeting of the panel in December 2012;
subsequently, draft guidelines were prepared by the sub-
panels which were then circulated to the entire group
for consensus ratification during 2013. Preliminary
recommendations were also presented to the Canadian
psychiatric community for input in September 2012 at
the Canadian Psychiatric Association annual conference.
These guidelines are presented in 10 sections, the first
of which is this introduction. In the following section, the
principles of diagnosis and management of anxiety and
related disorders are covered. That section provides an
overview of the differential diagnoses associated with
anxiety and related disorders in general, discusses issues
that affect all anxiety disorders, and presents the general
advantages and disadvantages of psychological treatment
and pharmacotherapy options. In the subsequent six sec-
tions (Sections 3 through 8), the specific diagnosis and
management of the individual anxiety and related disor-
ders (panic disorder, specific phobia, SAD, OCD, GAD,
and PTSD) are reviewed and recommendations are made
for psychological and pharmacological treatments. Sec-
tion 9 discusses issues that may warrant special attention
pertaining to anxiety and related disorders in children
and adolescents, pregnant or lactating women, and the
elderly. The last section of these guidelines addresses
clinical issues that may arise when treating patients with
anxiety and related disorders who are also diagnosed
with comorbid psychiatric conditions such as major
depressive disorder (MDD), bipolar disorder, or other
psychoses, and attention deficit/hyperactivity disorder
(ADHD), or medical comorbidities, such as pain syn-
dromes, cardiovascular disease, and diabetes/metabolic
syndrome.
Principles of diagnosis and management of
anxiety and related disorders
Epidemiology
Prevalence and impact
Anxiety and related disorders are among the most com-
mon mental disorders, with lifetime prevalence rates as
high as 31% [1-5] and 12-month prevalence rates of
about 18% [3,4]. Rates for individual disorders vary
widely. Women generally have higher prevalence rates
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
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for most anxiety disorders, compared with men [4,5,9].
Anxiety and related disorders are associated with an
increased risk of developing a comorbid major depres-
sive disorder [10-12].
Anxiety and related disorders put a significant burden
on patients and their family members [13]. They are
associated with substantial functional impairment, which
increases as the severity of anxiety [14] or the number of
comorbid anxiety disorders increases [7,15]. In addition,
studies have demonstrated quality of life impairments in
patients with various anxiety and related disorders
[16,17]. Anxiety has a considerable economic impact on
society as well, being associated with greater use of health
care services [5,18] and decreased work productivity
[18,19].
Importantly, studies report that about 40% of patients
diagnosed with anxiety and related disorder are
untreated [5,7].
Suicide risk
In large surveys, anxiety and related disorders were
independently associated with a significant 1.7-2.5 times
increased risk of suicide attempts [20-23]; however, data
are conflicting as to whether the risk is moderated by
gender [20,23]. Increased risk of suicide attempts or
completed suicide has been reported for patients with
panic disorder, PTSD [20,24], and GAD [24], even in
the absence of a comorbid mood disorder. These data
indicate that patients with an anxiety disorder warrant
explicit evaluation for suicide risk. The presence of a
comorbid mood disorder significantly increases the risk
of suicidal behavior [22,25].
Initial assessment of patients with anxiety
The management of patients presenting with anxiety
symptoms should initially follow the flow of the five
main components outlined in Table 3.
Screen for anxiety and related symptoms
Anxiety and related disorders are generally characterized
by the features of excessive anxiety, fear, worry, and avoid-
ance. While anxiety can be a normal part of everyday life,
anxiety disorders are associated with functional impair-
ment; as part of the key diagnostic criteria for anxiety dis-
orders is the requirement that the symptoms cause
clinically significant distress or impairment in social, occu-
pational, or other important areas of functioning [26].
Table 3 Overview of the management of anxiety and
related disorders
Screen for anxiety and related symptoms
Conduct differential diagnosis (consider severity, impairment, and
comorbidity)
Identify specific anxiety or related disorder
Psychological and/or pharmacological treatment
Perform follow-up
Page 3 of 83
Asking patients if they are feeling nervous, anxious or
on edge, or whether they have uncontrollable worry, can
be useful to detect anxiety in patients in whom the clini-
cian suspects an anxiety or related disorder [7]. The
DSM-5 suggests the questions shown in Table 4 for the
identification of anxiety-related symptoms; items scored
as mild or greater may warrant further assessment [26].
If anxiety symptoms are endorsed, they should be
explored in more detail by including questions about
the onset of the anxiety symptoms, associations with life
events or trauma, the nature of the anxiety (i.e., worry,
avoidance, or obsession), and the impact they have had
on the patients current functioning.
Table 5 presents suggested screening questions for
individual anxiety and related disorders, from various
validated screening tools [27-30], some of which are
freely available online (e.g., http://www.macanxiety.com/
online-anxiety-screening-test).
Conduct differential diagnosis
The differential diagnosis of anxiety and related disor-
ders should consider whether the anxiety is due to
another medical or psychiatric condition, is comorbid
with another medical or psychiatric condition, or is
medication-induced or drug-related [32].
When a patient presents with excessive or uncontrolla-
ble anxiety it is important to identify other potential
causes of the symptoms, including direct effects of a sub-
stance (e.g., drug abuse or medication) or medical condi-
tion (e.g., hyperthyroidism, cardiopulmonary disorders,
traumatic brain injury), or another mental disorder [26].
However, since comorbid conditions are common, the
presence of some of these other conditions may not pre-
clude the diagnosis of an anxiety or related disorder.
Certain risk factors have been associated with anxiety
and related disorders and should increase the clinicians
index of suspicion (Table 6) [4,9,33-37]. A family [33] or
personal history of mood or anxiety disorders [34,35] is
an important predictor of anxiety symptoms. In addi-
tion, family history is associated with a more recurrent
course, greater impairment, and greater service use [33].
A personal history of stressful life events is also asso-
ciated the development of anxiety and related disorders
[36,37], in particular, childhood abuse [37].
Women generally have higher prevalence rates across
all anxiety and related disorders, compared with men
[4,5,9]. The median of age of onset is very early for some
Table 4 General screening questions
During the past two weeks how much have you been bothered by
the following problems?
Feeling nervous, anxious, frightened, worried, or on edge
Feeling panic or being frightened
Avoiding situations that make you anxious
Adapted from reference [26].
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Table 5 Screening questions for specific anxiety and related disorders

Panic disorder MACSCREEN [29,30]
Do you have sudden episodes/spells/attacks of intense fear or discomfort that are unexpected or out of the blue?
If you answered YES then continue
Have you had more than one of these attacks?
Does the worst part of these attacks usually peak within several minutes?
Have you ever had one of these attacks and spent the next month or more living in fear of having another attack or worrying about
the consequences of the attack?
SAD (Based on Mini-SPIN [28])
Does fear of embarrassment cause you to avoid doing things or speaking to people?
Do you avoid activities in which you are the center of attention?
Is being embarrassed or looking stupid among your worst fears?
GAD [31]
During the past 4 weeks, have you been bothered by feeling worried, tense, or anxious most of the time?
Are you frequently tense, irritable, and having trouble sleeping?
OCD MACSCREEN [29,30]
Obsessions:
Are you bothered by repeated and unwanted thoughts of any of the following types:
Thoughts of hurting someone else
Sexual thoughts
Excessive concern about contamination/germs/disease
Preoccupation with doubts (what if questions) or an inability to make decisions
Mental rituals (e.g., counting, praying, repeating)
Other unwanted intrusive thoughts
If you answered YES to any of the above Do you have trouble resisting these thoughts, images, or impulses when they come into
your mind?
Compulsions:
Do you feel driven to perform certain actions or habits over and over again, or in a certain way, or until it feels just right? Such as:
Washing, cleaning
Checking (e.g., doors, locks, appliances)
Ordering/arranging
Repeating (e.g., counting, touching, praying)
Hoarding/collecting/saving
If you answered YES to any of the above Do you have trouble resisting the urge to do these things?
PTSD MACSCREEN [29,30]
Have you experienced or seen a life-threatening or traumatic event such as a rape, accident, someone badly hurt or killed, assault,
natural or man-made disaster, war, or torture?
If you answered YES then continue
Do you re-experience the event in disturbing (upsetting) ways such as dreams, intrusive memories, flashbacks, or physical reactions to
situations that remind you of the event?

phobias and for separation anxiety disorder (seven to
14 years), but later for GAD, panic disorder, and PTSD
(24-50 years) [1,2].
Loneliness [38], low education [38], and adverse parent-
ing [39], as well as chronic somatic illnesses, such as cardi-
ovascular disease, diabetes, asthma, and obesity may
increase the risk for a lifetime diagnosis of anxiety [34,40].
Comorbid medical and psychiatric disorders Anxiety
and related disorders frequently co-occur with other psy-
chiatric disorders [3]. More than half of patients with an
anxiety disorder have multiple anxiety disorders [3,15],
Table 6 Common risk factors in patients with anxiety and
related disorders
Family history of anxiety [33]
Personal history of anxiety or mood disorder [34,35]
Childhood stressful life events or trauma [36,37]
Being female [4,9]
Chronic medical illness [34,40]
Behavioral inhibition [41,42]
and almost 30% will have three or more comorbid anxiety
or related disorders [3]. Anxiety is often comorbid with
substance use and mood disorders [3,40]. An estimated
52% of patients with bipolar disorder [43], 60% of patients
with MDD [44], and 47% of those with ADHD [45] will
have a comorbid anxiety or related disorder. Therefore,
anxiety disorders should be considered in these patients.
The high frequency of comorbidity must be consid-
ered when diagnosing anxiety and related disorders
since this can have important implications for diagnosis
and treatment [32]. Anxiety disorders comorbid with
other anxiety or depressive disorders are associated with
poorer treatment outcomes, greater severity and chroni-
city [46-49], more impaired functioning [46], increased
health service use [50], and higher treatment costs [51].
The impact tends to increase with an increasing number
of comorbid conditions [46].
Patients with anxiety disorders have a higher preva-
lence of hypertension and other cardiovascular condi-
tions, gastrointestinal disease, arthritis, thyroid disease,
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respiratory disease, migraine headaches, and allergic con-
ditions compared to those without anxiety disorders
[16,52]. Comorbid anxiety and related disorders have a
significant impact on quality of life (QoL) in patients
with medical conditions [52].
Baseline assessment Baseline assessment should include
a review of systems, prescribed medications, over-the-
counter agents, alcohol use, caffeine intake, and illicit
drug use, in addition to evaluation of the anxiety symp-
toms and functioning [32]. Table 7 lists potential investi-
gations that can be considered based on an individual
patients presentation and specific symptoms (e.g., dizzi-
ness or tachycardia). Ideally, a physical examination and
baseline laboratory investigations should be performed
before pharmacotherapy is initiated, with repeat assess-
ments according to best practice guidelines [32]. Patients
with anxiety and related disorders should be monitored
initially every one to two weeks and then every four
weeks for weight changes and adverse effects of medica-
tions, as this is a major factor contributing to disconti-
nuation of medication.
Closer monitoring may be required in children younger
than 10 years of age, older or medically ill patients,
patients on medications associated with metabolic
changes, and those on multiple medications [32].
Identify specific anxiety or related disorder
The fifth edition of the Diagnostic and Statistical Manual
of Mental Disorders (DSM-5) has been finalized by the
American Psychiatric Association (APA) [26]. The new
DSM-5 provides diagnostic criteria for psychiatric disor-
ders based on scientific reviews of the literature, field
trial data, internal evaluations, public comments, and a
final review by APAs Board of Trustees.
The anxiety disorders chapter now includes panic
disorder, agoraphobia, GAD, selective mutism, separation
anxiety disorder, SAD (social phobia), specific phobia,
substance/medication-induced anxiety disorder, as well
as anxiety disorder due to another medical condition or
not elsewhere classified. OCD and PTSD have been
moved to separate chapters on obsessive-compulsive and
Table 7 Considerations for baseline laboratory
investigations (as needed based on patients presenting
symptoms)
Basic lab tests
Complete blood count Fasting glucose
Fasting lipid profile (TC, vLDL, LDL, HDL, TG) Thyroid-stimulating
hormone
Electrolytes Liver enzymes
If warranted
Urine toxicology for substance use
Adapted from references [32,53]. HDL = high density lipoprotein; LDL = low
density lipoprotein; TC = total cholesterol; TG = triglyceride; vLDL = very low
density lipoprotein.
Page 5 of 83
related disorders and trauma- and stressor-related disor-
ders, respectively [26].
Table 8 provides a brief summary of the key DSM-5
diagnostic features of the anxiety and related disorders
that are included in these guidelines [26]. While the
DSM-5 is the most up-to-date diagnostic criteria, it is
important to note that the evidence for treatment is
based on studies using DSM-IV criteria (or earlier) for
inclusion of patients. However, most of the diagnostic
criteria have not changed substantially (see Sections 39
for more information on diagnosis); the exception being
agoraphobia, which is now designated as a separate
diagnosis.
Specific individual anxiety and related disorders
should be diagnosed with the DSM-5 criteria in the sec-
tions devoted to each anxiety disorder. An accurate
diagnosis is important to help guide treatment.
Psychological and pharmacological treatment
Treatment options for anxiety and related disorders
include psychological and pharmacological treatments. All
patients should receive education about their disorder,
efficacy (including expected time to onset of therapeutic
effects) and tolerability of treatment choices, aggravating
factors, and signs of relapse [32]. Information on self-help
materials such as books or websites may also be helpful.
The choice of psychological or pharmacological treat-
ment depends on factors such as patient preference and
motivation, ability of the patient to engage in the treat-
ment, severity of illness, clinicians skills and experience,
availability of psychological treatments, patients prior
response to treatment, and the presence of comorbid med-
ical or psychiatric disorders [32].
A brief overview of psychological and pharmacological
treatments is provided below, with more specific recom-
mendations in the individual sections for each anxiety
and related disorder.
Overview of psychological treatment Psychological
treatments play an important role in the management of
anxiety and related disorders. Regardless of whether for-
mal psychological treatment is undertaken, patients should
receive education and be encouraged to face their fears.
Meta-analyses have demonstrated the efficacy of psycholo-
gical treatments in group and individual formats in
patients with panic disorder [54-56], specific phobia [57],
SAD [58,59], OCD [60-63], GAD [55,64,65], or PTSD
[66-69], particularly exposure-based and other cognitive
behavioral therapy (CBT) protocols [70,71], as well as
mindfulness-based cognitive therapy (MBCT) [72]. When
choosing psychological treatments for individual patients,
the forms of therapy that have been most thoroughly eval-
uated in the particular anxiety or related disorder should
be used first.
CBT is not a single approach to treatment, but rather
a process that focuses on addressing the factors that
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Table 8 Key features of specific anxiety and related disorders

Disorder Key features
Panic disorder Recurrent unexpected panic attacks, in the absence of triggers
Persistent concern about additional panic attacks and/or maladaptive change in behavior related to the attacks
Agoraphobia Marked, unreasonable fear or anxiety about a situation
Active avoidance of feared situation due to thoughts that escape might be difficult or help unavailable if panic-like
symptoms occur
Specific phobia Marked, unreasonable fear or anxiety about a specific object or situation, which is actively avoided (e.g., flying,
heights, animals, receiving an injection, seeing blood)
Social anxiety disorder (SAD) Marked, excessive or unrealistic fear or anxiety about social situations in which there is possible exposure to
scrutiny by others
Active avoidance of feared situation
Generalized anxiety disorder Excessive, difficult to control anxiety and worry (apprehensive expectation) about multiple events or activities (e.g.,
(GAD) school/work difficulties)
Accompanied by symptoms such as restlessness/feeling on edge or muscle tension
Obsessivecompulsive Obsessions: recurrent and persistent thoughts, urges, or images that are experienced as intrusive and unwanted
disorder (OCD) and that cause marked anxiety or distress
Compulsions: repetitive behaviors (e.g., hand washing) or mental acts (e.g., counting) that the individual feels driven
to perform to reduce the anxiety generated by the obsessions
Posttraumatic stress disorder Exposure to actual or threatened death, serious injury, or sexual violation
(PTSD) Intrusion symptoms (e.g., distressing memories or dreams, flashbacks, intense distress) and avoidance of stimuli
associated with the event
Negative alterations in cognitions and mood (e.g., negative beliefs and emotions, detachment), as well as marked
alterations in arousal and reactivity (e.g., irritable behavior, hypervigilance)
Adapted from reference [26].

caused and maintain the individual patients anxiety
symptoms [73]. Some of the core components of CBT
are shown in Table 9 [73].
CBT can be effectively delivered as individual or group
therapy for most anxiety and related disorders. In addi-
tion, a variety of self-directed or minimal intervention
formats (e.g., bibliotherapy/self-help books, or internet/
computer-based programs with or without minimal
therapist contact) have demonstrated significant
improvements in anxiety symptoms [74-79]. Meta-ana-
lyses have also shown that exposure therapy can be
effectively administered in a virtual reality format
[80,81]. These strategies may be particularly useful in
cases where real-life exposure is difficult due to inconve-
nience, expense, or patient reluctance.
Psychotherapy and pharmacotherapy generally demon-
strate about equivalent efficacy for the treatment of most
anxiety and related disorders [71,82]. Results with combi-
nation therapy vary for the different anxiety disorders,
and results have been conflicting [82,83] (see Sections 3
9 for evidence and references regarding combination
therapy). Therefore, current evidence does not support
the routine combination of CBT and pharmacotherapy as
initial treatment. However, when patients do not benefit
from CBT or have a limited response, a trial of pharma-
cotherapy is advisable. Similarly, patients who show lim-
ited benefit from pharmacotherapy may benefit from
CBT. All patients being treated with pharmacotherapy
should be instructed to gradually face their fears (expo-
sure to decrease avoidance).

Table 9 Components of cognitive behavioral interventions

Exposure Encourage patients to face fears
Patients learn corrective information through experience
Extinction of fear occurs through repeated exposure
Successful coping enhances self-efficacy
Safety response Patients restrict their usual anxiety-reducing behaviors (e.g., escape, need for reassurance)
inhibition Decreases negative reinforcement
Coping with anxiety without using anxiety-reducing behavior enhances self-efficacy
Cognitive strategies Cognitive restructuring, behavioral experiments, and related strategies target patients exaggerated perception of danger
(e.g., fear of negative evaluation in SAD)
Provides corrective information regarding the level of threat
Can also target self-efficacy beliefs
Arousal management Relaxation and breathing control skills can help patient control increased anxiety levels
Surrender of safety Patient relinquishes safety signals (e.g., presence of a companion, knowledge of the location of the nearest toilet)
signals Patients learn adaptive self-efficacy beliefs
Adapted from reference [73].
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Overview of pharmacological treatment This section
provides a general overview of some of the commonly
recommended pharmacological agents. Evidence and
recommendations for specific medications are described
in the individual sections for each of the anxiety and
related disorders.
Table 10 shows medications that have Health Canada
approved indications for use in different anxiety and
related disorders [84], and dosing suggestions are shown
in Additional file 1. Various antidepressants including
selective serotonin reuptake inhibitors (SSRIs), serotonin
norepinephrine reuptake inhibitors (SNRIs), noradrenergic
and specific serotonergic antidepressants (NaSSAs), tricyc-
lic antidepressants (TCAs), monoamine oxidase inhibitors
(MAOIs), and reversible inhibitors of monoamine oxidase
A (RIMAs) have demonstrated some efficacy in the treat-
ment of anxiety and related disorders (see Sections 39
for evidence and references). SSRIs and SNRIs are usually
preferred as initial treatments, since they are generally
safer and better tolerated than TCAs or MAOIs [32].
Benzodiazepines may be useful as adjunctive therapy
early in treatment, particularly for acute anxiety or agi-
tation, to help patients in times of acute crises, or while
waiting for onset of adequate efficacy of SSRIs or other
antidepressants [32]. Due to concerns about possible
dependency, sedation, cognitive impairment, and other
side effects, benzodiazepines should usually be restricted
to short-term use, and generally dosed regularly rather
than as-needed [32].
Several anticonvulsants and atypical antipsychotics
have demonstrated efficacy in some anxiety and related
disorders, but for various reasons, including side effects,
as well as limited randomized controlled trial (RCT)
data and clinical experience, these agents are generally
recommended as second-line, third-line, or adjunctive
therapies (see Sections 39 for evidence and references).
The choice of medication should take into considera-
tion the evidence for its efficacy and safety/tolerability
for the treatment of the specific anxiety and related dis-
order, as well as for any comorbid conditions the patient
might have, in both acute and long-term use.
Safety and side effects Antidepressants: The most com-
mon side effects seen with SSRIs and SNRIs include
headache, irritability, gastrointestinal complaints, insom-
nia, sexual dysfunction, weight gain, increased anxiety,
drowsiness, and tremor [85-88]. Patients report that the
most common bothersome side effects are sexual dys-
function, drowsiness, fatigue, and weight gain [87,88].
Most side effects occur early and transiently during the
first two weeks of treatment, but others, such as sexual
dysfunction and weight gain, may persist for the dura-
tion of treatment [85,87,89].
Use of SSRIs or SNRIs has been associated with an
increased risk of upper gastrointestinal bleeding,

Table 10 Medications with Health Canadaapproved indications for anxiety and related disorders
Anxiety Panic Social anxiety Obsessivecompulsive Generalized anxiety Posttraumatic stress
disorders disorder disorder disorder disorder disorder
ANTIDEPRESSANTS
SSRIs
Escitalopram (Cipralex) X X
Fluoxetine (Prozac) X
Fluvoxamine (Luvox) X
Paroxetine (Paxil) X X X X X
Paroxetine CR (Paxil CR) X X
Sertraline (Zoloft) X X
TCAs
Clomipramine X
Other antidepressants
Venlafaxine XR (Effexor X X X
XR)
Duloxetine (Cymbalta) X
AZAPIRONES
Buspirone (BuSpar, X
Buspirex)
BENZODIAZEPINES* X
Data from respective Canadian product monographs [84].
*Multiple generic and brand name products, consult product monographs: alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, lorazepam, and
oxazepam are indicated for anxiety disorders; alprazolam is also indicated for panic disorder.
CR = controlled release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release.
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particularly when used in combination with nonsteroidal
anti-inflammatory drugs (NSAIDs) [90,91]. SSRI use has
also been associated with low bone mineral density
[92,93], as well as an increased risk of fractures [94] and
hyponatremia [95].
Abrupt discontinuation of SSRIs or SNRIs can lead to
a discontinuation syndrome with gastrointestinal, psy-
chiatric, vasomotor, and other symptoms [85,96].
Health Canada and the US Food and Drug Administra-
tion (FDA) require antidepressants to include a warning
regarding an increased risk of suicidal ideation and beha-
vior in children and adolescents [97,98]. The increased
risk of suicidal behavior reported in pediatric patients [99]
does not appear to be seen in adults, and may in fact be
decreased [99,100]. Careful monitoring for evidence of
self-harming or suicidal thoughts or behaviors is impor-
tant in both adult and pediatric patients.
SSRIs and SNRIs are generally better tolerated and
safer than TCAs and MAOIs, having less anticholinergic
effects, toxicity, lethality, and psychomotor or cognitive
impairment [85,101]. MAOIs are generally reserved for
second- or third-line treatment because of side effects,
drug interactions, and dietary restrictions [32].
Anxiolytics: The most common side effects associated
with benzodiazepines include primarily sedation, fatigue,
ataxia, slurred speech, memory impairment, and weak-
ness [85]. Benzodiazepines are associated with withdra-
wal reactions, rebound, and dependence, with the risk
being greater with short- and intermediate-acting com-
pared to long-acting agents [102]. These agents should
be used with caution in patients with SUDs [85,103].
Older patients (generally over 65 years of age) may be at
high risk for falls and fractures due to psychomotor
impairment associated with benzodiazepines [104,105].
Cognitive impairment has been reported [106], some of
which may persist after cessation of therapy [107]. In par-
ticular, memory impairment has been associated with
high-dose or high-potency benzodiazepines, particularly
in older people [102,107].
Reported side effects of azapirones (buspirone) include
dizziness, drowsiness, and nausea [32,108].
Atypical antipsychotics: Atypical antipsychotics are
associated to varying degrees with weight gain, diabetes,
and other metabolic side effects, including alterations in
glucose and lipid levels [109-116]. Metabolic disturbances
generally appear to be higher with olanzapine, intermedi-
ate with risperidone and quetiapine, and lower with aripi-
prazole, asenapine, lurasidone, and ziprasidone [109-114].
Atypical antipsychotics have varying sedative effects,
with quetiapine, clozapine, asenapine, and olanzapine gen-
erally causing more sedation than ziprasidone, risperidone,
lurasidone, or aripiprazole [111,115]. Data on cognitive
effects are conflicting, with some studies suggesting
improvements [111], while other data suggest greater
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cognitive dysfunction in patients using, versus those not
using, antipsychotics [117].
Because of the risks of diabetes and weight gain, and
the fact that there is limited RCT evidence of the effi-
cacy of these agents in anxiety and related disorders,
atypical antipsychotics are generally recommended as
second-line, third-line, or adjunctive therapies (see Sec-
tions 39 for evidence and references).
Anticonvulsants: Anticonvulsants are associated with
gastrointestinal side effects, somnolence, weight gain,
tremor, as well as dermatologic and hematologic side
effects [111,118]. In addition, several anticonvulsants
have a potential risk of serious rash, erythema multi-
forme, Stevens-Johnson syndrome, or toxic epidermal
necrolysis [111]. Regular monitoring of serum medica-
tion levels and liver function is required for patients on
divalproex [84,111].
Follow-up
Anxiety and related disorders are often chronic and a
systematic approach to treatment should include patient
education, assessment of comorbidities, and evidence-
based pharmacological and psychological interventions
with adequate monitoring and duration. Pharmacological
treatment is often associated with a delay of about two to
eight weeks in onset of symptom relief, with full response
taking up to 12 weeks or more. Longer-term therapy has
been associated with continued symptomatic improve-
ment and the prevention of relapse, and therapy should be
continued for at least 12-24 months for most patients [32].
Medication should be initiated at low doses and
titrated to the recommended dosage range at one- to
two-week intervals over four to six weeks. Once the
therapeutic range has been achieved, improvement is
usually seen over the next four to eight weeks. Follow-
up should occur at two-week intervals for the first six
weeks and monthly thereafter [32].
For a patient undergoing psychotherapy, the treatment
schedule is structured around weekly contact with a thera-
pist for about 12-20 weeks, although shorter protocols and
minimal intervention programs have also proven effective
(see Sections 39 for evidence and references). A follow-
up appointment four weeks later and then every two to
three months is usually sufficient [32].
Assessing response to treatment Therapy should seek to
improve symptoms and distress. The optimal goal is full
remission of symptoms and return to a premorbid level
of functioning [32,85]. However, goals may need to be
individualized for some patients with disorders that have
been present since childhood as they may never have had
adequate premorbid functioning. A response to therapy
is often defined as a percentage reduction in symptoms
(usually 25-50%) on an appropriate scale. Remission is
often defined as loss of diagnostic status, a pre-specified
low score on an appropriate disorder-specific scale, and
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no functional impairment in fully recovered patients as
measured by a scale such as the Sheehan Disability Scale
or SF-36 [32,119,120].
Objective scales can be used to help assess a patients
progress. The Clinical Global Impression (CGI) scale is
brief, comprehensive, and can easily be used at each
appointment to assess improvement. The clinician-rated
Hamilton Anxiety Rating Scale (HARS) can assess anxi-
ety symptoms in general and is often used in clinical
trials but is less practical in clinical practice. A variety
of self-report and clinician-rated scales are available to
assess the specific anxiety or related disorder.
Panic disorder and agoraphobia
Epidemiology
The lifetime and 12-month prevalence of panic disorder
have been estimated at 4.7-5.1% and 2.1-2.8%, respec-
tively [121,122]. The estimated prevalence of panic
attacks is considerably greater at 28.3% (lifetime) and
6.4-11.2% (12-month) [121,123]. Youth with panic
attacks (which often do not meet diagnostic criteria for
panic disorder) will frequently have or develop other
psychiatric disorders including mood disorders (bipolar
disorder and MDD), other anxiety or related disorders,
SUDs, eating disorders, psychotic disorders, and person-
ality disorders [122,124,125]. Annually, 8-10% of the gen-
eral public will have a panic attack without ever
developing any identifiable psychopathology [126]. About
40-70% of patients with panic disorder experience noc-
turnal panic (waking from sleep in a state of panic) [127].
Rates of 12-month and lifetime agoraphobia (without
panic) are quite low, at 0.8% and 1.4%, respectively [2,3].
The risk of panic disorder and agoraphobia is higher
in women than men, and patients who are middle-aged,
widowed/divorced, and those of low income [122]. In
the Canadian Community Health Survey 1.2 (CCHS 1.2)
there were no differences in the rates of panic disorder
or agoraphobia in urban versus rural settings [128].
Panic disorder has a negative impact on both psycho-
logical and physical functioning, and puts a substantial
burden on the patients family [13]. Patients with panic
disorder have more QoL impairment and dissatisfaction
[16,17], greater likelihood of suicide attempts [20], and
increased cognitive and emotional dysfunction [129-133]
compared to healthy controls. Panic disorder is also
associated with substantial societal costs [134], both in
terms of health care utilization [135] and loss of work-
place productivity [136]. In a 2012 survey, panic disor-
der conferred a substantial rate of work absenteeism
(mean: 36.0 days/year) [136].
Comorbidity
Patients with panic disorder, or those experiencing panic
attacks, have significantly increased odds of being diag-
nosed with a comorbid disorder, including another anxiety
Page 9 of 83
or related disorder, mood disorder, impulse-control disor-
der, or SUD [121,137]. MDD is very common, occurring
in an estimated 35-40% of patients with panic disorder
[121]. Panic disorder also frequently co-occurs with agora-
phobia [138].
Panic disorder is more prevalent in patients with med-
ical conditions, including thyroid disease, cancer,
chronic pain, cardiac disease, irritable bowel syndrome,
migraine, as well as allergic and respiratory diseases
compared with the general population [85,139-141]. The
presence of medical comorbidity is associated with
greater severity of panic disorder symptoms and disabil-
ity [140,142].
Diagnosis
For a diagnosis of panic disorder, a patient must have
had recurrent, unexpected panic attacks (Table 11), fol-
lowed by at least one month of persistent concern or
worry about further attacks or their consequences, or a
significant maladaptive behavioral change related to
attacks (Table 12) [26].
A panic attack continues to be considered a noncod-
able event in the DSM-5, with only minor revisions,
including removal of the 10-minute window, changing
hot flushes to heat sensations, and the re-ordering of
the list of symptoms to increase clinical utility [26,143].
Compared to the DSM-IV-TR [144], changes to the
diagnostic criteria for panic disorder largely consisted of
minor phrasing changes to improve clinical utility, with
the most substantial change being the title of the disor-
der [26,143]. The DSM-5 now lists agoraphobia (anxiety
about having a panic attack in certain situations, which
are avoided or endured with marked distress) as a sepa-
rate codable disorder, whereas previously panic disorder
could be diagnosed as panic disorder with agoraphobia
or panic disorder without agoraphobia [26,145].
For a diagnosis of agoraphobia, a patient must have
intense fear about at least two different types of
Table 11 DSM-5 criteria for panic attacks
An abrupt surge of intense fear or intense discomfort that reaches a
peak within minutes, and includes 4 of the following symptoms:
(1) Palpitations, pounding heart, or accelerated heart rate
(2) Sweating
(3) Trembling or shaking
(4) Sensations of shortness of breath or smothering
(5) Feelings of choking
(6) Chest pain or discomfort
(7) Nausea or abdominal distress
(8) Feeling dizzy, unsteady, light-headed, or faint
(9) Chills or heat sensations
(10) Paresthesias (numbness or tingling sensations)
(11) Derealization (feelings of unreality) or depersonalization (being
detached from oneself)
(12) Fear of losing control or going crazy
(13) Fear of dying
Adapted from reference [26].
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Table 12 DSM-5 diagnosis of panic disorder may be PTSD [26,85], and those related to being kid-
The person has experienced both of the following: napped by extraterrestrials may be schizophrenia [26].
Recurrent unexpected panic attacks Some medical conditions that can be associated with
1 of the attacks followed by 1 month of 1 or both of the
following:
panic symptoms include hyper- or hypothyroidism,
Persistent concern or worry about additional panic attacks or hypoglycemia, seizure disorders, and cardiac conditions
their consequences [26,85]. Panic attacks may also be associated with intoxi-
Significant maladaptive change in behavior related to the
attacks
cation or withdrawal from drugs of abuse, medications
such as decongestants, stimulants, or beta-adrenergic
Adapted from DSM-5 [26].
agonist inhalers, or caffeine [85].
situations, with the fear resulting from thoughts that
Psychological treatment
escape may be difficult or help may be unavailable if
CBT has been extensively studied, and is an efficacious
panic-like symptoms occur (Table 13) [26,145]. The situa-
psychological treatment for panic disorder (Level 1)
tions provoke anxiety and are avoided or endured with
[56,70,146,147]. In fact, CBT was significantly favored
intense fear or anxiety, or may require that a companion
over medications for the treatment of panic disorder in a
be present. The resultant fear or anxiety is out of propor-
meta-analysis [71]. In a meta-analysis of 42 studies, expo-
tion to any actual danger from the situation, causes sub-
sure and combinations of exposure, cognitive restructur-
stantial functional impairment, and usually lasts for six
ing and other CBT techniques had the most consistent
months or longer [26].
evidence of efficacy for the treatment of panic disorder
While the most up-to-date DSM-5 diagnostic criteria
[56]. Strategies that included exposure were the most
are presented here, the treatment data described within
effective for panic measures. For measures of agorapho-
this section are based on studies involving patients
bia, combined strategies were more effective than single
meeting DSM-IV panic criteria (or older).
techniques, which did not result in significant improve-
Establishing the context in which panic attacks occur,
ments. Factors that improved the effectiveness of treat-
and whether there is any prior history of recurrent,
ments were the inclusion of homework and a follow-up
unexpected panic attacks, is important for accurate diag-
program [56]. Another meta-analysis also found that
nosis. Panic attacks frequently occur in other psychiatric
CBT that included interoceptive exposure was superior
disorders (e.g., MDD, PTSD), and medical conditions
to relaxation therapy for panic symptoms [55]. CBT can
(e.g., cardiac, respiratory), and the DSM-5 has identified
be effectively delivered in both individual and group set-
panic attacks as a specifier to be used in the absence of
tings [56,148,149]. Conducting exposure in virtual reality
a diagnosable panic disorder [85]. Another disorder may
appears to be effective when used as part of a CBT proto-
better account for the panic attacks; for example, panic
col [150-154].
attacks in social situations may be SAD, those related to
Minimal intervention formats, such as self-help books
defined phobic objects or situations may be specific
(bibliotherapy) [75,76,155-158], treatment via telephone/
phobia, those related to reminders of traumatic events
videoconferencing [75,159-161], and internet-based CBT
(ICBT) [75,79,162-169] have been shown to be more
Table 13 DSM-5 diagnosis of agoraphobia effective than wait-list or relaxation controls, as effective
Marked fear or anxiety about 2 of the following 5 groups of as face-to-face CBT, and may be cost-effective options
situations:
(1) Public transportation (e.g., traveling in automobiles, buses, trains,
particularly for agoraphobic patients who are unwilling
ships, or planes) or unable to attend a clinic. When using bibliotherapy,
(2) Open spaces (e.g., parking lots, market places, or bridges) providing information all at one time was as effective as
(3) Being in shops, theatres, or cinemas
(4) Standing in line or being in a crowd
pacing [157], and therapist support does not appear to
(5) Being outside of the home alone in other situations be essential [75,158]. Most ICBT programs have some
The individual fears or avoids these situations due to thoughts that therapist contact by either telephone or email, and once
escape might be difficult or help might not be available in the event of weekly contact appeared to be as effective as more fre-
panic-like symptoms
quent contact [168].
The agoraphobic situations almost always provoke fear or anxiety
CBT panic disorder protocols usually involve 12-14
The situations are actively avoided, require presence of a companion,
or endured with marked fear or anxiety
weekly sessions, but briefer strategies of six to seven ses-
The fear or anxiety is out of proportion to actual danger posed by
sions have been shown to be as effective [148,149,170].
agoraphobic situation In addition, compressing the duration of therapy by
The fear, anxiety, or avoidance is persistent, typically lasting 6 months administering 13 sessions over three weeks has also
The fear, anxiety, and avoidance cause clinically significant distress or been shown to be as effective as traditional weekly CBT
functional impairment [171]. Patients with higher baseline severity, disability,
Adapted from DSM-5 [26]. or comorbidity may have better outcomes with standard
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CBT [172]. CBT programs sometimes include one or
more follow-up or booster sessions [170,173].
Predictors of decreased response to CBT were severity
of panic disorder, strength of blood/injury fears, earlier
age of initial onset of panic symptoms, comorbid social
anxieties, and degree of agoraphobic avoidance [174,175].
Changes in symptoms are preceded by changes in beliefs
during therapy [176], and change in beliefs and avoidance
behaviors are considered key process variables [170,176].
Eye movement desensitization and reprocessing
(EMDR) does not appear to offer advantages over the
same strategy without the eye movement component for
the treatment of panic disorder [177,178].
Combined psychological and pharmacological treatment
A meta-analysis of 21 trials found that combination psy-
chotherapy and pharmacotherapy with antidepressants
was superior to CBT or pharmacotherapy alone during
the acute treatment phase and while medication was con-
tinued [179,180]. After termination of treatment, com-
bined therapy was more effective than pharmacotherapy
alone and was as effective as psychotherapy [179,180].
Prior meta-analyses have reported similar findings
[54,146,181], suggesting that CBT alone or CBT combined
with pharmacotherapy should be considered as first-line
treatment.
A meta-analysis of the combination of psychotherapy
and benzodiazepines included only three trials, and
found no benefit to combination therapy compared with
psychotherapy or medication alone [182]. The follow-up
data suggested that the combination might be inferior to
behavior therapy alone [182].
Adding self-administered CBT to SSRI therapy did
not result in significant improvements overall, but
patients did report a significantly greater rate of
decline in fear of bodily sensations compared to medi-
cation alone [183]. Early results suggest a benefit of
MBCT as an adjunct to pharmacotherapy in relieving
anxiety and depressive symptoms in patients with
panic disorder [184,185].
Providing CBT sessions around the time of medication
discontinuation was associated with a lower relapse rate
during follow-up among patients treated with antidepres-
sants [186]. In addition, CBT has been shown to be helpful
in facilitating benzodiazepine discontinuation [187,188].
A cost-effectiveness study found that combined CBT
and pharmacotherapy was associated with a robust clini-
cal improvement compared to usual care, with only a
moderate increase in costs [189].
In a RCT, buspirone enhanced the effects of CBT in
the short-term, but had no significant benefit over CBT
alone during long-term follow-up [190].
Data on the efficacy of d-cycloserine as an adjunct to
CBT are conflicting, with one study suggesting signifi-
cant benefits at posttreatment and one-month follow-up
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[191], while another found an acceleration of symptom
reduction in severely ill patients but no significant
improvement in outcomes overall [192] compared to
CBT plus placebo. Another compound acting at the
N-methyl-D-aspartate (NMDA) receptor, Org 25935,
demonstrated no benefit over placebo in augmenting
CBT for panic disorder [193].
Long-term effects of psychological treatment
In naturalistic long-term follow-up studies, the benefits of
CBT were maintained for up to three years [148,169,
170,188]. At two-year follow-up, individual, group, and
brief CBT were associated with lower relapse rates com-
pared to the wait-list control [148]. A long-term follow-up
study of patients who had become panic-free with expo-
sure therapy found that 93% remained in remission after
two years and 62% after 10 years [194].
A meta-analysis found that at six to 24 months follow-
up, remission/response rates with the combination of
psychotherapy and antidepressants continued to be
superior to antidepressants alone, or to psychotherapy
as long as therapy was continued [179,180].
Pharmacological treatment
The management of patients with panic disorder should
follow the principles discussed in Section 2. Pharmaco-
logical interventions that have good evidence for efficacy
in treating panic disorder include SSRIs, TCAs, and
other antidepressants, as well as benzodiazepines. Treat-
ments that have been investigated for use in panic disor-
der have been assessed according to the criteria for
strength of evidence (Tables 1 and 2) and are summar-
ized in Tables 14 and 15.
First-line agents
SSRIs: Evidence from meta-analyses [195-197] and RCTs
supports the use of the SSRIs citalopram [198-200],
fluoxetine [201-204], fluvoxamine [195,205-210], paroxe-
tine [211-219], and sertraline [183,220,221,223,224] (all
Level 1), as well as escitalopram [198] and paroxetine
controlled-release (CR) [225] (both Level 2) for the
treatment of panic disorder. In meta-analyses, SSRIs
demonstrated significant improvements in panic symp-
toms, agoraphobic avoidance, depressive symptomatol-
ogy, and general anxiety [195-197,226]. Effect sizes for
SSRIs and TCAs are similar [195,196], although dropout
rates may be lower with SSRIs [195].
SNRIs: Venlafaxine extended-release (XR) has been
shown to be useful in reducing the severity of panic dis-
order symptoms in RCTs (Level 1) [215,216,227-229].
Two studies found significantly greater rates of panic-
free patients compared with placebo [215,216] while two
did not [228,229].
Second-line agents
TCAs: There is good evidence from RCTs to support the
use of the TCAs clomipramine [199,211,213,232,233]
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Table 14 Strength of evidence for pharmacotherapy for panic disorder

Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs TCAs
Citalopram [198-200] 1 Clomipramine [199,211,213,232,233] 1
Fluoxetine [201-204] 1 Imipramine [207,224,233-240] 1
Fluvoxamine [195,205-210] 1 MAOIs and RIMAs
Paroxetine [211-219] 1 Phenelzine [240] 2
Sertraline [183,220-224] 1 Moclobemide [204,232,241,242] 1*
Escitalopram [198] 2 Tranylcypromine [243] 3
Paroxetine CR [225] 2 Other antidepressants
SNRIs Reboxetine [200,219,244] 1
Venlafaxine XR [215,216,227-229] 1 Mirtazapine [203,245,246] 2
Duloxetine [230] 3 Bupropion SR [247,248] 3*
Milnacipran [231] 3
Other therapies
Anxiolytics Atypical antipsychotics
Benzodiazepines Risperidone [217,267] 2
Alprazolam [234,249-254] 1 Olanzapine [268] 3
Clonazepam [218,250,255-258] 1 Quetiapine [267] 3
Lorazepam [251,259,260] 1 Adjunctive aripiprazole [269] 3
Diazepam [261-263] 1 Adjunctive olanzapine [270] 3
Adjunctive clonazepam [264,265] 1 Adjunctive risperidone [271] 3
Adjunctive alprazolam ODT [266] 3 Anticonvulsants
Other treatments Divalproex [272-275] 3
Buspirone [254,282] 1 (-ve) Levetiracetam [276] 3
Trazodone [283] 2 (-ve) Gabapentin [277] 2 (-ve)
Propranolol [262,284,285] 2 (-ve) Tiagabine [278,279] 2 (-ve)
Adjunctive pindolol [286] 2 Carbamazepine [280] 3 (-ve)
Adjunctive divalproex [281] 3
*Conflicting data. No significant superiority over placebo in overall population, but significant benefits in subgroup of more severely ill patients. CR = controlled
release; MAOI = monoamine oxidase inhibitor; ODT = orally disintegrating tablets; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotonin
norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release;
(-ve) = negative.

and imipramine [207,224,233-240] in panic disorder
(Level 1). In meta-analyses, TCAs have demonstrated
efficacy for the treatment of panic symptoms and agora-
phobia [195-197,226]. Efficacy is generally equivalent to
SSRIs, however, since TCAs tend to be less well toler-
ated and have higher discontinuation rates than SSRIs
[195], they are recommended as second-line options.
Other antidepressants: Although there is level 1 evi-
dence to support the use of reboxetine [200,219,244],
limited experience with this agent in Canada, and its
side effect profile, which includes dry mouth, constipa-
tion, and insomnia [244], led to its recommendation as
a second-line option. Mirtazapine has demonstrated effi-
cacy for the treatment of panic disorder in several open

Table 15 Recommendations for pharmacotherapy for panic disorder

First-line Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, paroxetine CR, sertraline, venlafaxine XR
Second-line Alprazolam, clomipramine, clonazepam, diazepam, imipramine, lorazepam, mirtazapine, reboxetine
Third-line Bupropion SR, divalproex, duloxetine, gabapentin, levetiracetam, milnacipran, moclobemide, olanzapine, phenelzine, quetiapine,
risperidone, tranylcypromine
Adjunctive Second-line: alprazolam ODT, clonazepam
therapy Third-line: aripiprazole, divalproex, olanzapine, pindolol, risperidone
Not Buspirone, propranolol, tiagabine, trazodone
recommended
CR = controlled release; ODT = orally disintegrating tablets; SR = sustained release; XR = extended release.
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trials [245,246] and one small RCT [203] (Level 2). It
appears to be as effective as fluoxetine [203] and may be
a useful second-line choice.
Benzodiazepines: Alprazolam [234,249-254], clonaze-
pam [218,250,255-258], lorazepam [251,259,260], and
diazepam [261-263] have demonstrated efficacy for the
treatment of panic disorder (Level 1). While it has been
suggested that alprazolam may be more effective, a meta-
analysis found no evidence that it was superior to other
benzodiazepines for the treatment of panic disorder
[252]. Although benzodiazepines are second-line options,
they may be useful at any time during therapy for the
short-term management of acute or severe agitation or
anxiety. They may also be useful at the initiation of SSRI
treatment to hasten response (Level 1) [264-266].
Third-line agents
MAOIs and RIMAs: Results with moclobemide for the
management of panic disorder have been conflicting
(Level 1). In clinical trials, moclobemide demonstrated
efficacy similar to that of clomipramine and fluoxetine
[204,232], but was not superior to placebo [241,242].
However, significant efficacy in more severely ill patients
[241], suggests it may be useful in treatment-resistant
patients. In a RCT, phenelzine was more effective than
placebo and as effective as imipramine (Level 2) [240]. In
a small randomized, uncontrolled trial, tranylcypromine
demonstrated efficacy for patients with comorbid panic
and social anxiety disorders (Level 3) [243].
Atypical antipsychotics: There is some evidence that
atypical antipsychotics may have some benefits in the
treatment of patients with refractory panic disorder
[217,267,268]. In a RCT, risperidone monotherapy was as
effective as paroxetine (Level 2) [217]. Open-label data
also support the use of risperidone [267], olanzapine
[268], and quetiapine [267]. There are also open-label
data supporting the use of some atypical antipsychotics
as adjunctive therapy (see below).
Other therapies: The antidepressants duloxetine [230],
milnacipran [231], and bupropion sustained release (SR)
[247,248] have shown some efficacy in open trials, as
have the anticonvulsants divalproex [272-275] and leve-
tiracetam [276] (all Level 3). In a RCT, gabapentin was
superior to placebo in patients who were more severely
ill, but not in the overall group (Level 2, negative) [277].
These agents are recommended only as third-line
options in patients with refractory panic disorder.
Adjunctive therapy
There is good evidence that adjunctive clonazepam
[264,265] (Level 1), and open-label evidence that adjunc-
tive alprazolam orally-disintegrating tablet (ODT) [266]
(Level 3), used short-term (<8 weeks including taper) at
the initiation of SSRI treatment, can lead to a more
rapid response [264-266].
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In a RCT, pindolol added to fluoxetine therapy in
patients with treatment-resistant panic disorder was
associated with significant improvement in panic disor-
der symptoms compared with fluoxetine plus placebo
(Level 2) [286]. Open-label data also support the use of
the atypical antipsychotics aripiprazole [269], olanzapine
[270], and risperidone [271] (all Level 3), as well as the
anticonvulsant divalproex [281], as adjunctive strategies
for patients with treatment-resistant panic disorder.
Not recommended
Buspirone (Level 1, negative) [254,282], propranolol
(Level 2, negative) [262,284,285], tiagabine [278,279]
(Level 2, negative), and trazodone (Level 2, negative)
[283] have not demonstrated efficacy and are not recom-
mended for the treatment of panic disorder. Carbamaze-
pine (Level 3, negative) [280] also does not appear to be
effective in this disorder.
Maintenance pharmacological treatment
In long-term, open, follow-up studies, citalopram
[287,288], fluoxetine [204,288], fluvoxamine [288], par-
oxetine [288-290], and moclobemide [204], as well as
clomipramine [287,289] and imipramine [291,292]
demonstrated maintenance of benefits and continued
improvements over six months to three years of ongoing
treatment. In a RCT, sertraline and imipramine were
equally effective over a six month period [224]. How-
ever, in another RCT, imipramine was not superior to
placebo in the proportion of panic-free patients after
eight months of therapy [293].
Venlafaxine XR [294] and imipramine [295] have been
shown to prevent relapse in randomized, placebo-con-
trolled, discontinuation studies. After three months of
acute treatment, relapse rates were significantly lower
with ongoing venlafaxine XR [294] or imipramine [295]
therapy compared with switching to placebo during six
to 12 months of follow-up.
Benzodiazepines are generally recommended for short-
term use only. However, several trials have demon-
strated the benefits of up to two years of alprazolam
maintenance therapy [291,293]. There was no evidence
of tolerance, but up to one-third of patients were unable
to discontinue therapy [293]. The efficacy of clonazepam
was maintained over a three-year course of treatment
[290], and patients who had been asymptomatic for at
least one year were able to successfully discontinue the
medication, using a slow tapering strategy over four to
seven months, and improvement in panic disorder was
maintained [296].
Biological and alternative therapies
Biological therapies: In open-label case series, noninvasive
brain stimulation using a radioelectric asymmetric con-
veyor (REAC) demonstrated efficacy for panic symptoms
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and agoraphobia (Level 3) [297,298]. A small case series
suggested repetitive transcranial magnetic stimulation
(rTMS) could improve panic and anxiety in patients with
panic disorder with comorbid MDD (Level 4) [299]. How-
ever, a small RCT found no additional benefit of rTMS
compared to sham rTMS as an add-on to SSRI therapy in
patients with panic disorder (Level 2, negative) [300].
Alternative therapies: In a RCT, capnometry-assisted
respiratory training was as effective as cognitive training
in reducing panic symptom severity and panic-related
cognitions and improving perceived control (Level 2)
[301]. However, breathing training did not significantly
improve reactivity or recovery after a respiratory chal-
lenge in another small trial (Level 2, negative) [302]. In
a RCT, patients with panic disorder randomized to the
exercise groups (plus paroxetine or placebo) had a trend
toward better improvement compared to relaxation
training, but this was not significant (Level 2, negative)
[303]. However, in an open cross-over study, acute aero-
bic exercise was found to reduce anxiety as well as
panic attack frequency and intensity in patients with
panic disorder compared to a quiet rest condition (Level
3) [304]. These therapies may be useful for some
patients; however, more data are needed.
Summary
As much as 40% of the general population has experi-
enced a panic attack at some point in their lifetime.
However, patients with actual panic disorder experience
recurrent, unexpected panic attacks as well as persistent
concern or behavioral change around further attacks.
Data support pharmacotherapy, CBT alone, and CBT
combined with pharmacotherapy as initial treatments for
panic disorder. CBT alone may be insufficient in patients
with comorbid moderate-to-severe major depression, or
in those with severe, frequent panic attacks, or rapid wor-
sening of agoraphobia, and/or suicidal ideation, as well as
in situations where one might consider initial rescue
treatment with a benzodiazepine to minimize or stop the
panic attacks while waiting the 4-12 weeks for the first-
line pharmacotherapy to become effective. Also there are
patients who are not motivated to participate in CBT
(preferring medication as initial treatment) or are too
fearful to engage in any kind of exposure before being
treated with a first-line pharmacotherapeutic agent. At
the very least, if agoraphobic distress or avoidance per-
sists, these patients need instruction and support to
engage in exposure exercises. For panic symptoms, stra-
tegies should include exposure; and combined strategies
should be considered for patients with agoraphobia. CBT
can be effectively delivered in both individual and group
settings, as well as via self-help books, virtual reality, and
internet-based programs. The benefits of CBT are
Page 14 of 83
maintained during follow-up. In addition, data suggest
that combination of psychotherapy and pharmacotherapy
may be superior to pharmacotherapy alone during fol-
low-up.
Pharmacotherapeutic approaches should begin with a
first-line agent. If response to optimal dosing is inade-
quate or the agent is not tolerated, treatment should be
switched to another first-line agent before considering
second-line medications. First-line options for the treat-
ment of panic disorder include citalopram, fluoxetine,
fluvoxamine, paroxetine, sertraline, venlafaxine XR, esci-
talopram, or paroxetine CR. Second-line choices include
the TCAs (clomipramine and imipramine), mirtazapine,
reboxetine, or benzodiazepines (alprazolam, clonazepam,
lorazepam, and diazepam).
Patients who do not respond to first- or second-line
agents are considered to have treatment-refractory ill-
ness. In such patients it is important to reassess the diag-
nosis and consider comorbid medical (e.g., ischemic
heart disease) and psychiatric conditions (e.g., SUDs) that
may be affecting response to therapy. Third-line agents,
adjunctive therapies, as well as biological and alternative
therapies may be useful when patients fail to respond to
an optimal treatment trial of first- and second-line thera-
pies used alone and in combination.
Specific phobia
Epidemiology
A specific phobia is an intense fear of a specific object or
situation and is usually associated with avoidance of the
feared object. The most prevalent phobia types include
animal (e.g., insects, snakes), natural environment (e.g.,
heights, storms, water), situational (e.g., flying, enclosed
spaces), and blood-injection-injury (B-I-I) (e.g., blood,
dentists, hospitals) [305,306]. Large US and European
epidemiologic surveys report lifetime prevalence esti-
mates of 10-13% and 12-month prevalence rates of 7-9%
[2,3,305,307]. Rates among adolescents may be particu-
larly high with lifetime prevalence estimates of 36.5% and
12-month prevalence rates of 27.3% being reported [308].
Specific phobias are more common in women than men
[306]. Age of onset is usually in the range of five to 12
years (median: seven years) [2]; however, this varies by
type of phobia. Animal and B-I-I phobias generally begin
in childhood, whereas situational phobias (e.g., driving
phobia, claustrophobia) have a later onset, typically dur-
ing late adolescence or early adulthood [306].
Specific phobias are associated with significant dis-
tress, regardless of the number of feared stimuli
reported [305]. Specific phobias have a negative impact
on social/occupational functioning and lead to restric-
tion of usual daily activities, which increases with an
increasing number of fears [305].
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Comorbidities
Specific phobias tend to co-occur with other specific
phobias, with less than 10% of patients having only one
fear [305]. The mean number of fears, in one survey,
was three [305]. In addition, specific phobias are fre-
quently comorbid with other psychiatric disorders,
including SUDs, mood disorders, and other anxiety or
related disorders (particularly panic disorder, SAD, and
GAD), as well as personality disorders [305,309,310].
Diagnosis
To receive a DSM-5 diagnosis of specific phobia a
patient must experience marked (intense) fear or anxi-
ety about a specific object or situation, which is asso-
ciated with significant distress or functional impairment
(Table 16) [26]. The object or situation will be actively
avoided or endured with intense anxiety. Compared to
the DSM-IV-TR criteria for specific phobia [144], few
changes were made in the DSM-5 [26,306]. Of note,
recognition that the fear is excessive or unreasonable
has been removed and a new criterion stating the fear
or anxiety is out of proportion to danger posed has
been added. Avoidance has been clarified as actively
avoided to distinguish the avoidance seen in specific
phobias from passive avoidance that may occur for
other reasons [26,306].
While the most up-to-date DSM-5 diagnostic criteria
are presented here, it is important to note that most of
the treatment data described within this section are
based on patients meeting DSM-IV criteria (or older).
Specific phobias are delineated into five types: animal
type, natural environment type, B-I-I type, situational
type, or other type (Table 17) [26]. The fear of contract-
ing an illness has been removed because of high related-
ness to OCD and anxiety disorder related to medical
condition [26].
Specific phobias can be difficult to distinguish from
panic disorder [311]. It is important to consider the
focus of apprehension (e.g., fear of crashing while on an
airplane versus fear of having a panic attack on an air-
plane), the types of panic attacks experienced (e.g.,
expected versus unexpected), and the range of situations
associated with fear and avoidance [311].
Table 16 DSM-5 diagnosis of specific phobia
Marked fear or anxiety about a specific object or situation (e.g., flying,
seeing blood)
The phobic object or situation almost always provokes immediate fear
or anxiety and is actively avoided or endured with marked fear or
anxiety
The fear or anxiety is out of proportion to the actual danger posed by
the specific object or situation
The fear, anxiety, or avoidance is persistent, typically 6 months
There is marked distress or functional impairment
Adapted from DSM-5 [26].
Page 15 of 83
Table 17 Specific phobia specifiers in DSM-5
Specifier Examples
Animal Spiders, insects, dogs
Natural Heights, storms, water
environment
Blood-injection- Needles, invasive medical procedures
injury
Situational Airplanes, elevators, enclosed spaces
Other Choking or vomiting. In children, loud sounds or
costumed characters
Adapted from DSM-5 [26].
Psychological treatment
Psychosocial interventions, particularly exposure-based
treatments, are the treatments of choice and are asso-
ciated with a high degree of success in providing remis-
sion of specific phobias [311]. Both in vivo exposure and
virtual reality exposure (VRE) can be effective
[57,311,312], with in vivo exposure being shown to be
superior to alternative types (e.g., imaginal, virtual rea-
lity, etc.) at posttreatment but not at follow-up [57].
In general, exposure-based therapy has been shown to
be more effective if: sessions are grouped closely together;
exposure is prolonged, real (not imagined), and provided
in multiple different settings; and there is some degree of
therapist involvement (not entirely self-directed) [32,311].
While one-session treatments have demonstrated efficacy
[313], a meta-analysis found that a greater number of ses-
sions predicted more favorable outcomes [57].
There is no evidence that either flooding or gradual
exposure is more effective [314], however, progressive
exposures are generally more tolerable to patients [311].
An example of graded exposure in a patient with ara-
chnophobia would be to look at pictures of spiders, hold
a rubber spider, look at a live spider in a jar, touch the jar
containing the spider, stand two feet from a live spider,
and finally touch a live spider. This approach can be used
to guide exposure depending on the patients symptom
severity and tolerance to each level of exposure.
While a meta-analysis of 33 RCTs of psychological
approaches found that treatment outcomes were not
moderated by type of specific phobia [57], studies have
suggested that certain subtypes may respond more
favorably to specific types of treatment (Table 18).
For patients with B-I-I phobias, exposure therapy
combined with muscle tension exercises (applied ten-
sion) designed to prevent fainting [311] has been shown
to be effective [315,316]. Use of stress-reducing medical
devices, such as decorated butterfly needles and syr-
inges, has been shown to significantly reduce needle
phobia and stress in both pediatric and adult patients
[317]. CBT reduced avoidance of oral injections and
decreased anxiety in patients with dental phobias [318].
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Table 18 Psychological treatments with demonstrated efficacy in specific phobias
Psychological treatment
Exposure-based treatments
Virtual reality exposure
Computer-based self-help programs
Applied muscle tension (exposure combined with muscle tension
exercises)
Cognitive therapy and exposure
Fear of flying has been effectively treated with group
CBT [319,320]. In addition, computer-generated VRE has
demonstrated efficacy [319,321-324], which was compar-
able to standard exposure therapy in several studies
[322,324], and can have long-term benefits [325,326].
Bibliotherapy was found to be less effective than VRE or
CBT for patients with fear of flying [319]. VRE has also
been shown to be effective for patients with a fear of
heights [327-329], and those with claustrophobia [330].
This approach may also be useful for treating fears for
which in vivo exposure may not be practical (e.g., fear of
storms) [32].
Arachnophobia has been successfully treated with in
vivo [331] and VR [331,332] exposure, with little differ-
ence between the two modalities [331]. A spiderless form
of VRE, which presented images that were not spiders,
but had some of the characteristics of spiders, was shown
to be useful in patients with severe arachnophobia who
were reluctant to undergo direct exposure or VRE [333].
An internet-based self-help program was associated with
improvement, but was not as effective as one session of
in vivo exposure at the post-treatment assessment,
although results were similar at follow-up [334]. How-
ever, even one session of VRE was associated with greater
fear reduction compared to a control group, and may be
a useful self-help intervention to reduce fear of spiders
[335]. Computer-based self-help has also shown promise
for other small-animal phobias (e.g., cockroaches, mice)
[336,337].
Combined psychological and pharmacological treatment
It has been speculated that d-cycloserine, a partial agonist
at the NMDA receptor, may improve extinction of fear in
patients with phobias undergoing behavioral exposure
therapy [338]. In a RCT (n=28), d-cycloserine as an
adjunct to VRE resulted in significantly larger reductions
of acrophobia symptoms compared with VRE alone [338].
In another study (n=100), adjunctive d-cycloserine did not
improve the reduction of spider fears compared to expo-
sure-based therapy alone, however, patients had heigh-
tened, but subclinical, spider fears [339].
In two RCTs, use of adjunctive cortisol, a glucocorti-
coid, significantly enhanced the benefits of exposure ther-
apy compared with placebo in patients with acrophobia
Page 16 of 83
Phobia
All specific phobias [57,311,312]
Heights [327-329], flying [319,321-324], spiders [331,332], claustrophobia
[330]
Spiders [334,335], flying [323], small animals [336,337]
Blood-injection-injury type [311,315,316]
Dental [318], flying [319,320]
(n=40) [340] and arachnophobia (n=20) [341], with evi-
dence suggesting that cortisol may facilitate the extinc-
tion of phobic fear at follow-up.
Enhanced emotional memory may be stimulated
through elevated noradrenaline levels, and data suggest
that yohimbine hydrochloride, a noradrenaline agonist,
can facilitate fear extinction. In RCTs, there were no sig-
nificant VRE-enhancing effects with adjunctive yohim-
bine compared with placebo in patients with fear of
flying (n=48) [342] or claustrophobia (n=24) [343]. How-
ever, in the claustrophobia study, patients treated with
yohimbine showed greater improvements in outcomes at
the one-week follow-up [343].
In contrast, naltrexone was found to render one-ses-
sion exposure therapy less effective compared with pla-
cebo or no treatment in 15 patients with specific phobias
(animals) [344].
Long-term effects of psychological treatment
Long-term treatment of specific phobia is rare. As dis-
cussed above, CBT and exposure therapies have demon-
strated sustained benefits at long-term follow-up
assessments [325,326].
Pharmacological treatment
There is a minimal role for pharmacotherapy in the
treatment of specific phobias, largely due to the lack of
research on medications in this condition, and the suc-
cess of exposure-based therapies [32,311].
Antidepressants have been investigated in two small
RCTs [345,346]. In a small RCT, paroxetine was signifi-
cantly more effective than placebo in resolving anxiety
in patients with specific phobias (n=11) [345]. Similarly,
escitalopram was associated with a strong treatment
effect in a small RCT (n=12); however, the trial was
under-powered to show statistically significant superior-
ity over placebo on the primary outcome [346]. In addi-
tion, cases of successful treatment of flying phobias with
fluoxetine [347], and storm phobia with fluvoxamine
[348], have been reported.
Benzodiazepines have usually been assessed as
adjuncts to exposure therapy, and these studies have
found no additional benefit with medication [349-351].
Benzodiazepines are often used in clinical practice to
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provide acute symptom relief when it is necessary for a
patient with a specific phobia to face a feared situation
(e.g., dental procedure, magnetic resonance imaging
[MRI], unexpected flight) [32]. Nasal midazolam has
proven useful in facilitating MRI in claustrophobic
patients [352,353].
Summary
Specific phobia is quite common, particularly among
adolescents. Patients with specific phobia exhibit an
intense fear or anxiety about a specific object or situa-
tion which is associated with significant distress or func-
tional impairment. The most prevalent phobia types
include animal, natural environment, situational, and
B-I-I.
Exposure-based techniques, including virtual exposure,
are highly effective, and are the foundation of treatment
for specific phobias. Pharmacotherapy is generally
unproven, and thus not a recommended treatment for
most cases.
Social anxiety disorder
Epidemiology
SAD is one of the most common anxiety disorders, with
lifetime prevalence estimates ranging from 8-12%
among the international general population [2,354-356].
It is more common in women than men [355,357-360],
and higher rates have been reported in developed (6.1%)
versus developing (2.1%) countries [361]. SAD has an
early age of onset, typically during adolescence (mean
12 years), and tends to have a chronic and unremitting
course [2,362,363]. Factors such as low educational
achievement, low socioeconomic status, being single or
separated, and having comorbid MDD have been asso-
ciated with a higher prevalence of SAD in epidemiologi-
cal studies [359,360,364].
SAD is associated with significant impairments includ-
ing problems with educational and occupational perfor-
mance, family functioning, and an overall reduced QoL
[14,15,17,354,363,365-369]. SAD also confers a substan-
tial economic burden upon afflicted individuals and
society in terms of work days missed and health care
costs [370,371]. Canadians with SAD were twice as
likely to report at least one disability day in the past two
weeks, compared to those without SAD [356].
Psychiatric comorbidity
SAD is associated with significant comorbidity, with up
to 72% of patients reporting criteria for another psychia-
tric disorder [372]. The highest rates of comorbidity
have been found with MDD and other anxiety or related
disorders [355,356,360]. Avoidant personality disorder
[373], body dysmorphic disorder [374,375], SUD
[356,376], ADHD [377,378], and schizophrenia [379]
also commonly occur with SAD.
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Diagnosis
SAD is characterized by a persistent fear that in social
and performance situations the individual will say or do
something that will lead to humiliation, embarrassment,
or negative evaluation by others (Table 19) [26]. Social
situations are actively avoided or endured with distress,
and the individual recognizes the fears as excessive or
unreasonable. The avoidance or anxiety induced by
these fears incurs significant functional impairment and
distress [144]. Compared to the DSM-IV-TR [144],
changes to the diagnostic criteria for SAD in the DSM-5
have been minimal, largely consisting of minor phrasing
changes to improve clinical utility [26]. The criterion
that the person recognizes that the fear is excessive or
unreasonable has been changed to out of proportion
to the actual threat posed by the social situation. Since
patients with SAD are often unable to recognize that
their fear may be excessive the clinician may be in a bet-
ter position to judge this.
The DSM-IV-TR criteria excluded social fears/avoidance
associated with and secondary to medical conditions,
however, the DSM-5 recognizes that SAD may be sec-
ondary to a medical condition. Some patients experience
excessive social anxiety about their medical symptoms
(e.g., stuttering, tremulousness from Parkinsons disease,
obesity, disfigurement from burns or injury), and may
experience disability due to their social anxiety [26].
In addition, the generalized subtype specifier
included in DSM-IV-TR has been removed, while the
performance only specifier has been added [26,380] for
DSM-5. This change was made because there was little
supporting evidence for the generalized specifier, and
the evidence that SAD symptoms fall along a continuum
of severity characterized by the number of fears [380].
The performance only specifier appears to represent
a subset of SAD patients typically experiencing
Table 19 DSM-5 diagnosis of SAD (social phobia)
Marked fear or anxiety about social situations in which the person
may be exposed to scrutiny by others
Fear that actions or showing anxiety symptoms will cause negative
evaluation (e.g., embarrassment, humiliation) or offend others
The social situation:
Almost always provokes fear or anxiety
Is actively avoided or endured with marked fear or anxiety
The fear, anxiety, or avoidance:
Is out of proportion to the actual threat posed by the social
situation
Is persistent, typically 6 months
Causes significant distress or functional impairment
If another medical condition is present (e.g., stuttering, obesity), the
disturbance is unrelated or out of proportion to it
Specify performance only if the fear is restricted to speaking or
performing in public
Adapted from DSM-5 [26].
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impairment from performance fears primarily related to
their professional lives [26].
While the most up-to-date DSM-5 diagnostic criteria
are presented here, it is important to note that all of the
treatment data described within this section are based
on patients meeting DSM-IV criteria (or older).
Psychological treatment
Psychological treatment, in the form of CBT, is consid-
ered to be the gold-standard nonpharmacological treat-
ment in SAD. Cognitive techniques involved in CBT for
SAD include restructuring and challenging of maladap-
tive thoughts, while the behavioral component is typi-
cally in the form of exposure therapy. The efficacy of
CBT compared with placebo, treatment-as-usual, or
wait-list conditions, is supported by many RCTs as well
as meta-analytic evidence [58,59,70,71,381]. Although
results vary, several studies of acute SAD treatment
have also found a similar efficacy between CBT and
pharmacotherapy [382-387]. Some reports suggest that
after treatment discontinuation, gains achieved with
CBT may persist longer than those achieved with phar-
macotherapy [388,389]. CBT for SAD can be adminis-
tered in group or individual formats. Although some
studies have reported that individual CBT is superior to
group CBT [390,391], meta-analyses have failed to find
significant differences in efficacy between the two mod-
alities [58,59,381].
The treatment literature has also examined the efficacy
of the individual components of CBT. There is evidence
to support the effectiveness of exposure therapy alone
[389,392], however the efficacy of exposure alone com-
pared with CBT is equivocal in the current treatment lit-
erature [392-395].
There are several variants of CBT that have been exam-
ined in the literature. For example, videotaped feedback
was not shown to enhance the effects of exposure-based
treatment [396]. However, CBT with VRE was found to
be more effective than wait-list control and as effective as
CBT with imaginal or in vivo exposure according to two
meta-analyses [80,150].
A form of CBT focused on interpersonal behavior
found similar improvements in social anxiety compared
to standard CBT but also increased relationship satisfac-
tion and social approach behaviors [397]. Evidence to
support interpersonal therapy (IPT) in SAD is conflicting
[398-400]; while some results have been negative [398], it
is likely that IPT is more effective than wait-list control
[399], but less effective than traditional CBT [399,400].
Similarly, while less effective than traditional CBT,
mindfulness-based therapy (MBT) has been associated
with improvements in symptoms of SAD [401]. In addi-
tion, small studies of attentional bias training suggest
there may be some benefit associated with training
Page 18 of 83
patients to disengage from negative social cues, but data
are conflicting [402,403].
ICBT is a newer treatment that may increase the avail-
ability of CBT for anxiety and mood disorders in the
future. Studies have evaluated this treatment in compari-
son to individual and group CBT. ICBT has demon-
strated efficacy in RCTs of SAD, significantly improving
social anxiety symptoms compared to wait-list control
conditions [404-410]. Most ICBT programs include mini-
mal therapist contact via email [404-410] or telephone
[405,409]. Many programs involve a component of inter-
action with other participants through the use of internet
discussion groups [411]. However, it remains unclear
whether the therapist component is necessary, and stu-
dies comparing guided with unguided ICBT have yielded
conflicting results. In one RCT, clinician-assisted ICBT
was more effective than a self-guided ICBT, and the
self-guided ICBT was not significantly better than the
wait-list condition [406]. Similarly, a self-help program
augmented with minimal therapist contact was more use-
ful than a pure self-help strategy [412]. However, several
other RCTs have found that unguided ICBT self-help
was as effective as ICBT with therapist involvement
[410,411]. A few ICBT programs included face-to-face in
vivo exposure sessions [409,413], but one RCT found
that adding this component did not significantly improve
outcomes versus ICBT with self-directed exposure [413].
In addition, several RCTs have shown ICBT (with mini-
mal therapist contact) to be as effective as face-to-face
CBT [414,415], while being more cost-effective [416]. As
with other RCTs, research on ICBT has involved pre-
screening of participants in-person or by telephone, with
posttreatment and follow-up assessments by telephone or
through self-report measures. Little is known about the
effectiveness of self-administered treatments (ICBT or
self-help books) used with no pre-screening or planned
follow-up contacts.
Combined psychological and pharmacological treatments
When used in combination, pharmacotherapy has not
been shown to add to the benefits of CBT in some studies
[387,417], while one study found the combination of phe-
nelzine and CBT superior to either modality alone [418].
D-cycloserine has also been found to enhance treatment
outcomes when used during exposure exercises as an
adjunct to exposure alone [419,420]. In addition, a study
of psychodynamic group therapy with or without the addi-
tion of clonazepam also found combination treatment to
be superior to clonazepam treatment alone [421].
Long-term effects of psychological treatment
The benefits of CBT have been found to be maintained at
six to 12 month follow-up visits [58,382,390,393,409,
413,422,423], with sustained improvement being reported
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at five years posttreatment [424,425]. Long-term assess- First-line agents

ments post-ICBT have shown sustained improvement at
one to five years follow-up [409,413,423,424]. Long-term
benefits with psychotherapy appear to be more enduring
than those of pharmacotherapy after treatment disconti-
nuation [388,389].
Pharmacological treatment
The management of patients with SAD should follow
the principles discussed in Section 2. Pharmacological
interventions that have good evidence for efficacy in
treating SAD include SSRIs, SNRIs, anticonvulsants, and
benzodiazepines. Treatments that have been investigated
for use in SAD have been assessed according to the cri-
teria for strength of evidence (Tables 1 and 2) and are
summarized in Tables 20 and 21.
Antidepressants: Meta-analyses demonstrate that SSRIs
and SNRIs are significantly more effective than placebo
[58,426-429] and RIMAs [426,428] for the treatment of
SAD. There is level 1, RCT evidence supporting the use
of the SSRIs escitalopram [430,431], fluvoxamine
[433-435], fluvoxamine CR [436,437], paroxetine
[431,438-444], and sertraline [445-448], as well as the
SNRI venlafaxine XR [439,441,454-456], for the first-line
treatment of SAD. There is also good evidence for the
efficacy of paroxetine CR (Level 2) [452].
Pregabalin: Pregabalin has also demonstrated efficacy
versus placebo for the treatment of SAD in RCTs at higher
(600 mg/day) but not lower dose levels (150-300 mg/day)
(Level 1) [474,475]. Although there is Level 1 evidence for
pregabalin, it is not clear how its efficacy compares to that

Table 20 Strength of evidence of pharmacotherapy for SAD

Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs [58,426-429] 1 TCAs
Escitalopram [430-432] 1 Clomipramine [458,459] 3
Fluvoxamine [433-435] 1 Imipramine [460] 3 (-ve)
Fluvoxamine CR [436,437] 1 MAOIs and RIMAs
Paroxetine [431,438-444] 1 Phenelzine [384,386,418,461,462] 1
Sertraline [445-448] 1 Moclobemide [417,462-466] 1*
Fluoxetine [382,387,449] 1* Other antidepressants
Citalopram [450,451] 2 Mirtazapine [467,468] 1*
Paroxetine CR [452] 2 Bupropion SR [469] 3
Adjunctive paroxetine [453] 3
SNRIs
Venlafaxine XR [439,441,454,255,456] 1
Duloxetine [457] 2
Other therapies
Anxiolytics Anticonvulsants
Benzodiazepines Pregabalin [474,475] 1
Clonazepam [385,470,471] 1 Gabapentin [476,477] 2
Alprazolam [386] 2 Levetiracetam [478-480] 2 (-ve)
Bromazepam [472] 2 Divalproex [481] 3
Adjunctive clonazepam [473] 2 (-ve) Tiagabine [477,482] 3
Topiramate [483] 3
Other treatments Atypical antipsychotics
Atenolol [461,484] 1 (-ve) Olanzapine [493] 2
Buspirone [383,485] 1 (-ve) Quetiapine [494,495] 2 (-ve)
Atomoxetine [486,487] 1* Adjunctive aripiprazole [496] 3
Propranolol [488] 2 (-ve) Adjunctive risperidone [271] 3
Selegiline [489] 3
Pergolide [490] 3 (-ve)
Adjunctive buspirone [491] 3
Adjunctive pindolol [492] 2 (-ve)
*Conflicting data. CR = controlled release; MAOI = monoamine oxidase inhibitor; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotonin
norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release;
(-ve) = negative.
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Table 21 Recommendations for pharmacotherapy for SAD

First-line Escitalopram, fluvoxamine, fluvoxamine CR, paroxetine, paroxetine CR, pregabalin, sertraline, venlafaxine XR
Second-line Alprazolam, bromazepam, citalopram, clonazepam, gabapentin, phenelzine
Third-line Atomoxetine, bupropion SR, clomipramine, divalproex, duloxetine, fluoxetine, mirtazapine, moclobemide, olanzapine, selegiline,
tiagabine, topiramate
Adjunctive Third-line: aripiprazole, buspirone, paroxetine, risperidone
therapy Not recommended: clonazepam, pindolol
Not Atenolol*, buspirone, imipramine, levetiracetam, propranolol*, quetiapine
recommended
CR = controlled release; SR = sustained release; XR = extended release.
*Beta-blockers have been successfully used in clinical practice for performance situations such as public speaking.
Note: although there is limited evidence for citalopram in SAD, it is likely as effective as the other SSRIs, in contrast there are negative trials of fluoxetine in SAD
suggesting it may be less effective than other SSRIs [382,449].

of SSRIs. In addition, SSRIs may have a broader spectrum
of efficacy for common comorbid conditions.
Second-line agents
Benzodiazepines: In RCTs, the benzodiazepines clonaze-
pam (Level 1) [470][385,471], alprazolam [386], and bro-
mazepam [472] (both Level 2) have demonstrated
efficacy in the treatment of SAD.
Although, a meta-analysis found benzodiazepines to be
as effective as SSRIs [58], these agents are recommended
as second-line options because of the lack of effect on
common comorbidities and the potential for abuse/
dependence in individuals with a history of SUDs.
Antidepressants: In RCTs, citalopram was found to be
significantly more effective than placebo [451], and as
effective as moclobemide [450] (Level 2). Although there
is limited evidence for citalopram in SAD, it is likely as
effective as the other SSRIs.
The efficacy of phenelzine has been established in mul-
tiple RCTs (Level 1) [384,386,418,461,462]; however, this
agent is recommended as a second-line option because of
concerns regarding dietary restrictions, drug interactions,
and the potential for hypertensive crisis.
Anticonvulsants: Gabapentin was significantly more
effective than placebo in a RCT [476], and as effective
as tiagabine in a small cross-over study (Level 2) [477].
Third-line agents
Antidepressants: Results with fluoxetine have been
mixed (Level 1, conflicting) [382,387,449]. A large RCT
found that fluoxetine was more effective than placebo
and as effective as CBT [387]. However, in two other
small RCTs, fluoxetine alone or when added to self-
exposure showed no benefit over placebo, with or with-
out self-exposure [382,449]. These negative trials with
fluoxetine suggest it may be less effective than other
SSRIs [382,449].
Similarly, results with moclobemide have also been
mixed (Level 1, conflicting) [417,462-466], with some
RCTs demonstrating significantly higher response rates
with moclobemide compared with placebo (Level 1)
[462-464], while others have not [465,466]. Moclobemide
was found to be superior to CBT early in treatment; how-
ever, after six months CBT was found to be superior.
Data from two small RCTs assessing mirtazapine were
also mixed (Level 1, conflicting), with one showing sig-
nificant improvements over placebo [468] and the other
showing no differences [467].
In a dose-finding study in which patients treated with
open-label duloxetine 60 mg/day were randomized to
continue or double their dose, both doses improved
symptoms, but there was no significant advantage to the
higher dose (Level 2) [457].
Small open-label trials have also suggested that bupro-
pion SR [469] and clomipramine [458,459] (both Level 3)
may be effective in patients with SAD.
Anticonvulsants: Open-label studies have demonstrated
some efficacy with divalproex [481], topiramate [483],
and tiagabine [482] (all Level 3). In addition, tiagabine
was comparable to gabapentin in a small RCT, crossover
study in eight adults [477].
Other treatments: Olanzapine was effective in a small
RCT (Level 2) [493], and selegiline demonstrated efficacy
in a small, open-label trial (Level 3) [489]. In a RCT, ato-
moxetine significantly improved SAD symptoms com-
pared with placebo [487]; however, in a another small
RCT, atomoxetine showed no significant difference in out-
comes compared with placebo (Level 1, conflicting) [486].
All of these agents are recommended as third-line
options, and may be useful in refractory patients after
first- and second-line monotherapies and adjuncts have
been unsuccessful.
Adjunctive therapy
Adjunctive strategies have generally been studied in
patients who have had an inadequate response to anti-
depressant therapy and can be considered for patients
with treatment-resistant SAD.
Third-line adjunctive therapies: Open-label studies and
case series have suggested that patients with refractory
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SAD may benefit from adjunctive therapy with aripipra-
zole [496], risperidone [271], buspirone [491], or paroxe-
tine [453] (all Level 3).
Not recommended adjunctive or combination therapies:
In RCTs, clonazepam [473] combined with paroxetine and
pindolol augmentation of paroxetine [492] (both Level 2,
negative) were not significantly superior to placebo in aug-
menting the effects of SSRI treatment for SAD.
Not recommended
In RCTs there was no evidence of benefits with the beta-
blockers atenolol (Level 1, negative) [461,484] or proprano-
lol (Level 2, negative) [488], or for the following treatments:
buspirone [383,485], levetiracetam [478-480] (both Level 1,
negative), or quetiapine (Level 2, negative) [494,495]. These
agents are not recommended for SAD. Imipramine [460]
and pergolide (both Level 3, negative) [490] also do not
appear to be effective in this disorder.
Maintenance pharmacological treatment
Long-term therapy has been evaluated in relapse preven-
tion and naturalistic follow-up studies. Relapse-prevention
studies are those in which responders to medication are
randomized to continued active treatment or placebo.
A meta-analysis of four relapse prevention studies
included 760 patients with SAD and found a highly signifi-
cant reduction in relapse rates with continued SSRI treat-
ment compared with placebo over three to six months.
The relative risk (RR) for relapse was 0.39 (95% CI 0.30
0.49) and number needed to treat (NNT) was 3.57 (95%
CI 2.944.76) [497]. The anticonvulsant pregabalin has
also demonstrated reductions in relapse rates over six
months [498].
In RCTs, escitalopram [431], fluvoxamine CR [499],
and venlafaxine XR [456] have demonstrated continued
improvement compared with placebo over approxi-
mately six months. Additional open follow-up data sup-
port the long-term efficacy of moclobemide over six to
24 months [464,500].
Biological and alternative therapies
Biological therapies: In an open-label study, neuro psy-
cho physical optimization-radio electric asymmetric con-
veyor (NPPO-REAC) (a brain stimulation technique)
was as effective as sertraline for the treatment of SAD
(Level 3) [501].
Alternative therapies: St Johns wort failed to demon-
strate superiority over placebo, and is not recommended
for the treatment of SAD (Level 2, negative) [502].
Summary
SAD is one of the most common anxiety disorders,
occurring more often in women than men. SAD has a
negative impact on QoL, functional and occupational
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outcomes, and is often associated with other comorbid
disorders, including MDD and other anxiety and related
disorders. SAD is characterized by intense fear or anxi-
ety relating to social or performance situations where
the individual is exposed to scrutiny by others. These
situations are often actively avoided.
CBT and exposure therapy alone are effective first-line
options for the treatment of SAD, although limited data
suggest that CBT may be more effective in maintaining
benefits during follow-up. VRE and internet-based pro-
grams have also demonstrated efficacy. The benefits of
CBT are maintained over one to five years of follow-up.
CBT and pharmacotherapy appear to have similar effi-
cacy for the acute treatment of SAD, but after treatment
discontinuation, gains achieved with CBT appear to per-
sist longer than those achieved with pharmacotherapy. In
most studies, adding pharmacotherapy has not been
shown to increase the benefits of CBT.
Pharmacotherapeutic approaches should begin with a
first-line antidepressant such as escitalopram, fluvoxa-
mine, fluvoxamine CR, paroxetine, paroxetine CR, sertra-
line, or venlafaxine XR, or the anticonvulsant pregabalin.
If response to optimal doses is inadequate or the agent is
not tolerated, therapy should be switched to another
first-line agent before considering a second-line medica-
tion. Second-line choices include the benzodiazepines
alprazolam, bromazepam, and clonazepam, as well as
citalopram, gabapentin, and phenelzine. Pregabalin has
also been shown to maintain benefits and prevent relapse
in a six-month study.
Patients who do not respond to several medication
trials and/or CBT are considered to have treatment-
refractory illness. In such patients it is important to
reassess the diagnosis and consider comorbid medical
and psychiatric conditions that may be affecting
response to therapy. Third-line agents and adjunctive
therapies may be useful when patients fail to respond to
optimal treatment trials of first- and second-line thera-
pies used alone and in combination.
Generalized anxiety disorder
Epidemiology
The estimated 12-month prevalence of GAD ranges from
1-4%, and the lifetime prevalence is approximately 6%
[2,3,16,503]. GAD is more frequent in Caucasians com-
pared to other groups [504]. The usual age of onset varies
and may be bimodal with the median age of onset being
approximately 31 years [2] and mean age of onset being
32.7 years [505]. The prevalence of GAD is estimated to
be 3% in children and 10.8% in adolescents [506], with
the age of onset for children and adolescents being
between ages 10 and 14 [507]. Some data suggest that
women may be two to three times more likely to suffer
from GAD than men [16,508], and GAD may be more
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common in older adults [509,510]. This disorder is
reportedly frequently under-recognized with less than
one-third of patients being adequately treated [511,512].
This is further complicated in children because of the
previous designation of Overanxious Disorder of Child-
hood and its possible differentiation of childhood GAD
from GAD in adults.
GAD is associated with functional [15,511,513], occupa-
tional [511], and QoL impairments [16,511], as well as sub-
stantial economic costs [511,514]. In addition, in primary
care 60-94% of patients with GAD report painful physical
symptoms [515,516], and these were the main reason for
initial presentation to a physician in 72% of cases [516].
Comorbidity
GAD is associated with high rates of comorbid psychia-
tric conditions including other anxiety or related disor-
ders and MDD [16]. The risk of medical conditions is
also elevated [16], including pain syndromes [16,517],
hypertension [16], as well as cardiovascular and gastric
conditions [16,518]. The presence of comorbid depres-
sion increases the severity of illness, functional impair-
ment [519], and economic costs [514].
Diagnosis
GAD is characterized by excessive anxiety and worry
about multiple events or activities such as school or work
difficulties, which is apparent on a majority of days over
the previous six months (Table 22) [26]. In addition, GAD
is associated with restlessness, muscle tension, fatigue,
concentration difficulties, irritability, and sleep issues [26].
The diagnostic criteria for GAD underwent one minor
revision in the DSM-5 [26] compared to the DSM-IV-
TR [144], the requirement that the disturbance not
occur exclusively during a mood, psychotic, or pervasive
developmental disorder was removed. However, it
remains important to note that most of the treatment
data described within this section are based on patients
meeting DSM-IV criteria (or older).
Psychological treatment
Meta-analyses clearly demonstrate that CBT significantly
reduces GAD symptoms and is markedly more effective
Table 22 DSM-5 diagnosis of GAD
Excessive anxiety and worry (apprehensive expectation) about a
number of events or activities (e.g., school/work performance)
The individual finds it difficult to control the worry
Excessive anxiety and worry are associated with 3 of the following
symptoms (with at least some occurring more days than not for 6
months):
Restlessness or feeling keyed-up or on edge, being easily fatigued,
difficulty concentrating, irritability, muscle tension, or sleep disturbance
The disturbance causes clinically significant distress or functional
impairment
Adapted from DSM-5 [26].
Page 22 of 83
than placebo or wait-list control conditions for GAD
(Level 1) [55,64,65,70,520]. Few studies have compared
CBT and pharmacotherapy alone in the same trial, but
the magnitude of benefits appear to be comparable for
both groups [521-523]. Individual and group therapy
appear to be equally effective in terms of anxiety symp-
tom reduction, but individual therapy may lead to ear-
lier improvement in worry and depression symptoms
[65,520].
The intensity of therapy was assessed in a meta-analy-
sis of 25 studies [65]. Regimens including fewer than
eight sessions were as effective as those of eight or more
for anxiety symptoms, but the more intense regimens
were more effective in improving symptoms of worry
and depression compared with fewer sessions [65].
Several studies have demonstrated the utility of internet-
based or computer-based CBT programs [79,524-526].
ICBT has been shown to be significantly more effective
than wait-list control [79,524,525], with benefits being
maintained at long-term follow-up [525]. In addition, a
peer-to-peer cognitive self-therapy program was as effec-
tive as treatment-as-usual, with a decreased need for
therapist contact [527].
A meta-analysis of five trials found no significant differ-
ences between CBT and relaxation therapy [55]. How-
ever, more recent studies suggest that applied relaxation
has limited efficacy [528-530]. One RCT found little evi-
dence that patients with GAD can learn to relax in ther-
apy or that a decrease in activation is associated with a
reduction in anxiety [529]. Balneotherapy, a relaxation
therapy involving spa-related treatments, demonstrated
potential advantages over SSRI pharmacotherapy in
improving anxiety scores and response rates in patients
with GAD in a large RCT [531]; however, while this
study may be interesting, concerns pertaining to blinding
and potential bias indicate further study is needed [531].
Several research-based variables have been specifically
identified among individuals with GAD in order to gener-
ate evidence-based CBT protocols for GAD, including:
intolerance of uncertainty, poor problem-solving confi-
dence, as well as positive and negative metacognitive
beliefs about the function or utility of worry [532]. Specific
psychotherapeutic protocols based upon models of the
disorder that target variables underlying GAD have been
developed to individualize therapy. Acceptance-based
behavior therapy [533], meta-cognitive therapy [528,534],
CBT targeting intolerance of uncertainty [530], and
adjunctive MBCT [184] have demonstrated efficacy for the
treatment of GAD. Targeting worry and relaxation [535],
as well as looming vulnerability (the tendency to generate
and maintain internal scenarios of increasing risk and dan-
ger) [536], may also be beneficial.
Psychodynamic therapy may also be of benefit, how-
ever the research findings to date are unclear. A RCT
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found that short-term psychodynamic psychotherapy
was as effective as CBT in improving anxiety scores, but
CBT was superior on measures of worry and depression
[537]. Another study found no significant differences
between brief psychodynamic therapy, pharmacotherapy,
or the combination [523].
No significant benefits were found with the addition of
interpersonal and emotional processing therapy to CBT
when compared with CBT plus supportive listening
[538]. However, pretreatment motivational interviewing
as an adjunct to CBT was shown to help reduce resis-
tance to therapy, improve homework compliance, and
improve worry outcomes this strategy may be particu-
larly useful in more severe cases [539,540].
In clinical practice, the approach may need to be indi-
vidualized to the problems experienced by the patient.
Psychological and pharmacological treatment
Few data are available on the use of combined psycholo-
gical and pharmacological treatment. A meta-analysis
concluded that combination pharmacotherapy and CBT
was more effective than CBT alone at posttreatment but
not at six-month follow-up [83]. While large effect sizes
were found for GAD, data were available from only two
studies, and these compared CBT plus diazepam or
buspirone with CBT alone [83]. Compared to pharma-
cotherapy alone, the few studies that have assessed the
benefits of adjunctive psychotherapy have been conflict-
ing [184,523,541,542]. One study suggested benefits of
the combination [184], while two other studies did not
[523,541]. However, adjunctive CBT was shown to facili-
tate benzodiazepine tapering in patients with GAD [542].
There is no current evidence to support the routine
combination of CBT and pharmacotherapy. However, as
in other anxiety and related disorders, when patients do
not benefit from CBT or have a limited response, a trial
of pharmacotherapy is advisable. Similarly, patients who
show limited benefit from pharmacotherapy may benefit
from CBT.
Long-term effects of psychological treatment
Long-term follow-up data from a meta-analysis [520]
and RCTs [523,525,535,543] suggest that benefits of psy-
chological treatments are maintained at one to three
years follow-up after treatment.
Pharmacological treatment
The management of patients with GAD should follow
the principles discussed in Section 2. Pharmacological
interventions that have good evidence for efficacy in
treating GAD include SSRIs, SNRIs, TCAs, benzodiaze-
pines, pregabalin, quetiapine XR, and other therapies.
Treatments that have been investigated for use in GAD
have been assessed according to the criteria for strength
of evidence (Tables 1 and 2) and are summarized in
Tables 23 and 24.
Page 23 of 83
First-line agents
Antidepressants (SSRIs & SNRIs): Evidence from RCTs
supports the use of SSRIs including escitalopram
[544-552] and sertraline [556,559-561], as well as the
SNRIs duloxetine [566-571] and venlafaxine XR
[548,553,570-580] (all Level 1) for the first-line treat-
ment of GAD. Similar evidence exists for paroxetine
[546,547,553-558] supporting its use as a first-line
option. Paroxetine CR has a similar active ingredient,
and although there are less data supporting its use, it is
likely interchangeable with paroxetine as a first-line
agent (Level 3) [564,565]. In head-to-head comparisons,
the efficacy of SSRIs and SNRIs appear to be similar
[546,547,549,556,558,570,571]. Some data suggest that
escitalopram may be less effective than venlafaxine XR
[548] or quetiapine XR [551]. Efficacy of venlafaxine was
similar to pregabalin in one RCT [576], but less effective
in another [577].
Other antidepressants: In two 12-week, double-blind
RCTs, agomelatine was found to be more effective than
placebo (Level 1) [584,585], and as effective as escitalo-
pram [585].
Pregabalin: The anticonvulsant pregabalin was more
effective than placebo in RCTs [576,577,592,593,597,613]
and as effective as benzodiazepines [592,593,597] in
patients with GAD (Level 1). Pregabalin was more effective
than venlafaxine XR in one RCT [577], but equivalent in
another [576].
Second-line agents
Benzodiazepines: Alprazolam [589-593], bromazepam
[589,594], diazepam [583,589,595,596], and lorazepam
[589,593,597-601] all have demonstrated efficacy for the
treatment of GAD (all Level 1). While these agents have
level 1 evidence for efficacy, they are recommended as
second-line therapy, and usually only for short-term use,
because of side effects, dependence, and withdrawal issues.
TCAs and other antidepressants: In RCTs, imipramine
was superior to placebo and as effective as benzodiaze-
pines for the treatment of GAD (Level 1) [553,581-583].
However, because of side effects and potential toxicity
in overdose, imipramine is recommended as a second-
line option. While there are little data on bupropion XL
(Level 2), in a 12-week RCT in patients with GAD it
was as effective as escitalopram (a first-line option), sup-
porting its use as a second-line option [549].
Vortioxetine is a so-called serotonin modulator
because of its activity in a variety of serotonin receptors.
Results from two similar, eight-week, placebo-controlled
RCTs with vortioxetine were conflicting, with one trial
being positive [587] and the other negative (Level 1,
conflicting) [586]. The differences in outcomes may be
related to differences in recruitment between the two
studies [623], and data suggest that vortioxetine may be
useful in GAD.
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Table 23 Strength of evidence for pharmacotherapy for GAD

Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs TCAs
Escitalopram [544-552] 1 Imipramine [553,581-583] 1
Paroxetine [546,547,553-558] 1 Other antidepressants
Sertraline [556,559-561] 1 Agomelatine [584,585] 1
Citalopram [562] 3 Vortioxetine [586,587] 1*
Fluoxetine [563] 3 Bupropion XL [549] 2
Paroxetine CR [564,565] 3 Trazodone [583] 2
SNRIs Mirtazapine [588] 3
Duloxetine [566-571] 1
Venlafaxine XR [548,553,570-580] 1
Other therapies
Anxiolytics Atypical antipsychotics
Benzodiazepines Quetiapine XR [551,557,602,603] 1
Alprazolam [589-593] 1 Adjunctive quetiapine [565,604,605] 1*
Bromazepam [589,594] 1 Adjunctive risperidone [606,607] 1*
Diazepam [583,589,595,596] 1 Adjunctive olanzapine [608] 2
Lorazepam [589,593,597-601] 1 Adjunctive aripiprazole [269,609] 3
Adjunctive quetiapine XR [610] 3
Adjunctive or monotx ziprasidone [611,612] 2 (-ve)
Anticonvulsants Other treatments
Pregabalin [576,577,592,593,597,613] 1 Buspirone [108,561,572,589,598,618,619] 1
Divalproex chrono [614] 2 Hydroxyzine [594,619,620] 1
Tiagabine [615,616] 1 (-ve) Pexacerfont [552] 2 (-ve)
Adjunctive pregabalin [617] 2 Propranolol [621] 2 (-ve)
Memantine [622] 4 (-ve)
*Conflicting data. SNRI = serotoninnorepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XL = extended
release; XR=extended release; (-ve) = negative.

Quetiapine XR: There is good evidence for the efficacy
of quetiapine XR for the management of GAD (Level 1)
[551,557,602,603]. Two meta-analyses [115,116] concluded
that quetiapine was significantly superior to placebo and
equivalent to antidepressants [115] for the treatment of
GAD. However, quetiapine was associated with more
weight gain and sedation, and higher dropout rates due to
adverse events compared with placebo or antidepressants
[115,116]. Due to tolerability and long-term safety con-
cerns with atypical antipsychotics, this treatment is recom-
mended as a second-line option for patients who cannot
be provided antidepressants or benzodiazepines.
Other treatments: Buspirone was more effective than
placebo and as effective as benzodiazepines in several

Table 24 Recommendations for pharmacotherapy for GAD

First-line Agomelatine, duloxetine, escitalopram, paroxetine, paroxetine CR, pregabalin, sertraline, venlafaxine XR
Second-line Alprazolam*, bromazepam*, bupropion XL*, buspirone, diazepam*, hydroxyzine, imipramine, lorazepam*, quetiapine XR*,
vortioxetine
Third-line Citalopram, divalproex chrono, fluoxetine, mirtazapine, trazodone
Adjunctive Second-line: pregabalin
therapy Third-line: aripiprazole, olanzapine, quetiapine, quetiapine XR, risperidone
Not recommended: ziprasidone
Not Beta blockers (propranolol), pexacerfont, tiagabine
recommended
CR = controlled release; XL = extended release; XR=extended release.
*Note: These have distinct mechanisms, efficacy and safety profiles. Within these second-line agents, benzodiazepines would be considered first in most cases,
except where there is a risk of substance abuse, while bupropion XL would likely be reserved for later. Quetiapine XR remains a good choice in terms of efficacy,
but given the metabolic concerns associated with atypical antipsychotic, it should be reserved for patients who cannot be provided antidepressants or
benzodiazepines. Please refer to text for further rationale for the recommendations.
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RCTs (Level 1) [108,561,572,589,598,618,619]. There are
limited data comparing buspirone to antidepressants,
with it being less effective than venlafaxine XR in one
study [572], but as effective as sertraline in another
[561]. Limited effectiveness in clinical practice relegates
buspirone to a second-line agent.
Hydroxyzine has demonstrated efficacy superior to
placebo and similar to benzodiazepines and buspirone in
RCTs (Level 1) [594,619,620]; however, clinical experience
with this agent in the treatment of GAD remains limited.
Third-line agents
The following agents are recommended as third-line
options because of limited data, side effects, or lack of
clinical experience as a primary therapy for the treat-
ment of GAD.
Antidepressants: In open-label studies or case series, the
antidepressants citalopram [562], fluoxetine [563], paroxe-
tine CR [564,565], and mirtazapine [588] have demon-
strated efficacy in patients with GAD (all Level 3). In a
RCT, trazodone was as effective as diazepam (Level 2)
[583].
Other treatments: Divalproex chrono was superior to
placebo for the treatment of GAD (Level 2) [614], how-
ever this formulation is not widely available.
Adjunctive therapy
Adjunctive strategies have generally been studied in
patients who have had an inadequate response to SSRI
therapy, and can be considered for patients with treat-
ment-resistant GAD.
Second-line adjunctive therapies: Adjunctive pregabalin
demonstrated good efficacy in a large RCT in patients
with GAD who had an inadequate response to prior
treatments (Level 2) [617].
Third-line adjunctive therapies: A meta-analysis of five
RCTs of adjunctive atypical antipsychotics found no sig-
nificant improvement in response rates but higher dis-
continuation rates versus placebo in patients with
refractory GAD [116].
Two RCTs suggest that adjunctive risperidone (Level 1,
conflicting) [606,607] may be useful in some patients, but
in the larger RCT it demonstrated superiority over pla-
cebo only in patients with moderate to severe residual
symptoms at baseline [607]. Similarly, data on adjunctive
quetiapine have been inconsistent (Level 1, conflicting)
[565,604,605], with one RCT being negative [565], while
another, unblinded RCT showed some, but limited bene-
fits [605]. Adjunctive olanzapine demonstrated efficacy in
a small RCT in patients who remained symptomatic after
six weeks of SSRI therapy [608]. Adjunctive treatment
with quetiapine XR [610] or aripiprazole [269,609] (both
Level 3) also had some benefit in open trials.
Because of the limited evidence for efficacy and their
potential for weight gain and metabolic side effects,
atypical antipsychotics should be reserved for highly
Page 25 of 83
treatment-refractory cases of GAD, and other than que-
tiapine XR, used only as an adjunctive treatment.
Not recommended adjunctive therapies: Ziprasidone
does not appear to be effective as adjunctive therapy
(Level 2, negative) [611].
Not recommended
Propranolol [621] and pexacerfont [552] (both Level 2,
negative) have not demonstrated efficacy and are not
recommended in the treatment of GAD. While a small
randomized, open-label trial suggested that tiagabine was
as effective as paroxetine, the results of three placebo-
controlled RCTs do not support the efficacy of tiagabine
in patients with GAD (Level 1, negative) [615,616]. Mem-
antine also does not appear to be effective in this disorder
(Level 4, negative) [622].
Maintenance pharmacological treatment
Long-term therapy has been evaluated in relapse preven-
tion and naturalistic follow-up studies. Relapse-prevention
studies are those in which responders to SSRI therapy are
randomized to continued active treatment or placebo. A
meta-analysis of three relapse prevention studies included
1342 patients with GAD and found a highly significant
reduction in relapse rates with continued SSRI treatment
compared with placebo over six to 12 months (odds ratio
for relapse was 0.20) [497].
In RCT discontinuation studies, duloxetine [624], esci-
talopram [625], paroxetine [626], and venlafaxine XR
[627] have demonstrated significantly lower relapse rates
over six to 18 months in the range of 10-20% with active
treatment compared to 40-56% with placebo. Pregabalin
[628] and quetiapine XR [629] have also demonstrated
significantly lower relapse rates over six to 12 months of
continued treatment in discontinuation trials.
In long-term RCT studies, escitalopram [546], paroxe-
tine [546], and venlafaxine XR [578,579] have demon-
strated continued improvement compared with placebo
over approximately six months.
Biological and alternative therapies
In general, these therapies may be useful for some
patients; however, more data are needed.
Biological therapies: In a small open trial, rTMS was
effective as monotherapy or as an adjunct to SSRIs in
patients with GAD (Level 3) [630], and improvements
were largely maintained six months after treatment [631].
Alternative therapies: Several herbal preparations have
demonstrated efficacy comparable to lorazepam for
the treatment of GAD including silexan (lavender oil)
(Level 1) [600,632] and Galphimia glauca extract (Level 2)
[601]. Cochrane meta-analyses found two studies of passi-
flora (passion flower) indicating it was as effective as
benzodiazepines (Level 2) [633], and one study of valerian
which found no significant differences between placebo,
valerian, or diazepam (Level 2, negative) [634,635].
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Unfortunately, because these preparations are poorly stan-
dardized and have substantial variation in proportion of
the active ingredient in different products, they cannot be
widely recommended.
A RCT of adjunctive resistance training (weightlifting)
or aerobic exercise found significant symptomatic
improvements compared to a wait-list condition (Level 2)
[636]. A systematic review included four studies of
acupuncture in GAD or anxiety neurosis, and while all
trials reported positive findings, methodological details
were lacking and the authors concluded that there was
insufficient evidence to determine efficacy (Level 2) [637].
Open-label studies suggest that adjunctive meditation and
yoga-based treatments may be useful in patients with
GAD (Level 3) [638,639].
Not recommended alternative therapy: In a RCT, there
were no significant improvements with bright light ther-
apy compared with placebo (Level 2, negative) [640],
and this treatment is not recommended.
Summary
The lifetime prevalence of GAD is approximately 6%, it
is more frequent in women than in men, with age of
onset reflecting a bimodal distribution (onset in late-
teens to early-twenties, and again in the 30s and 40s).
GAD is associated with substantial functional impair-
ment and a high prevalence of comorbid psychiatric and
medical disorders. According to DSM-5 criteria, GAD is
characterized by excessive anxiety and worry about mul-
tiple situations and is associated with restlessness, mus-
cle tension, and behavioral changes.
CBT is an effective first-line option for the treatment of
GAD and is as effective as pharmacotherapy. Internet-
based and computer-based CBT have also demonstrated
efficacy. Evidence does not support the routine combina-
tion of CBT and pharmacotherapy, but when patients do
not benefit from CBT, a trial of pharmacotherapy is advi-
sable, and vice versa.
Pharmacotherapeutic approaches should begin with
one of the first-line options including an SSRI such as
escitalopram, paroxetine, or sertraline, an SNRI such as
duloxetine or venlafaxine XR, or other antidepressant
such as agomelatine. The anticonvulsant pregabalin is
also a recommended first-line therapy.
If response to optimal doses is inadequate or the agent is
not tolerated, therapy should be switched to another first-
line agent before considering second-line medications.
Second-line choices include bupropion XL, buspirone,
hydroxyzine, imipramine, quetiapine XR, vortioxetine, as
well as the benzodiazepines, alprazolam, bromazepam,
diazepam, and lorazepam.
Patients who do not respond to multiple courses of
therapy are considered to have treatment-refractory
illness. In such patients it is important to reassess the
Page 26 of 83
diagnosis and consider comorbid medical and psychia-
tric conditions that may be affecting response to ther-
apy. Third-line agents, adjunctive therapies, as well as
biological and alternative therapies may be useful when
patients fail to respond to an optimal treatment trial of
first- and second-line therapies used alone and in
combination.
Obsessive-compulsive disorder
Epidemiology
OCD is a relatively uncommon, yet severe, mental disor-
der, with an estimated lifetime and 12-month prevalence
of 1.0-2.3% and 0.7%-1.2% in adults, respectively
[2,3,641,642]. Mean age of onset of OCD is ~20 years of
age, but symptoms can occur below the age of 10, with
few new cases after the early 30s [2,641,643]. Rates of
treatment-seeking have been estimated to be only about
14-56% of patients, suggesting that OCD may be under-
recognized and under-treated [644,645]. Social isolation,
history of physical abuse, and negative emotionality are
risk factors for the development of OCD [646].
OCD is associated with a substantial negative impact
on QoL for both patients [647,648] and their caregivers
[649]. Patients experience cognitive, social, and occupa-
tional impairments [642,645,650,651]. In addition, up to
one-quarter of patients with OCD have attempted suicide
[645,652]. OCD symptoms are associated with increased
rates of health care utilization compared to those without
OCD symptoms [642], with health care costs estimated
at $10.6 billion/year (2005) in the US [653].
Comorbidity
About 60-90% of patients with OCD also have a comorbid
disorder [641,645]. Patients with OCD or OCD symptoms
have a three-times higher rate of comorbidity compared to
those without OCD symptoms [642]. Common comorbid-
ities include mood, anxiety, and somatoform disorders, as
well as SUDs, psychotic disorders, and bipolar disorders
[641,642,645].
Diagnosis
A diagnosis of OCD requires the presence of obsessions
and/or compulsions (Table 25) [26]. Obsessions are
defined as recurrent, persistent, and intrusive thoughts,
images, or urges that cause marked anxiety, and compul-
sions are defined as repetitive behaviors or mental acts
that the patient feels compelled to perform to reduce the
obsession-related anxiety [26]. The obsessions or com-
pulsions are time consuming and cause significant
impairment in social or occupational functioning.
In the DSM-5, OCD has been moved from the anxi-
ety disorders [144] to a new diagnostic category called
obsessive-compulsive and related disorders. In addition
to OCD, this new category also includes diagnostic cri-
teria for body dysmorphic disorder, hoarding disorder,
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Table 25 DSM-5 diagnosis of OCD
Presence of either obsessions, compulsions, or both
Obsessions are defined by the following:
Recurrent and persistent thoughts, urges, or images that are
experienced as intrusive and unwanted and that cause marked anxiety
or distress
The individual attempts to ignore or suppress such thoughts,
urges, or images, or to neutralize them with other thoughts or actions
Compulsions are defined by the following:
Repetitive behaviors (e.g., hand washing, ordering, checking) or
mental acts (e.g., praying, counting, repeating words silently) that the
individual feels driven to perform in response to an obsession or
according to rigid rules
Compulsions are aimed preventing or reducing anxiety or
preventing some dreaded situation or event; however, they are not
connected in a realistic way with what they are designed to neutralize
or are clearly excessive
The obsessions or compulsions are time-consuming (e.g., take >1
h/day) or cause clinically significant distress or functional impairment
Specify patients degree of insight as to reality of OCD beliefs:
Good or fair insight (i.e., definitely or probably not true)
Poor insight (i.e., probably true)
Absent insight (i.e., completely convinced beliefs are true)
Specify if tic-related OCD
Adapted from DSM-5 [26].
hair-pulling disorder (trichotillomania), and skin picking
disorder [26].
Most of the other modifications to the OCD diagnostic
criteria in the DSM-5 were minor wording changes
designed to enhance clarity or further operationalize con-
cepts that were considered too vague [26]. In particular,
the definitions of obsessions and compulsions were clari-
fied and simplified [26,654]. The requirement that the
patient recognizes that the obsessions or compulsions are
excessive or unreasonable has been deleted, since these
terms are subject to interpretation and patients can have
varying levels of insight. As a result, the previous DSM-
IV-TR specifier of poor insight has been expanded to
include: good or fair, poor, and absent insight [26]. Finally,
a specifier of tic-related OCD has been added [26].
While the most up-to-date DSM-5 diagnostic criteria
are presented here, it is important to note that most of
the treatment data described within this section are
based on patients meeting DSM-IV criteria (or older).
Psychological treatment
Meta-analyses support the beneficial effects of psychologi-
cal treatment for OCD, mainly CBT, generally including
exposure with response prevention (ERP) [60-63,70,71,
655-657]. CBT is equivalent or superior to pharmacother-
apy [71,658-660]. Results with CBT were generally similar
in comparisons of interventions with an emphasis on ERP
and those with an emphasis on cognitive elements
[60,63,655]. A treatment specifically designed to address
fear of contamination with infectious substances, using a
cognitive intervention that includes no direct exposure
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(danger ideation reduction therapy, DIRT), was found to
be more efficacious than ERP [661,662]. Cognitive interven-
tions may be important in patients who do not have overt
compulsions, which can make ERP more difficult. One
meta-analysis found that exposure in vivo combined
with imaginal exposure was better than exposure in vivo
alone [60].
Several meta-analyses have demonstrated no significant
differences in efficacy between group and individual CBT
[60,62,663]. However, results of head-to-head trials are
conflicting, with some RCTs finding no significant differ-
ences in efficacy between group and individual therapy
[663,664], and others showing individual therapy to be
superior [665-667]. Differences in results may be explained
by the fact that in individual therapy the therapist may
have the advantage of being more aware of the patients
dysfunctional beliefs, however, the group therapy setting
may offer the advantages of group encouragement, reci-
procal support, imitation, and interpersonal learning
which may result in an increased motivation and reduced
discontinuation of treatment [62].
An important practical question concerns the intensity
and duration of treatment. The intensive ERP program
described by Foas group involves 15 two-hour sessions
scheduled five days a week over three weeks [658,668]. A
similar program administered twice-weekly (a more prac-
tical approach for many patients and therapists) was as
effective at the end of follow-up as the intensive five-
days/week strategy [669]. A step-care approach in which
patients received six weeks of low-intensity counseling
with ERP bibliotherapy followed by standard ERP for
non-responders only was found to be as effective as
initial therapy with standard ERP (17 sessions twice
weekly), but was significantly less costly [670].
Other techniques that may be useful include accep-
tance and commitment therapy (ACT) [671], modular
cognitive therapy (CT) addressing OCD beliefs [672,673],
CT addressing obsessional doubt [674], organizational
training [675,676], and mindfulness training [677]. RCTs
on the benefits of adding motivational interviewing to
CBT have been conflicting, with one showing no addi-
tional benefits [678], while another demonstrated
improved symptom reduction and remission rates com-
pared with CBT alone [679]. While EMDR was more
effective than an SSRI in a RCT [680], data are limited
and this technique is not generally recommended for
patients with OCD.
Data suggest that therapist-guided exposure is better
than self-exposure [60]. While both treatment condi-
tions showed significant symptom reduction, therapist-
administered ERP was superior to self-administered ERP
in improving OCD symptoms and self-reported func-
tional impairment [681]. Other data suggest that ERP
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delivered by telephone is equivalent to face-to-face ERP
[682]. Bibliotherapy in the form of self-help manuals
delivered to patients via email has demonstrated signifi-
cantly greater improvements in OCD symptoms
compared with wait-list control groups in two RCTs
[683,684].
ICBT is an easily accessible treatment that has the
potential to reach untreated patients and motivate them
for face-to-face psychotherapy if necessary [684,685].
Several RCTs have demonstrated that ICBT programs
are significantly more effective than supportive therapy
or relaxation control strategies [685-687]. ICBT was as
effective as therapist-led CBT only when patients com-
pleted at least one self-exposure session [687]. ICBT was
associated with significantly better outcomes when it
included brief, scheduled, therapist-initiated telephone
support compared with on-demand phone support [688].
Family accommodation (i.e., family members taking
part in the performance of rituals, avoidance of anxiety-
provoking situations, or modification of daily routines to
assist a relative with OCD) has been associated with
poorer response to both behavioral and pharmacological
treatments [689]. Clinicians may want to consider target-
ing family accommodation in order to improve treatment
outcomes for some patients.
Although hoarding disorder is now a separate diagnosis
[690], the limited data available on the treatment of
hoarding will be mentioned in this section on OCD. One
RCT found that group CBT significantly reduced hoard-
ing and depression symptoms while bibliotherapy alone
was associated with very limited improvements [691].
The addition of posttreatment, nonclinician, home assis-
tance did not significantly improve outcomes.
Combined psychological and pharmacological treatment
The combination of psychological and pharmacological
treatment has been shown to be superior to medication
alone [657,658,692-694], but not to CBT alone [83,658,
692,694,695]. These findings suggest that if pharma-
cotherapy is required or preferred, adding CBT to phar-
macological treatment of OCD may enhance response
rates and reduce relapse rates. Unlike in some anxiety
and related disorders, there does not appear to be any
contraindication to combining CBT with medications in
patients with OCD [696], and combined treatment may
improve relapse prevention [697].
Adding d-cycloserine may hasten the onset of improve-
ments with ERP, with significant benefits over placebo
during the first four or five ERP sessions [698-700], but
this effect has not been seen in all studies [701].
Long-term effects of psychological treatment
Follow-up studies suggest that the benefits of CBT are
maintained at one to five years of follow-up [664,695,
702-704].
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Pharmacological treatment
The management of patients with OCD should follow
the principles discussed in Section 2. SSRIs are recom-
mended first-line pharmacological interventions for
OCD, while SNRIs, clomipramine, and other antidepres-
sants are recommended second- and third-line treat-
ments. Treatments that have been investigated for use
in OCD have been assessed according to the criteria for
strength of evidence (Tables 1 and 2) and are summar-
ized in Tables 26 and 27.
First-line agents
SSRIs: Evidence from RCTs and meta-analyses support
the use of SSRIs, including escitalopram [705-709], fluox-
etine [660,710-716], fluvoxamine [711,713,714,717-719],
paroxetine [705,720-722], and sertraline [659,710,711,
713,714,723-725] (all Level 1), in the treatment of OCD.
In meta-analyses, response rates with SSRIs are generally
twice those of placebo [809], at 40-60% with treatment
versus <20% with placebo [711,713,714,740,741]. Pooled
response rates are not significantly different between
SSRIs [809]. In meta-analyses and head-to-head trials,
compared with clomipramine, the SSRIs fluoxetine, flu-
voxamine, paroxetine, and sertraline had similar efficacy
but better tolerability [711,713,714,716-718,720,724].
Dimensional analyses have suggested that symmetry/
hoarding symptoms may be associated with a poorer
response to SSRI therapy [810,811], while aggressive/
religious/sexual symptoms may predict better outcomes
[810,812]. It has been hypothesized that the symmetry/
hoarding symptom dimension may be mediated by the
dopamine system and aggressive behaviors by the sero-
tonin system [810,812].
Second-line agents
Clomipramine: There is good evidence to support the
use of clomipramine in the treatment of OCD (Level 1)
[658,711,713,714,716-718,720,724,740,741]. Clomipra-
mine has efficacy similar to SSRIs, but SSRIs are gener-
ally better tolerated [711,713,714,716-718,720,724]. Side
effects and safety are issues with clomipramine and there-
fore it is recommended as a second-line choice. Common
adverse effects include anticholinergic effects such as dry
mouth, constipation, and blurred vision, as well as urinary
retention, orthostatic hypotension, weight gain, and seda-
tion [813,814]. The major safety concerns are cardiac
arrhythmias, seizures, drug interactions, and toxicity in
overdose [813,814].
Antidepressants: In RCTs, citalopram was more effec-
tive than placebo but less effective than psychotherapy
(Level 2) [680,726]. Additional data from augmentation
studies support the efficacy of citalopram for the treat-
ment of OCD [727,728]. However, given that other
SSRIs have much stronger evidence, citalopram was
designated a second-line option. The only RCT data on
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Table 26 Strength of evidence of pharmacotherapy for OCD

Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs MAOIs
Escitalopram [705-709] 1 Phenelzine [737,738] 2*
Fluoxetine [660,710-716] 1 Tranylcypromine [739] 4
Fluvoxamine [711,713,714,717-719] 1 TCAs
Paroxetine [705,720-722] 1 Clomipramine [658,711,713,714,716-718,720,724,740,741] 1
Sertraline [659,710,711,713,714,723-725] 1 IV clomipramine [742-744] 2
Citalopram [680,726-728] 2 Desipramine [723,745] 2 (-ve)
IV citalopram [729] 3 Adjunctive clomipramine [746,747] 2 (-ve)
Adjunctive citalopram [730] 3 Other antidepressants
SNRIs Mirtazapine [748] 2
Venlafaxine XR [721,731-733] 2 Bupropion [749] 3 (-ve)
Duloxetine [734-736] 4 Adjunctive mirtazapine [727] 3
Other therapies
Antipsychotics Anxiolytics
Adjunctive aripiprazole [750-755] 1 Benzodiazepines
Adjunctive risperidone [755-761] 1* Clonazepam [771] 2 (-ve)
Adjunctive olanzapine [760,762,763] 1* Adjunctive clonazepam [772] 2 (-ve)
Adjunctive quetiapine [728,746,747,764-768] 1* Other treatments
Adjunctive haloperidol [758,769] 2 Clonidine [773] 2 (-ve)
Adjunctive amisulpride [770] 3 Adjunctive pindolol [774-776] 1*
Adjunctive ziprasidone [767] 4 Adjunctive celecoxib [777] 2
Anticonvulsants Adjunctive granisetron [778] 2
Adjunctive topiramate [795-798] 1* Adjunctive IV ketamine [779,780] 2
Adjunctive lamotrigine [799,800] 2 Adjunctive memantine [622,781-783] 2
Adjunctive pregabalin [801,802] 3 Adjunctive ondansetron [784,785] 2
Adjunctive gabapentin [803,804] 3 (-ve) Adjunctive N-acetylcysteine [786,787] 2
Opioids Adjunctive riluzole [788,789] 3
Tramadol [805,806] 4 Adjunctive lithium [790,791] 1 (-ve)
Naltrexone [807] 3 (-ve) Adjunctive buspirone [792,793] 2 (-ve)
Adjunctive morphine [808] 2 Adjunctive minocycline [794] 4 (-ve)
*Conflicting data. IV = intravenous; MAOI = monoamine oxidase inhibitor; SNRI = serotoninnorepinephrine reuptake inhibitor; SSRI = selective serotonin
reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release; (-ve) = negative.

the use of mirtazapine in OCD are from a discontinua- the treatment of OCD (Level 2) [721,731-733]. In RCTs,
tion study in which continued mirtazapine was associated venlafaxine XR was more effective than placebo [732],
with continued improvement (Level 2) [748]. There is and as effective as paroxetine [721] and clomipramine
some evidence to support the use of venlafaxine XR for [731]. In a double-blind extension of a RCT [721],

Table 27 Recommendations for pharmacotherapy for OCD

First-line Escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
Second-line Citalopram, clomipramine, mirtazapine, venlafaxine XR
Third-line IV citalopram, IV clomipramine, duloxetine, phenelzine, tramadol, tranylcypromine
Adjunctive First-line: aripiprazole, risperidone
therapy Second-line: memantine, quetiapine, topiramate
Third-line: amisulpride, celecoxib, citalopram, granisetron, haloperidol, IV ketamine, mirtazapine, N-acetylcysteine, olanzapine,
ondansetron, pindolol, pregabalin, riluzole, ziprasidone
Not recommended: buspirone, clonazepam, lithium, morphine
Not Clonazepam, clonidine, desipramine
recommended
IV = intravenous; XR = extended release.
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paroxetine was more efficacious than venlafaxine in the
treatment of non-responders to previous treatment with
the alternate antidepressant [733].
Third-line agents
Intravenous clomipramine: In a RCT, intravenous (IV)
clomipramine was more effective than placebo in
patients with OCD (Level 2) [742]. Initiating therapy
with IV then switching to oral therapy does not appear
to be associated with greater benefit compared with oral
therapy alone [743,744].
Other agents: IV citalopram [729] (Level 3), as well as
duloxetine [734-736], tramadol [805,806], and tranylcy-
promine [739] (all Level 4) have demonstrated some
efficacy in open trials or case reports. Results with phe-
nelzine have been inconsistent. In one RCT, phenelzine
was not significantly better than placebo [738], but in
another it was as effective as clomipramine (Level 2)
[737]. In the placebo-controlled trial, post-hoc analysis
suggested that phenelzine may be beneficial in patients
with symmetry or other atypical obsessions [738].
These agents are recommended as third-line options,
and may be useful in refractory patients after first- and
second-line monotherapies and adjuncts have been
unsuccessful.
Adjunctive therapy
Adjunctive strategies have generally been studied in
patients who have had an inadequate response to SSRI
therapy, and can be considered for patients with treat-
ment-resistant OCD. A meta-analysis demonstrated that
response rates with adjunctive medication were twice
those of placebo, however these were still quite low
(31.8% versus 13.6%) [815]. Meta-analyses of RCTs
found that adding risperidone (and possibly quetiapine)
to antidepressants increased efficacy but decreased toler-
ability, while adjunctive olanzapine did not improve
response rates [816,817].
First-line adjunctive therapies: In RCTs, adjunctive ari-
piprazole was significantly more effective than placebo
(Level 1) [750,754], and may be as effective as risperi-
done [755]. Additional open-label data also support the
beneficial effects of adjunctive aripiprazole [751-753].
As adjunctive therapy for treatment-resistant OCD, ris-
peridone was more effective than placebo (Level 1)
[756-759] and as effective as olanzapine [760] and aripi-
prazole overall [755]. Compared with aripiprazole, risperi-
done may provide greater improvement in obsessions
[755]. Risperidone was also as effective as haloperidol for
obsessions, but less so for compulsions, however it was
better tolerated [758]. More recently an open, randomized
study found that while augmentation with ERP was super-
ior to risperidone or pill placebo, risperidone was not sig-
nificantly more effective than placebo [761]. However,
patients in this study had some response to SSRI therapy
and may have been less refractory compared to those in
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other studies. Considering the tolerability concerns of aty-
pical antipsychotics, these data reinforce that this augmen-
tation strategy should be reserved for patients with
treatment-resistant OCD.
Second-line adjunctive therapies: RCT evidence
demonstrated that adjunctive memantine was superior
to placebo (Level 2) [783]. Additional open-label data
also support this therapy [622,781,782]. Another option
which may be useful as an adjunctive therapy in those
with refractory OCD is the atypical antipsychotic quetia-
pine (Level 1, conflicting) [728,746,747,764-766,768].
Data from small RCTs suggest that topiramate may be
a useful adjunctive therapy, but data are conflicting
(Level 1) [796,797]. In one RCT, adjunctive topiramate
significantly improved Yale-Brown Obsessive Compul-
sive Scale (Y-BOCS) scores compared with placebo
[797], while in another trial, adjunctive topiramate sig-
nificantly improved compulsions but not obsessions
[796]. Additional open-label data support the use of
adjunctive topiramate [795,798].
Third-line adjunctive therapies: The agents discussed
below are recommended as third-line adjunctive options,
since some data are available to suggest they may be
useful but there is conflicting or inadequate evidence to
warrant stronger recommendations. These agents may
be useful for some patients, but more data are needed.
Other atypical antipsychotics have been assessed as
adjunctive therapies in patients with refractory OCD,
including olanzapine (Level 1, conflicting) [760,762,763],
amisulpride (Level 3) [770], and ziprasidone (Level 4)
[767].
There is level 2 evidence to support the use of adjunc-
tive haloperidol in patients with refractory OCD
[758,769], and although it may be as effective as adjunc-
tive risperidone, it is a third-line choice because it was
less well tolerated [758].
Adjunctive mirtazapine was associated with an earlier
onset of response of OCD symptoms compared with cita-
lopram alone, but there was no advantage of the combi-
nation over time (Level 2) [727]. Some data also support
the efficacy of adjunctive citalopram for treatment-
resistant OCD (Level 3) [730].
Adjunctive anticonvulsants may be useful for some
patients with refractory illness [799-802]. In a small
RCT, adjunctive lamotrigine improved both obsessions
and compulsions compared to SSRI therapy (Level 2)
[799]. Open-label data also suggest that adjunctive preg-
abalin may be useful (Level 3) [801,802].
Other agents that have been studied as adjunctive
therapy for treatment-resistant OCD include celecoxib
[777], granisetron [778], IV ketamine [779,780], ondan-
setron [784,785], N-acetylcysteine [786,787] (all Level 2),
and riluzole (Level 3) [788,789]. There is little clinical
experience with these agents for refractory OCD,
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therefore they are recommended as third-line adjunctive
options only.
Results with pindolol augmentation have been inconsis-
tent, with significant improvements in one small RCT
[774], but not in other randomized or open trials (Level 1,
conflicting) [775,776].
In two randomized, quetiapine-controlled trials,
adjunctive clomipramine was not superior to SSRI ther-
apy (Level 2, negative) [746,747]. Clinical experience
suggests that some patients may benefit from adjunctive
clomipramine; however, plasma levels should be moni-
tored because of the risk of drug interactions with SSRIs
[747,813].
Not recommended
Clonazepam [771], clonidine [773], and desipramine (all
Level 2, negative) [723,745] have not demonstrated effi-
cacy and are not recommended in the treatment of
OCD. Bupropion [749] and naltrexone (both Level 3,
negative) [807] also do not appear to be effective in this
disorder.
Adjunctive buspirone [792,793], clonazepam [772]
(Level 2, negative), or lithium [790,791] (Level 1, nega-
tive) have not demonstrated efficacy for the treatment of
OCD. There is currently no evidence for the efficacy of
adjunctive gabapentin (Level 3, negative) [803,804] or
minocycline (Level 4, negative) [794], but there are insuf-
ficient data to make recommendations at this time. In a
RCT, adjunctive once-weekly oral morphine was effective
in patients who had failed six SSRI trials (Level 2) [808],
however, morphine is not generally recommended
because of its potential for abuse.
Maintenance pharmacological treatment
Long-term therapy has been evaluated in relapse preven-
tion and naturalistic follow-up studies. Relapse-prevention
studies are those in which responders to SSRI therapy are
randomized to continued active treatment or placebo. A
meta-analysis of six relapse prevention studies included
951 patients with OCD and found a highly significant
reduction in relapse rates with continued SSRI treatment
compared with placebo over six to 12 months (odds ratio
for relapse was 0.38) [497]. In RCTs, escitalopram [818],
paroxetine [722], sertraline [819], and high-dose fluoxetine
[820] have demonstrated reductions in relapse rates. In
RCT discontinuation studies, mirtazapine [748] and clomi-
pramine [821] have demonstrated continued improvement
compared with placebo over approximately six to
12 months. Additional data support the long-term efficacy
of fluoxetine, fluvoxamine XR, and sertraline over six to
24 months [710,822-824].
Biological and alternative therapies
Biological therapies: Biological therapies may be useful
in patients with OCD who have not responded to CBT
and multiple medication trials. Open trials have
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suggested that rTMS may be a promising adjunctive
therapy in patients with treatment-refractory OCD
[825,826]. However, results of sham-controlled trials are
conflicting, with some trials finding significant improve-
ments [827,828] and others concluding that rTMS was
ineffective for treatment-resistant OCD (Level 1, con-
flicting) [829-831]. Some data suggest that rTMS may
improve comorbid depressive symptoms in patients with
OCD [829,830].
Several very small studies have suggested that deep
brain stimulation may improve symptoms and function-
ality in up to two-thirds of patients with highly treat-
ment-refractory OCD (Level 4) [832-834].
Open trials suggest that capsulotomy (Level 3)
[835-839] or cingulotomy (Level 3) [840-842] may be
effective in reducing symptoms in patients with severe,
treatment-refractory OCD, however these treatments are
usually considered last resorts.
Alternative therapies: A meta-analysis of meditation
therapies found only two small studies and showed that
transcendental meditation and Kundalini yoga were
likely no more effective than other kinds of relaxation
therapies in treating OCD (Level 3, negative) [843].
Open studies suggest that adjunctive moderate-intensity
aerobic exercise may help improve OCD symptoms
(Level 3) [844,845].
Small RCTs and open trials have suggested that herbal
therapies such as milk thistle (Silybum marianum L.
Gaertn.) (Level 2) [715], valerian root (Valeriana offici-
nalis L.) (Level 2) [846], and St Johns wort (Hypericum
perforatum) (Level 3) [847] may be useful in patients
with OCD. Unfortunately, because these preparations
are poorly standardized and have substantial variation in
the proportion of the active ingredient in different pro-
ducts, they cannot be widely recommended. These
therapies may be useful for some patients; however,
more data are needed.
Summary
OCD is a relatively rare, yet severe, mental disorder,
with an onset in the 20s or earlier. It is characterized by
the presence of obsessions (persistent, intrusive
thoughts) and/or compulsions (repetitive behaviors the
individual feels compelled to perform). OCD is asso-
ciated with substantial functional impairment and a high
prevalence of comorbid disorders.
CBT, and notably ERP, are effective first-line options for
the treatment of OCD, being equivalent or superior to
pharmacotherapy. CBT can be effectively delivered in both
individual and group settings, as well as via self-exposure,
self-help books, telephone, and internet-based programs.
The benefits of CBT are maintained over one to five years
of follow-up. The combination of psychotherapy and phar-
macotherapy appears to be superior to pharmacotherapy
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alone, but not to CBT alone, and data suggest that adding
CBT to pharmacological treatment may yield better long-
term outcomes.
Pharmacotherapeutic approaches should begin with a
first-line SSRI such as escitalopram, fluoxetine, fluvoxa-
mine, paroxetine, or sertraline. If response to optimal
doses is inadequate or the agent is not tolerated, therapy
should be switched to another first-line agent before con-
sidering second-line medications. Second-line choices
include citalopram, clomipramine, mirtazapine, and venla-
faxine XR. OCD can be difficult to treat; therefore, in
order to preserve any benefits of a therapy, adjunctive stra-
tegies may be important early in treatment.
Patients who do not respond to multiple courses of ther-
apy are considered to have treatment-refractory illness. In
such patients it is important to reassess the diagnosis and
consider comorbid medical and psychiatric conditions that
may be affecting response to therapy. Third-line agents,
adjunctive therapies, as well as biological and alternative
therapies may be useful when patients fail to respond to
optimal treatment trials of first- and second-line therapies
used alone and in combination.
Posttraumatic stress disorder
Epidemiology
The lifetime prevalence of PTSD in Canada was esti-
mated to be 9.2%, and current (1-month) rates were 2.4%
[848]. Over 76% of Canadians reported exposure to a
significantly traumatic event [848]. US and European
community studies report lifetime prevalence rates of
6.4-6.8% and 12-month rates of 1.1-3.5% [2,849,850]. The
most common forms of trauma resulting in PTSD
included unexpected death of someone close, sexual
assault, serious illness or injury to someone close, having
a child with serious illness, and being beaten by a partner
or caregiver [848-850]. Onset is generally in the mid to
late 20s [2], and the prevalence is about twice as high
among women versus men [849,851].
PTSD was associated with significant QoL [852] and
functional impairments [848,853-855], which increase
with increasing severity of symptoms [855]. In addition,
PTSD is associated with high rates of chronic pain
[856-859], sleep problems [860], and sexual dysfunction
[861], as well as cognitive dysfunction [862,863] and
alexithymia [864]. The risk of suicide attempts is
increased two- to three-fold by the presence of PTSD
[20,849,865].
In primary care, PTSD was associated with more and
longer hospitalizations as well as a greater use of mental
health care [866]. Among Canadian military personnel,
greater use of mental health care was associated with
cumulative lifetime trauma exposure, index trauma type,
PTSD symptom interference, suicidal ideation, female
gender, and comorbid MDD [867,868].
Page 32 of 83
Comorbidity
An estimated 75% of patients with PTSD have another
comorbid psychiatric disorder [3,848]; and rates are par-
ticularly high for other anxiety and related disorders
[3,849,859,869,870], MDD [3,849,859,871,872], opposi-
tional defiant disorder [3], ADHD [3], SUD [849], alco-
hol dependence [3,873], and borderline personality
disorder (BPD) [874]. Comorbid panic or mood disor-
ders have been associated with greater functional
impairment than PTSD alone [870,871]. Patients with
comorbid PTSD and BPD had a poorer QoL, more
comorbidity with other psychiatric conditions, and
increased odds of a lifetime suicide attempt versus
patients with either condition alone [20,874].
Diagnosis
By definition PTSD requires exposure to trauma, includ-
ing actual or threatened death, serious injury, or sexual
violation [26]. It is characterized by intrusive and distres-
sing memories or dreams, dissociative reactions, and sub-
stantial psychological or physiological distress related to
the event (Table 28) [26]. A diagnosis of PTSD requires
the disturbances to be present for longer than one
month; symptoms of >3 days but less than one month
may be diagnosed as acute stress disorder (ASD), if the
required ASD criteria are met [26].
Compared to the DSM-IV-TR [144], changes to the diag-
nostic criteria for PTSD in the DSM-5 include adjusting
the symptom clusters, adding some new symptoms, and
re-classifying PTSD as a trauma- and stressor-related dis-
order instead of an anxiety disorder [26,875]. In addition
to PTSD, this new category also includes diagnostic criteria
for reactive attachment disorder, disinhibited social engage-
ment disorder, ASD, and adjustment disorders [26]. The
DSM-5 diagnostic criteria for PTSD sharpens the definition
of traumatic event, and there are now four symptom
clusters rather than three with the avoidance and numb-
ing of responsiveness being separated (Table 28). The
DSM-5 also eliminated the acute and chronic PTSD speci-
fiers. The PTSD diagnostic criteria apply to adults, adoles-
cents, and children >6 years of age. A subtype has been
added for children 6 years of age, as well as a dissociative
symptoms specifier for patients of all ages [26].
While the most up-to-date DSM-5 diagnostic criteria
are being presented here, it is important to note that
the treatment data described within this section are
based on patients meeting DSM-IV criteria (or older).
PTSD is frequently comorbid with other psychiatric
disorders, including other anxiety and related disorders,
MDD, and SUDs, which may complicate diagnosis and
management [849,859]. In addition, patients with PTSD
frequently present with somatic symptoms and pain
[859]. It is important to ask patients with psychological
or somatic symptoms about trauma [32,859].
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Table 28 DSM-5 diagnosis of PTSD

The person has been exposed to actual or threatened death, serious injury, or sexual violation in 1 of the following ways:
Directly experienced or witnessed the traumatic event, learned that trauma occurred to close family member or friend (actual or threatened
death must have been violent or accidental), experienced repeated exposure to aversive details of trauma
Presence of 1 of the following intrusion symptoms associated with the trauma:
Recurrent, involuntary, and intrusive distressing memories, distressing dreams, dissociative reactions (e.g., flashbacks), psychological or
physiological distress at reminders of trauma
Persistent avoidance of stimuli associated with the trauma, including 1 of the following:
Avoidance of distressing memories or feelings and external reminders (e.g., people, places) of the trauma
Negative alterations in cognitions and mood associated with the trauma, including 2 of the following:
Inability to recall important aspect of the trauma, diminished interest or participation in activities, feeling of detachment or estrangement from
others, persistent negative beliefs, distorted blame, and negative emotional state
Marked alterations in arousal and reactivity associated with the trauma, including 2 of the following:
Irritable or aggressive behavior, reckless or self-destructive behavior, hypervigilance, exaggerated startle response, problems with concentration,
sleep disturbance
Duration of disturbance >1 month
Symptoms cause clinically significant distress or impaired functioning
Specify whether with dissociative symptoms (depersonalization or derealization) or with delayed expression (full criteria not met until at least 6
months after the event)
Adapted from DSM-5 [26].

Prevention and early intervention
A number of studies have assessed early intervention
with psychological and pharmacological strategies for
the prevention of PTSD. Meta-analyses do not support
the efficacy of wide spread use of single-session
[876,877] or multiple-session [878] psychological
debriefing after trauma in preventing or reducing the
intensity of PTSD in individuals who have been exposed
to a traumatic event but have not been identified as suf-
fering from any specific psychological difficulties. In
fact, these interventions may have an adverse effect on
some individuals [876,878]. These findings pertain to
individual debriefings only; there is insufficient evidence
to comment on the utility of group debriefings.
Conversely, meta-analyses have demonstrated the ben-
efit of multisession trauma-focused-CBT (TF-CBT) in
patients with ASD or PTSD [879,880]. Therefore, debrief-
ing of all trauma victims is not recommended, rather,
screening and treating appropriate individuals is pre-
ferred [876]. For the prevention of chronic PTSD in
patients with ASD or acute PTSD, brief TF-CBT was
more effective than both wait-list and supportive coun-
seling interventions, but there was no evidence of the
effectiveness of structured writing compared to minimal
intervention [880].
There are few data on the use of pharmacotherapy for
the prevention of PTSD. In a cohort study and a RCT,
the early use of benzodiazepines following trauma was
not beneficial, and may increase the risk of developing
PTSD [881,882]. Similarly, retrospective data suggested
that gabapentin or pregabalin had no effect on PTSD
development [883]. Data from cohort studies on the use
of the beta-blocker propranolol have been conflicting
[884-888], but one small RCT did show a significant
decrease in the severity of PTSD symptoms and lower
likelihood of developing subsequent PTSD [889]. SSRI
therapy was significantly more effective than placebo in
preventing PTSD symptoms according to parent reports
but not child reports in a RCT in children [890]. Cohort
studies suggest that the early use of morphine during
trauma care may reduce the risk of the subsequent devel-
opment of PTSD in children and adults [891-894].
Psychological treatment
Psychological therapies for PTSD generally include educa-
tion about the disorder and its treatment, as well as expo-
sure to cues relating to the traumatic event. Psychotherapy
has demonstrated significant efficacy, although a meta-
analysis suggested it may be less effective than pharma-
cotherapy in improving PTSD and comorbid depression
symptoms [895].
Meta-analyses of over 30 RCTs of psychological inter-
ventions provide evidence of the efficacy of several CBT
approaches for the management of chronic PTSD com-
pared with wait-list or usual care control groups [66,67].
There was evidence that individual TF-CBT, EMDR, stress
management, and group TF-CBT were effective, while
other nontrauma focused psychological treatments (sup-
portive therapy, nondirective counseling, psychodynamic
therapy, and hypnotherapy) did not reduce PTSD symp-
toms as significantly [66,67]. Individual TF-CBT and
EMDR appeared to be equally effective, but superior to
stress management in the treatment of PTSD [66]. Another
meta-analysis also found EMDR and TF-CBT were equally
effective [68]. However, in a head-to-head RCT, EMDR
resulted in faster recovery compared with the more gradual
improvement with brief TF-CBT [896]. Cognitive therapy
approaches have been used effectively in treating PTSD fol-
lowing sexual or interpersonal violence [897-901], civilian
trauma [902-908], and military trauma [909-914].
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Cognitive processing therapy (CPT) is an effective pro-
tocol that combines cognitive therapy and written
accounts [899-901,910-913]; however, an analysis of the
components found no differences in outcomes with
either component alone or the combined protocol [899].
Prolonged exposure (PE) is a widely studied CBT
approach. A meta-analysis of 13 RCTs concluded that PE
therapy was more effective than wait-list or psychological
placebo control conditions, and as effective as other
active treatments (e.g., CBT, CPT, EMDR) [69]. One
study found that 30-minute imaginal exposure sessions
were as effective as 60-minute sessions [915]. Imaginal
appears to be as effective as in vivo exposure [69,916].
Data are conflicting as to the benefits of adding cogni-
tive restructuring to exposure therapy; several studies
suggest that exposure alone is superior to the combina-
tion [917-919], however, another large RCT found the
combination to be significantly better than imaginal or
in vivo exposure alone [916]. When used as an adjunct to
exposure therapy, cognitive restructuring may improve
non-fear problems like anger and guilt, and may be a use-
ful adjunct in patients in which these emotions predomi-
nate [920,921]. Similarly, the addition of social emotional
rehabilitation to exposure therapy did not improve PTSD
symptoms but did improve social functioning in male
combat veterans with chronic PTSD [922].
Meta-analyses and systematic reviews reveal two cur-
rent limitations of CBT for PTSD. The first is that about
one-third to one-half of patients experience substantial
residual symptoms and functional impairments posttreat-
ment, still report symptoms meeting diagnostic criteria at
follow-up, or relapse and require booster sessions
[923-925]. The second issue pertains to external validity.
While CBT for PTSD has been shown to be efficacious in
RCTs, there is a dearth of effectiveness studies to suggest
that CBT can be generalized to many patients commonly
found in clinical practice. Many RCTs have excluded
patients with complex clinical profiles including child-
hood abuse histories, current SUDs, personality disor-
ders, suicidality or self-injurious behavior, homelessness,
refugees, intimate partner violence, and significant disso-
ciative symptoms among others [926,927]. In this regard,
Bradley et al. [923] found a positive association between
the number of exclusion criteria and the strength of
effect sizes, such that studies with stricter inclusion cri-
teria tended to report larger treatment effects. Addition-
ally, numerous studies fail to report whether patients
experience any adverse effects from psychological treat-
ments [66], or whether dropout rates (ranging between
0-50%) result from treatment demands.
Dialectical behavior therapy (DBT), which was devel-
oped to reduce self-harm behavior in patients with BPD,
was shown to be useful in patients with PTSD [928-930].
When used as a pretreatment, DBT reduced self-harm
Page 34 of 83
behaviors allowing over half of patients to become suita-
ble candidates for PTSD treatment [929].
Another study [931] demonstrated some success with
PE treatment of PTSD and comorbid substance abuse.
Results of a recent expert clinician survey on best prac-
tices suggests that CBT is useful for fear-based PTSD,
while this treatment approach may require an additional
treatment module targeting affective regulation for
patients presenting with a diagnosis of Disorders of
Extreme Stress (DESNOS) or complex PTSD [932].
Internet-based treatments are being increasingly investi-
gated, in part because they can be administered remotely
and anonymously to under-served or disaster-stricken
areas at a relatively low-cost [933]. RCTs have shown that
therapist-assisted ICBT is more effective than wait-list or
supportive care control strategies in improving PTSD
symptoms, depression, anxiety, and disability [934-940].
In addition, a strong therapeutic relationship can be estab-
lished through the internet, which improved the treatment
process [936]. VRE therapy has also demonstrated
some utility in improving PTSD symptoms [941-943].
Compared to face-to-face CBT, video-conference CBT
was equally effective [944] but telehealth CBT was less
effective [914]; however, both were effective compared
with pre-treatment.
Combined psychological and pharmacological treatment
Research evaluating combined treatment in PTSD is lim-
ited; a meta-analysis found only four small trials [945].
Combination SSRI plus psychotherapy was not superior
to psychotherapy alone in two RCTs [946,947], but was
superior to pharmacotherapy alone in the other two trials
[948,949]. In contrast, a more recent RCT found that
combination therapy was superior to psychotherapy
alone [950]. The role of combining psychotherapy and
medication requires further study.
Adjunctive propranolol with trauma reactivation therapy
was found to help prevent reconsolidation of the traumatic
memory and thus decreased physiological responses and
PTSD symptoms during subsequent follow-up in rando-
mized and open trials [951,952]. Two RCTs have found
that use of d-cycloserine did not enhance the overall treat-
ment effects of exposure therapy [953,954], and may in
fact decrease response to psychotherapy [954].
Long-term effects of psychological treatment
Open follow-up data of psychological treatments suggest
that benefits are maintained at six- to 18-month assess-
ments after treatment [923,955-958]. Longer-term fol-
low-up of patients treated with EMDR showed that
benefits were maintained at three years, with the majority
of patients who had initially remitted being at full work-
ing capacity [959]. Very long-term follow-up showed that
improvements in PTSD and related symptoms achieved
with CPT and PE were maintained over an extended five
to 10 year period [901].
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Pharmacological treatment
The management of patients with PTSD should follow
the principles discussed in Section 2. Pharmacological
interventions that have good evidence for efficacy in
treating PTSD include fluoxetine, paroxetine, sertraline,
and venlafaxine XR. Treatments that have been investi-
gated for use in PTSD have been assessed according to
the criteria for strength of evidence (Tables 1 and 2)
and are summarized in Tables 29 and 30.
First-line agents
Antidepressants (SSRIs & SNRIs): Evidence from meta-
analyses [895,1060] and RCTs supports the use of the
SSRI paroxetine [966-970] and the SNRI venlafaxine XR
[975,989] (both Level 1) for the first-line treatment of
PTSD. Data with fluoxetine are mixed, with both posi-
tive [960-962] and negative [963-965] RCTs (Level 1,
conflicting). Similarly, RCTs with sertraline have yielded
both positive [971,972,975,976,978] and negative
[973,974,977] results (Level 1, conflicting). However,
there appear to be sufficient data from the larger RCTs
to suggest that these agents can be effective first-line
options. Conflicting results may be related to the types of
traumas, symptom clusters, and comorbidities included
in the various studies.
Second-line agents
Antidepressants: The efficacy of mirtazapine was demon-
strated in one small RCT (Level 2) [1000] and three
open trials [999,1001,1002]. In a randomized, open-label

Table 29 Strength of evidence of pharmacotherapy for core symptoms of PTSD

Agent Level of evidence Agent Level of evidence
Antidepressants
SSRIs TCAs
Fluoxetine [960-965] 1* Imipramine [992,993] 1
Paroxetine [966-970] 1 Amitriptyline [994] 2
Sertraline [971-978] 1* Desipramine [970,995] 2*
Fluvoxamine [979-984] 2 MAOIs and RIMAs
Escitalopram [985] 3 Phenelzine [992,993,996] 1*
Citalopram [974,986,787,988] 2 (-ve) Moclobemide [997,998] 3
SNRIs Other antidepressants
Venlafaxine XR [975,989] 1 Mirtazapine [999-1002] 2
Duloxetine [990,991] 3 Reboxetine [984] 2
Bupropion SR [1003] 3
Tianeptine [997,1004] 3
Adjunctive bupropion SR [1005] 2 (-ve)
Other therapies
Anxiolytics Anticonvulsants
Benzodiazepines Topiramate [1009,1010] 1*
Alprazolam [1006] 2 (-ve) Lamotrigine [1011] 2
Clonazepam [881,1007,1008] 3 (-ve) Carbamazepine [1012,1013] 3
Atypical antipsychotics Divalproex [1014-1017] 1 (-ve)
Risperidone [1030] 2 Tiagabine [1018] 2 (-ve)
Aripiprazole [1031-1033] 3 Adjunctive gabapentin [1019,1020] 4
Quetiapine [1034,1035] 3 Adjunctive levetiracetam [1021] 4
Olanzapine [1036-1038] 2 (-ve) Adjunctive pregabalin [1022] 4
Adjunctive risperidone [1039-1044] 1* Adjunctive tiagabine [1023-1025] 4
Adjunctive olanzapine [1045] 2 Adjunctive topiramate [1026-1029] 2 (-ve)
Adjunctive aripiprazole [1033,1046,1047] 3 Other treatments
Adjunctive quetiapine [1048-1050] 3 Buspirone [1051,1052] 4
Trazodone [1053] 4
Memantine [1054] 4
Adjunctive eszopiclone [1055] 2
Adjunctive clonidine [1056] 3
Adjunctive guanfacine [1057,1058] 1 (-ve)
Adjunctive zolpidem [1059] 2 (-ve)
*Conflicting data. MAOI = monoamine oxidase inhibitor; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotoninnorepinephrine reuptake
inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR=extended release; (-ve) = negative.
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
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Table 30 Recommendations for pharmacotherapy for core symptoms of PTSD
First-line Fluoxetine, paroxetine, sertraline, venlafaxine XR
Second-line Fluvoxamine, mirtazapine, phenelzine
Third-line Amitriptyline, aripiprazole, bupropion SR, buspirone, carbamazepine, desipramine, duloxetine, escitalopram, imipramine,
lamotrigine, memantine, moclobemide, quetiapine, reboxetine, risperidone, tianeptine, topiramate, trazodone
Adjunctive Second-line: eszopiclone, olanzapine, risperidone
therapy Third-line: aripiprazole, clonidine, gabapentin, levetiracetam, pregabalin, quetiapine, reboxetine, tiagabine
Not recommended: bupropion SR, guanfacine, topiramate, zolpidem
Not Alprazolam, citalopram, clonazepam, desipramine, divalproex, olanzapine, tiagabine
recommended
SR = sustained release; XR = extended release.
trial, response rates were significantly higher with mirta-
zapine than sertraline [1001].
Fluvoxamine demonstrated efficacy for PTSD in open
trials [979-983], and in a RCT was as effective as rebox-
etine (Level 2) [984].
Phenelzine was more effective than placebo in two RCTs
[992,993], but not significantly different from placebo in a
RCT crossover study (Level 1, conflicting) [996]. Caution
is needed when using MAOIs because of the dietary
restrictions and potential for drug interactions.
Third-line agents
The following agents are recommended as third-line
options because of limited data, side effects, or lack of
clinical experience as a primary therapy for the treatment
of PTSD.
Antidepressants: In small RCTs, imipramine (Level 1)
[992,993] and amitriptyline (Level 2) [994] demonstrated
some efficacy in patients with PTSD. Data with desipra-
mine are mixed, with one RCT showing significant benefit,
which were comparable to paroxetine [970], and the other
showing improvements in depression only [995]. While
RCTs with the TCAs suggest some benefit with these
agents, it appears to be limited.
Reboxetine and fluvoxamine were equally effective in a
small RCT (both Level 2) [984], and open-label studies
suggest that bupropion SR [1003], duloxetine [990,991],
escitalopram [985], moclobemide [997,998], and tianep-
tine [997,1004] (all Level 3) may be useful in PTSD.
Anticonvulsants: Data on topiramate are mixed, with
one RCT finding significant benefits over placebo [1010],
while the other did not [1009] (Level 1, conflicting).
There are also limited data suggesting efficacy of other
anticonvulsants, including lamotrigine (Level 2) [1011]
and carbamazepine (Level 3) [1012,1013].
Atypical antipsychotics: Some data suggest that the atypi-
cal antipsychotics, risperidone (Level 2) [1030], aripiprazole
(Level 3) [1031,1032], and quetiapine (Level 3) [1034,1035]
may be a useful alternative to SSRIs for some patients with
PTSD. A meta-analysis of seven RCTs using atypical anti-
psychotics, either as monotherapy or adjunctively, con-
cluded that these agents may be beneficial in the treatment
of PTSD, particularly for the symptom of intrusion [1061].
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Other therapies: Small, open case series have suggested
benefits with trazodone [1053], buspirone [1051,1052],
and memantine [1054] (all Level 4).
Adjunctive therapies
Adjunctive strategies have generally been studied in
patients who have had an inadequate response to ade-
quate antidepressant therapy, and can be considered for
patients with treatment-resistant PTSD.
Second-line adjunctive therapies: In a RCT, adjunctive
eszopiclone was significantly more effective than placebo
in improving PTSD and sleep symptoms (Level 2) [1055].
There is RCT evidence for the use of adjunctive atypical
antipsychotics, including risperidone (Level 1, conflicting)
[1039-1044] and olanzapine (Level 2) [1045], for patients
with treatment-resistant PTSD. While a number of small
RCTs demonstrated benefits with adjunctive risperidone
[1039-1042], a large, six-month trial in approximately 250
patients failed to show improvements in PTSD symptoms
compared with placebo [1043].
Third-line adjunctive therapies: Open-label trials and
case series suggest that adjunctive quetiapine [1048-1050]
or aripiprazole [1033,1046,1047] (both Level 3) are useful
in patients with refractory PTSD.
Similarly, there are some data suggesting adjunctive
anticonvulsants including: gabapentin [1019,1020], levetir-
acetam [1021], pregabalin [1022], or tiagabine [1023-1025]
(all Level 4), as well as the alpha-adrenergic agonist cloni-
dine (Level 3) [1056], can improve symptoms in patients
with treatment-resistant PTSD.
Not recommended adjunctive therapies: Small RCTs
failed to show the superiority of adjunctive therapy with
guanfacine (Level 1, negative) [1057,1058], bupropion SR
[1005] (Level 2, negative), or zolpidem [1059] (Level 2,
negative). While case series suggested that adjunctive
topiramate [1026,1027,1029] may be effective in treat-
ment-resistant PTSD, a RCT failed to show superiority
over placebo [1028] (Level 2, negative).
Treatments for specific PTSD-associated symptoms
Several agents have been used to target particular symp-
toms associated with PTSD. Prazosin has demonstrated
significant efficacy for reducing trauma nightmares and
improving sleep quality in patients with PTSD compared
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
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with placebo (Level 1) [1035,1062-1066]. Some open-
label data suggest that naltrexone may help reduce flash-
backs (Level 3) [1067-1070], and fluphenazine may
improve trauma re-experiencing symptoms (Level 3)
[1037].
Cyproheptadine was not effective for nightmares or
sleep problems in patients with PTSD and may actually
exacerbate sleep disturbance (Level 2, negative) [1071].
Not recommended
In general, data do not currently support the use of dival-
proex [1014-1017] (Level 1, negative), alprazolam [1006],
citalopram [974,986-988], olanzapine [1036-1038], tiaga-
bine [1018] (all Level 2, negative), or clonazepam (Level 3,
negative) [881,1007,1008].
Maintenance pharmacological treatment
Long-term therapy has been evaluated in relapse-
prevention and naturalistic follow-up studies. Relapse-
prevention studies are those in which responders to
SSRI therapy are randomized to continued active treat-
ment or placebo. A meta-analysis of three relapse-
prevention studies included 272 patients with PTSD,
and found a highly significant reduction in relapse
rates with continued SSRI treatment compared with
placebo over approximately six months (odds ratio for
relapse was 0.25) [497].
In RCT discontinuation studies, fluoxetine [1072,1073]
and sertraline [1074] have demonstrated significantly
lower relapse rates over six months in the range of
5-22% with active treatment compared to 16-50% with
placebo [1072-1074]. However, in a small discontinua-
tion RCT, tiagabine was not superior to placebo in pre-
venting relapse [1075].
Open follow-up studies with paroxetine [1076] and
sertraline [1077] have demonstrated sustained and con-
tinued improvement over six to 12 months of continued
SSRI therapy.
Biological and alternative therapies
In general, these therapies may be useful for some
patients; however, more data are needed.
Biological therapies: In RCTs, rTMS was effective as
monotherapy or as an adjunct to SSRIs in patients with
PTSD (Level 1) [1078-1080], and at least some improve-
ments were maintained at two to three months after treat-
ment [1078,1079]. Open prospective and retrospective
data suggest that adjunctive electroconvulsive therapy may
be helpful in patients with refractory PTSD (Level 3)
[1081,1082].
Alternative therapies: In a RCT, acupuncture was
more effective than a wait-list control and as effective as
group CBT (Level 2) [1083]. Adjunctive use of symp-
tom-oriented hypnotherapy [1059] or mantra repetition
[1084] (both Level 2) improved PTSD symptoms in
small trials; and in a small case series, patients with
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PTSD benefited from transcendental meditation
(Level 4) [1085].
Summary
The lifetime prevalence of PTSD is around 6-9%; it is
more frequent in women than in men, with an onset gen-
erally in the mid to late 20s. PTSD is associated with high
rates of functional impairment, somatic complaints, sui-
cide risk, and comorbid psychiatric disorders. A diagnosis
of PTSD requires evidence of exposure to trauma, and is
characterized by intrusive and dissociative symptoms.
Evidence does not support the wide spread use of early
intervention with psychological strategies for the preven-
tion of PTSD. Debriefing of all trauma victims is not
recommended, rather, screening and treating appropriate
individuals is preferred. In general, there is little evidence
supporting the use of pharmacotherapy for the preven-
tion of PTSD, with most studies suggesting no preventive
benefits.
CBT is an effective first-line option for the treatment of
PTSD. Effective approaches include TF-CBT, EMDR, PE,
and stress management therapy. ICBT and VRE have also
demonstrated efficacy. Benefits are maintained during
long-term follow-up of up to one to 10 years after treat-
ment. Research evaluating combined psychological and
pharmacological treatments in PTSD is limited, and this
requires further study.
Pharmacotherapeutic approaches should begin with
one of the first-line options which include SSRIs such as
fluoxetine, paroxetine, or sertraline, or the SNRI venla-
faxine XR. If response to optimal doses is inadequate or
the agent is not tolerated, therapy should be switched to
another first- or second-line agent, or a second-line agent
should be added. Patients with PTSD may make few
gains during treatment, and it is important to preserve
even small gains achieved with initial therapy. Therefore,
augmentation with second- or third-line agents may be
important early in treatment.
Patients who do not respond to multiple courses of ther-
apy are considered to have treatment-refractory illness. In
such patients it is important to reassess the diagnosis and
consider comorbid medical and psychiatric conditions that
may be affecting response to therapy. Third-line agents,
adjunctive therapies, as well as biological and alternative
therapies may be useful when patients fail to respond to
an optimal treatment trial of first- and second-line thera-
pies used alone and in combination.
Special populations
Women during pregnancy and the postpartum period
Epidemiology
Women have been found to be at higher risk for anxiety
and related disorders than men [2]. Anxiety disorders
during the perinatal period are increasingly gaining
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research attention. Although further investigation is
needed, data from a large national survey suggest the
overall prevalence of anxiety and related disorders is
unchanged in women during pregnancy [1086]; however,
other data have found an increased risk for individual
disorders, such as GAD [1087,1088]. Similarly, some
data suggest that anxiety disorders are also not more
prevalent during the postpartum period [1086], but
other studies suggest higher rates of OCD and GAD
during this period [1089,1090]. In addition, PTSD can
develop as a result of pregnancy complications that are
experienced as traumatic [1091,1092].
Anxiety and related disorders during pregnancy or
postpartum may have a negative impact on the preg-
nancy, the child, or the mother. While studies report that
maternal anxiety disorders are associated with adverse
pregnancy outcomes such as a shorter gestational age,
premature delivery, or elective cesarean delivery
[1093-1095], a meta-analysis found no relationship
between anxiety symptoms per se and adverse perinatal
outcomes [1096]. Anxiety symptoms during pregnancy
have been associated with depressive symptoms, sub-
stance use, and anemia, as well as decreased use of prena-
tal vitamins [1093,1097-1099].
Parenting may also be affected by maternal anxiety and
related disorders. Mothers with anxiety disorders have
been found to be less promoting of psychological auton-
omy than those mothers without anxiety [1100]. Maternal
anxiety has been found to be predictive of child cognitive
development [1101], associated with behavioral/emotional
problems in childhood [1101,1102], and maternal anxiety
and related disorders have been found to be related to
subsequent development of an anxiety disorder in the
child [1103].
Treatment issues
Psychosocial treatments, with CBT specifically, have
strong empirical support for the treatment of anxiety and
related disorders [63,70,71,1104], but evidence of their
efficacy in perinatal women with anxiety disorders is
lacking. Cohort studies have shown beneficial effects of
group CBT in pregnant women with B-I-I phobia [1105],
and individual CBT in women with OCD in the postnatal
period [1106]. Arch et al. argued that although exposure-
based CBT or behavioral therapy may have been avoided
in the past because of concerns of potential harm, they
likely can be viable, safe alternatives in pregnancy [1107].
The lack of data on the use of structured psychosocial
interventions for anxiety and related disorders during the
perinatal period is a significant gap in the literature.
It is important to consider the risks and benefits of
pharmacotherapy during pregnancy and while breastfeed-
ing during the postpartum period. Risks to the fetus and
newborn should be weighed against that of the potential
harm of untreated anxiety and related disorders, an area
Page 38 of 83
that is gaining increasingly more research attention.
Treatment decisions should attempt to optimize out-
comes for both mother and baby.
Detailed recommendations on the use of psychiatric
medications during pregnancy and lactation are available
from the American Congress of Obstetricians and Gyne-
cologists (ACOG) Practice Bulletin [1108]. Although it is
over five years old, risks associated with various psychotro-
pic medications are summarized [1108]. The FDA preg-
nancy risk category system has been criticized as being
insufficient [1109] and is currently under the process of
revision. The Canadian Hospital for Sick Children
Motherisk website (http://www.Motherisk.org) is also a
useful resource.
Antidepressants: There appears to be little evidence of an
association between maternal antidepressant use and
increased risks of congenital malformations in general, and
major congenital malformations in infants [1110-1113].
The exception is a statistically increased risk of cardiac
defects with antidepressants, and with paroxetine specifi-
cally, although the clinical significance of this has been
questioned [1108,1113-1117]. There have been reports of
increased rates of spontaneous abortion following antide-
pressant use during pregnancy; in the most recent meta-
analysis, this was not supported using data from studies
with higher study quality but found by others who included
all studies [1118-1120]. In terms of delivery outcomes, a
recent meta-analysis found a statistically increased risk for
preterm birth, lower gestational age, birth weight, and
APGAR scores but the effects were small, generally in
the normal range, and of questionable clinical significance
[1118]. However, data support an increased risk for poor
neonatal adaptation syndrome (PNAS) [1121-1123], while
findings of increased risk for persistent pulmonary hyper-
tension in the antenatally exposed infant have not been
consistent [1124-1127]. Systematic reviews suggest that
overall prenatal exposure to antidepressants does not
appear to be associated with changes in long-term neuro-
cognitive or behavioral development in children
[1128-1130] and that illness itself appears to play a role in
negative outcomes (although this study examined the
effects of maternal depression) [1131]. Two reports link
prenatal antidepressant use to childhood autism spectrum
disorders [1132,1133] and two others link bupropion expo-
sure to childhood ADHD [1134,1135]. These studies have
limitations and further research is required.
In terms of breastfeeding, potential risks of antidepres-
sant use during lactation must be weighed against the
recognized benefits for the infant. Antidepressants are
excreted into breast milk and although data are limited,
the majority are found in very low amounts with few iso-
lated instances of adverse signs [1108]. If antidepressant
treatment is indicated, sertraline or paroxetine is preferred
[1136]. Long-term data on potential neurobehavioral
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
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effects are lacking. Clinicians can consult LactMed at
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT for
the latest information available.
Benzodiazepines: The data on benzodiazepines remain
more limited. A recent meta-analysis did not find an
increased risk of major malformations or cardiac defects
following prenatal benzodiazepine exposure, but con-
cluded the significant increase in risk of oral cleft remains
based on data derived from case-control studies [1137],
although another meta-analysis reported the absolute
risk is small (<1%) [1138]. A case-control study published
in 2002 examining exposure to five benzodiazepines
(including clonazepam) and not included in the above
meta-analyses, with over 60,000 infants, did not find an
association with various congenital malformations or oral
clefts [1139]. Although there are a lack of meta-analytic
data, neonatal withdrawal or toxicity syndrome has been
described with antenatal benzodiazepine exposure and
close monitoring of the infant has been recommended
[1108]. The neurobehavioral effects on the child over the
long-term due to antenatal exposure have been topics of
debate and remain uncertain [1108]. Benzodiazepines are
excreted into breast milk at low levels generally. A recent
study with 124 mothers documented low levels of
adverse effects (sedation in particular) and supported the
initiation of breastfeeding [1140]. Caution may be advised
regardless however in infants who poorly metabolize ben-
zodiazepines [1108].
Atypical antipsychotics: Data on the use of antipsycho-
tics during pregnancy continue to be limited [1141].
Thus far, there does not appear to be an increased risk
for malformations although inconsistent data have been
reported with some suggesting the data are inconclusive
[1141-1143]. These drugs have been found to be asso-
ciated with both increased and decreased birth weight as
well as increased risk for preterm birth [1144-1149]. The
second-generation antipsychotics can increase the risk of
complications given the risk of metabolic syndrome, and
thus diabetes, in the mother. Monitoring has been
recommended [1150]. Both the FDA and Health Canada
have issued safety alerts advising of the potential risk for
abnormal muscle movements and withdrawal symptoms
in infants exposed to antipsychotic medications during
the 3 rd trimester of pregnancy [1151-1153]. Data on
breastfeeding are more limited, but levels in breast milk
have typically been shown to be low although adverse
effects have been reported [1154].
Summary
The management of anxiety and related disorders in
women who are pregnant or lactating requires careful
consideration of both the potential risks of any treatment
option as well as risks of an untreated anxiety disorder.
Antidepressants are generally associated with low terato-
genic risk and adverse delivery outcomes. Patients should
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be counseled about PNAS and its management. Less is
known about the risk of benzodiazepine and atypical
antipsychotic exposure during pregnancy as the data are
more limited. Treatment must be individualized and
decisions should be made with the most up-to-date infor-
mation with the best course of action decided upon with
the patient. Poorly or untreated psychiatric illness carries
its own risks, both in the short- and long-term.
Children and adolescents
Epidemiology
Anxiety and related disorders were the most common
psychiatric disorders noted in the National Comorbidity
Survey-Adolescent supplement (NCS-A) (age 13-18
years), with a lifetime and 12-month prevalence of
31.9% and 24.9%, respectively [1155,1156]. Prevalence
rates for individual anxiety and related disorders are
shown in Table 31 [1155,1156].
Specific phobias are very common in children. How-
ever, although most adolescents reported at least one
fear (77%), lifetime prevalence rates are in the range of
10-35% [308,1156]. A study including children as young
as five years of age found lower rates of diagnosed speci-
fic phobias (1%) [1157]. B-I-I and animal fears are the
most common types reported in pediatric populations
[308,1157]. The prevalence of OCD is only 0.25% in
children [1158], but is 1-2% in adolescents, which is
comparable to the rate seen in adults [2,1159,1160].
In the adolescent population, anxiety and related dis-
orders were found to have the earliest median age of
onset (six years), compared to other psychiatric disor-
ders (11-15 years) [1156]. Similarly, in the adult popula-
tion, the median age of onset was earliest for anxiety
and related disorders (11 years) compared to other psy-
chiatric disorders (20-30 years) [2]. Separation anxiety
disorder and the phobias (seven to 14 years) have much
earlier median ages of onset compared to OCD, GAD,
panic disorder, or PTSD (20-30 years) [1,2,1161].
Anxiety and related disorders can have a substantial
long-term impact, putting children at elevated risk for
Table 31 Prevalence estimates of anxiety and related
disorders among youths in the NCS-A (age 13-18 years)
Anxiety and related disorder Estimated prevalence (%)
12-month Lifetime
Any anxiety disorder 24.9 31.9
Separation anxiety disorder 1.6 7.6
Specific phobia 15.8 19.3
Social anxiety disorder 8.2 9.1
Posttraumatic stress disorder 3.9 5.0
Panic disorder 1.9 2.3
Generalized anxiety disorder 1.1 2.2
Adapted from references [1155,1156]. NCS-A = National Comorbidity Survey-
Adolescent supplement
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MDD, other anxiety disorders, and SUD in adulthood
[11,12]. Anxiety and related disorders among younger
patients are associated with high rates of comorbid psy-
chiatric conditions [1162-1165], SUD [1166-1169], sleep
problems [1170-1173], somatic symptoms [1174], and
suicidality [1175], as well as problems with cognition/
attention [1164,1176,1177], academic performance
[1178,1179], and peer relationships [1180].
Diagnostic issues
Diagnostic evaluation of pediatric patients should be
based on DSM-5 criteria, but use developmentally
appropriate language, and consider collateral informa-
tion from parents and teachers. Children may express
anxiety through crying, tantrums, freezing, or clinging,
as well as through play. The DSM-5 provides some
modifications to adult criteria to assist in the diagnosis
of anxiety and related disorders in children (Table 32)
[26]. In particular, a separate subtype for patients 6
years of age has been added to the criteria for PTSD to
make it more developmentally sensitive to young chil-
dren [26].
Prevention strategies
Psychoeducational programs for children and adolescents
aimed at preventing the development of an anxiety or
related disorder have shown small, but significant effects
[1181]. Both universal (administered to all children
within target population) [1182] and indicated prevention
programs (administered to children demonstrating highly
anxious symptoms) [1183,1184] demonstrate benefits,
but indicated programs are associated with larger effect
sizes than universal programs [1181].
Both psychological and pharmacological strategies
have been assessed for the prevention of PTSD. An
early psychological intervention with children involved
in road traffic accidents failed to result in any significant
benefits over a control group [1185].
In a RCT in burn victims, sertraline was more effec-
tive in preventing PTSD symptoms than placebo accord-
ing to parent report but not child report [890]. Data do
not support the use of propranolol in preventing PTSD
[1186] or ASD [886] in pediatric injury patients.
Treatment issues
Psychological treatment Psychological therapies for
children often need to be adapted to suit the chronologi-
cal and developmental ages of young patients and to
include parental involvement. Meta-analyses support the
efficacy of CBT for the treatment of anxiety and related
disorders in children and adolescents [1187-1191]. A
meta-analysis of 24 clinical trials showed that almost 70%
of youths who received CBT no longer met diagnostic
criteria for their anxiety disorder compared to only 13%
of wait-list controls [1189]. Meta-analyses and RCTs
have confirmed the efficacy of CBT in children with SAD
[1192-1197], panic disorder [1198], OCD [1199-1204],
PTSD [946,1205-1211], school refusal [1212-1215], and
separation anxiety disorder [1216].

Table 32 DSM-5 diagnostic criteria for anxiety and related disorders specific to children
Anxiety or related DSM-5 diagnoses specific to children
disorder
Separation anxiety Developmentally inappropriate and excessive fear or anxiety concerning separation from those to whom the individual is
disorder attached, as evidenced by 3 of the following:
Distress when separation occurs, worry about loss or separation, reluctance to leave home, be alone, or go to sleep
because of fear of separation, nightmares involving separation, or complaints of physical symptoms (e.g., headaches, upset
stomach) when separation occurs
Duration of at least 4 weeks
Onset before 18 years of age
The disturbance causes clinically significant distress or impairment in social, academic (occupational), or other important
areas of functioning
Selective mutism Consistent failure to speak in specific social situations in which there is an expectation for speaking (e.g., at school)
despite speaking in other situations
Anxiety or related Changes to adult DSM-5 diagnostic criteria specific to children
disorder
Specific phobia The fear or anxiety may be expressed by crying, tantrums, freezing, or clinging
Other specifiers: loud sounds or costumed characters
SAD (social phobia) The anxiety must occur in peer settings, not just during interactions with adults
The fear or anxiety may be expressed by crying, tantrums, freezing, clinging, shrinking, or failure to speak in social
situations
OCD, panic disorder No pediatric specific criteria
PTSD Qualifiers in children
Intrusion symptoms: repetitive play may occur in which themes or aspects of the traumatic event(s) are expressed;
there may be frightening dreams without recognizable content; trauma-specific re-enactment may occur in play
Specific subtype for children 6 years of age
GAD Less stringent criteria for symptoms than in adults
Adapted from DSM-5 [26].
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CBT has demonstrated efficacy in both group and
individual formats [1189,1190,1194,1217,1218], as well
as in computer- or internet-based formats [1219,1220].
One commonly used pediatric CBT protocol is the
Coping Cat program [1221,1222], which has demon-
strated efficacy in RCTs [1221,1223,1224] and in long-
term follow-up studies [1222,1225]. In a RCT, Coping Cat
CBT was as effective as pharmacotherapy with an SSRI,
but less effective than combination therapy [1223,1224].
Additional specific psychological approaches that have
demonstrated efficacy in treating anxiety in children and
adolescents include: attention bias modification (ABM)
[1226], MBCT [1195], and social effectiveness therapy
(SET) [1227,1228] for SAD; ERP [1229,1230], family-based
CBT [1231,1232], and meta-cognitive therapy [1229] for
OCD; cognitive behavioral writing therapy (CBWT)
[1233], spiritual-hypnosis assisted therapy (SHAT) [1234],
emotion regulation therapy [1235], exposure therapy
[1236], and EMDR [905,1237,1238] for PTSD; and expo-
sure therapy for specific phobias [313].
Approaches that include parental or family involvement
may have some additional benefit over strategies that
include children only [1239-1245], especially when parents
suffer from an anxiety or related disorder themselves
[1246]. Parental training only has also demonstrated benefi-
cial effects on children with an anxiety disorder [1247,1248].
The presence of comorbidities may have a negative
impact on the efficacy of CBT in pediatric patients [1249].
However, integrated CBT protocols designed to target
both conditions have demonstrated efficacy in youths with
anxiety and related disorders and comorbid ADHD
[1250], aggression [1251], or comorbid SUD [1252].
Long-term follow-up studies have shown sustained
benefits of CBT over two to seven years posttreatment
[1218,1225,1228,1253,1254].
Pharmacological treatment Complete treatment recom-
mendations for the management of anxiety and related
disorders in youths are beyond the scope of these guide-
lines and the reader is referred to specific guidelines for
the assessment and treatment of children and adolescents
with anxiety disorders, such as those developed by the
American Academy of Child and Adolescent Psychiatry
(AACAP) [1255-1258].
For children and adolescents, psychological treatments
are generally preferred over pharmacotherapy, or if war-
ranted combination therapy may be an option. RCTs
comparing combined pharmacological and psychological
treatments in younger patients with anxiety have demon-
strated efficacy equal or superior to either treatment
alone [1199,1223,1224,1259]. In the pediatric population,
safety concerns associated with antidepressants (see
Safety Issues) should be weighed against the potential
benefits of therapy. Medication may be warranted in chil-
dren and adolescents with severe impairment or those
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who are unlikely to respond to CBT due to cognitive
or other issues. A start low and go slow approach
is advised when using medications in this patient
population.
The strength of evidence for pharmacotherapeutic
agents in the treatment of pediatric patients is shown in
Table 33. When pharmacotherapy is felt to be war-
ranted, SSRIs are generally preferred for children and
adolescents with anxiety and related disorders.
Antidepressants: SSRIs and TCAs have been well studied
in pediatric patients with anxiety and related disorders
(Table 33) [1260-1262], although these agents should be
used with caution in youths as discussed in the section on
safety issues below. Most of the data in pediatric patients
are in those with OCD [1204,1261,1263] or SAD [1197].
There is good evidence for the efficacy of SSRIs in chil-
dren and adolescents with OCD, including fluoxetine
(Level 1) [1264-1269], citalopram (Level 2) [1264,1270],
fluvoxamine (Level 2) [1271], paroxetine (Level 2) [1272],
and sertraline (Level 2) [1273], as well as for the TCA
clomipramine (Level 1) [1274-1276].
Similarly, there is good evidence for the efficacy of SSRIs
in SAD, including fluoxetine (Level 1) [1227,1277], fluvox-
amine (Level 2) [1278], paroxetine (Level 2) [1279], escita-
lopram (Level 3) [1280], and sertraline (Level 3) [1281], as
well as for the SNRI venlafaxine XR (Level 2) [1282], and
some evidence for mirtazapine (Level 3) [1283].
There is level 2 evidence for the efficacy of fluoxetine
[1277] and fluvoxamine [1278] in separation anxiety dis-
order, and for fluoxetine [1277], fluvoxamine [1278], and
sertraline [1284] in GAD. In school-refusing children and
adolescents, a small case-series suggested benefit with
citalopram (Level 4) [1285], and a RCT demonstrated
that imipramine as an adjunct to CBT was more effective
than CBT alone (Level 2) [1259].
In pediatric PTSD, sertraline alone [1286] or as an
adjunct to CBT [946] was not more effective than pla-
cebo or CBT (both Level 2, negative) and cannot be
recommended at this time.
Benzodiazepines: There are little data demonstrating
the efficacy of benzodiazepines in children and adoles-
cents with anxiety and related disorders (Table 33)
[1287-1292]. In fact, the few RCTs have demonstrated
no significant improvements in anxiety symptoms with
alprazolam over placebo in overanxious or avoidant
disorders (Level 2, negative) [1290] or school-refusal
(Level 2, negative) [1291], or with clonazepam in
separation anxiety disorder (Level 2, negative) [1292].
Benzodiazepines have limited utility in youths,
although they may be useful for short-term therapy in
specific situations where there is a need to achieve
rapid reduction in severe anxiety symptoms to allow
exposure-related psychotherapy (e.g., panic disorder,
school refusal behavior).
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Table 33 Strength of evidence of treatments for anxiety and related disorders in children and adolescents
Disorder Antidepressants Benzodiazepines and other treatments
OCD Fluoxetine (Level 1) [1264-1269] Antipsychotics
Clomipramine (Level 1) [1274-1276] Adjunctive aripiprazole (Level 3) [1293]
Citalopram (Level 2) [1264,1270] Other
Fluvoxamine (Level 2) [1271] Riluzole (Level 4) [1294]
Paroxetine (Level 2) [1272]
Sertraline (Level 2) [1273]
Panic disorder Anxiolytics
Clonazepam (Level 4) [1287,1288]
Alprazolam (Level 4) [1289]
SAD Fluoxetine (Level 1) [1227,1277] Anxiolytics
Fluvoxamine (Level 2) [1278] Alprazolam (Level 2, -ve) [1290]
Paroxetine (Level 2) [1279]
Venlafaxine XR (Level 2) [1282]
Escitalopram (Level 3) [1280]
Sertraline (Level 3) [1281]
Mirtazapine (Level 3) [1283]
Separation anxiety disorder Fluoxetine (Level 2) [1277] Anxiolytics
Fluvoxamine (Level 2) [1278] Clonazepam (Level 2, -ve) [1292]
GAD Fluoxetine (Level 2) [1277] Anxiolytics
Fluvoxamine (Level 2) [1278] Alprazolam (Level 2, -ve) [1290]
Sertraline (Level 2) [1284]
School-refusal Citalopram (Level 4) [1285] Anxiolytics
Adjunctive imipramine (Level 2) [1259] Alprazolam (Level 2, -ve) [1291]
PTSD Sertraline (Level 2, -ve) [1286]
Adjunctive sertraline (Level 2, -ve) [946]
XR = extended release; (-ve) = negative.

Other treatments: In open trials in pediatric patients
with treatment-resistant OCD, the atypical antipsychotic
aripiprazole (Level 3) [1293] and the glutamate antago-
nist riluzole (Level 4) [1294] have demonstrated some
efficacy.
Combination psychological and pharmacological
therapies The combination of sertraline and CBT was sig-
nificantly superior to both monotherapies in a large RCT
in pediatric patients with separation anxiety disorder,
GAD, or SAD [1223]. In pediatric patients with OCD, the
addition of CBT in those with a partial response to SSRIs
resulted in significantly greater response rates compared
with the SSRI alone [1199], while the addition of d-cyclo-
serine to CBT was not superior to placebo [1295].
Alternative therapies There is currently little evidence
supporting the efficacy of exercise in reducing anxiety
symptoms in pediatric populations [1296], although
some open data suggest it may have a small beneficial
effect in pediatric PTSD [1297,1298].
Safety issues An important consideration when using
antidepressant medications in children and adolescents is
the potential for an increased risk of suicidality. Clinicians
should be aware of the potential activating side effects of
SSRIs (insomnia, agitation, tremor, and anxiety), especially
in young children [1299-1301]. Regulatory bodies in many
countries have issued black-box warnings about suicidal
ideation/suicide attempts with the use of antidepressants
in patients younger than 19 years. However, in a compre-
hensive analysis, the pooled absolute risk difference for
suicidal thinking or behavior between SSRI- and placebo-
treated youth with anxiety and related disorders was non-
significant (0.5-0.7%), and lower than the risk for youth
treated for MDD (0.9%) [1302]. Anxiety and related disor-
ders also increase the risk of suicidality nearly eight
times for suicidal ideation and six times for suicide
attempts compared with not having an anxiety disorder
[1175]. Therefore, risks and benefits of treatment should
be discussed with both children and their parents.
The most common antidepressant adverse events are
generally activation and vomiting in children, and som-
nolence in adolescents [1303]. More conservative dosing
strategies may be needed especially in younger children
or those with low body weight [1301].
Summary
The management of anxiety and related disorders in chil-
dren and adolescents can be challenging. Diagnostic eva-
luation of pediatric patients should use developmentally
appropriate language and consider collateral information
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from parents and teachers. Children may express anxiety
through crying, tantrums, freezing, or clinging, as well as
through play. For children and adolescents, psychological
therapies are generally preferred over pharmacotherapy,
or if warranted combination therapy may be an option.
Psychological therapies often need to be adapted to suit
the chronological and developmental ages of young
patients and to include parental involvement. When
pharmacotherapy is warranted, SSRIs are generally pre-
ferred, although antidepressants should be used with cau-
tion in pediatric patients.
Elderly
Epidemiology
The lifetime and 12-month prevalence of any anxiety or
related disorder among those age 65 or older is estimated
to be 13.6% and 7.0%, respectively, compared with 27.8%
and 17.8% in the overall adult population [1304]. Including
subthreshold anxiety increases the 12-month prevalence
from about 6% to over 26% in older adults [1305]. The
prevalence rates of anxiety and related disorders have gen-
erally been shown to decline with age, and as in younger
age groups, the prevalence is higher in women than in
men [509,1304,1306,1307]. The decline in prevalence may
be related to age biases in the assessment of anxiety and
the masking effect of other risk factors that increase with
aging [1308]. Under-diagnosis is common, with one study
finding that only 34% of older patients with GAD had pre-
viously had anxiety symptoms documented [1309].
Among older adults (55 years) with mood or anxiety
and related disorders, 60-70% do not use mental health
care services [1310,1311], although use is higher among
those with comorbid disorders [1312]. Older adults with
anxiety and related disorders have higher rates of sleep
disturbances [1313-1315] and greater impairment in cog-
nitive functioning [1316-1319] compared to those with-
out anxiety disorder. In addition, anxiety negatively
impacts physical functioning and mobility [1320,1321],
and health related QoL [1321,1322].
Comorbidities Depression is among the most common
comorbid disorders among older adults with anxiety and
related disorders [1323-1325], and is associated with poorer
outcomes of both disorders [1326]. Approximately 80% of
adults 65 years of age have at least one chronic medical
condition, and this may be even higher among those with
anxiety disorders [1327]. Older patients with anxiety and
related disorders report higher rates of diabetes, gastroin-
testinal conditions, and dementia [1325,1327,1328].
Chronic urinary incontinence, hearing impairment,
hypertension, respiratory disease, and poor sleep were
associated with elevated rates of anxiety symptoms or
disorders [1315,1329]. Comorbid anxiety in patients with
medical illnesses, particularly cardiovascular disease, has
been associated with an increased risk of mortality
Page 43 of 83
[1330,1331]. Furthermore, the relationship between anxi-
ety and related disorders in the elderly and cognitive
impairment remains largely neglected [1332].
Diagnostic issues
The recognition and accurate diagnosis of anxiety and
related disorders in older patients can be challenging
[1333]. Modifications to the DSM-5 diagnostic criteria
may assist clinicians in more accurately recognizing and
diagnosing anxiety and related disorders in the elderly
[1333].
Older patients with anxiety often present differently
than younger patients [1327,1334]. Avoidance and
excessive anxiety may be difficult to detect in older
patients [1333]. Older adults may describe symptoms
differently; for example, they may discuss concerns
rather than worries [1327,1333]. They are less likely to
attribute symptoms to anxiety and related disorders, but
rather may attribute them to physical illness and they
may have difficulty remembering symptoms [1327,1335].
Obtaining information from collateral sources may be
useful. Assessing impact on work or social functioning
may also be complicated by changes in responsibilities
associated with aging (e.g., retirement) [1333]. It may be
helpful to ask about activities relevant to older adults,
such as visiting grandchildren. Similarly, avoidance may
be harder to detect because of limitations in physical
mobility or visual problems, leading to a decline in
activities outside the home [1336].
Chronic medical illness or the use of medications can
also complicate the diagnosis of anxiety and related dis-
orders [1333]. Determining which came first, the physical
illness or the anxiety symptoms can be helpful. However,
when a medical illness is chronic, this precludes the like-
lihood that the anxiety would resolve when the medical
condition resolves.
Late-onset anxiety and related disorders are relatively
unusual [2], therefore older patients with new onset anxi-
ety should be investigated for potential causative factors
(e.g., physical illness, medication side effects).
Psychological treatment
Relaxation training, CBT, supportive therapy, and CT
have support for the treatment of anxiety symptoms and
disorders in older patients [1337]. Meta-analyses suggest
the efficacy of psychological treatment is similar to that
of pharmacotherapy for the treatment of anxiety and
related disorders in older patients [1338,1339].
In meta-analyses, CBT was an effective option in redu-
cing anxiety symptoms among older patients compared to
wait-list or active controls [1340-1342]. Some data suggest
that CBT may be less effective for anxiety and related dis-
orders in older patients than in working-age adults
[1337,1342]. Older patients may benefit from the inclusion
of learning- and memory-aids with standard CBT
[1343,1344]. In RCTs in older patients, CBT demonstrated
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efficacy for the treatment of GAD [1337,1343,1345-1347]
and panic disorder [1348,1349]. Exposure therapy, with or
without CBT, demonstrated efficacy in case-controlled
studies in patients with PTSD [1350] or specific phobias
[1351]. CBT may also be effectively delivered via
telephone, although improvements may not be long lasting
[1352].
In a case-control study, regular physical exercise
reduced the risk of developing anxiety disorders among
older adults [1353].
Pharmacological treatment
Data suggest that pharmacotherapy including antidepres-
sants or anticonvulsants is likely as effective in older adults
as it is in younger patients [575]. Most of the studies in
older patients include those 60 or 65 years and have been
conducted in patients with GAD or panic disorder.
The most robust data in elderly patients with GAD are
from a large RCT (n=273), which demonstrated signifi-
cant improvements and good tolerability with pregabalin
compared with placebo [1354]. Pregabalin was also effec-
tive as adjunctive therapy in an open trial in older
patients with comorbid GAD and depression [1355].
Pooled analyses of subsets of older patients from mul-
tiple RCTs demonstrate that duloxetine [1356] and ven-
lafaxine [575] were effective for the treatment of GAD.
Citalopram was effective in an eight-week RCT [1357]
and in an open study over six months of treatment
[1358]. Some data suggest that escitalopram may be use-
ful in older patients with GAD [550,1359]; although in
one RCT, response rates were not significantly different
than placebo in the intention-to-treat analysis [550].
Sertraline was more effective than CBT [1349], particu-
larly at a one-year follow-up assessment [1360], and was
as effective as buspirone [561] in older adults with GAD.
In older patients with panic disorder, paroxetine was as
effective as CBT and more effective than a wait-list con-
trol, and results were sustained at a six-month follow-up
[1348]. Escitalopram [1361] and citalopram [1361] were
equally effective in a small, open trial. A small, open trial
also showed fluvoxamine to be effective in older patients
with GAD, panic disorder, or OCD [1362]. Data in
patients with MDD, suggest that mirtazapine may have
beneficial anxiolytic effects in the elderly [1363,1364].
Data show that 45-60% of older patients (>55 years)
with anxiety and related disorders are prescribed a ben-
zodiazepine, which is higher than the rate of antidepres-
sant use [1365-1367]. The very high use of these agents is
a cause for concern since they are not a preferred long-
term treatment strategy and elderly patients may be
more sensitive to their negative effects [1365,1366].
Safety issues The elderly maybe more susceptible to
adverse drug events and drug-drug interactions (DDIs)
due to gradual age-related physiologic changes that affect
the pharmacokinetic and pharmacodynamic properties of
Page 44 of 83
many medications [1368,1369]. Factors which may alter
drug metabolism and plasma concentrations among
elderly patients include frailty, reduced homoeostatic
mechanisms, and psychosocial issues [1368]. Age-related
changes in body composition can result in increases or
decreases of drug volume distribution, and hepatic or
renal dysfunction can impair drug metabolism and drug
clearance [1369,1370]. All of these changes are highly
variable in elderly patients, further complicating use of
medications in this population [1368,1369]. A review of
the literature found that almost half of available antide-
pressants are associated with age-related clearance
changes and identified at least 45 medications that could
interact with specific antidepressants [1371].
DDIs may be more common in older adults because of
the greater number of concomitant medication they may
be taking to treat multiple comorbid conditions. In one
study of US community-dwelling older adults, almost
30% used at least five prescription medications, 80% used
at least one prescription medication, and almost half
used over-the-counter and dietary supplements [1372].
Psychotropic medications have been associated with an
increased risk of fractures [1369,1373,1374]. In a meta-
analysis, the RR of fractures was 1.34 for benzodiaze-
pines, 1.60 for antidepressants, 1.54 for anticonvulsants,
and 1.59 for antipsychotics [1373]. In a prospective
cohort study (The Rotterdam Study) of subjects over 55
years of age, the risk of non-vertebral fractures was 2.35
for current SSRI use versus non-use [1375]. The
increased risk for hip fracture associated with benzodia-
zepines was further increased with increasing dose and
the use of concomitant interacting drugs [1369,1374].
There does not appear to be any difference between aty-
pical antipsychotic agents in the increased risk of falls or
fractures [1376].
An increased mortality risk has been associated with
the use antipsychotics in older patients with dementia
[1377-1379], which appears to be greater with conven-
tional compared to atypical antipsychotics [1378-1380].
Antidepressants are frequently used to treat symptoms
of anxiety in older adults who suffer from comorbid medi-
cal conditions such as heart disease. In a meta-analysis of
SSRIs versus placebo or no antidepressant therapy in
patients with coronary heart disease (CHD) and depres-
sion, SSRIs were associated with lower rates of all-cause
mortality and readmissions for CHD, indicating that treat-
ment may improve CHD prognosis [1381]. Clinicians
should weigh the risks associated with antidepressants
against the potential benefits when making prescribing
decisions.
Summary
While onset of anxiety and related disorders in late-life
is uncommon, they do persist into older age and can
have substantial impact on QoL and functionality. Older
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patients can present differently compared to younger
patients, and diagnosis can be complicated by communi-
cation barriers, changes in role functioning, memory dif-
ficulties, and comorbid medical conditions.
Few treatment studies are conducted in older
patients; however, data suggest that psychological
treatment and pharmacotherapy appear to be similarly
effective in older patients. Using pharmacotherapy in
elderly patients can be challenging, and should con-
sider patient factors such as body mass, hepatic and
renal function, comorbid conditions, and use of conco-
mitant medications.
Anxiety with comorbid conditions
Overview
Anxiety and related disorders often present together with
other psychiatric or medical conditions [3,16,43,
1382,1383]. About 60-80% of patients with an anxiety
disorder have at least one other comorbid psychiatric
condition, which most commonly include another anxi-
ety or related disorder, MDD, bipolar disorder, ADHD,
and SUD [3]. The presence of comorbid disorders has
a negative impact on most aspects of care. Patients
with psychiatric comorbidities have more severe symp-
toms [46,1384], poorer treatment outcomes for both dis-
orders [47,1385-1387], greater functional impairment
[46,871,1384], poorer QoL [1388,1389], and an increased
risk of suicide [652].
Medical conditions and pain disorders are also common
comorbidities in patients with anxiety and related disor-
ders. Medical conditions frequently reported in patients
with anxiety and related disorders include cardiovascular
disease, gastrointestinal disease, arthritis, respiratory dis-
ease, thyroid disease, migraine, and allergic conditions
[16,52]. Patients with both anxiety disorders and medical
conditions experience elevated disability, including more
psychiatric comorbidity and depressive symptoms, as well
as poorer interpersonal and physical functioning [52,142].
Patients with chronically painful conditions such as arthri-
tis, back pain, or migraine are at a two- to four-fold higher
risk of having an anxiety or related disorder, particularly
panic disorder or PTSD [1390].
The high probability of comorbid disorders should
be considered when diagnosing and treating patients
with anxiety and related disorders. In patients with
comorbid psychiatric conditions, such as another anxi-
ety disorder or mood disorder, consider therapies that
are effective for both disorders [32]. Benzodiazepines
should be prescribed with additional caution in
patients with comorbid SUDs. In patients with comor-
bid medical conditions, the clinician must weigh the
benefits and risks of medication for the anxiety or
related disorder, but should also consider the impact
of untreated anxiety [32].
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Major depressive disorder (MDD)
Q. What is the prevalence and impact of comorbid MDD
and anxiety/related disorders?
MDD is very common in patients with anxiety, being
reported in 20-36% of patients [121,310,360,1382]; and
conversely, about 60% of patients with MDD will have a
comorbid anxiety or related disorder [44]. In patients
with anxiety, comorbid depression has been associated
with more severe symptoms [46,1384], lower likelihood
of remission [47], greater functional impairment
[46,871,1384], an increased risk of suicide [652], and a
greater risk of having another comorbid anxiety disorder
[360]. Similarly, in patients with MDD, comorbid anxi-
ety and related disorders were associated with poorer
treatment outcomes including higher recurrence rates
[1385-1387], poorer QoL [1391], and an increased risk
of suicide [24,1387,1392,1393].
Q. What pharmacological treatment may be useful for
patients with an anxiety/related disorder and comorbid MDD?
Guidelines generally recommend antidepressants (most
commonly SSRIs and SNRIs) as first-line treatments in
patients with both anxiety and depressive symptoms
[32,1394]. SSRIs and SNRIs in patients with anxiety and
related disorders, including panic disorder, GAD, OCD, or
PTSD, with comorbid MDD have been shown to be effec-
tive in improving both disorders [224,723,1359,1395].
Among the atypical antipsychotics, quetiapine has been
found to have efficacy as monotherapy in both MDD
[1396] and GAD [1397], as well as MDD with anxiety
[1398], while case series suggest that aripiprazole augmen-
tation of antidepressants [496], and risperidone monother-
apy [267] may also reduce comorbid depressive and
anxiety symptoms.
Bipolar disorder or psychoses
Q. What is the prevalence and impact of comorbid bipolar
disorder or psychoses with anxiety/related disorders?
Among patients with anxiety and related disorders, almost
14% also met criteria for bipolar I or II disorder [121].
However, among patients with bipolar disorder the rates
of comorbid anxiety disorders are very high compared to
the general population, and the DSM-5 notes anxiety dis-
orders as the most common comorbidities in patients with
bipolar disorder [26]. In epidemiological surveys, the life-
time comorbidity rates for any anxiety or related disorder
among patients with bipolar disorder was 52% in Canada
[43] and 60-75% in the US [1389,1399]. In a clinic popula-
tion, the rate of anxiety and related disorders was 22% in
patients with bipolar disorder, compared to 17% in
patients with schizophrenia, and 30% in those with schi-
zoaffective disorder [1400]. A meta-analysis of prevalence
studies found that the rates of various anxiety disorders in
patients with schizophrenia and related psychotic disor-
ders ranged from 10-15% [1401].
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
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Comorbid anxiety and related disorders in patients with
bipolar disorder were associated with a greater risk of MDD
and drug use disorders, a poorer bipolar course, lower QoL,
and lower psychosocial functioning [1388,1389]. Data are
conflicting on the impact of anxiety and related disorders
on suicidal tendencies in patients with bipolar disorder,
with some analyses finding an increased risk [1389,1402],
but not all [1403]. Similar findings have been reported in
patients with schizophrenia, where comorbid anxiety and
related disorders have been associated with more past
SUDs, lower social adjustment and overall QoL, and greater
suicidality [1404,1405].
Q. What pharmacological treatment may be useful for
patients with an anxiety/related disorder and comorbid
bipolar disorder or psychoses?
The management of patients with anxiety and related dis-
orders and comorbid bipolar disorder, schizophrenia, or
other psychosis should consider therapies that are effective
for both disorders [32]. Atypical antipsychotics are recom-
mended treatments for bipolar disorder and schizophrenia
[111,1406], while the long-term use of antidepressants
may destabilize patients with bipolar I disorder [111,1394].
Data in patients with a diagnosed anxiety or related dis-
order and comorbid bipolar disorder or psychosis are
limited. In a RCT, risperidone monotherapy was shown
to be no more effective than placebo for patients with
bipolar and comorbid panic disorder or GAD [1407].
However, in a single-blind trial, olanzapine or lamotri-
gine when added to lithium demonstrated improvements
in anxiety disorder symptoms in patients with remitted
bipolar disorder [1408]; and in an open trial, switching to
aripiprazole significantly improved social anxiety and
psychosis in patients with SAD and schizophrenia [379].
In addition, atypical antipsychotics have demonstrated
efficacy in RCTs in patients with anxiety and related dis-
orders (see specific disorder sections for evidence), and
data show that these agents can significantly reduce anxi-
ety symptoms in patients with bipolar disorder
[1409-1413]. Taken together, these data suggest these
agents may be useful in comorbid patients.
Anticonvulsants have also demonstrated efficacy in the
treatment of some anxiety and related disorders (see spe-
cific disorder sections for evidence) and are often used
for the treatment of bipolar disorder [111]. In patients
with bipolar disorder, adjunctive valproate and gabapen-
tin have demonstrated efficacy for the treatment of panic
disorder [281,1414] and resulted in reductions in anxiety
symptoms [1415,1416].
ADHD
Q. What is the prevalence of comorbid ADHD and anxiety/
related disorders?
It is estimated that the lifetime rate of ADHD in chil-
dren is 6-9%, with 70% persistence into adolescence and
Page 46 of 83
50-60% into adulthood [45,1417,1418]. In a community-
based survey, the estimated prevalence of current self-
reported adult ADHD was 4.4% [45]. While ADHD has
long been known to persist into adulthood [1419,1420],
it has only recently become the focus of widespread
clinical attention [1421-1423].
Of adults identified with ADHD in the National
Comorbidity Survey-Replication (NCS-R), only one in
10 had received treatment within the previous year [45].
Of these individuals, it is estimated that approximately
47% meet criteria for an anxiety or related disorder
within 12 months of assessment, with the most common
being SAD (29.3%), followed by specific phobia (22.7%),
PTSD (11.9%), panic disorder (8.9%), and GAD (8.0%)
[45]. Patients with an anxiety or related disorder were
reportedly four times more likely to meet criteria
for ADHD than the general population [45]. Similar
results were found in a Canadian survey of patients in an
anxiety disorders clinic, where the rate of adult ADHD
was 28% [378].
Q. What factors should be considered when treating patients
with an anxiety/related disorder and comorbid ADHD?
When managing a patient with ADHD, it may be
important to differentiate ADHD with anxious symp-
toms from comorbid ADHD and anxiety/related disor-
ders. This can be challenging, as anxiety symptoms are
frequently related to a sense of being overwhelmed or to
compensatory skills in patients with ADHD. Stimulants
may play a larger role in managing ADHD in patients
with anxiety symptoms [1424,1425]; however, in an
open trial, atomoxetine improved ADHD and comorbid
symptoms of depression and anxiety [1426].
Treatment of patients with comorbid ADHD and an
anxiety or related disorder may be more complicated.
Generally, in patients with comorbid anxiety disorders
and ADHD the diagnostic and treatment priority should
be determined by the relative severity of symptoms and
risks of each disorder [1427]. There are limited data on
the role of stimulants in patients with ADHD and an
anxiety disorder. In a RCT, atomoxetine significantly
improved ADHD and SAD symptoms compared with
placebo [487]. In separate open trials, adjunctive atomox-
etine [1428] and adjunctive extended release mixed
amphetamine salts [1429] significantly improved anxiety
symptoms in patients with ADHD and GAD refractory to
antidepressants alone.
Medical comorbidities
Q. What is the prevalence and impact of comorbid medical
conditions and anxiety/related disorders?
Medical conditions are also common comorbidities that
must be considered when prescribing medication for
patients with anxiety and related disorders. Medical con-
ditions are reported in over 60% of patients with anxiety
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
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and related disorders including cardiovascular diseases,
gastrointestinal diseases, arthritis, respiratory diseases
such as asthma, thyroid disease, migraine headaches,
back pain, and allergic conditions [16,52,1430-1432].
Comorbidities are particularly common among patients
with GAD, panic disorder, and PTSD [16,140,515,
517,1390,1433].
Patients with anxiety and related disorders and medi-
cal conditions experience more psychiatric comorbidity,
depressive symptoms, and more severe anxiety disorder
symptoms, as well as poorer interpersonal and physical
functioning [52,140,142,515].
Q. What factors should be considered when treating
patients with an anxiety/related disorder and comorbid
chronic pain?
Chronically painful conditions (i.e., arthritis, back pain,
and migraine) are commonly associated with anxiety
[515,1390,1430,1434]. Patients with anxiety and related
disorders are twice as likely to have painful physical
symptoms compared to of those without, 45-60% versus
28% [515,1433]. About 60-70% of patients with anxiety
disorders report migraine headaches [140,141].
For the management of anxiety and related disorders in
patients with pain it may be helpful to consider treat-
ments that have demonstrated efficacy in both anxiety
disorders as well as pain. While there are few data avail-
able, duloxetine has demonstrated efficacy for both GAD
and pain symptoms in RCTs [1435-1437]. TCAs, and to
a lesser extent SSRIs, have been shown to reduce head-
ache attacks in patients with migraine [1438], and pro-
vide moderate relief of neuropathic pain [1439].
Q. What factors should be considered when treating
patients with an anxiety/related disorder and comorbid
cardiovascular disease?
Although panic attacks can sometimes be mistaken for
cardiovascular symptoms, it is important to be aware that
patients with anxiety and related disorders do have a two-
to three-times greater risk of cardiovascular disease com-
pared to the general population [1431,1432]. In addition,
anxiety disorders have been associated with increased risk
of cardiovascular hospitalization rates and mortality risk
[1440-1442]. In patients with cardiovascular or cerebrovas-
cular comorbidity, it is important to consider the impact
of treatments used for anxiety on heart rate, blood pres-
sure, and lipid measures [1443-1445].
Q. What factors should be considered when treating
patients with an anxiety/related disorder and comorbid
diabetes and metabolic syndrome?
Patients with anxiety symptoms have an elevated risk of
type 2 diabetes [1446]. While glycemic measures do not
appear to be affected by anxiety symptoms [1447], some
treatments, particularly some atypical antipsychotics,
alter glucose parameters, lipid levels, and cause weight
Page 47 of 83
gain [109-116,1443]. Some antidepressants, including
amitriptyline, mirtazapine, and paroxetine have also been
associated with weight gain [1448].
Canadian Anxiety Guidelines Initiative Group
Additional authors
Martin M. Antony1, Stphane Bouchard2, Alain Brunet3,
Martine Flament4, Sophie Grigoriadis5, Sandra Mendlo-
witz6, Kieron OConnor7, Kiran Rabheru4, Peggy M.A.
Richter5, Melisa Robichaud8, John R. Walker9
1
Department of Psychology, Ryerson University,
Toronto, M5B 2K3, Canada; 2Department of Psychoe-
ducation and Psychology, University of Qubec in Out-
aouais, Gatineau, J9A 1L8, Canada; 3 Department of
Psychiatry, McGill University, Montreal, H3A 1A1,
Canada; 4 Department of Psychiatry, University of
Ottawa, Ottawa, K1Z 7K4, Canada; 5 Department of
Psychiatry, University of Toronto, Toronto, M5S 1A1,
Canada; 6Department of Child Psychiatry, University of
Toronto, Toronto, M5S 1A1, Canada; 7Department of
Psychiatry, University of Montreal, Montreal, H3C 3J7,
Canada; 8 Departments of Psychiatry and Psychology,
University of British Columbia, Vancouver, V6T 2A1,
Canada; 9 Department of Clinical Health Psychology,
University of Manitoba, Winnipeg, R3E 3N4, Canada
Email: Martin M. Antony - mantony@psych.ryerson.ca;
Stphane Bouchard - stephane.bouchard@uqo.ca; Alain
Brunet - alain.brunet@mcgill.ca; Martine Flament - mar-
tine.flament@theroyal.ca; Sophie Grigoriadis - sophie.gri-
goriaidis@sunnybrook.ca; Sandra Mendlowitz - sandra.
mendlowitz@sickkids.on.ca; Kieron OConnor - kieron.
oconnor@umontreal.ca; Kiran Rabheru - kiranrabheru@-
hotmail.com; Peggy M.A. Richter - peggy.richter@sunny-
brook.ca; Melisa Robichaud - robichau@mail.ubc.ca; John
R. Walker - jwalker@cc.umanitoba.ca
Additional contributors to the comorbidity section
Gordon Asmundson10, Larry J. Klassen11, Raymond W.
Lam12, Roger S. McIntyre13, Isaac Szpindel14
10
Department of Psychology, University of Regina,
Regina, S4S 0A2, Canada; 11Department of Psychiatry,
Faculty of Medicine, University of Manitoba, Winnipeg,
R3T 2N2, Canada; 12Department of Psychiatry, Univer-
sity of British Columbia, Vancouver, V6T 2A1, Canada;
13
Departments of Psychiatry and Pharmacology, Univer-
sity of Toronto, Toronto, M5S 1A1, Canada; 14Attention
and Learning Related Disorders, START Clinic, Tor-
onto, M4W 2N4, Canada
Email: Gordon Asmundson - gordon.asmundson@ur-
egina.ca; Larry J. Klassen - larryjklassen@hotmail.com;
Raymond W. Lam - r.lam@ubc.ca; Roger S. McIntyre -
roger.mcintyre@uhn.ca; Isaac Szpindel - iszpindel@start-
clinic.ca
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
http://www.biomedcentral.com/1471-244X/14/S1/S1
Additional material
Additional file 1: Suggested dosing ranges Dosing ranges of various
psychiatric medications
List of abbreviations used
AACAP: American Academy of Child and Adolescent Psychiatry; ABM:
attention bias modification; ACOG: American Congress of Obstetricians and
Gynecologists; ADHD: attention-deficit/hyperactivity disorder; APA: American
Psychiatric Association; ASD: acute stress disorder; B-I-I: blood-injection-injury;
BPD: borderline personality disorder; CBT: cognitive behavioral therapy;
CBWT: cognitive behavioral writing therapy; CCHS: Canadian Community
Health Survey; CHD: coronary heart disease; CPT: cognitive processing
therapy; CR: controlled release; DBT: dialectical behavioral therapy; DDI: drug-
drug interactions; DIRT: danger ideation reduction therapy; DSM-5:
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; EMDR: eye
movement desensitization and reprocessing; ERP: exposure with response
prevention; FDA: Food and Drug Administration; GAD: generalized anxiety
disorder; HARS: Hamilton Anxiety Rating Scale; HDL: high-density lipoprotein;
ICBT: internet-based CBT; IPT: interpersonal therapy; IV: intravenous; LDL: low-
density lipoprotein; MAOI: monoamine oxidase inhibitor; MBCT: mindfulness-
based cognitive therapy; MBT: mindfulness-based therapy; MDD: major
depressive disorder; Mini-SPIN: Mini-Social Phobia Inventory; MRI: magnetic
resonance imaging; N/A: not available; NaSSA: noradrenergic and specific
serotonergic antidepressant; NCS-A: National Comorbidity Survey
Adolescent supplement; NCS-R: National Comorbidity Survey Replication;
NMDA: N-methyl-D-aspartate; NNT: number needed to treat; NPPO-REAC:
neuro psycho physical optimization-radio electric asymmetric conveyor;
NSAID: nonsteroidal anti-inflammatory drug; OCD: obsessive-compulsive
disorder; ODT: orally disintegrating tablet; PNAS: poor neonatal adaptation
syndrome; PTSD: posttraumatic stress disorder; QoL: quality of life; RCT:
randomized controlled trial; REAC: radioelectric asymmetric conveyor; RIMA:
reversible inhibitors of monoamine oxidase A; RR: relative risk; rTMS:
repetitive transcranial magnetic stimulation; SAD: social anxiety disorder; SET:
social effectiveness therapy; SHAT: spiritual-hypnosis assisted therapy; SNRI:
serotoninnorepinephrine reuptake inhibitor; SR: sustained release; SSRI:
selective serotonin reuptake inhibitor; SUD: substance use disorder; TC: total
cholesterol; TCA: tricyclic antidepressant; TF-CBT: trauma-focused-CBT; TG:
triglycerides; vLDL: very-low-density lipoprotein; VRE: virtual reality exposure;
XL: extended release; XR: extended release; Y-BOCS: Yale-Brown Obsessive
Compulsive Scale.
Competing interests
Unrestricted educational grants for the development of these guidelines
were provided by Astra Zeneca Canada, Eli-Lilly Canada, Janssen Inc.,
Lundbeck Canada, Pfizer Canada, Purdue Canada, Servier Canada Inc., Shire
Canada, and Valeant Canada. None of the members received payment for
participating in the development of these guidelines.
The following authors do not have any competing interests to declare:
AB, GA, JRW, KO, MMA, MF, LK, MR, SM.
Advisory board/speakers bureau: Astra Zeneca (KK, KR, MK, P. Bleau, P.
Blier, RWL, RSM), Biovail (RWL), Boehringer Ingelheim (MK), BMS (KK, KR, MK,
P. Bleau, P. Blier, PC, RWL, RSM), Canadian Institutes of Health Research
(CIHR) (RWL), Canadian Network for Mood and Anxiety Treatments
(CANMAT) (RWL), Canadian Psychiatric Association (CPA) Foundation (RWL),
Eli Lilly Canada (MK, P. Bleau, P. Blier, PC, SG, RWL, RSM, IS), France
Foundation (RSM), GlaxoSmithKline (MK, P. Blier, RSM, SG), Janssen Ortho (KK,
MK, P. Blier, PC, RSM), Labopharm (P. Blier), Litebook Company (RWL),
Lundbeck (KK, KR, MK, P. Bleau, P. Blier, PC, RWL, RSM, SG), Lundbeck
Institute (RWL), Organon (MK, RSM), Merck (P. Blier, RSM), Mochida (RWL),
Otsuka (KK), Pfizer (P. Bleau, P. Blier, PC, RWL, RSM, SG), Pierre Fabre (P. Blier),
Purdue (IS), Servier (P. Blier, RWL, SG), Shire (MK, RSM, IS), Solvay (MK), St.
Judes Medical (RWL), Sunovion (KK, P. Blier), Takeda (P. Blier, RWL), UBC
Institute of Mental Health/Coast Capital Savings (RWL), Valeant (P. Blier, IS),
Wyeth (P. Bleau, MK, SG)
Consultation fees: AstraZeneca (MK), BMS (MK), Boehringer Ingelheim (MK),
Clinique et Dveloppement In Virtuo Inc. (SB), Eli Lilly Canada (MK, SG),
Page 48 of 83
GlaxoSmithKline (MK, SG), Janssen Ortho (MK), Lundbeck (MK, PR, SG),
Organon (MK), Pfizer (SG), Servier (SG), Shire (MK), Solvay (MK), Wyeth (MK,
SG)
Educational support: Astra Zeneca (RSM), BMS (RSM), CME Outfitters (RSM),
Eli Lilly Canada (RSM, IS), France Foundation (RSM), I3CME (RSM), Merck
(RSM), Optum Health (RSM), Pfizer (RSM), Physicians Postgraduate Press
(RSM), Shire (IS)
Research grants/clinical trial funding: AstraZeneca (KK, MK, P. Bleau, RSM,
RWL), Biovail (RWL), BMS (KK, P. Bleau, RWL), Canadian Foundation for
Innovation (MK), Canadian Institutes of Health Research (CIHR) (MK, RWL, SG),
Canadian Network for Mood and Anxiety Treatments (CANMAT) (RWL),
Canadian Psychiatric Association (CPA) Foundation (MK, RWL), Centre for
Addiction and Mental Health Foundation (MK), CR Younger Foundation (SG),
Eli Lilly Canada (MK, P. Bleau, PR, RSM, RWL), Genuine Health (MK),
GlaxoSmithKline (MK), Janssen Ortho (MK, RSM), Litebook Company (RWL),
Lundbeck (KK, MK, P. Bleau, RSM, RWL), Lundbeck Institute (RWL), Mochida
(RWL), National Alliance for Research on Schizophrenia and Depression
(NARSAD) (RSM), National Institutes of Mental Health (NIMH) (RSM), Ontario
Ministry of Health (SG), Ontario Mental Health Foundation (SG), Organon
(MK), Pfizer (P. Bleau, RSM, RWL), Roche (PR), Servier (RWL), Sick Kids
Foundation (MK), Solvay (MK), St. Judes Medical (RWL), Shire (MK, RSM),
Stanley Medical Research Institute (RSM), Takeda (RWL), UBC Institute of
Mental Health/Coast Capital Savings (RWL), Wyeth (MK, P. Bleau)
Unrestricted grants: Astra Zeneca Canada (MK), Eli Lilly Canada (MK),
Janssen Inc. (MK), Lundbeck Canada (MK), Pfizer (MK), Purdue Pharma (MK),
Servier Canada (MK), Shire Canada (MK), Valeant Canada (MK)
Reimbursements, fees, funding, or salary: In the past five years, MVA
received reimbursements, fees, funding, or salary from: Astra Zeneca, Biovail,
Canadian Foundation for Innovation (CFI), Cephalon, Eli Lilly, Forest
Laboratories, GlaxoSmithKline, Hamilton Academic Health Sciences
Organization (HAHSO) Innovation Grant (AFP Innovation Grant), Janssen
Ortho, Labo Pharm, Lundbeck, National Institutes of Health (NIH), Novartis,
Pfizer Inc., Servier, Shire, Sunovion, Valeant, Wyeth-Ayerst
Stock/share ownership: Clinique et Dveloppement In Virtuo Inc. (SB)
Authors contributions
We thank all co-authors for their considerable expertise in generating these
guidelines. Authors who were members of the executive committee (MK, PB,
PB, PC, KK, MVA) took part in teleconferences and a meeting in December
2012 to reach consensus on the strength of evidence and treatment
recommendations. Draft guidelines were then developed by the core
committee and revised by all co-authors. The entire content was
subsequently circulated to all members of the Canadian Anxiety Guidelines
Initiative Group for additional comments and approval during 2013. GA, LJK,
RWL, RSM, and IS provided additional reviews of the comorbidity section.
The final manuscript was then circulated to external reviewers (MP, DS, LDM)
and revisions were made based on input from the core committee.
Acknowledgements
The consensus group would like to thank Astra Zeneca Canada, Eli-Lilly
Canada, Janssen Inc., Lundbeck Canada, Pfizer Canada, Purdue Canada,
Servier Canada Inc., Shire Canada, and Valeant Canada for their generous
support of the guideline process with unrestricted educational grants. Funds
were used for editorial assistance and meeting logistics; none of the
members received payment for participating in the guideline development
process. The consensus group would also like to thank Pauline Lavigne and
Steven Portelance who provided medical writing services on their behalf.
Declarations
The development and publication of these guidelines was supported by
unrestricted educational grants provided by Astra Zeneca Canada, Eli-Lilly
Canada, Janssen Inc., Lundbeck Canada, Pfizer Canada, Purdue Canada, Servier
Canada Inc., Shire Canada, and Valeant Canada. None of the members
received payment for participating in the development of these guidelines.
This article has been published as part of BMC Psychiatry Volume 14
Supplement 1, 2014: Canadian Anxiety Disorders Guidelines Initiative: Clinical
practice guidelines for the management of anxiety, posttraumatic stress and
obsessive-compulsive disorders. The full contents of the supplement are
available online at http://www.biomedcentral.com/bmcpsychiatry/
supplements/14/S1.
Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1
http://www.biomedcentral.com/1471-244X/14/S1/S1
Authors details
1
Department of Psychiatry, University of Toronto, Toronto, ON, M5S 1A1,
Canada. 2Department of Psychiatry, McGill University, Montreal, QC, H3A 1A1,
Canada. 3Department of Psychiatry and Cellular/Molecular Medicines,
University of Ottawa, Ottawa, ON, K1Z 7K4, Canada. 4Department of
Psychiatry, University of Alberta, Edmonton, AB, T6G 2R7, Canada.
5
Department of Psychiatry, University of British Columbia, Vancouver, BC, V6T
2A1, Canada. 6Department of Psychiatry and Behavioural Neuroscience,
McMaster University, Hamilton, ON, L8N 3K7, Canada.
Published: 2 July 2014
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doi:10.1186/1471-244X-14-S1-S1
Cite this article as: Katzman et al.: Canadian clinical practice guidelines
for the management of anxiety, posttraumatic stress and obsessive-
compulsive disorders. BMC Psychiatry 2014 14(Suppl 1):S1.
525674
research-article2014
JOP0010.1177/0269881114525674Journal of PsychopharmacologyBaldwin et al.

BAP Guidelines

Evidence-based pharmacological treatment

of anxiety disorders, post-traumatic stress
disorder and obsessive-compulsive disorder: Journal of Psychopharmacology

A revision of the 2005 guidelines from the

1 37
The Author(s) 2014
Reprints and permissions:
British Association for Psychopharmacology sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/0269881114525674
jop.sagepub.com

David S Baldwin1,2, Ian M Anderson3, David J Nutt4, Christer

Allgulander5, Borwin Bandelow6, Johan A den Boer7,8, David M
Christmas9, Simon Davies10, Naomi Fineberg11, Nicky Lidbetter12,
Andrea Malizia13, Paul McCrone14, Daniel Nabarro15, Catherine ONeill12,
Jan Scott16, Nic van der Wee17 and Hans-Ulrich Wittchen18

Abstract
This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders
provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination
treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts
in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines
are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical
decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines
management and formulary committees.

Keywords
Anticonvulsants, antidepressants, antipsychotics, anxiety disorders, anxiolytics, benzodiazepines, cognitive behaviour therapy, evidence-based
guidelines, generalised anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, pregabalin, separation anxiety
disorder, serotonin-noradrenaline reuptake inhibitor, social anxiety disorder, specific phobia, selective serotonin reuptake inhibitor, treatment.

1. Introduction
The British Association for Psychopharmacology (BAP; www. meetings, fostering research and teaching, encouraging publica-
bap.org.uk) aims to advance education and research in the sci- tion of research results, and providing guidance and information
ence and practice of psychopharmacology by arranging scientific on matters relevant to psychopharmacology. As part of this

1Faculty of Medicine, University of Southampton, Southampton, UK 11Postgraduate Medical School, University of Hertfordshire, Hatfield, UK
2Department of Psychiatry and Mental Health, University of Cape Town, 12Anxiety UK, Manchester, UK
Cape Town, South Africa 13North Bristol NHS Trust, Bristol, UK
3Neuroscience and Psychiatry Unit, University of Manchester, 14Institute of Psychiatry, Kings College London, London, UK

Manchester, UK 15OCD Action, London, UK

4Division of Experimental Medicine, Imperial College London, 16Newcastle University, Newcastle, UK

London, UK 17Department of Psychiatry, Leiden University Medical Center, Leiden,

5Karolinska Institutet, Stockholm, Sweden The Netherlands
6Department of Psychiatry and Psychotherapy, University of 18Institute of Clinical Psychology and Psychotherapy, Technical

Goettingen, Goettingen, Germany University Dresden, Dresden, Germany

7Department of Nuclear Medicine and Molecular Imaging, University

Medical Centre Groningen (UMCG), Groningen, The Netherlands Corresponding author:

8PRA International Zuidlaren,The Netherlands David Baldwin, University Department of Psychiatry, University of
9Cambridge and Peterborough NHS Foundation Trust, Cambridge, UK Southampton, College Keep, 4-12 Terminus Terrace, Southampton,
10Centre for Addiction and Mental Health, University of Toronto, SO14 3DT, UK.
Toronto, ON, Canada Email: dsb1@soton.ac.uk
2 Journal of Psychopharmacology
process the BAP has developed and periodically revised a series
of consensus statements on the use of psychotropic drugs in
patients with psychiatric and other disorders, with an emphasis
on making concise and realistic recommendations based on a
review of the evidence [IV] (Anderson etal., 2000, 2008; Barnes
and Schizophrenia Consensus Group of British Association for
Psychopharmacology, 2011; Burns and OBrien., 2006; Goodwin,
2003, 2005; Goodwin etal., 2008; Lingford-Hughes etal., 2004,
2012; National Institute for Health and Clinical Excellence,
2011; OBrien and Burns, 2010; Nutt etal., 2006; Wilson etal.,
2010).
Anxiety symptoms and disorders are common in community
settings, and in primary and secondary medical care. The per-
sonal and societal burden associated with anxiety disorders is
considerable, but many people who might benefit from treatment
are not recognised or treated. Likely factors in this sub-optimal
management include the range of different anxiety disorders,
their co-morbidity with other disorders (particularly mood disor-
ders), a widespread lack of awareness of anxiety disorders by
affected individuals and health practitioners, and the low confi-
dence of many practitioners in their management. Conversely,
some patients with only mild or transient anxiety symptoms
receive unnecessary or inappropriate treatment. Given the con-
siderable room for improvement, the BAP previously produced
evidence-based guidelines for the pharmacological treatment of
anxiety disorders [IV] (Baldwin etal., 2005): this revision of
those guidelines provides an update on key steps in diagnosis and
treatment.
2. Caveats
Clinical guidelines are systematically derived statements that aim
to inform treatment decisions in clinical care. Recommendations
are graded according to the strength of evidence, and whenever
possible are derived from the findings of systematic reviews and
randomised controlled trials. Principal recommendations apply
to the management of typical patients and hence apply much of
the time: we therefore use expressions such as clinicians should
consider in the summary boxes. But there are many patients
and many clinical decision points where slavish adherence to
guideline recommendations may be unhelpful and possibly
harmful. In situations where the evidence is weaker we summa-
rise potential management options, recognising that their imple-
mentation depends upon clinician experience, patient clinical
features and preference, and local circumstance [IV] (Haynes
etal., 2002). Some of our recommendations may be regarded as
standards of clinical care that are largely driven by custom and
practice: these are standards which are intended to be applied
routinely.
There is often a tension between existing established clinical
practice and the possible implications of new research findings
for changing practice. Existing practice may be accepted on the
basis of prolonged clinical experience but limited good quality
evidence: new treatments may have proven superiority to pla-
cebo in methodologically robust randomised controlled trials, but
lack comparator data against established treatments. We attempt
to strike a balance between the risks of advocating specific novel
treatment recommendations that may prove premature and adher-
ing to established routines when the evidence supporting them is
questionable.
3. Process for achieving consensus
The revision of the original BAP guidelines started in February
2011, with a consensus meeting attended by experts in the field
and representatives of patient groups (all who attended are named
in the acknowledgments). Brief presentations were made on key
areas, with an emphasis on systematic reviews and randomised
controlled trials. Each presentation was followed by discussion,
to identify areas of consensus or uncertainty.
A literature review was then performed to ascertain the valid-
ity of the consensus points. Logistical factors made it impossible
to perform a systematic review of all possible data from primary
sources. Existing systematic reviews and randomised controlled
trials were identified from MEDLINE and EMBASE searches
and from the Cochrane Database, as well as from recent previous
guidelines and reviews [IV] (Baldwin etal., 2011b; Bandelow
etal., 2008a; Batelaan etal., 2012; Blanco etal., 2013; Fineberg
etal., 2012; Ipser and Stein, 2012), through cross-referencing,
and through discussion with experts in the field. We also drew on
recent guidelines for generalised anxiety disorder, panic disorder,
social anxiety disorder, post-traumatic stress disorder and obses-
sive-compulsive disorder developed by the National Institute for
Health and Clinical Excellence (2005, 2011a, 2011b, 2013).
Particular attention was paid to research findings which had
appeared since 2005, the year of publication of the original
guidelines. Draft versions of the consensus statement, with rec-
ommendations based on the level of supporting evidence, were
circulated repeatedly to the presenters and other participants and
their comments were incorporated into the final version of the
guidelines. Given the range and depth of the subject area it was
not possible for all participants in the wider group to achieve full
consensus on all points.
4. Levels of evidence and strength of
recommendations
The categories of evidence for causal relationships and the grad-
ing of recommendations have their origin in the methodology of
the North of England Evidence-Based Guideline Development
Project undertaken by the Centre for Health Services Research,
University of Newcastle upon Tyne and the Centre for Health
Economics, University of York [IV] (Shekelle etal., 1999).
Given current debates about their competing merits, we have
accorded a similar level (I) in the hierarchy of evidence to the
findings of systematic reviews and to the results of randomised
controlled trials, noting the evidence source which is available
for each statement and recommendation (Table 1). Weaker levels
of recommendations do not necessarily imply a reduced level of
clinical importance. As in some previous guidelines we have
included a category denoted as S (representing a standard of
care), for a recommendation that reflects important consensus on
good clinical practice rather than on empirical evidence.
5. Aim and scope of the guidelines
We hope the guidelines will prove relevant to most doctors treat-
ing patients with anxiety and related disorders, in primary, sec-
ondary and tertiary medical care settings. Each of the principal
disorders generalised anxiety disorder, panic disorder, specific
Baldwin et al. 3

Table 1. Levels of evidence and strength of recommendations.

Categories of evidence relevant to treatment

I [M] Evidence from meta-analysis of randomised double-blind placebo-controlled trials
I [PCT] Evidence from at least one randomised double-blind placebo-controlled trial
II Evidence from at least one randomised double-blind comparator-controlled trial (without placebo)
III Evidence from non-experimental descriptive studies
IV Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
Categories of evidence relevant to observational findings and associations
I Evidence from large representative population samples
II Evidence from small, well designed but not necessarily representative samples
III Evidence from non-representative surveys, case reports
IV Evidence from expert committee reports or opinions and/or clinical experience of respected authorities
Strength of recommendations
A Directly based on category I evidence (either I [M] or I [PCT])
B Directly based on category II evidence or an extrapolated recommendation from category I evidence
C Directly based on category III evidence or an extrapolated recommendation from category I or II evidence
D Directly based on category IV evidence or an extrapolated recommendation from other categories
S Standard of clinical care

(or simple) phobia, social anxiety disorder (also known as social
phobia), post-traumatic stress disorder, and obsessive-compulsive
disorder is considered in turn, following key steps in manage-
ment (acute treatment; longer-term treatment; combination with
psychological approaches; treatment resistance). The continued
inclusion or otherwise of obsessive-compulsive disorder within
the broad category of anxiety disorders is the subject of continu-
ing debate, given evidence of its dissimilarity from other anxiety
disorders and its resemblance to other conditions characterised by
compulsivity and impulsivity: but the principles of pharmacologi-
cal treatment of anxiety disorders and obsessive-compulsive dis-
order share many common features, and so we have chosen to
retain obsessive-compulsive disorder within these guidelines. We
also include separation anxiety disorder, given its inclusion within
anxiety disorders in the Diagnostic and Statistical Manual (DSM-
5) (American Psychiatric Association, 2013), though evidence
relating to its treatment in adults is at present very sparse. We also
summarise the evidence for treatment of patients with health anxi-
ety (illness anxiety disorder), partly because of the overlap in
clinical features with those of generalised anxiety disorder.
We expect the guidelines will be most useful in informing
decisions in primary and secondary care, regarding pharmaco-
logical treatment in patients aged between 1865 years. The
nature and prevalence of anxiety disorders changes during child-
hood and adolescence and the mean age of onset in adult patients
varies between anxiety disorders. Most adults with anxiety disor-
ders report an onset of symptoms in childhood or adolescence
(Jones, 2013; Kessler etal., 2005), and some recommendations
(for example those pertaining to obsessive-compulsive disorder
and social phobia) will therefore be potentially applicable to ado-
lescent patients. Similarly the recommendations are also likely to
be pertinent to elderly patients although we did not specifically
review evidence in those aged over 65 years.
6. Epidemiology of anxiety symptoms
and disorders
Anxiety symptoms are common in the general population and
in primary and secondary medical care. Symptoms may be
mild, transient and without associated impairment in social and
occupational function, but many patients are troubled by severe
and persistent symptoms that cause significant personal dis-
tress, impair function and reduce quality of life. To meet the
diagnosis of an anxiety disorder, patients have to experience a
certain number of symptoms for more than a minimum speci-
fied period, the symptoms causing significant personal dis-
tress, with an associated impairment in everyday function.
Most research in the field has been based on the diagnostic
categories for anxiety disorders in the fourth edition of the
Diagnostic and Statistical Manual (DSM-IV) [IV] (American
Psychiatric Association, 1994) which are broadly similar to
those in the tenth edition of the International Classification of
Diseases (ICD-10) [IV] (World Health Organisation, 1992).
The DSM system has recently been revised, and it is uncertain
whether the approach to anxiety disorders within ICD-11 will
differ substantially from ICD-10 or DSM-5.
We give simplified versions of the principal clinical features
of the anxiety disorders, post-traumatic stress disorder and obses-
sive-compulsive disorder in Table 2: a simple algorithm for ini-
tial delineation of anxiety and depressive symptoms into disorders
is suggested in Figure 1.
Epidemiological studies in the general population indicate
that when taken together anxiety disorders have a 12-month
period prevalence of approximately 14% [I] (Wittchen etal.,
2011) (see Table 3), and a lifetime prevalence of approximately
21% [I] (Wittchen and Jacobi, 2005). Individual disorders are
less frequent, with estimated 12-month prevalence rates rang-
ing between 0.7% (obsessive-compulsive disorder) and 6.4%
(specific phobia), and estimated lifetime prevalence rates
between 0.8% (obsessive-compulsive disorder) and 13.2%
(specific phobia). The age and sex distribution of individual
disorders varies: for example, specific phobias are markedly
more common in women than men across all age bands, whereas
panic disorder is almost as frequent in men and women in mid-
dle age. Despite this variation within individual anxiety disor-
ders, the pattern for all disorders taken together is fairly constant
with an overall female: male ratio of approximately 2:1 across
the age range.
4 Journal of Psychopharmacology

Table 2. Principal clinical features of the anxiety disorders, post-traumatic stress disorder, and obsessive-compulsive disorder.

Generalised anxiety disorder

Generalised anxiety disorder is characterised by excessive and inappropriate worrying that is persistent (lasting more than a few months) and not
restricted to particular circumstances. Patients have physical anxiety symptoms and key psychological symptoms (restlessness, fatigue, difficulty
concentrating, irritability, muscle tension and disturbed sleep). Generalised anxiety disorder is often co-morbid with major depression, panic disor-
der, phobic anxiety disorders, health anxiety and obsessive-compulsive disorder.
Panic disorder (with or without agoraphobia)
Panic disorder is characterised by recurrent unexpected surges of severe anxiety (panic attacks), with varying degrees of anticipatory anxi-
ety between attacks. Panic attacks are discrete periods of intense fear or discomfort, accompanied by multiple physical or psychological anxiety
symptoms. Panic attacks typically reach their peak within 10 min and last around 3045 min. Most patients develop a fear of having further panic
attacks. Around two-thirds of patients with panic disorder develop agoraphobia, defined as fear in places or situations from which escape might be
difficult or in which help might not be available, in the event of having a panic attack. These situations include being in a crowd, being outside
the home, or using public transport: they are either avoided or endured with significant personal distress.
Social phobia (social anxiety disorder)
Social phobia is characterised by a marked, persistent and unreasonable fear of being observed or evaluated negatively by other people, in social
or performance situations, which is associated with physical and psychological anxiety symptoms. Feared situations (such as speaking to unfamiliar
people or eating in public) are either avoided or are endured with significant distress.
Specific phobia
Specific, simple or isolated phobia is characterised by excessive or unreasonable fear of (and restricted to) single people, animals, objects, or situa-
tions (for example, dentists, spiders, lifts, flying, seeing blood) which are either avoided or are endured with significant personal distress.
Separation anxiety disorder
Separation anxiety disorder is characterised by fear or anxiety concerning separation from those to whom an individual is attached: common
features include excessive distress when experiencing or anticipating separation from home, and persistent and excessive worries about potential
harms to attachment figures or untoward events that might result in separation.
Post-traumatic stress disorder
Post-traumatic stress disorder is characterised by a history of exposure to trauma (actual or threatened death, serious injury, or threats to the
physical integrity of the self or others) with a response of intense fear, helplessness or horror; with the later development of intrusive symptoms
(such as recollections, flashbacks or dreams), avoidance symptoms (for example efforts to avoid activities or thoughts associated with the trauma),
negative alterations in cognitions and mood, and hyper-arousal symptoms (including disturbed sleep, hypervigilance and an exaggerated startle
response).
Obsessive-compulsive disorder
Obsessive-compulsive disorder is characterised by recurrent obsessive ruminations, images or impulses, and/or recurrent physical or mental rituals;
which are distressing, time-consuming and cause interference with social and occupational function. Common obsessions relate to contamination,
accidents, and religious or sexual matters; common rituals include washing, checking, cleaning, counting and touching.
Illness anxiety disorder
A somatic symptom related disorder characterised by excessive or disproportionate preoccupations with having or acquiring a serious illness, with
excessive health-related behaviours and high levels of alarm about personal health status.

6.1. Course of anxiety symptoms and

Significant anxiety-
related symptoms and
impaired function,
disorders
Longitudinal studies in community samples indicate that many
Also
moderate/ Yes individuals with anxiety symptoms that are below the threshold
Treat
severe depression for an anxiety disorder diagnosis experience an episodic condi-
depression?
tion with prolonged periods of remission: reappearance or wors-
No
Predominant symptom focus
ening of symptoms being associated with adverse life events and
Trauma
Obsessions +
Uncontrollable intermittent panic/anxiety other psychosocial stressors. By contrast, follow-up studies in
history and worry about
flashbacks? compulsions
several areas
attacks and avoidance
patient groups demonstrate that anxiety disorders tend to run a
chronic course, often over many years, with symptoms fluctuat-
Fear of Discrete Some ing in severity between periods of remission and relapse, the
social
scrutiny
object/ uncued/
situation spontaneous
course of illness varying between disorders [II] (Bruce etal.,
2005).
Generalised anxiety disorder tends to run a waxing and wan-
Check for Check for Check for Check for Check for Check for
PTSD OCD GAD social specific panic ing course in non-clinical samples [I] (Angst etal., 2009), and a
phobia phobia disorder
prolonged course in primary care [I] (Rodriguez etal., 2006): but
may also switch to other diagnoses particularly depression and
Figure 1. Suggested scheme for exploring a suspected anxiety disorder. somatoform disorders [II] (Rubio and Lopez-Ibor, 2007a). Social
GAD: generalised anxiety disorder; OCD: obsessive-compulsive disorder; anxiety disorder tends to run a chronic course in primary [I]
PTSD: post-traumatic stress disorder. (Beard etal., 2010) and secondary medical care settings [II]
Baldwin et al. 5
Table 3. Twelve-month prevalence of anxiety disorders within the European Union.
Diagnosis (DSM-IV) Inter-quartile range (%)
Anxiety disorders Not applicableb
Panic disorder 0.42.0
Agoraphobia 0.42.0
Social anxiety disorder 1.14.4
Specific phobias 3.47.1
Generalised anxiety disorder 0.62.2
Obsessive-compulsive disorder 0.51.1
Post-traumatic stress disorder 0.72.5
aAccording to Eurostat Directorate General of European Commission (Eurostat 2010) for the age groups used.
bAggregate data from single study. 95% confidence interval, 13.415.6%.
cAge range 1465 years, 1.7%; age 65+ years, 3.4%.
dAge range 1434 years, 2.9%; age range 3565 years, 1.3%; age 66+ years, 1.1%.
Best estimates represent consensus view of experts on most probable estimate from identified range. Full data available in Wittchen etal. (2011). DSM-IV refers to the
Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association (1994).
(Bruce etal., 2005; Ramsawh etal., 2009). For panic disorder,
prospective studies reveal high degrees of symptom chronicity
[I] (Batelaan etal., 2010b), relapse after remission [I] (Batelaan
etal., 2010a), and switching to other diagnoses [II] (Rubio and
Lopez-Ibor, 2007b). Childhood separation anxiety disorder often
resolves with entry into adolescence [I] (Copeland etal., 2014).
Retrospective longitudinal studies in obsessive-compulsive dis-
order suggest a very poor outcome, though prospective studies in
non-clinical [I] (Fineberg etal., 2013) and clinical samples [II]
(Eisen etal., 2010; Kempe etal., 2007) indicate a more favoura-
ble prognosis. Cohort studies which have examined the course of
symptoms following traumatic experiences suggest that post-
traumatic stress disorder emerges in only a minority of affected
individuals (for example, [II] Mayou etal., 2001) the course of
established post-traumatic stress disorder is not established,
though a chronic course was seen in almost one-half of adoles-
cents and young adults [I] (Perkonigg etal., 2005).
Recommendations: increased awareness of anxiety
disorders
Become familiar with the main features of the anxiety
disorders, post-traumatic stress disorder and obsessive-
compulsive disorder: and with the main symptoms
which distinguish between them [S]
Develop systematic questions to ask about the nature,
severity, duration, distress and associated impairment
in patients with anxiety symptoms, to decide whether
an anxiety disorder, post-traumatic stress disorder or
obsessive-compulsive disorder is present [S]
Become familiar with the fluctuating nature of symp-
toms in patients with anxiety disorders, and with the ten-
dency for symptoms to change in nature over time [S]
6.2. Co-existing psychological symptoms and
co-morbid mental disorders
Anxiety symptoms often co-exist with other psychological symp-
toms, especially depressive symptoms, which are particularly
Best estimate (%) Number affected (millions)a
14.0 61.5
1.8 7.9
2.0 8.8
2.3 10.1
6.4 22.7
1.73.4c 8.9
0.7 2.9
1.12.9d 7.7
frequent among those individuals with more severe anxiety
symptoms. Cross-sectional studies in European community and
clinical settings [I] (Fehm etal., 2005; Goodwin, 2005; Lieb etal.,
2005) and in UK primary medical care [I] (Nease and Aikens,
2003) reveal a significant correlation between measures of anxi-
ety and depressive symptom severity. Many patients with anxiety
disorders also simultaneously fulfil diagnostic criteria for another
disorder, this pattern typically being named co-morbidity. High
levels of co-morbidity are seen between the anxiety disorders,
and with major depression [I] (Wittchen and Jacobi, 2005), bipo-
lar disorder [II] (Gaudiano and Miller, 2005; Henry etal., 2003),
schizophrenia (IV) (Buckley etal., 2009) substance misuse
(Castle, 2008; Crippa etal., 2009; Robinson etal., 2009;
Ziedonis etal., 2008) and physical illness [IV] (Davies etal.,
2007; Roy-Byrne etal., 2008).
The presence of a comorbid anxiety disorder is associated
with both a longer time to recovery and with a greater risk of end-
ing treatment prematurely in patients with major depression [II]
(Brown etal., 1996). An early systematic review found that
patients with comorbid conditions generally had worse outcomes
than those with anxiety disorder or depressive disorder alone [I]
(Emmanuel etal., 1998). This is supported by the findings of the
US National Comorbidity Survey which demonstrated that indi-
viduals with comorbid generalised anxiety disorder and major
depression were significantly more likely to remain symptomatic
than individuals with depression or generalised anxiety disorder
alone [I] (Kessler etal., 2008).
Detection of co-morbid depression can sometimes lead to
simultaneous recognition of an underlying primary anxiety disor-
der. For example, a French primary care study of the prevalence,
recognition and treatment of social phobia found that detection
rates were increased in the presence of comorbid depression
(66%, compared with 53% in those without depression) [I]
(Weiller etal., 1996). However the presence of a seemingly more
pressing comorbid condition can result in sub-optimal treatment
for the anxiety disorder. Data from a United Kingdom general
practice cluster randomised controlled trial of the impact of men-
tal health guidelines, which found that only 54% of patients with
a common mental disorder (depression or anxiety) were offered
active treatment, revealed that patients with anxiety or mixed
anxiety-depression were significantly less likely to be offered
6 Journal of Psychopharmacology
treatment than patients with depression alone [I] (Hyde etal.,
2005). Analysis of a Dutch primary care database involving
patients with a newly diagnosed anxiety disorder found that ben-
zodiazepines were significantly more frequently prescribed in
patients with psychiatric comorbid conditions, and antidepres-
sants significantly more frequently prescribed in patients with
comorbid physical illness: in both forms of comorbidity, the pre-
scription pattern of benzodiazepines was inconsistent with cur-
rent guideline recommendations [I] (Smolders etal., 2007).
The presence of marked co-existing depressive symptoms is
an important consideration in treatment decisions. Where anxiety
symptoms are present within the context of a depressive disorder,
antidepressant drug treatment is often effective in reducing anxi-
ety (IV) (Anderson etal., 2008). Where depression follows or is
comorbid with an anxiety disorder it is generally indicative of
greater severity and associated with poorer prognosis (II) (Albus
and Scheibe, 1993; Brown etal., 1995; Cowley etal., 1996;
Erwin etal., 2002; Martinsen etal., 1998; Rief etal., 2000; the majority of cases of anxiety disorder diagnosed through a
Shalev etal., 1998). Clinical practice has usually been to direct
treatment towards the depressive disorder in the first instance,
choosing treatments that also have action against the symptoms
of the anxiety disorder: though some guidance notes that when a
patient has an anxiety disorder and comorbid depression or
depressive symptoms, treating the anxiety disorder first should
also be considered, as effective treatment of the anxiety disorder
will often improve the depression or depressive symptoms
(National Institute for Health and Clinical Excellence, 2011).
Recommendations: enquiring about coexisting symp-
toms and comorbid disorders
Check for anxiety symptoms in patients presenting
with symptoms of other mental disorders, including
depression, bipolar disorder, psychosis and substance
misuse [A]
Remember that coexisting depressive symptoms in
patients with anxiety disorders are associated with
greater functional impairment and a longer duration of
illness [B]
Assess for comorbid depression and treat if depressive
symptoms are of more than mild intensity [S]
7. Detection of anxiety symptoms in
primary medical care settings
Within the setting of primary medical care (general practice),
most patients with anxiety or depression have relatively mild
and transient symptoms, which tend to resolve without the need
for intervention: but many have severe, persistent and disabling
symptoms, which are likely to benefit from psychological or
pharmacological treatment. However, many patients with anxi-
ety and depressive symptoms do not present to primary medical
care services [I] (Andrews and Carter, 2001; Roness etal.,
2005). Even when patients do consult their general practitioner,
anxiety symptoms are usually not their presenting complaints.
The general practitioner therefore faces a significant challenge,
in detecting the sample of patients most in need of treatment,
from among the wider group, in many of whom intervention
may be unnecessary.
The limited detection of anxiety disorders in primary care has
been observed in multiple countries over many years. A Dutch
study found a low (47%) rate of detection of anxiety and depres-
sion, recognition being more likely in anxiety disorders of shorter
duration [I] (Ormel etal., 1991). A German study, in which 5.3%
of patients fulfilled diagnostic criteria for generalised anxiety
disorder, and 1.6% for comorbid major depressive episode and
generalised anxiety disorder, found that whilst the majority (over
70%) of affected individuals were recognised as having clinically
significant emotional problems, accurate diagnosis was less com-
mon (34.4% for generalised anxiety disorder) [I] (Wittchen etal.,
2002). A United States investigation of older patients with gener-
alised anxiety disorder found low rates of recording of anxiety
symptoms (34%) or anxiety disorder (9%) despite much use of
health services [I] (Calleo etal., 2009). A Canadian study found
structured clinical interview did not have a recorded diagnosis
(generalised anxiety disorder, 71.0%; panic disorder, 85.8%;
social anxiety disorder, 97.8%) [I] (Vermani etal., 2011).
Limited recognition is partly related to difficulty in discussing
emotional difficulties: many patients do not express emotional
symptoms and many doctors find it hard to raise concerns about
potential psychological distress. A United Kingdom general prac-
tice survey involving patients whose questionnaire scores indi-
cated likely psychiatric caseness found the vast majority had
not mentioned emotional problems in the consultation, mainly
through fears of either being unable to cope with the ensuing dis-
tress or of embarrassment, or through not wishing to trouble their
doctor: but many also felt there would be either insufficient time,
or the doctors could do nothing to help [II] (Cape and McCulloch,
1999). A United States primary care study found that doctors who
were more sensitive to non-verbal communications were more
likely to make diagnoses; but those who tended to blame
patients made fewer psychological assessments, and were less
accurate in detecting distress [II] (Robbins etal., 1994).
Fortunately general practice is structured in such a way that
many patients present repeatedly, which provides an opportunity
for recognition of symptoms at subsequent consultations, if an
anxiety disorder is not detected at the first visit. In a United
Kingdom longitudinal study of the detection of depression and
anxiety which found that many cases were not detected at the
initial appointment, the vast majority of undetected cases of
depression or anxiety were recognised at follow-up [I] (Kessler
etal., 2002). A Dutch primary care practice survey found that
patients with an anxiety disorder were less likely to be diagnosed
than patients with a depressive episode, but the likelihood of
diagnosis in both conditions increased with the number of con-
sultations, and the expression of more severe psychological
symptoms [I] (Verhaak etal., 2006).
Recommendations: increasing skills in detecting anxi-
ety symptoms
Remember that many patients are either reluctant to
present with psychological symptoms or find it hard
discuss emotional problems [A]
Baldwin et al. 7
Be sensitive to non-verbal expression of psychological
distress [B]
Use the opportunity provided by repeated consulta-
tions in primary care to ask follow-up questions about
possible anxiety symptoms when these were suspected
but not established at earlier appointments [A]
Routine screening of all patients for the presence of
anxiety symptoms is not recommended [A]
8. Screening for anxiety disorders in
primary care settings
In theory, patients and health professionals might benefit from
the use of screening tools for detecting anxiety disorders, which
can lead to discussion of psychological symptoms at both the
index and subsequent appointments. A Danish primary care study
of the potential value of screening for common mental disorders
found that disclosure of scores on screening questionnaires
increased the recognition of mental disorders by doctors with
moderate or low recognition rates; and also resulted in increased
discussion of psychological concerns and planned follow-up con-
sultations in patients who had screened positive [I] (Christensen
etal., 2005). However, use of screening questionnaires needs to
be accompanied by other changes in practice structure, and it is
uncertain whether routine screening and disclosure of screened
positive patients with anxiety disorders leads to improved clini-
cal outcomes. An educational intervention involving this design,
among United States primary care patients found no evidence for
an improvement in patient outcomes [I] (Mathias etal., 1994).
The criteria for diagnosing psychiatric disorders are mainly
from clinical observations in psychiatric outpatients and inpa-
tients and so may not be appropriate for routine use in screening
for common mental disorders, among the more mildly ill
patients in primary care. Primary care doctors often have reser-
vations about the usefulness of DSM-IV criteria for diagnosis in
primary care, and many of their patients are reluctant to accept
any offered diagnoses or undergo psychotropic drug treatment
[II] (Van Rijswijk etal., 2009). Although general practitioners
sometimes find using screening questionnaires to be trouble-
some within a standard consultation, patients do not object to
completing them [II] (Leydon etal., 2011). The use of question-
naires for detecting and following up patients with depressive
symptoms has become part of routine primary care practice in
the United Kingdom, suggesting that use of a similar question-
naire for detecting anxiety disorders is feasible in practice [IV]
(Buszewicz and Chew-Graham, 2011).
9. Increasing awareness of anxiety
disorders in particular patient
populations
When compared with the general population, anxiety disorders
are more common among patients with other mental disorders,
with chronic physical illness, and in certain demographic groups.
Patients with long-standing socioeconomic problems, and those
from certain ethnic populations, may be at greater risk of receiv-
ing sub-optimal care and treatment. A Dutch primary care
investigation, which included a nested case-control study of care
received by patients with or without psychosocial problems,
found that individuals with associated problems were signifi-
cantly more likely to receive benzodiazepines and less likely
to receive antidepressants: which may have contributed to
their poorer outcomes [I] (Van Rijswijk etal., 2006). A cross-
sectional study of anxiety and depressive symptoms in Australian
family practices found that unemployed patients, when com-
pared to employed patients, were significantly more likely to
report affective symptoms, to have greater symptom severity, to
have previously undergone treatment and to be prescribed psy-
chotropic medication: but were no more likely to be referred to
mental health services than were employed patients [I] (Comino
etal., 2000).
Data from the United States indicate that black and Hispanic
patients were less likely than white patients to receive care for
depression and anxiety, or to receive antidepressant prescriptions
(and for Hispanic patients, to undergo counselling) in primary
care; and black patients were less likely than white patients to
receive antidepressant prescriptions from a psychiatrist [II]
(Lagomasino etal., 2011). Similar discrepancies were seen in a
treatment review among United States primary care patients with
anxiety disorders, where non-white individuals were signifi-
cantly less likely to receive treatment [II] (Weisberg etal., 2007).
This situation may not necessarily apply in all countries, as a
Dutch general practice study of the quality of care for anxiety and
depression across ethnic minority groups found that all groups
(with the exception of individuals originating from Surinam and
the Antilles) were as likely to receive guideline-concordant medi-
cal care [I] (Fassaert etal., 2010).
Recommendations: paying particular attention to
certain patient groups
Remember that anxiety symptoms tend to persist
longer in patients who are experiencing long-standing
socioeconomic difficulties [B]
Ensure that the presence of socioeconomic disadvan-
tage or membership of a minority ethnic group among
patients in your practice is not associated with a
reduced chance of their undergoing evidence-based
pharmacological or psychological treatment [S]
10. Identifying which patients with
anxiety disorders should undergo
treatment
Many anxious individuals have mild symptoms of recent onset
that are associated with stressful life events or troublesome situ-
ations, which will often improve without needing specific treat-
ment. However, the chronic nature and significant associated
disability of anxiety disorders means that most patients who fulfil
the diagnostic criteria for an anxiety disorder in terms of sever-
ity, duration, distress and impairment are likely to benefit from
some form of treatment, whether this is psychological or pharma-
cological. The need for treatment is influenced by the intensity
and duration of illness, the impact of symptoms on everyday life,
the presence of co-existing depressive symptoms and comorbid
8 Journal of Psychopharmacology
disorders, and the presence of concomitant medication; together
with other features such as a good response to, or poor tolerabil-
ity of, previous treatments. The choice of a particular treatment
should be influenced by the supporting evidence base, by patient
characteristics (such as co-morbid physical illness, previous
response, or treatment contraindications), the preferences of
patients and experience of doctors, and the local availability of
any proposed intervention [IV] (Haynes etal., 2002).
However, many patients with anxiety disorders who might
benefit from treatment do not receive it. A United States longitu-
dinal primary care study of the use of health services by patients
with panic disorder found that 64% had undergone some form of
intervention over 410 months, but only 22% had been given
appropriate pharmacological treatment, and only 12% had
received appropriate psychological treatment [II] (Roy-Byrne
etal., 1999). The quality of treatment in those who do receive it
may be enhanced through making an accurate diagnosis and by
regular monitoring of progress. Another United States primary
care study of the treatment of patients with panic disorder found
that inadequate dosage and insufficient duration of treatment
were both common, and suggested that enhanced patient educa-
tion and an increased frequency of appointments would be more
likely to facilitate adequate treatment than would physician edu-
cation [II] (Roy-Byrne etal., 2002). A study of adherence to evi-
dence-based guidelines for depression and anxiety disorders
within the setting of Dutch primary medical care found that only
27% of patients with anxiety disorders received guideline-
consistent care: symptom severity had no influence on adher-
ence, but documentation of a diagnosis by the general practitioner
significantly increased the likelihood of receiving guideline-
consistent care [I] (Smolders etal., 2009).
Media reports in many countries have raised concerns about
the medicalisation of anxiety, shyness, worrying and adjust-
ment to trauma, and about the inappropriate prescribing of psy-
chotropic drugs to patients who are experiencing life stresses or
situational problems. This may be a factor in some settings,
though most studies find a low level of inappropriate prescribing
and a high level of unmet need. For example, a Norwegian pri-
mary care study involving over 1300 patients found some of evi-
dence of overtreatment (including inappropriate counselling,
prescription of psychotropic medication, or specialist referral) in
11% of individuals without a formal psychiatric diagnosis, but
also found substantial rates of under-treatment for individuals
with the diagnoses of major depressive episode (49%) or gener-
alised anxiety disorder (64%) [I] (Olsson etal., 2006).
Recommendations: deciding when and which treat-
ment is required
Assess the severity and duration of anxiety symptoms,
and the associated distress and impairment, when
deciding which patients should be offered pharmaco-
logical or psychological treatment [S]
Remember to ask about coexisting depressive symp-
toms and other potential comorbid disorders [S]
Consider other factors such as the presence of physical
illness, current concomitant medication, and a history
of good response to, or poor tolerability of, previous
treatments [S]
Record the diagnosis and review this at subsequent
appointments [A]
The choice of a particular treatment should be influ-
enced by the supporting evidence base, by clinical
characteristics (such as treatment contraindications and
expected impact of potential side effects), the prefer-
ences of patients, personal experience, and the local
availability of any proposed intervention[S]
11. Anticipating common concerns
about potential adverse effects of
psychotropic drugs
Many patients experience unwanted and distressing adverse
effects of psychotropic drug treatment, such as sexual dysfunc-
tion with selective serotonin reuptake inhibitors (SSRIs), exces-
sive perspiration with serotonin-noradrenaline reuptake inhibitors
(SNRIs), drowsiness with pregabalin and the benzodiazepines, or
weight gain with antipsychotic drugs. Others fear developing a
tolerance or becoming dependent on medication, and so are
reluctant to start, letalone continue, pharmacological treatment.
In addition, many patients and health professionals and some
commentators consider pharmacological intervention to be a
merely symptomatic and not a definitive treatment. For these rea-
sons, many of those who might benefit from treatment do not
receive it, and many of those who do undergo treatment stop it
early because of the emergence of unwanted effects.
Opinions about the potential value and drawbacks of psy-
chotropic drug treatment vary widely. A United States cross-
sectional study of patients with panic disorder attending primary
care found high levels of willingness to see a psychiatrist or psy-
chotherapist, or to undergo pharmacological treatment [III]
(Johnson etal., 2000). However a United Kingdom primary care
qualitative study of patients views on anxiety and depression
found marked preferences regarding their perceived health
needs, and much scepticism about the value of pharmacological
treatments [II] (Kadam etal., 2001). Certain patient groups may
be particularly reticent about starting or continuing psychotropic
drug treatment. For example, in a United States study of beliefs
about psychotherapy and psychotropic drug treatment for an
anxiety disorder which found few differences between diagnos-
tic groups, coexisting depression was associated with more
favourable views regarding drug treatment, whereas individuals
from black and minority ethnic groups were less favourably
inclined towards pharmacological or psychological treatments
[II] (Wagner etal., 2005).
Adherence to prescribed treatment may be enhanced by pro-
viding relevant information about treatment and minimising
administrative challenges. A qualitative study of experiences of
care among groups of treatment-adherent and non-adherent eco-
nomically disadvantaged patients with panic disorder found that
providing information was empowering and reduced a sense of
isolation; that patients used a continuing process to evaluate the
benefits and risks of treatment; and that barriers to treatment
were primarily logistical [II] (Craske etal., 2005). Another inves-
tigation of perceived barriers to care suggested that difficulties in
the continuing treatment of panic disorder were primarily admin-
istrative, such as being uncertain where to seek help, worrying
Baldwin et al. 9
about potential costs, a lack of health insurance cover, and a
delay in receiving appointments [II] (Mukherjee etal., 2006).
Recommendations: ascertaining attitudes to care and
treatment
Explore attitudes and expectations about pharmaco-
logical and psychological treatment and correct any
misconceptions with patients prior to making a specific
treatment recommendation [S]
Review patient attitudes and experiences periodically
during the course of treatment [B]
Consider the administrative aspects of practice organi-
sation to see whether these facilitate the care and treat-
ment of patients with anxiety disorders [S]
12. Pharmacological treatments in
patients with anxiety disorders
It has often proved difficult to demonstrate the benefit of antide-
pressant drug treatment in patients with mild depressive symp-
toms and the same difficulty is likely to be seen in patients with
milder forms of anxiety disorders. Randomised controlled trials
across a range of anxiety disorders also often demonstrate a high
placebo response [IV] (Baldwin etal., 2011b; Batelaan etal.,
2012; Blanco etal., 2013; Fineberg etal., 2013, 2012; Ipser and
Stein, 2012) which suggests that non-specific effects of assess-
ment and monitoring can play a large part in overall improvement.
It should be emphasised that treatment response is not immediate;
that a transient worsening of symptoms can sometimes occur; that
prolonged courses are needed to maintain an initial treatment
response; and that psychotropic medications and psychological
treatments can have additive effects in some disorders.
The selection of a particular drug class (and of a specific drug
within that class) should be determined principally by the evi-
dence base supporting its use, and also by whether the patient has
previous experience of treatment with that compound. The
absence of a licensed indication does not necessarily mean an
absence of evidence for the proposed treatment intervention:
conversely it should not be assumed that all drugs within a class
are likely to be efficacious in the treatment of a particular anxiety
disorder, when one member of that class has proven efficacy [IV]
(Aquilina etal., 2007; Baldwin and Kosky, 2007; Royal College
of Psychiatrists, 2007). The presence of coexisting depressive
symptoms of moderate or greater severity should guide treatment
choice towards the prescription of antidepressant drugs rather
than benzodiazepines.
12.1. SSRIs and SNRIs
SSRIs have broad spectrum efficacy in both short-term and
long-term treatment, and are generally well tolerated; and for
these reasons are widely considered to be the first-line pharmaco-
logical approach in patients with anxiety disorders or obsessive-
compulsive disorder. However SSRIs have potentially
troublesome adverse effects, including initial increased nervous-
ness, insomnia, nausea and sexual dysfunction [I (M)] (Gartlehner
etal., 2011; Serretti and Chiesa, 2009; Sinclair etal., 2009).
Fluoxetine and paroxetine are inhibitors of some cytochrome
P450 enzymes and hence may interact with some other psycho-
tropic drugs and treatments for physical illness [IV] (Muscatello
etal., 2012). When stopped abruptly, and even when tapered
slowly, SSRIs can produce a discontinuation syndrome charac-
terised by dizziness, insomnia and flu-like symptoms [I (M)]
(Baldwin etal., 2007; Schatzberg etal., 2006): this seems more likely
with paroxetine and least likely with fluoxetine [II] (Tint etal., 2008).
The SNRIs duloxetine and venlafaxine have proven efficacy
in short-term and long-term treatment of generalised anxiety dis-
order [IV] (Baldwin etal., 2011b), and placebo-controlled trials
indicate that venlafaxine is also efficacious in the acute treatment
and prevention of relapse in panic disorder [IV] (Batelaan etal.,
2012). Although the tolerability profiles of SSRIs and SNRIs in
patients with anxiety disorders are not established fully, system-
atic reviews of studies in depressed patients suggest that duloxe-
tine and venlafaxine may be less well tolerated than the SSRIs [I
(M)] (Cipriani etal., 2012; Schueler etal., 2011). Both duloxe-
tine and venlafaxine have been associated with discontinuation
symptoms after abrupt withdrawal [I(M)] (Baldwin etal., 2007;
Perahia etal., 2005) in adult patients, data being limited in chil-
dren and adolescents [IV] (Hosenbocus and Chahal, 2011).
Although evidence is mixed (Harrison etal., 2004; Mbaya etal.,
2007; Thase, 1998) venlafaxine is sometimes associated with an
increase in blood pressure, and monitoring is recommended with
higher daily doses [IV] (Joint Formulary Committee, 2012). A
systematic review [I (M)] (McIntyre etal., 2008) and the findings
of pharmacoepidemiological studies [I (M)] (Strombom etal.,
2008; Wernicke etal., 2008a, 2008b) provide no consistent evi-
dence of an increased risk of hepatotoxicity with duloxetine, but
it is recommended that duloxetine is avoided in patients with
known liver disease and patients considered to be at risk of
hepatic dysfunction [IV] (Joint Formulary Committee, 2012).
12.2. Other antidepressant drugs
Certain tricyclic antidepressants (TCAs) [IV] (Baldwin etal.,
2011b; Bandelow etal., 2008a; Batelaan etal., 2012; Blanco
etal., 2013; Fineberg etal., 2012; Ipser and Stein, 2012) are effi-
cacious in some anxiety disorders, but TCAs are associated with
a greater burden of adverse effects than either SSRIs or SNRIs
[IV] (Anderson etal., 2008), and for this reason should be gener-
ally be reserved for use after a non-response to or poor tolerance
of initial treatment with an SSRI or SNRI. TCAs should be
avoided in patients considered to be at risk of suicide, due to their
potential fatal toxicity after overdose [IV] (Thanacoody and
Thomas, 2005; Woolf etal., 2007). As with some SSRIs, many
possible pharmacokinetic interactions limit their use in patients
taking concomitant medication (listed in Appendix 1 of the
British National Formulary, Joint Formulary Committee, 2012).
As with other antidepressants, stopping TCAs abruptly can cause
a discontinuation syndrome [IV] (Schatzberg etal., 2006).
The traditional irreversible monoamine oxidase inhibitor
(MAOI) phenelzine has proven efficacy in panic disorder and
social phobia: but side effects and the need to follow dietary
restrictions limit its use, so it should generally be reserved for
when patients have not responded to, or proved intolerant of,
other treatment approaches. Phenelzine overdose is potentially
fatal [III] (White etal., 2008), and it should usually be avoided in
patients considered to be at risk of suicide. Interactions involving
10 Journal of Psychopharmacology
traditional MAOIs and serotonergic antidepressants such as
SSRIs and clomipramine can be hazardous (Lane and Baldwin,
1997). Moclobemide, a reversible inhibitor of mono-amine oxi-
dase A (RIMA) has proven efficacy in social phobia [IV] (Blanco
etal., 2013) and some evidence of benefit in panic disorder [I
(PCT)] (Ross etal., 2010): the reversibility of its action reduces
the need for dietary restrictions at lower daily doses though
avoidance of tyramine-containing foods is advisable at higher
dosage [I (PCT)] (Dingemanse etal., 1998).
Agomelatine has proven efficacy in acute treatment (Stein
etal., 2008a) and prevention of relapse (Stein etal., 2012) in
generalised anxiety disorder: sexual dysfunction is less likely
than with SSRI or SNRI antidepressants [I (M)] (Serretti and
Chiesa, 2009), as are discontinuation symptoms [I (PCT)]
(Goodwin etal., 2009; Montgomery etal., 2004): elevations of
hepatic enzymes occur in more than 1% of treated patients and
regular monitoring of liver function tests is required in the early
months of treatment [IV] (McAllister-Williams etal., 2010). The
evidence for the efficacy of mirtazapine in patients with anxiety
disorders is limited and inconsistent (Andrisano etal., 2013;
Muehlbacher etal., 2005; Schutters etal., 2010), but in depressed
patients treatment-emergent sexual dysfunction is probably less
frequent than with SSRIs [I (M)] (Watanabe etal., 2011).
12. 3. Benzodiazepines
Some benzodiazepines have proven efficacy in the treatment of
patients with panic disorder, generalised anxiety disorder and
social anxiety disorder [IV] (Baldwin etal., 2011b; Bandelow
etal., 2008b; Batelaan etal., 2012; Blanco etal., 2013). However be reserved for treatment after a non-response to other interven-
benzodiazepines can cause troublesome sedation and cognitive
impairment in both short-term and long-term treatment, and tol-
erance and dependence can occur (especially in predisposed
patients) with prolonged use: and it is hard to identify those
patients at risk of developing long-term problems [IV] (DellOsso
and Lader, 2012). It is uncertain whether benzodiazepines are
efficacious in relieving depressive symptoms in patients with
anxiety disorders but there is no evidence of efficacy for benzo-
diazepines in the acute treatment of patients with minor depres-
sion [I (M)] (Barbui etal., 2011) and antidepressants should
therefore be preferred in patients with significant coexisting
depressive symptoms. Benzodiazepines will usually be reserved
for the further treatment of patients who have not responded to at
least three previous treatments (such as after non-response to
both an SSRI and an SNRI and a psychological intervention); but
it has been argued that concerns about potential problems in
long-term use should not prevent their use in patients with persis-
tent, severe, distressing, and impairing anxiety symptoms, when
other treatments have proved ineffective [IV] (Baldwin and Talat,
2012; Nutt, 2005).
12. 4. Pregabalin
Pregabalin has proven efficacy in both acute treatment and pre-
vention of relapse in generalised anxiety disorder [IV] (Baldwin
etal., 2011b) and social anxiety disorder. In generalised anxiety
disorder, it is efficacious in relieving depressive symptoms of
mild to moderate intensity [I (M)] (Stein etal., 2008a), and in
reducing the severity of sleep disturbance (Holsboer-Trachsler
and Prieto, 2013). Common adverse effects include drowsiness
and dizziness though it may be better tolerated than other medi-
cations in the acute treatment of generalised anxiety disorder [I
(M)] (Baldwin etal., 2011a). Long-term treatment is accom-
panied by weight gain in approximately 20% of patients
[III] (Montgomery etal., 2013). It is not subject to hepatic metab-
olism and is excreted unchanged in the urine, which is a potential
advantage in patients with hepatic impairment and in patients
taking other drugs metabolised by the liver, but potentially disad-
vantageous in patients with renal disease. There is no known
untoward interaction with lithium. Spontaneous reports of
adverse sexual side effects are uncommon but the incidence of
treatment-emergent sexual dysfunction with pregabalin is uncer-
tain [IV] (Baldwin etal., 2013). Discontinuation symptoms after
abrupt withdrawal of pregabalin have been reported, as has the
abuse of pregabalin generally in individuals with a history of
other substance abuse: but the relative potential for developing
tolerance and abuse, when compared to with medications, is not
established [IV] (Baldwin etal., 2013).
12. 5. Other agents
Antipsychotic drugs are often prescribed to patients with anxiety
disorders, but the strongest evidence for benefit is restricted to
acute treatment and prevention of relapse with quetiapine in gen-
eralised anxiety disorder [IV] (Baldwin etal., 2011b), and the
augmentation of SSRI antidepressants in patients with obsessive-
compulsive disorder [IV] (Fineberg etal., 2012). The tolerability
profile of antipsychotic drugs is such that they should generally
tions [IV] (National Institute for Health and Clinical Excellence,
2011). The azapirone drug buspirone is efficacious in the acute
treatment of generalised anxiety disorder [I (M)] (Chessick etal.,
2006), as is the anti-histamine drug hydroxyzine [I (M)] (Guaiana
etal., 2010), though neither has published evidence of efficacy in
the prevention of relapse.
Recommendations: general aspects of pharmacologi-
cal treatment
Discuss the anticipated balance of potential benefits
and potential risks of specific psychotropic medica-
tions with patients before starting treatment [S]
Consider a SSRI for first-line treatment, as SSRIs are
effective across the anxiety and related disorders, in
both the short-term and long-term, and are generally
well tolerated [A]
Remain familiar with the evidence base for other
classes of medication, as many patients do not respond
to or are intolerant of SSRI treatment, but may respond
to other classes of psychotropic drug [S]
Discuss potential adverse effects early in treatment,
including increased nervousness, worsened agitation,
and review patient progress carefully over the first few
weeks of treatment [A]
Remember that benzodiazepines can be effective in
many patients with anxiety disorders [A], but recog-
nise that their use should generally only be short-term:
Baldwin et al. 11
and only considered beyond this in patients who have
not responded to a succession of other treatment
approaches [S]
Discuss the potential for experiencing discontinuation
or withdrawal symptoms during unforeseen abrupt
interruptions to treatment and after the planned end of
pharmacological treatment [S]
13. Psychological treatments in
patients with anxiety disorders
Many patients with anxiety disorders or obsessive-compulsive
disorder have a marked preference for psychological treatment
approaches [II] (Patel and Simpson, 2010; Zoellner etal., 2009).
Certain forms of psychotherapy, such as exposure therapy, cogni-
tive therapy and cognitive behavioural therapy (CBT), have
largely consistent evidence of efficacy in the treatment of anxiety
disorders [I (M)] (Hofmann and Smits, 2008). An early systematic
review of counselling for primary care patients with emotional
problems (including anxiety, depression, and stress) indicates
that the short-term (but not long-term) efficacy of counselling was
greater than that of standard general practitioner care, with or
without antidepressant treatment [I (M)] (Bower etal., 2001):
though a subsequent meta-analysis suggests that short-term coun-
selling is less beneficial than longer-term treatment with other
psychological interventions [I (M)] (Cape etal., 2010). Some psy-
chological interventions such as psychodynamic psychotherapy
- have not been subject to extensive controlled investigations
(Leichsenring, 2005; Lewis etal., 2008). Psychodynamic psycho-
therapy was reported to be superior to applied relaxation in
patients with panic disorder (Leichsenring etal., 2009; Milrod
etal., 2007), but has been found less beneficial than CBT in gen-
eralised anxiety disorder (Durham etal., 1999) . Many evaluations
of the efficacy of psychological treatments have not employed an
optimal psychological placebo control treatment: the use of wait-
ing list controls is inadequate to demonstrate potential efficacy.
The efficacy of psychological and pharmacological
approaches is broadly similar in the acute treatment of anxiety
disorders. In some studies, relapse rates are lower after an initial
response to cognitive therapy with exposure than after response
to drug treatment. For these reasons, patients should be offered a
choice of treatment approaches, selection being affected by
patient clinical features, needs and preference, and by the local
availability of services able to offer evidence-based psychologi-
cal interventions [IV] (Haynes etal., 2002). In most anxiety dis-
orders (generalised anxiety disorder, social anxiety disorder,
post-traumatic stress disorder, obsessive-compulsive disorder) it
is uncertain whether combining psychological and pharmaco-
logical treatments is associated with greater long-term benefit
than that which is seen with either treatment approach when
given alone. However, previous concerns that prescription of
psychotropic drugs might reduce the efficacy of psychological
treatment are probably unfounded: in some anxiety disorders sys-
tematic reviews suggest that psychotropic drug administration
can enhance the short-term efficacy of cognitive-behavioural
interventions. As with pharmacological approaches, it should be
emphasised that response to psychological treatment is not
immediate; that transient worsening of symptoms can sometimes
occur; that prolonged courses are often needed to maintain an
initial treatment response; that dependence on the therapist may
occur, with problems when treatment is stopped; and that encour-
aging short-term outcomes are no guarantee of good outcomes
over the longer-term.
Given uncertainty about the value of combination treatment
and widespread constraints in the availability of mental health ser-
vices, it may be best to plan sequential steps in patient manage-
ment [IV] (National Institute for Health and Clinical Excellence,
2005, 2011). When psychological treatment is recommended, it
should only be delivered by suitably trained and supervised staff,
able to demonstrate that their clinical practice adheres to evidence-
based treatment protocols [IV] (National Institute for Health and
Clinical Excellence, 2005). The potential effectiveness of initia-
tives designed to increase the uptake of psychological interven-
tions for patients with common mental health problems such as
the Improving Access to Psychological Therapies programme [IV]
(Brown etal., 2010; Clark, 2011) in the United Kingdom has not
been established through formal randomised controlled trials.
A general range of 820 h of sessions of CBT may be needed
in the treatment of anxiety disorders. In generalised anxiety dis-
order and panic disorder, a typical treatment course consists of
approximately 1620 h, up to half of which can be conducted by
the patient in supervised homework sessions, over a period of
approximately four months [IV] (National Institute for Health
and Clinical Excellence, 2011). In social anxiety disorder a
standard course should consist of up to 14 sessions of 90 min
duration over the course of four months [IV] (National Institute
for Health and Care Excellence, 2013). In post-traumatic stress
disorder, a standard course of psychological treatment might
involve 812 sessions of trauma-focused CBT, delivered at
weekly intervals [IV] (National Institute for Clinical Excellence
(NICE), 2005). In obsessive-compulsive disorder, a typical initial
treatment course might include approximately 16 h of interven-
tion based on exposure and response prevention, with longer and
more intensive treatment in housebound patients [IV] (National
Institute for Health and Clinical Excellence, 2005).
Recommendations: general aspects of psychological
treatment
Remember that the efficacy of psychological and phar-
macological approaches is broadly similar in the acute
treatment of patients with anxiety disorders [A]
Discuss the anticipated balance of potential benefits
and potential risks of specific psychological interven-
tions with patients before starting treatment [S]
Ensure that psychological treatments are only deliv-
ered by suitably trained and supervised staff, able to
demonstrate that their clinical practice adheres to evi-
dence-based treatment protocols [A]
Remind patients that response to psychological treatment
is not immediate and that a prolonged course is usually
needed to maintain an initial treatment response [S]
Plan sequential steps in patient management rather
than combining treatments from the start, as it is uncer-
tain whether combining is associated with greater long-
term benefit [D]
12 Journal of Psychopharmacology
14. The role of self-help and
complementary approaches in anxiety
disorders
Patient preference and the often sub-optimal effects of standard
pharmacological or psychological treatment approaches have
encouraged the development of a range of self-help techniques
and therapies in anxiety disorders; some undertaken as individu-
als, often through internet-based resources, and others in groups.
Many patients and their carers derive considerable practical and
emotional support from local self-help groups and national self-
help organisations (such as the United Kingdom organisations
Anxiety-UK and Obsessive Action): though formal evaluations
of the effectiveness of participation in such groups are sparse [I
(M)] (Pistrang etal., 2008).
There have been relatively few randomised controlled trials
of the efficacy and acceptability of self-help approaches under-
taken as individuals, and few studies have been conducted in
diagnostically homogenous groups, with reliable outcome meas-
ures and robust statistical analysis. An early systematic review of
six randomised controlled trials found evidence for the efficacy
of self-help in primary care patients with mixed anxiety disor-
ders, greater efficacy being seen with more detailed instruction in
use of self-help manuals [I (M)] (Van Boeijen etal., 2005). The
findings of a systematic review of 21 studies in patients with
depression or anxiety disorders suggest that guided self-help has
similar effectiveness to face-to-face psychotherapy [I (M)]
(Cuijpers etal., 2010): a subsequent systematic review of 31 ran-
domised controlled trials in anxiety disorders indicates that self-
help interventions are more effective than being placed on a
waiting list, but less effective than therapist-administered treat-
ments [I (M)] (Lewis etal., 2012). In addition, the evidence base
for self-help approaches in young people with anxiety disorders
is limited [IV] (Parslow etal., 2008; Rickwood and Bradford,
2012). In 2006, the UK National Institute for Clinical Excellence
concluded that there was insufficient evidence to recommend the
general introduction of computerised CBT for anxiety symptoms
or disorders (National Institute for Health and Clinical Excellence,
2006): however the findings of a systematic review of 26 studies
in individuals with depression or anxiety disorders suggest that
internet-based interventions offer promise, in overall manage-
ment [I (M)] (Griffiths etal., 2010); though there is a need to
further investigate factors associated with beneficial outcomes
(Andersson, 2012).
Many patients with anxiety disorders wonder whether tak-
ing herbal preparations or nutritional supplements might
prove beneficial, either instead of or in conjunction with
standard pharmacological or psychological treatments.
Systematic reviews find some evidence for the potential effec-
tiveness of a number of phytomedicines, including Passiflora
species extracts, Kava (Piper methysticum), and combinations
of l-lysine and l-arginine (Lakhan and Vieira, 2010; Sarris
etal., 2011b; Van der Watt etal., 2008). There is no current
convincing evidence for the effectiveness of homoeopathic
preparations in the treatment of patients with anxiety disor-
ders [I (M)] (Davidson etal., 2011; Pilkington etal., 2006).
Kava preparations appeared to have some beneficial effects in
patients with generalised anxiety disorder but have been with-
drawn in many countries due to potential hepatotoxic effects
[IV] (Sarris etal., 2011a).
Other complementary approaches include regular exercise
and interventions drawing on meditation techniques. A system-
atic review indicates that exercise training reduces anxiety symp-
toms in sedentary patients with long-term medical conditions [I
(M)] (Herring etal., 2010); and regular walking may enhance the
efficacy of group CBT, across a range of anxiety disorders [II]
(Merom etal., 2008). In panic disorder, regular exercise is mar-
ginally superior to relaxation [I (PCT)] (Wedekind etal., 2010);
but less effective than either the TCA clomipramine [I (PCT)]
(Broocks etal., 1998) or group CBT [II] (Hovland etal., 2012).
Preliminary evidence suggests that exercise training may be
effective in obsessive-compulsive disorder (Abrantes etal.,
2009), generalised anxiety disorder (Herring etal., 2012) and
social anxiety disorder (Jazaieri etal., 2012).
Meditation and yoga practices are often advocated, as part of
the overall management of patients with anxiety disorders. Early
systematic reviews found only minimal evidence for the effec-
tiveness of meditation therapy [I (M)] (Krisanaprakornit etal.,
2006) or mindfulness-based meditation [I (M)] (Toneatto and
Nguyen, 2007). However another systematic review indicated
that relaxation training (which often includes components of
meditation) is effective in reducing anxiety symptoms in non-
clinical and clinical groups [I (M)] (Manzoni etal., 2008): and
the findings of two recent systematic reviews suggest that medi-
tative therapies are effective in reducing anxiety symptoms
(though their effect in anxiety disorders is uncertain) [I (M)]
(Chen etal., 2012), and that mindfulness- and acceptance-based
interventions are effective in reducing anxiety and co-existing
depressive symptoms in patients with anxiety disorders [I (M)]
(Vllestad etal., 2012).
Recommendations: self-help and complementary
approaches
Remember that self-help approaches, such as use of
internet-based educational resources, are potentially
beneficial in patients with mild anxiety and depressive
symptoms [A]
Keep patients who use such resources under review as
many will not improve, and so will need to undergo
other forms of treatment [S]
Enquire about the use by patients of herbal preparations
or nutritional supplements, but remember that the evi-
dence base for their use is relatively slight, when com-
pared to the substantial evidence supporting the use of
pharmacological and psychological interventions [S]
15. Costs of illness and cost-
effectiveness of treatment
Anxiety disorders are associated with a substantial economic bur-
den: both in health care systems (mainly direct costs of assessment,
investigation, treatment and care), and in the wider society (includ-
ing premature mortality, unemployment, reduced productivity
losses) [I] (Andlin-Sobcki and Wittchen, 2005; Gustavsson etal.,
2011; Wittchen etal., 2011). Using estimates to calculate the size
of the population in the European Union that would be affected
(69.1 million people), it was estimated that, in 2010, anxiety disor-
ders (excluding post-traumatic stress disorder) cost close to 66
Baldwin et al. 13
billion [I] (Gustavsson etal., 2011). Treatment costs account for a
small proportion of the overall costs of health care, and it has been
argued that the increased costs of strategies to increase the recogni-
tion and evidence-based treatment in patients that would otherwise
remain undetected and untreated would be small, compared to the
saving arising from unemployment and reduced productivity at
work [IV] (Baldwin etal., 2010; Issakidis etal., 2004). However
there have been relatively few randomised controlled trials or sys-
tematic evaluations of the cost-effectiveness of pharmacological,
psychological or self-help interventions across the broad range of
anxiety disorders (Joesch etal., 2012; Konnopka etal., 2009;
Lewis etal., 2012; Poirier-Bisson etal., 2010).
Investigations of the costs of illness and cost-effectiveness of
individual anxiety disorders are limited. The cost-effectiveness
of Improving Access to Psychological Therapies (IAPT) services
within the UK is not established [III] (McCrone, 2013; Mukuria
etal., 2013). For generalised anxiety disorder, cost-effectiveness
studies provide evidence for the value of CBT, certain antide-
pressants, and pregabalin (Bereza etal., 2009; Heuzenroeder
etal., 2004; Iskedjian etal., 2008; Jorgensen etal., 2006; Vera-
Llonch etal., 2010). Cost-effectiveness studies in panic disorder
provide evidence for the value of CBT (Heuzenroeder etal.,
2004; Roberge etal., 2008) [II]; SSRI or tricyclic antidepressants
(Heuzenroeder etal., 2004; McHugh etal., 2007); lifestyle
approaches (Lambert etal., 2010) [III]; computerised interven-
tions (Klein etal., 2009; McCrone etal., 2009; Mihalopoulos
etal., 2005) and early intervention (Smit etal., 2009). Brief inter-
ventions (Klein etal., 2009), monotherapies (McHugh etal.,
2007) and self-directed approaches (McCrone etal., 2009) may
be more cost-effective than longer, combination treatment, or
clinician-led approaches, respectively. Treatment studies in
social anxiety disorder provide some evidence for the cost-effec-
tiveness of internet-delivered approaches [II] (Hedman etal.,
2011c; Titov etal., 2009), group CBT [II] (Hedman etal., 2011a),
and for long-term treatment with the SSRI escitalopram in the
prevention of relapse [I (PCT)] (Francois etal., 2008). The cost-
effectiveness of treatments for obsessive-compulsive disorder
has been investigated only rarely, with limited evidence for the
greater cost-effectiveness of stepped care compared to standard
CBT [II] (Tolin etal., 2011) and group CBT in children and ado-
lescents [III] (Farrell etal., 2012). In post-traumatic stress disor-
der, there is only modelled or limited evidence, for the
cost-effectiveness of trauma-focused CBT in the treatment of
sexually abused children, which may be enhanced when com-
bined with an SSRI [III] (Gospodarevskaya and Segal, 2012);
and for virtual reality graded exposure therapy in combat-related
trauma [III] (Wood etal., 2009).
16. Management of generalised
anxiety disorder
16. 1. Recognition and diagnosis
Generalised anxiety disorder is amongst the most common of
mental disorders in primary medical care, and is associated with
increased use of health services. However it is often not recog-
nised, possibly because only a minority of patients present
with anxiety symptoms (most present with physical symp-
toms), and doctors tend to overlook anxiety unless it is a pre-
senting complaint [I] (Munk-Jorgensen etal., 2006). The
degree of functional impairment associated with generalised
anxiety disorder is similar to that with major depression [I]
(Wittchen etal., 2000). Patients with co-morbid depression and
generalised anxiety disorder have a more severe and prolonged
course of illness and greater functional impairment (Tyrer etal.,
2004). Patients with co-morbid depression are more likely to be
recognised as having a mental health problem, though not neces-
sarily as having generalised anxiety disorder [I] (Weiller etal.,
1998; Wittchen etal., 2002).
16.2. Acute treatment
The findings of systematic reviews [I (M)] (Baldwin etal.,
2011b; National Institute for Health and Clinical Excellence,
2011) and randomised placebo-controlled trials of acute treat-
ment of patients with generalised anxiety disorder together pro-
vide substantial evidence for the efficacy of many antidepressant
drugs including SSRIs (citalopram, escitalopram, paroxetine,
sertraline), SNRIs (duloxetine, venlafaxine), the tricyclics imi-
pramine and opipramol, trazodone, and agomelatine [IV]
(Baldwin etal., 2011a). Other compounds with efficacy in pla-
cebo-controlled acute treatment studies include pregabalin [I
(M)] (Wensel etal., 2012), some benzodiazepines (alprazolam,
diazepam, lorazepam) [I (M)] (Martin etal., 2007), buspirone [I
(M)] (Chessick etal., 2006), some antipsychotic drugs (quetia-
pine, trifluoperazine) [I (M)] (Lalonde and Van Lieshout, 2011)
and the antihistamine hydroxyzine [I (M)] (Guaiana etal., 2010).
Beta-blockers are often used in primary medical management of
physical symptoms of anxiety but placebo-controlled evidence of
efficacy in acute treatment of patients with generalised anxiety
disorder is minimal [I (PCT)] (Meibach etal., 1987).
There have been relatively few randomised comparator-
controlled studies of acute treatment in generalised anxiety
disorder [I (M)] (Baldwin etal., 2011b; National Institute for
Health and Clinical Excellence, 2011) and most reveal no sig-
nificant differences in overall efficacy between active com-
pounds. An early analysis of randomised controlled trials of
acute treatment found an overall mean effect size of 0.39:
medications with higher effect sizes were pregabalin, hydrox-
yzine and SNRIs; and with lower effect sizes were benzodiaz-
epines, SSRIs and buspirone [I (M)] (Hidalgo etal., 2007). The
tentative findings of a mixed treatment comparison suggest
fluoxetine, sertraline and pregabalin have some advantages
over other medications: among currently licensed treatments in
the United Kingdom, duloxetine, escitalopram and pregabalin
may have some advantages over paroxetine and venlafaxine [I
(M)] (Baldwin etal., 2011b). It is uncertain whether antide-
pressant drugs, pregabalin and benzodiazepines differ in their
relative efficacy in reducing the severity of psychological or
somatic anxiety symptoms [IV] (Baldwin etal., 2011a). The
findings of fixed-dose randomised placebo-controlled trials
provide some evidence of a dose-response relationship for pre-
gabalin [I (M)] (Bech, 2007; Lydiard etal., 2010), but studies
with antidepressant drugs provide no consistent evidence for a
dose-relationship [IV] (Baldwin etal., 2011a). Although not an
antidepressant, a post hoc pooled analysis of randomised pla-
cebo-controlled trials with pregabalin indicate that it is effica-
cious in reducing depressive symptom severity in patients with
mild to moderate intensity of depressive symptoms [I (M)]
(Stein etal., 2008b).
14 Journal of Psychopharmacology
16.3. Longer term treatment
The findings of acute treatment studies indicate that the proportion
of responding patients steadily increases over time [IV] (Baldwin
etal., 2011a). Continuing with SSRI or SNRI treatment is associ-
ated with an increase in overall response rates: from 824 weeks
with escitalopram or paroxetine [II] (Bielski etal., 2005); from
412 weeks with sertraline [I (PCT)] (Allgulander etal., 2004a)
and from 824 weeks with venlafaxine [I (PCT)] (Montgomery
etal., 2002). However, the findings of post hoc analyses of data
from randomised double-blind placebo-controlled studies with
duloxetine [I (M)] (Pollack etal., 2008), escitalopram [I (M)
(Baldwin etal., 2009), and with alprazolam, pregabalin and venla-
faxine [I (M) (Baldwin etal., 2011a) all suggest that response is
likely only if there is an onset of effect within four weeks of treat-
ment. The findings of randomised placebo-controlled relapse-
prevention studies in patients who have responded to previous
open acute treatment of varying lengths reveal a significant
advantage for staying on active medication (agomelatine, duloxe-
tine, escitalopram, paroxetine, pregabalin, quetiapine, venlafaxine,
vortioxetine), when compared with switching to placebo, for peri-
ods of between 618 months (Baldwin etal., 2011b, 2012;
Katzman etal., 2011; Rickels etal., 2010).
16.4. Comparative efficacy of psychological,
pharmacological, and combination
treatments
Pharmacological or psychological treatments, when delivered sin-
gly, have broadly similar efficacy in acute treatment [I (M)]
(Bandelow etal., 2007a; National Institute for Health and Clinical
Excellence, 2011). The efficacy of CBT and applied relaxation
appears superior to that of other psychological interventions
(National Institute for Health and Clinical Excellence, 2011). A
randomised controlled trial found that augmentation of venlafax-
ine with CBT conferred no additional benefit, when compared
with venlafaxine alone [II] (Crits-Christoph etal., 2011) but it is
uncertain whether combining drug and psychological treatments
is associated with greater overall efficacy than is seen with either
treatment, when given alone [I (M)] (Bandelow etal., 2007a), and
a stepped care approach is recommended [IV] (National Institute
for Health and Clinical Excellence, 2011). Anxiety symptom
severity at follow-up after initial treatment is lower with CBT than
with other forms of psychological treatment [III] (Durham etal.,
2005): but the comparative efficacy of pharmacological and psy-
chological approaches over the long-term is not established.
16. 5. Further management after non-
response to initial treatment
Many patients do not respond to first-line pharmacological or
psychological interventions. There is only inconsistent evidence
for a dose-response relationship with antidepressant drugs, but
some patients who have not responded to an initial low dosage
may respond to a higher daily dose. The efficacy of pregabalin
when compared with placebo is more marked at higher daily
doses (200 mg or higher) [I (M)] (Bech, 2007; Lydiard etal.,
2010). Switching between pharmacological and psychological
treatments with proven efficacy may be helpful [IV] (National
Institute for Health and Clinical Excellence, 2011).
The addition of pregabalin to SSRI or SNRI antidepressant
drugs is superior to continued treatment with antidepressants alone
[I (PCT)] (Rickels etal., 2012). The findings of small randomised
placebo-controlled augmentation studies suggest that augmenta-
tion of antidepressants with antipsychotic drugs (olanzapine, que-
tiapine, risperidone) may be beneficial [I (PCT)] (Brawman-Mintzer
etal., 2005; Pollack etal., 2006; Altamura etal., 2011), but the
evidence for quetiapine augmentation is inconsistent [I (PCT)]
(Khan etal., 2011; Simon etal., 2008), and uncertain for ziprasi-
done augmentation [I (PCT)] (Lohoff etal., 2010).
Alternative treatments which have been found helpful in
some patients include multi-faith spiritually based intervention
[II] (Koszycki etal., 2010); Galphimia glauca (thyrallis) [I
(PCT)] (Herrera-Arellano etal., 2007), Matricaria recutita
extract (chamomile) [I (PCT)] (Amsterdam etal., 2009), Silexa
lavender oil preparation [I (PCT)] (Woelk and Schlaefke, 2010),
relaxing room therapy [III] (Sherman etal., 2010), yoga-based
breathing programme [III] (Katzman etal., 2012) and balneo-
therapy (hydrotherapy with message) [III] (Dubois etal., 2010):
but more investigation of these approaches is needed before they
can be recommended.
Recommendations: managing patients with general-
ised anxiety disorder
Detection and diagnosis
Become familiar with the symptoms and signs of gen-
eralised anxiety disorder [S]
Ask about the presence of coexisting depressive symp-
toms [A]
Ask about long-standing anxiety in patients with
depressive or unexplained physical symptoms [S]
Assess any comorbid physical illness and enquire
about excess alcohol consumption [S]
Acute treatment
Choose an evidence-based acute treatment [A]
pharmacological: most SSRIs (citalopram, escitalo-
pram, paroxetine, sertraline), duloxetine, venlafaxine,
pregabalin, agomelatine, quetiapine, some benzodi-
azepines (alprazolam, diazepam, lorazepam), imipra-
mine, buspirone, hydroxyzine and trazodone [A]
psychological: cognitive-behaviour therapy,
applied relaxation [A]
Take account of patient clinical features, needs and
preference and local service availability when choos-
ing treatment, as pharmacological and psychological
approaches have broadly similar efficacy in acute treat-
ment [S]
Consider an SSRI for first-line pharmacological treat-
ment [A]
SNRIs and pregabalin may be considered as alternative
initial treatments if SSRIs are judged to be unsuitable [A]
Remember that higher daily doses of pregabalin may
be associated with greater response rates [A]
Baldwin et al. 15
Advise the patient that treatment periods of up to 12 weeks
may be needed to assess efficacy [S] but recognise that an
absence of clinical benefit within four weeks warns that a
response to unchanged treatment is unlikely [A]
Longer-term treatment
Continue drug treatment for up to 18 more months in
patients who have responded to treatment [A]
Use a treatment approach that is known to be effica-
cious in preventing relapse [S]
Recommend CBT over other forms of psychological
treatment as it may reduce relapse rates better than
other psychological treatments [C]
Monitor effectiveness and acceptability regularly over
the course of treatment [S]
When stopping treatment, reduce the dose gradually
over an extended period to avoid discontinuation and
rebound symptoms [A]: in the absence of evidence a
minimum of three months is recommended for this
taper period [D]
Combination of drugs and psychological treatment
Routinely combining drug and psychological approaches
is not recommended for initial treatment [A]
When initial treatments fail
Consider raising the dosage of pregabalin if the current
dosage is well tolerated [A]
Consider switching to another evidence-based treatment
[D]
Consider combining evidence-based treatments only
when there are no contraindications [S]
Consider pregabalin augmentation after a non-response
to initial SSRI or SNRI treatment [A]
Consider use of benzodiazepines after a non-response
to SSRI, SNRI, pregabalin and buspirone treatment [S]
Consider combining drug treatment and cognitive-
behaviour therapy [D]
Consider referral to regional or national specialist ser-
vices in treatment refractory patients [S]
17. Management of panic disorder
17.1. Recognition and diagnosis
Accurate diagnosis of panic disorder is dependent upon estab-
lishing the presence of recurring panic attacks (i.e. short-lived
periods of severe psychological and physical symptoms of anxi-
ety, typically peaking within 10 min and resolving within 30
min), at least some of which are, or have been, unexpected. There
should be intervening periods of comparative freedom from anxi-
ety between attacks; but the presence of associated concern,
worry or change in behaviour due to an anticipated risk of having
further panic attacks [IV] (Roy-Byrne etal., 2006). There is sub-
stantial overlap between panic disorder and agoraphobia, in com-
munity and clinical samples [I] (Goodwin etal., 2005; Wittchen
etal., 2010). Patients with panic disorder are often not recognised
or accurately diagnosed in primary [IV] (National Collaborating
Centre for Mental Health, 2011) or secondary medical care [I]
(Burton etal., 2011; Deacon etal., 2008), despite their consider-
able use of emergency, cardiac, gastrointestinal, neurological and
mental health services [IV] (Roy-Byrne etal., 2006). There is
considerable co-morbidity with other mental disorders, including
anxiety disorders, bipolar disorder and major depression [IV]
(Roy-Byrne etal., 2006): co-morbid panic and depression is par-
ticularly common, and associated with greater disability and
impairment, and increased use of health services [I] (Roy-Byrne
etal., 2000).
17.2. Acute treatment
Systematic reviews demonstrate that a range of pharmacological
[IV] (Andrisano etal., 2013, Batelaan etal., 2012;), psychological
[IV] (Schmidt and Keough, 2010) and combination [I (M)]
(Furukawa etal., 2007; Watanabe etal., 2007) interventions are
effective in the acute treatment of patients with panic disorder.
Little is known about the efficacy of pharmacological or psycho-
logical treatment in patients with agoraphobia but without panic
attacks (Perna etal., 2011). The findings of randomised double-
blind placebo-controlled trials of antidepressants indicate that all
SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, parox-
etine, sertraline); the SNRI venlafaxine; the selective noradrena-
line reuptake inhibitor reboxetine; some TCAs (clomipramine,
desipramine, imipramine, lofepramine); the MAOI phenelzine;
some benzodiazepines (alprazolam, clonazepam, diazepam, loraz-
epam); and some anticonvulsants (gabapentin, sodium valproate)
are all efficacious in acute treatment [IV] (Batelaan etal., 2012).
The findings of randomised comparator-controlled studies
provide some evidence for beneficial effects with mirtazapine
[II] (Ribeiro etal., 2001) and moclobemide [II] (Kruger and
Dahl, 1999; Tiller etal., 1999). The relative efficacy and tolera-
bility of differing pharmacological treatments is uncertain, but
there may be efficacy advantages for venlafaxine, and tolerability
disadvantages for fluvoxamine and reboxetine [I (M)] (Andrisano
etal., 2013). A post hoc analysis of findings from a randomised
placebo-controlled trial suggests that escitalopram is superior to
citalopram [I (PCT)] (Bandelow etal., 2007b); and randomised
controlled trials suggest that some SSRIs (fluvoxamine, paroxe-
tine) are more effective than some noradrenaline reuptake inhibi-
tors (maprotiline, reboxetine) [II] (Bertani etal., 2004; Den Boer
and Westenberg, 1988). Medications with a lack of efficacy in the
acute treatment of patients with panic disorder include the antide-
pressant bupropion [I (PCT)] (Sheehan etal., 1983), the beta-
blocker propranolol [I (PCT)] (Munjack etal., 1989); and
buspirone[I (PCT)] (Sheehan etal., 1988). The potential value of
antipsychotic drug monotherapy in acute treatment is unknown [I
(M)] (Depping etal., 2010).
17.3. Longer term treatment
The findings of acute treatment studies indicate that the propor-
tion of responding patients steadily increases over time [IV]
(Batelaan etal., 2012). Double-blind studies indicate that con-
tinuing SSRI or clomipramine treatment from 1252 weeks is
associated with an increase in overall treatment response rates [I
(PCT)] (Ballenger, 1998; Lecrubier and Judge, 1997; Lepola
etal., 1998). The relative effectiveness and acceptability of
16 Journal of Psychopharmacology
differing medications over long-term treatment is uncertain, but a
12-month comparison of the efficacy and tolerability of differing
SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine) sug-
gests that fluvoxamine is less likely to be associated with weight
gain or sexual adverse effects [III] (Dannon etal., 2007); and the
findings of a randomised naturalistic parallel-group study of 34
months of continuation treatment with clonazepam or paroxetine
suggest that clonazepam is marginally more effective and better
tolerated [II] (Nardi etal., 2012).
Placebo-controlled and other relapse-prevention studies in
patients who have responded to previous acute treatment reveal a
significant advantage for staying on active medication (fluoxe-
tine, imipramine, paroxetine, sertraline, venlafaxine), compared
to switching to placebo, for periods of up to six months: but the
optimal duration of continuation treatment is uncertain [I (M)]
(Donovan etal., 2010).
17.4. Comparative efficacy of psychological,
pharmacological, and combination
treatments
The findings of pooled analyses and randomised controlled trials
together indicate that pharmacological and psychological treat-
ments, when delivered singly, have broadly similar efficacy in
acute treatment [I (M)] (Bandelow etal., 2007b; McHugh etal.,
2009). In acute treatment, the combination of psychotherapy with
antidepressants is superior to psychotherapy or an antidepressant,
when either is given alone (Furukawa etal., 2007; Koszycki
etal., 2011; Van Apeldoorn etal., 2010): the advantage over
monotherapies persists as long as the antidepressant is continued,
but combination treatment is more effective than antidepressant
treatment alone, though no different to psychological treatment
alone, in preventing relapse [I (M)] (Furukawa etal., 2007).
Based on limited data, the combination of psychotherapy with a
benzodiazepine is probably superior to a benzodiazepine when
given alone during acute treatment, but the relative efficacy of
combination treatment and monotherapies in the prevention of
relapse is uncertain [I (M)] (Watanabe etal., 2007). However
combination treatment appears no more cost-effective than anti-
depressant or CBT monotherapy [II] (McHugh etal., 2007).
Exploratory placebo-controlled studies suggest that the addition
of d-cycloserine may hasten the onset of effect [I (PCT)]
(Siegmund etal., 2011) or increase overall effectiveness [I
(PCT)] (Otto etal., 2010) of CBT in the acute treatment of
patients with panic disorder.
17. 5. Further management after non-
response to initial treatment
Many patients do not respond to first-line pharmacological or
psychological interventions. The findings of randomised fixed-
dose placebo-controlled studies suggest that higher daily doses of
some antidepressants [I (PCT)] (paroxetine, fluoxetine: Ballenger
etal., 1998; Michelson etal., 1998) but not others [I (PCT)] (cit-
alopram, venlafaxine: Pollack etal., 2007; Wade etal., 1997)
may be superior in efficacy to lower doses. However, the evi-
dence to support dose escalation after an initial lack of response
to lower doses is only limited [I (PCT)] (Michelson etal., 2001)
or negative [I (PCT)] (Simon etal., 2009).
Switching between pharmacological and psychological treat-
ments with proven efficacy may be helpful [IV] (National Institute
for Health and Clinical Excellence, 2011). A single-blind crosso-
ver study in non-responders suggests that switching between cit-
alopram and reboxetine may be worthwhile [II] (Seedat etal.,
2003). A randomised placebo-controlled study found that pindolol
augmentation of fluoxetine was superior to continued fluoxetine
alone [I (PCT)] (Hirschmann etal., 2000). A small open study
involving the addition of fluoxetine in patients taking a TCA, or
vice versa, found some evidence of benefit [III] (Tiffon etal.,
1994). Combined treatment with sodium valproate and clonaze-
pam may be beneficial in patients who have not responded to sev-
eral previous medications [III] (Ontiveros and Fontaine, 1992); as
has the addition of olanzapine to other medications [III] (Sepede
etal., 2006). Addition of lithium to clomipramine was found suc-
cessful in a single case report [III] (Cournoyer, 1986).
Augmentation of CBT with paroxetine may be superior to
continuing with CBT alone, in patients who did not previously
respond over 15 sessions [I (PCT)] (Kampman etal., 2002); and
addition of group CBT may be beneficial in non-responders to
pharmacological approaches [III] (Heldt etal., 2003; Otto etal.,
1999; Pollack etal., 1994). However a small study in multiply
treatment-resistant patients found no difference in effectiveness
between the augmentation of medication with CBT or medica-
tion optimisation (SSRI plus clonazepam) [I (PCT)] (Simon
etal., 2009).
Recommendations: managing patients with panic
disorder
Detection and diagnosis
Become familiar with the symptoms and signs of panic
attacks and panic disorder [S]
Ask about the presence of coexisting depressive symp-
toms [A]
Assess the level of agoraphobic avoidance to help
judge the severity of the condition [S]
Ask about panic attacks and agoraphobia in patients
with medically unexplained physical symptoms [D]
Acute treatment
Choose an evidence-based acute treatment [A]
pharmacological: all SSRIs, some TCAs (clomi-
pramine, desipramine, imipramine, lofepramine)
venlafaxine, reboxetine, some benzodiazepines
(alprazolam, clonazepam, diazepam, lorazepam),
some anticonvulsants (gabapentin, sodium val-
proate) [A]
psychological: cognitive-behaviour therapy [A]
Avoid prescribing propranolol, buspirone and bupro-
pion [A]
Take account of patient clinical features, needs and
preference and local service availability when choos-
ing treatment, as pharmacological and psychological
approaches have broadly similar efficacy in acute treat-
ment [S]
Consider an SSRI for first-line pharmacological treat-
ment [S]
Baldwin et al. 17
Consider increasing the dose if there is insufficient
response, but remember that the evidence for a dose-
response relationship with SSRIs and venlafaxine is
inconsistent [A]
Initial side effects can be minimised by slowly increasing
the dose or by adding a benzodiazepine for a few weeks
[D]
Advise the patient that treatment periods of up to 12
weeks may be needed to assess efficacy [A]
Longer-term treatment
Continue drug treatment for at least six months in
patients who have responded to treatment [A]
Use an approach that is known to be efficacious in pre-
venting relapse [S]
Monitor effectiveness and acceptability regularly over
the course of treatment [S]
When stopping treatment, reduce the dose gradually over
an extended period to avoid discontinuation and rebound
symptoms [A]: in the absence of evidence a minimum of
three months is recommended for this taper period [D]
Combination of drugs and psychological treatment
Consider combining cognitive therapy with antidepres-
sants as this has greater efficacy and may reduce
relapse rates better than drug treatment alone [A]
Consider combining cognitive therapy with benzodiaz-
epines (being mindful of potential long-term problems)
as this probably has greater efficacy than drug treat-
ment alone [A]
When initial treatments fail
Consider raising the dosage if the current dosage is
well tolerated [A]
Consider switching to another evidence-based treat-
ment [D]
Consider combining evidence-based treatments only
when there are no contraindications [S]
Consider combining evidence-based pharmacological
and psychological treatments [A]
Consider referral to regional or national specialist ser-
vices in treatment refractory patients [S]
18. Management of specific phobia
(also known as simple or isolated
phobia)
18.1. Recognition and diagnosis
Specific fears of objects, animals, people or situations are wide-
spread in children, adolescents and adults, but only a minority of
affected individuals reach the full diagnostic criteria for specific
phobia. Specific (or simple or isolated) phobia has an estimated
12-month prevalence of 6.4% [I] (Wittchen etal., 2011), and had
a lifetime prevalence of 9.4% in the United States National
Epidemiologic Survey on Alcohol and Related Conditions [I]
(Stinson etal., 2007). Many affected individuals have multiple
fears, whose presence is associated with an earlier onset, greater
severity and impairment, and more frequent psychiatric comor-
bidity [I] (Burstein etal., 2012; Stinson etal., 2007). Most indi-
viduals with specific phobia do not present for treatment of that
condition, presentation being more likely with comorbid anxiety
or mood disorders [I] (Mackenzie etal., 2012).
18.1 Treatment
The effectiveness and acceptability of psychological or pharma-
cological treatments for specific phobia has been relatively
under-researched when compared to other anxiety disorders. The
findings of a meta-analytic review of 33 randomised controlled
treatment studies indicate that exposure-based therapies (particu-
larly those involving in vivo exposure) are more effective than
other psychological interventions: effectiveness being seen
regardless of the nature of the specific phobia, and being some-
what greater with multiple rather than single sessions [I (M)]
(Wolitzky-Taylor etal., 2008).
Most patients respond to psychological approaches, but some
may benefit from pharmacological treatment. The findings of
small randomised placebo-controlled trials provide evidence for
the efficacy of escitalopram [I (PCT)] (Alamy etal., 2008) and
paroxetine [I (PCT)] (Benjamin etal., 2000). The findings of
small randomised placebo-controlled studies suggest that the
efficacy of exposure therapy can be enhanced through prior
administration of d-cycloserine [I (PCT)] (Nave etal., 2012;
Ressler etal., 2004): but not all evidence is consistent [I (PCT)]
(Guastella etal., 2007), and its administration after a session is
not associated with enhanced efficacy [I (PCT)] (Tart etal.,
2013). Prior administration of naltrexone may reduce the effec-
tiveness of exposure therapy [I (PCT)] (Kozak etal., 2007). It is
unclear whether concomitant use of benzodiazepines enhances or
reduces the efficacy of behavioural approaches.
Recommendations: managing patients with specific (or
simple) phobia
Become familiar with the symptoms and signs of spe-
cific phobia [S]
Assess the number of fears, the level of anxiety, and the
degree of impairment to judge severity [A]
Ask about symptoms of comorbid disorders in treat-
ment-seeking patients [A]
Use psychological treatments based on exposure tech-
niques as first-line treatment [A]
Consider SSRI treatment for patients who have not
responded to psychological interventions [A]
19. Management of social anxiety
disorder (also known as social
phobia)
19.1. Recognition and diagnosis
Social anxiety disorder is often not recognised in primary medi-
cal care [I] (Weiller etal., 1996) but detection can be enhanced
through the use of screening questionnaires in psychologically
distressed primary care patients [I] (Donker etal., 2010; Terluin
18 Journal of Psychopharmacology
etal., 2009). Social anxiety disorder is often misconstrued as
mere shyness but can be distinguished from shyness by the
higher levels of personal distress, more severe symptoms and
greater impairment [I] (Burstein etal., 2011; Heiser etal.,
2009). The generalised sub-type (where anxiety is associated
with many situations) is associated with greater disability and
higher comorbidity, but patients with the non-generalised sub-
type (where anxiety is focused on a limited number of situa-
tions) can be substantially impaired [I] (Aderka etal., 2012;
Wong etal., 2012). Social anxiety disorder is hard to distin-
guish from avoidant personality disorder, which may represent
a more severe form of the same condition [IV] (Reich, 2009).
Patients with social anxiety disorder often present with symp-
toms arising from comorbid conditions (especially depression),
rather than with anxiety symptoms and avoidance of social and
performance situations [I] (Stein etal., 1999). There are strong,
and possibly two-way, associations between social anxiety dis-
order and dependence on alcohol and cannabis [I] (Buckner
etal., 2008; Robinson etal., 2011).
19.2. Acute treatment
The findings of meta-analyses and randomised placebo-
controlled treatment studies indicate that a range of approaches
are efficacious in acute treatment [IV] (Blanco etal., 2013). CBT
is efficacious in adults [I (M)] (Hofmann and Smits, 2008) and
children [I (M)] (James etal., 2005): cognitive therapy appears
superior to exposure therapy [I (M)] (Ougrin, 2011), but the evi-
dence for the efficacy of social skills training is less strong [IV]
(Ponniah and Hollon, 2008).
Antidepressant drugs with proven efficacy include most
SSRIs (escitalopram, fluoxetine, fluvoxamine, paroxetine, sertra-
line), the SNRI venlafaxine, the MAOI phenelzine, and the
RIMA moclobemide: nefazodone is not efficacious and the evi-
dence for mirtazapine is inconsistent [I (M)] (De Menezes etal.,
2011). The potential efficacy of tricyclic antidepressants is
unknown. Some benzodiazepines (bromazepam and clonazepam,
but not alprazolam) and anticonvulsants (gabapentin and prega-
balin, but not levatiracetam), and the antipsychotic olanzapine
also appear efficacious in acute treatment [IV] (Blanco etal.,
2013). Neither the 5-hydroxytryptamine (5-HT1A) partial agonist
buspirone, nor the beta-blocker atenolol are efficacious in gener-
alised social anxiety disorder [IV] (Blanco etal., 2013), although
a number of small single-dose placebo-controlled cross-over
studies together suggest that beta-blockers can be beneficial in
reducing anxiety symptoms in individuals with performance
anxiety (for example, when speaking in public), which overlaps
with mild non-generalised social anxiety disorder) [IV] (Blanco
etal., 2013).
There have been relatively few randomised comparator-con-
trolled studies of acute treatment and most reveal no significant
differences in overall efficacy or tolerability between active com-
pounds. In randomised placebo- and comparator- controlled stud-
ies, phenelzine was superior to placebo, but atenolol was not [I
(PCT)] (Liebowitz etal., 1992); phenelzine was superior to pla-
cebo, but alprazolam was not [I (PCT)] (Gelernter etal., 1991);
and escitalopram was found superior to paroxetine [I (PCT)]
(Lader etal., 2004); venlafaxine and paroxetine had similar over-
all efficacy in two placebo-controlled studies [I (PCT)]
(Allgulander etal., 2004b; Liebowitz etal., 2005).
19.3. Longer term treatment
The findings of acute treatment studies indicate that the propor-
tion of responding patients increases steadily over time [IV]
(Blanco etal., 2013). Double-blind studies indicate that continu-
ing SSRI or SNRI treatment from 1224 weeks is associated with
an increase in overall treatment response rates [I (M)] (Lader
etal., 2004; Stein etal., 2002a, 2003). A post hoc analysis of the
clinical trial database for escitalopram indicates that response is
unlikely if there is no onset of clinical effect within the first four
weeks of treatment [I (PCT)] (Baldwin etal., 2009): however a
post hoc analysis of the clinical trial database with paroxetine
indicates that many non-responders to treatment at eight weeks
become responders with a further four weeks of double-blind
treatment [I (PCT)] (Stein etal., 2002a). The findings of ran-
domised placebo-controlled relapse-prevention studies in
patients who have responded to previous acute treatment reveal a
significant advantage for staying on active medication (clonaze-
pam, escitalopram, paroxetine, pregabalin, sertraline) for up to
six months [IV] (Blanco etal., 2013).
19.4. Comparative efficacy of
pharmacological, psychological and
combination treatments
Pharmacological and psychological treatments, when delivered
singly, have broadly similar efficacy in acute treatment [I (M)]
(Canton etal., 2012). However, acute treatment with cognitive
therapy (group or individual) is associated with a reduced risk of
symptomatic relapse at follow-up [I (M)] (Canton etal., 2012). It
is unlikely that the combination of pharmacological with psycho-
logical treatments is associated with greater overall efficacy than
with either treatment, when given alone, as only one in four stud-
ies of the relative efficacy of combination treatment found evi-
dence for superior efficacy [I (PCT)] (Blanco etal., 2010). The
findings of small randomised placebo-controlled studies suggest
that the efficacy of psychological treatment may be enhanced
through prior administration of d-cycloserine [I (PCT)] (Guastella
etal., 2008; Hofmann etal., 2006) or cannabidiol [I (PCT)]
(Bergamaschi etal., 2011).
19.5. Further management after non-
response to initial treatment
The findings of fixed-dose randomised controlled trials do not
provide consistent evidence of a dose-response relationship
with antidepressant drugs: but a fixed-dose study of pregabalin
found that only the higher daily dosage was efficacious [I
(PCT)] (Pande etal., 2004). A double-blind randomised con-
trolled dosage escalation trial found no advantage for increas-
ing to a higher daily dosage (120 mg) of duloxetine, when
compared to continuing treatment with a lower (60 mg) dosage
[II] (Simon etal., 2010). Switching between treatments with
proven efficacy may be helpful [IV] (Blanco etal., 2013). An
uncontrolled study of augmentation of SSRI treatment with
buspirone found some evidence of beneficial effects [III] (Van
Ameringen etal., 1996); but a placebo-controlled crossover-
study of the augmentation of paroxetine with pindolol found
no evidence of efficacy [I (PCT)] (Stein etal., 2001). A small
Baldwin et al. 19
placebo-controlled study of the augmentation of paroxetine
with clonazepam found the combination was marginally short
of superiority, when compared to paroxetine alone [I (PCT)]
(Seedat and Stein, 2004).
Recommendations: managing patients with social anx-
iety disorder
Detection and diagnosis
Become familiar with the symptoms and signs of social
anxiety disorder [S]
Assess the level of distress and disability to help distin-
guish social anxiety disorder from shyness [A]
Ask about the presence of coexisting depressive symp-
toms [A]
Ask about social anxiety symptoms when patients pre-
sent with depression, panic attacks restricted to social
situations, or alcohol and cannabis misuse [A]
Acute treatment
Choose an evidence-based acute treatment [A]
pharmacological: most SSRIs (escitalopram, fluoxe-
tine, fluvoxamine, paroxetine, sertraline), venlafaxine,
phenelzine, moclobemide, some benzodiazepines
(bromazepam, clonazepam) and anticonvulsants
(gabapentin, pregabalin), and olanzapine
psychological: cognitive-behaviour therapy
Avoid prescribing atenolol or buspirone in generalised
social anxiety disorder [A]
Take account of patient clinical features, needs and pref-
erence and local service availability when choosing treat-
ment, as pharmacological and psychological approaches
have broadly similar efficacy in acute treatment [S]
Consider an SSRI for first-line pharmacological treat-
ment [A]
Routine prescription of higher doses of SSRIs is not
recommended [A], but individual patients may benefit
from higher doses [D]
Advise the patient that treatment periods of up to 12
weeks may be needed to assess efficacy [A]
Longer-term treatment
Use an approach that is known to be efficacious in pre-
venting relapse [S]
Continue drug treatment for at least six months in
patients who have responded to treatment [A]
Consider cognitive therapy with exposure as this may
reduce relapse rates better than drug treatment [A]
Consider cognitive therapy after response to drug treat-
ment, in patients with a high risk of relapse [D]
Monitor effectiveness and acceptability regularly over
the course of treatment [S]
Combination of drugs and psychological treatment
Routinely combining drug and psychological approaches
is not recommended for initial treatment in the absence
of consistent evidence for enhanced efficacy over
each treatment when given alone [A]
When initial treatments fail
Consider raising the dosage if the current dosage is
well tolerated [D]
Consider switching to another evidence-based treat-
ment [D]
Consider combining evidence-based treatments only
when there are no contraindications [S]
Consider adding buspirone after partial response to an
SSRI [C]
Consider combining evidence-based pharmacological
and psychological treatments [A]
Consider benzodiazepines in patients who have not
responded to other approaches [D]
Consider referral to regional or national specialist ser-
vices in treatment refractory patients [S]
20. Management of post-traumatic
stress disorder
20.1. Recognition and diagnosis
Exposure to potentially life-damaging traumatic events is com-
mon, in both genders, during childhood, adolescence and adult life
[IV] (Nemeroff etal., 2006): but only a proportion of those exposed
to trauma develop psychological sequelae. For example, the US
National Comorbidity Survey found that 60.7% of men and 51.2%
of women reported exposure to at least one traumatic event, but
post-traumatic stress disorder had a lifetime prevalence of 7.8% [I]
(Kessler etal., 1995). In the UK, post-traumatic stress disorder was
present in only a minority of individuals exposed to motor vehicle
accidents, at three-month (11%) and 12-month (5%) follow-up [I]
(Mayou etal., 2001). The 12-month prevalence of post-traumatic
stress disorder is estimated to be 1.12.9%, being more common in
younger than older adults [I] (Wittchen etal., 2011).
Post-traumatic stress disorder shows considerable co-morbid-
ity with other mental disorders [I] (Loewe etal., 2011). Suicidal
thoughts are common but the increased risk of completed suicide
is probably due to the presence of comorbid depression [I (M)]
(Krysinska and Lester, 2010). Post-traumatic stress disorder is
associated with increased use of health services, but is often not
recognised in primary or secondary care [I] (Liebschutz etal.,
2007). Diagnosis can be established through eliciting the history
of exposure to trauma (actual or threatened death, serious injury,
or threats to the physical integrity of the self or others); with a
response of intense fear, helplessness or horror; and the presence
of re-experiencing symptoms (such as intrusive recollections,
flashbacks or dreams); avoidance symptoms (such as efforts to
avoid activities or thoughts associated with the trauma); and
hyper-arousal symptoms (including disturbed sleep, hypervigi-
lance and an exaggerated startle response).
20.2. Prevention of post-traumatic disorder
after experiencing trauma
There is some scope for preventing the emergence of psychologi-
cal post-traumatic symptoms in people subject to major trauma.
Early administration of benzodiazepines after trauma may not
20 Journal of Psychopharmacology
prevent the emergence of post-traumatic symptoms [III] (Gelpin
etal., 1996). A small randomised placebo-controlled study found
that acute administration of propranolol (160 mg/day) was supe-
rior to placebo in reducing subsequent post-traumatic symptoms
and physiological hyper-activity to reminders of trauma, but not
the emergence of post-traumatic stress disorder, at one month [I
(PCT)] (Pitman etal., 2002). A naturalistic study suggests acute
administration of propranolol (120 mg/day) prevented the emer-
gence of syndromal post-traumatic stress disorder at two months
[III] (Vaiva etal., 2003): but not all evidence is consistent [I
(PCT)] (Nugent etal., 2010, Stein etal., 2007b). Intravenous
administration of hydrocortisone has been found superior to pla-
cebo in preventing post-traumatic symptoms, in intensive care
adult patients with septic shock (median interval, 31 months) [I
(PCT)] (Schelling etal., 2001), in patients undergoing cardiac
surgery (interval, six months) [I (PCT)] (Schelling etal., 2004),
and in patients experiencing acute stress reactions following a
range of traumatic experiences [I (PCT)] (Zohar etal., 2011). The
findings of small randomised placebo-controlled treatment stud-
ies find evidence for the efficacy for sertraline [I (PCT)]
(Stoddard etal., 2011), but not for gabapentin [I (PCT)] (Stein
etal., 2007b) or escitalopram [I (PCT)] (Shalev etal., 2012), in
preventing post-traumatic symptoms. The findings of systematic
reviews suggest that trauma-focused CBT is potentially benefi-
cial in preventing chronic post-traumatic symptoms, when pro-
vided within six months of the incident [I (M)] (Roberts etal.,
2009); but approaches with limited efficacy include single-ses-
sion debriefing [I (M)] (Van Emmerik etal., 2002) and multi-
ple-session early intervention [I (M)] (Roberts etal., 2009).
20.3. Acute treatment of post-traumatic
disorder
The findings of randomised placebo-controlled treatment studies
indicate that there is evidence for the efficacy of a range of anti-
depressants including some SSRIs (fluoxetine, paroxetine, ser-
traline), amitriptyline, imipramine, mirtazapine, nefazodone,
phenelzine and venlafaxine (Ipser and Stein, 2011). There is also
evidence for the efficacy of the antipsychotics risperidone
(Padala etal., 2006), olanzapine (Carey etal., 2012) and the anti-
convulsant topiramate; (Yeh etal., 2011). Medications which
have not been found efficacious in placebo-controlled trials
include citalopram, alprazolam, and the anticonvulsants tiagabine
and divalproex. However when 37 randomised placebo-con-
trolled trials are subject to meta-analysis (restricted to compari-
sons of outcome data using validated scales), only paroxetine,
sertraline and venlafaxine were found to have superiority over
placebo [I (M)] (Ipser and Stein, 2011). Probably due to the small
size of certain patient sub-groups (men vs women, civilians vs
military veterans) neither paroxetine nor sertraline have been
found consistently beneficial across all patient groups: though a
post hoc analysis suggests that venlafaxine is potentially effica-
cious in reducing post-traumatic symptom severity in men and
women, and across all trauma types [I (PCT)] (Rothbaum etal.,
2008a). There have been few controlled comparisons of the
effectiveness and acceptability of differing medications, though
venlafaxine was found superior to placebo, when sertraline was
not [I (PCT)] (Davidson etal., 2006b); reboxetine had similar
effectiveness but lower overall tolerability than fluvoxamine [II]
(Spivak etal., 2006); and mirtazapine had somewhat greater than
effectiveness than sertraline, in a randomised but open trial [II]
(Chung etal., 2004).
20.4. Longer term treatment
Although many patients with post-traumatic stress disorder expe-
rience a prolonged illness, there is some uncertainty about the
course of the condition, as most longitudinal studies in post-trau-
matic stress disorder are retrospective in design. Few prospective
studies have been published, although the findings of a prospec-
tive study in adolescents and young adults with post-traumatic
stress disorder or sub-threshold post-traumatic stress disorder
indicate that around 50% will experience a chronic course of ill-
ness [I] (Perkonigg etal., 2005). The findings of acute and con-
tinuation treatment studies indicate that the proportion of
responding patients increases steadily over time (Davidson etal.,
2006a; Ipser and Stein, 2011; Londborg etal., 2001). A small
number of randomised double-blind placebo-controlled relapse
prevention studies find evidence for the efficacy of longer-term
treatment, for fluoxetine [I (PCT)] (Martenyi etal., 2002) and
sertraline [I (PCT)] (Davidson etal., 2005), but not tiagabine [I
(PCT)] (Connor etal., 2006).
20.5. Comparative efficacy of
pharmacological, psychological and
combination treatments
Meta-analyses demonstrate that trauma-focused CBT and eye
movement desensitisation and reprocessing (EMDR) are both
efficacious and superior to stress management [I (M)] (Bisson
and Andrew, 2007), and appear to have similar overall efficacy [I
(M)] (Seidler and Wagner, 2006). There have been very few direct
comparisons of the efficacy of psychological and pharmacologi-
cal treatments, in either acute or long-term treatment of patients
with post-traumatic stress disorder. A small unblinded 12-week
comparison of paroxetine and trauma-focused CBT [III]
(Frommberger etal., 2004) suggested that CBT may have certain
advantages, in reducing the severity of post-traumatic and depres-
sive symptoms. A systematic review of four studies of the combi-
nation of pharmacological with psychological treatments could
find insufficient evidence to draw conclusions about the relative
efficacy of combination treatment compared to monotherapy [I
(M)] (Hetrick etal., 2010), although a more recent randomised
placebo-controlled trial found evidence that paroxetine could
enhance the effectiveness of prolonged (10 sessions) exposure
therapy [I (PCT)] (Schneier etal., 2012). The findings of two ran-
domised placebo-controlled studies of the potential augmenta-
tion of exposure therapy through administration of d-cycloserine
could find no evidence of increased efficacy [I (PCT)] (De
Kleine etal., 2012; Litz etal., 2012). The findings of two small
exploratory randomised placebo-controlled trials in patients
with treatment-resistant post-traumatic stress disorder suggest
that the short-term efficacy of psychological treatment may be
enhanced through concurrent administration of 3,4-methylene-
dioxymethamphetamine (MDMA) [I (PCT)] (Mithoefer etal.,
2011; Oehen etal., 2013): with some evidence of persisting
improvement at two-year follow-up [III] (Mithoefer etal., 2013).
Baldwin et al. 21
20.6. Further management after non-
response to initial treatment
Many patients with post-traumatic stress disorder do not respond
to initial pharmacological or psychological treatment. Switching
between treatments with proven efficacy may be beneficial [IV]
(National Institute for Clinical Excellence (NICE), 2005). The
findings of small randomised placebo-controlled augmentation
studies provide evidence for the efficacy of the alpha-adrenergic
agonist prazosin in reducing nightmares and other PSTD symp-
toms [I (PCT)] (Raskind etal., 2003), for olanzapine in reducing
post-traumatic and depressive symptoms and sleep disturbance [I
(PCT)] (Stein etal., 2002b) and risperidone in reducing comor-
bid psychotic symptoms [I (PCT)] (Hamner etal., 2003), in
reducing irritable aggression [I (PCT)] (Monnelly etal., 2003),
and in reducing overall post-traumatic symptoms [I (PCT)]
(Bartzokis etal., 2005; Rothbaum etal., 2008b). However a large
randomised placebo-controlled trial found no evidence of benefit
for risperidone augmentation of a range of pharmacological and
psychological treatments [I (PCT)] (Krystal etal., 2011).
Recommendations: managing patients with post-
traumatic stress disorder
Detection and diagnosis
Ask about a history of traumatic events when patients
present with psychological symptoms [S]
Become familiar with the symptoms and signs of post-
traumatic stress disorder [S]
Ask about the presence of coexisting depressive
symptoms [A]
Prevention of post-traumatic symptoms
After major trauma, discuss the potential for preventing
the emergence of post-traumatic symptoms, and provid-
ing there are no contra-indications, consider preventive
treatment with propranolol or sertraline [A] or trauma-
focused CBT [A]
Do not recommend routine single-session or multiple-
session debriefing [A]
Acute treatment of chronic post-traumatic stress disorder
Choose an evidence-based acute treatment [A]
pharmacological: paroxetine, sertraline, venlafaxine [A]
psychological: trauma-focused individual CBT or
EMDR [A]
Consider an SSRI for first-line pharmacological treat-
ment [A]
Take account of patient clinical features, needs and
preference and local service availability when choos-
ing treatment, as the comparative efficacy of drug and
psychological approaches is not established [S]
Advise the patient that treatment periods of up to 12
weeks may be needed to assess efficacy [A].
Longer-term treatment
Use an approach that is known to be efficacious in pre-
venting relapse [S]
Continue drug treatment for at least 12 months in
patients who have responded to treatment [A]
Monitor effectiveness and acceptability regularly over
the course of treatment [S]
Combination of drugs with psychological treatment
Routinely combining drug and psychological approaches
is not recommended for initial treatment in the absence
of consistent evidence for enhanced efficacy over each
treatment when given alone [A]: but paroxetine may
enhance the effectiveness of exposure therapy [A]
When initial treatments fail
Consider raising the dosage if the current dosage is
well tolerated [D]
Consider switching to another evidence-based treatment [D]
Consider combining evidence-based treatments only
when there are no contraindications [S]
Consider combining evidence-based pharmacological
and psychological treatments [A]
Consider augmentation of antidepressants with olan-
zapine [A] risperidone [A] or prazosin [A]
Consider referral to regional or national specialist ser-
vices in treatment refractory patients [S]
21. Management of obsessive-
compulsive disorder
21.1. Recognition and diagnosis
Obsessive-compulsive disorder has an estimated 12-month prev-
alence of 0.71.0% [I] (Kessler etal., 2012; Wittchen etal.,
2011), and an estimated lifetime morbid risk of 2.7% [I] (Kessler
etal., 2012). The female preponderance, early age of onset and
typical presence of coexisting obsessions and compulsions are
common features across societies, but the content of obsessions
varies between cultures [I (M)] (Fontenelle etal., 2004). The dis-
order usually follows a chronic course, waxing and waning in
severity; and has substantial co-morbidity with major depression
and anxiety disorders [IV] (Zaudig, 2011), and with tic disorders
[I] (Fibbe etal., 2012). Distinguishing obsessive-compulsive dis-
order from obsessive-compulsive personality disorder is diffi-
cult, and patients often fulfil diagnostic criteria for both
conditions: their comorbidity is associated with greater illness
severity [I] (Coles etal., 2008; Garyfallos etal., 2010; Lochner
etal., 2011). Patients often present with symptoms arising from
the co-morbid conditions, rather than with obsessional rumina-
tions and compulsive rituals [I] (Torres etal., 2007).
21.2. Acute treatment of obsessive-
compulsive disorder
The findings of systematic reviews and meta-analyses of ran-
domised double-blind placebo-controlled trials indicate that the
TCA antidepressant clomipramine, and the SSRIs (citalopram,
escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) [I
(M)] (Soomro etal., 2008) are all efficacious in acute treatment, in
reducing symptom severity and in improving health-related quality
22 Journal of Psychopharmacology
of life [IV] (Fineberg etal., 2012). Pharmacological approaches
are efficacious in treating children and adolescents with obsessive-
compulsive disorder [I (M)] (Watson and Rees, 2008).
There have been few evaluations of the relative efficacy and
tolerability of differing pharmacological treatments. The findings
of meta-analysis suggest that the efficacy of clomipramine is on
the margins of superiority over that of SSRIs [I (M)] (Ackerman
and Greenland, 2002; National Institute for Health and Clinical
Excellence, 2005) but in randomised controlled trials the tolerabil-
ity of SSRIs is generally superior [IV] (Fineberg and Gale, 2005).
The findings of a randomised comparator controlled trial suggest
that paroxetine and venlafaxine had comparable effectiveness and
acceptability [II] (Denys etal., 2003). Fixed-dose randomised con-
trolled studies provide inconsistent evidence for a dose-response
relationship with SSRIs, higher doses being associated with greater
overall efficacy in some but not all studies: however the findings of
meta-analysis of nine treatment studies involving SSRIs finds
some evidence for greater efficacy (though poorer tolerability)
with higher daily dosages [I (M)] (Bloch etal., 2010).
Meta-analyses of controlled studies involving psychologi-
cal treatment approaches find evidence for the efficacy of
behaviour therapy based on exposure with response prevention
alone, for cognitive restructuring alone, and for exposure with
response prevention plus cognitive restructuring [I (M)] (Rosa-
Alcazar etal., 2008). Internet-delivered CBT is superior to
online supportive therapy [I (PCT)] (Andersson etal., 2012),
though therapist-led CBT appears more effective than comput-
erised CBT [I (M)] (Tumur etal., 2007). The relative effective-
ness of individual and group CBT approaches is uncertain [I
(M)] (Jonsson and Hougaard, 2009). Psychological approaches
are efficacious in treating children and adolescents with obses-
sive-compulsive disorder [I (M)] (Watson and Rees, 2008).
21.3. Longer term treatment
The findings of acute treatment studies indicate that the proportion
of responding patients increases steadily over time. Long-term (up
to 12 months) double-blind randomised controlled studies demon-
strate an advantage for continuing with medication, in patients who
have responded to acute treatment [I (PCT)] (Greist etal., 1995;
Katz etal., 1990; Tollefson etal., 1994). A randomised placebo-
controlled trial with paroxetine as an active comparator found that
a low dosage of escitalopram only became efficacious in the sec-
ond half of a 24-week study [I (PCT)] (Stein etal., 2007a). Most
(but not all) placebo-controlled relapse-prevention studies in
patients who have responded to previous acute treatment reveal a
significant advantage for staying on active medication (escitalo-
pram, fluoxetine at higher daily doses, paroxetine, sertraline),
compared with switching to placebo, for up to 12 months [I (PCT)]
(Fineberg etal., 2007), but the optimal duration of continuation
treatment is uncertain [I (M)] (Donovan etal., 2010).
21.4. Comparative efficacy of
pharmacological, psychological and
combination treatments
It is probable, but not certain, that the combination of pharmaco-
logical and psychological treatment is superior to psychological
approaches or medication, when either is given alone. The evi-
dence for enhanced efficacy of exposure therapy with clomi-
pramine compared with exposure alone is inconsistent (Foa
etal., 2005; Marks etal., 1988; Rachman etal., 1979), though
fluvoxamine has been shown to enhance the efficacy of expo-
sure therapy [I (PCT)] (Cottraux etal., 1990) and multi-modal
CBT [I (PCT)] (Hohagen etal., 1998). The combination of expo-
sure and response prevention with varying SSRIs has been found
superior to SSRI treatment alone [II] (Simpson etal., 2008); the
addition of behaviour therapy after completion of acute treat-
ment was superior to continuing with SSRI treatment alone in
another study [II] (Tenneij etal., 2005); and the addition of CBT
(but not CBT instructions) to SSRI treatment was found superior
to medication management alone, in children and adolescents
[II] (Franklin etal., 2011). However the value of combination
treatment over psychological or pharmacological treatments
given alone over the long term is uncertain. A series of small
randomised placebo-controlled studies suggest that administra-
tion of d-cycloserine may hasten the response to CBT, but pro-
vide no evidence that the overall effectiveness of CBT is
enhanced [I (PCT)] (Kushner etal., 2007; Storch etal., 2010;
Wilhelm etal., 2008).
21.5. Further management after non-
response to initial treatment
Many patients do not respond to first-line pharmacological or
psychological interventions. Switching between pharmacologi-
cal or psychological treatments with proven efficacy is helpful in
some patients. Increasing the dose of an SSRI, sometimes beyond
formulary limits, may be beneficial (Ninan etal., 2006; Pampaloni
etal., 2010). A placebo-controlled study found that intravenous
clomipramine infusion was efficacious after non-response to oral
clomipramine, but the necessary arrangements limit its useful-
ness in practice [I (PCT)] (Fallon etal., 1998).
The findings of some, but not all, randomised double-blind
placebo-controlled augmentation studies indicate that the addi-
tion of the antipsychotics aripiprazole, haloperidol, olanzapine,
quetiapine or risperidone to continuing antidepressant treatment
can be efficacious in patients who have not responded to initial
treatment with clomipramine or SSRIs, the evidence currently
being most strong for augmentation with risperidone [I (M)]
(Dold etal., 2011). The findings of small randomised placebo-
controlled augmentation studies with 5-HT3 antagonists provide
evidence for the efficacy of the addition of ondansetron to fluox-
etine [I (PCT)] (Soltani etal., 2010) and for the addition of grani-
setron to fluvoxamine [I (PCT)] (Askari etal., 2012). Three
relatively small randomised placebo-controlled anticonvulsant
augmentation studies indicate that the addition of topiramate to
SSRIs reduces the severity of compulsions [I (PCT)] (Berlin
etal., 2011), and of obsessive-compulsive symptoms [I (PCT)]
(Mowla etal., 2010); and the addition of lamotrigine to SSRIs
reduces the severity of obsessive-compulsive and affective
symptoms [I (PCT)] (Bruno etal., 2012). The evidence for aug-
mentation with pindolol is mixed, but placebo-controlled or com-
parator-controlled augmentation studies find no evidence for the
efficacy of augmentation with buspirone, clonazepam, desipra-
mine, inositol, liothyronine, lithium, naltrexone or oxytocin [IV]
(Fineberg and Gale, 2005).
Baldwin et al. 23

The findings of a randomised comparator-controlled trial of

dextroamphetamine or caffeine augmentation of SSRI or SNRI When initial treatments fail
antidepressants suggest both compounds were beneficial in
Consider raising the dosage if the current dosage is
reducing symptom severity [II] (Koran etal., 2009). Other
well tolerated [A]
potential but as yet unproven approaches in the management of
Consider switching to another evidence-based treat-
patients with treatment-resistant obsessive-compulsive disorder
ment [D]
include monotherapy with once-weekly morphine [I (PCT)]
Consider combining evidence-based treatments only
(Koran etal., 2005); and the glutamate-modulating compounds
when there are no contraindications [S]
riluzole [III] (Coric etal., 2005; Pittenger etal., 2008), meman-
Consider combining evidence-based pharmacological
tine [III] (Stewart etal., 2010), and glycine [I (PCT)(Greenberg
and psychological treatments [A]
etal., 2009). Some patients with treatment-refractory obses-
Consider augmentation of an SSRI or clomipramine
sive-compulsive disorder may benefit from deep brain stimula-
with an antipsychotic drug [A]
tion and other neurosurgical approaches [IV] (Blomstedt etal.,
Consider augmentation of an SSRI or clomipramine
2012; De Koning etal., 2011; Greenberg etal., 2010).
with a 5-HT3 antagonist [A]
Consider augmentation of an SSRI with topiramate [A]
or lamotrigine [A]
Recommendations: managing patients with obsessive-
Consider augmentation of an SSRI with morphine [A]
compulsive disorder
Consider augmentation of an SSRI with riluzole [C]
Detection and diagnosis Consider referral to regional or national specialist
obsessive-compulsive disorder services in treatment
Become familiar with the symptoms and signs of refractory patients [S]
obsessive-compulsive disorder [S]
Assess the time engaged in obsessive-compulsive behav-
iour, the associated distress and impairment, and the
degree of attempted resistance to confirm the diagnosis [S] 22. Management of other anxiety
Ask about obsessive-compulsive symptoms when disorders
patients present with depression [S]
Ask about the presence of coexisting depressive symp- 22.1. Marked health anxiety (illness anxiety
toms [A] disorder)
Acute treatment The DSM-5 ((American Psychiatric Association, 2013) includes
illness anxiety disorder within the group of somatic symptom
Choose an evidence-based acute treatment [A]
and related disorders. The condition is characterised by excessive
pharmacological: clomipramine and all SSRIs [A]
concern over health, constant fear of undiagnosed disease that phy-
psychological: exposure therapy, cognitive-behav-
sicians may have missed, and the characteristic behaviours of
iour therapy, cognitive therapy [A]
repeated checking and need for medical reassurance.
Take account of patient clinical features, needs and
Pharmacological treatment is not normally acceptable to patients,
preference and local service availability when choos-
as those with marked health anxiety are typically very sensitive to
ing treatment [S]: drug and psychological approaches
adverse effects of medication: but fluoxetine showed some benefit
have broadly similar efficacy in acute treatment
over placebo, though this was not pronounced and occurred late in
Consider an SSRI for first-line pharmacological treat-
treatment (812 weeks [I (PCT)] (Fallon etal., 2008). Psychological
ment [D]
treatments have been found beneficial [I (M)] (Thomson and Page,
Consider increasing the daily dosage of SSRIs if there
2007), and include behavioural stress management (Clark etal.,
is insufficient response at lower dosage [A]
1998) ([II]), cognitive behaviour therapy, in both face-to-face and
Advise the patient that initial treatment periods beyond
internet format (Hedman etal., 2011b; Seivewright etal., 2008;
12 weeks may be needed to assess efficacy [A]
Srensen etal., 2011) ([II]), and mindfulness based CBT
Longer-term treatment (McManus etal., 2012) ([II]). A recent large randomised controlled
trial found efficacy for an adapted form of CBT in medical patients,
Use an approach that is known to be efficacious in pre-
in which significant benefits over standard care were still present
venting relapse [S]
two years after therapy had ended [II] (Tyrer etal., 2014).
Continue drug treatment for at least 12 months in
patients who have responded to treatment [A]
Monitor effectiveness and acceptability regularly over 22.2 Separation anxiety disorder in adults
the course of treatment [S]
Though traditionally regarded as having an onset in childhood,
Combination of drugs with psychological treatments separation anxiety disorder is now recognised as both continuing
Consider combining an SSRI or clomipramine with an into and having an onset during adult life: and as such is grouped
evidence-based psychological treatment when efficacy with other anxiety disorders within the DSM-5 (American
needs to be maximised [D] Psychiatric Association, 2013). The efficacy of psychological or
pharmacological treatment in adults with separation anxiety
24 Journal of Psychopharmacology
disorder has not been studied extensively, and treatment studies in
children have often involved mixed diagnostic groups [IV] (Bgels
etal., 2013). Psychological treatment studies in children find some
evidence of benefit with CBT, parent-child interaction training,
and summer camp programmes [IV] (Ehrenreich etal., 2008).
The findings of randomised placebo-controlled trials of pharmaco-
logical treatment in children with separation anxiety disorder pro-
vide no convincing evidence of benefit for any medication,
although fluvoxamine (Walkup etal., 2001) and sertraline have
been found efficacious among the separation anxiety disorder sub-
group within mixed diagnostic samples (Walkup etal., 2008).
Recommendations: treatment of children and
adolescents
Reserve pharmacological treatments for children and
teenagers who have not responded to psychological
interventions, and in whom the anticipated benefits are
expected to outweigh any potential risks [S]
Choose from the same range of treatments as considered
for adult patients, considering an SSRI for first-line
pharmacological treatment: fluoxetine may be the SSRI
with the best balance of potential benefit and risk [B]
Ensure that the daily dosage takes account of the age
and weight of the patient, and start with low dosage,
recognising that more rapid metabolism may lead to
the need for adult doses [S]
Monitor patients carefully, especially for any evidence
of increased anxiety and agitation, and remember that
many children and adolescents find it hard to describe
emotional states and possible psychological adverse
effects [D]
23. Special considerations in
particular patient groups
23.1. Children and adolescents
When compared with investigations in individuals aged between
1865 years, there have been relatively few randomised placebo-
controlled studies of the potential benefits and risks of psycho-
tropic drug treatment in younger people, and little is known about
the value of long-term treatment [I (M)] (Ipser etal., 2009). The
findings of randomised placebo-controlled trials in children and
adolescents indicate that SSRI treatment can be effective in chil-
dren and adolescents with generalised anxiety disorder, separa-
tion anxiety disorder or social anxiety disorder [I (M)] (Dieleman
and Ferdinand, 2008), and also in post-traumatic stress disorder
[IV] (Strawn etal., 2010), and obsessive-compulsive disorder
[IV] (Gentile, 2011). Psychological treatments also have evi-
dence of efficacy [I (M)] (Gillies etal., 2012; James etal., 2005;
Kircanski etal., 2011; Kowalik etal., 2011) but the relative effi-
cacy of pharmacological and psychological treatment approaches,
alone and in combination, is not established: although combina-
tion treatment was found optimal in obsessive-compulsive disor-
der (March etal., 2004).
In 2004, the United Kingdom Committee on Safety of
Medicines stated that the balance of risks and benefits for the
treatment of depressive illness in people under the age of 18 years
was judged to be unfavourable for some SSRIs (escitalopram, cit-
alopram, paroxetine and sertraline), mirtazapine and venlafaxine
[IV] (Committee on Safety of Medicines, 2004), and advised cau-
tion when treating depressed adults aged 1830 years with SSRIs.
A recent meta-analysis cautiously concluded that the balance of
benefit and risk in the treatment of depressed children and adoles-
cents may be most favourable with fluoxetine [I (M)] (Hetrick
etal., 2012).
The balance of risks of harm and benefit in the treatment of
children and adolescents with anxiety disorders, when compared
to the treatment of depression, is more favourable [IV] (Holtkamp
and Herpertz-Dahlmann, 2008). However careful monitoring is
advisable, due to possible diagnostic uncertainty, the presence of
co-morbid depression, problems associated with estimating the
optimal dosage, and the difficulties young people might have in
describing untoward effects of psychotropic drug treatment. It
may be preferable to reserve pharmacological treatments for
patients who do not respond to evidence-based psychological
approaches.
23.2. Elderly patients and patients with
cardiac or neurological disease
Many elderly patients are troubled by anxiety symptoms, but
anxiety disorders in those over 65 years may be less common
than in younger age groups [IV] (Wolitzky-Taylor etal., 2010).
When compared with investigations in individuals aged between
1865 years, there have been relatively few randomised con-
trolled studies of the potential benefits and risks of psychological
or pharmacological treatment for anxiety disorders in older peo-
ple [IV] (Oude Voshaar, 2013), and little is known about the rela-
tive effectiveness and acceptability of differing treatments, or
about the value of long-term treatment [I (M)] (Goncalves and
Byrne, 2012; Gould etal., 2012; Pinquart and Duberstein, 2007;
Thorp etal., 2009). Clearance of many drugs is slower in the
elderly, so lower doses may be required than in younger patients.
Tricyclic antidepressants and some antipsychotic drugs are
best avoided in patients with cardiac disease, as they can increase
heart rate, induce orthostatic hypotension, slow cardiac conduc-
tion and have significant quinidine-like effects on conduction
within the myocardium [IV] (Vieweg etal., 2009). Other type 1A
antiarrhythmics (quinidine, moricizine) carry an increased risk of
mortality in patients with ventricular arrhythmias and ischaemic
heart disease, and TCAs should be regarded as relatively contrain-
dicated in these situations. SSRIs have relatively minor effects on
cardiovascular function and may have potentially beneficial
effects on platelet aggregation (Bismuth-Evenzal etal., 2012;
Lopez-Vilchez etal., 2009). Higher doses (more than 40 mg per
day) of citalopram may be associated with a slightly increased risk
of QT interval prolongation on the electrocardiogram, and should
be avoided in patients with known cardiac risk factors including
hypokalaemia and hypomagnesaemia [IV] (US Food and Drug
Administration, 2012): though a recent large pharmacoepidemio-
logical study found no evidence of elevated risks of ventricular
arrhythmia or all-cause, cardiac or non-cardiac mortality associ-
ated with higher citalopram dosages [I] (Zivin etal., 2013).
Anxiety symptoms and disorders have an increased prevalence
in patients with common neurological conditions, including
migraine [IV] (Buse etal., 2012), epilepsy [IV] (Beyenburg etal.,
2005), and in the aftermath of stroke [I (M)] (Campbell Burton
Baldwin et al. 25
etal., 2012). SSRI and SNRI antidepressants should be used with
caution in patients with migraine undergoing prophylaxis with
triptans [IV] (Evans etal., 2010). Despite widespread belief that
antidepressant drugs can lower the seizure threshold, systematic
review of data from placebo-controlled trials with psychotropic
drugs, submitted to the United States Federal Drug Administration,
indicates that that the frequency of seizures is significantly lower
with most antidepressants than with placebo [I (M)] (Alper etal.,
2007). Pharmacokinetic interactions between medications used
for treating anxiety disorders and anticonvulsants are not uncom-
mon and it is always advisable to establish the potential for unto-
ward drug-drug interactions when treating epileptic patients with
anxiety disorders [IV] (Muscatello etal., 2012). SSRI treatment
may improve overall recovery after stroke [I (M)] (Mead etal.,
2012), but little is known about the potential efficacy of psycho-
logical or pharmacological interventions in the treatment of anxi-
ety disorders in the aftermath of stroke [I (M)] (Campbell Burton
etal., 2011).
Recommendations: treatment in elderly and physically
ill patients
Remember that anxiety symptoms and disorders are
common in elderly and physically ill patients, and that
many individuals will benefit from evidence-based
pharmacological or psychological treatments [S]
Manage elderly patients in a broadly similar way to
younger patients, being mindful of the possibility of
drug interactions, the potential need for lower doses in
patients with renal or hepatic impairment, and the risk of
worsening any pre-existing cognitive impairment
through the use of medications with sedative effects [S]
Avoid prescribing tricyclic antidepressants to patients
with cardiovascular disease [D]
23.3. Pregnant and breastfeeding women
Anxiety disorders are not uncommon during pregnancy and in
the post-partum period [I (M)] (Ross and McLean, 2006).
Symptoms will remit during pregnancy in some women [III]
(George etal., 1987). Many doctors consider the scope for with-
drawing psychotropic drugs in pregnant women (particularly in
the first trimester), and using psychological rather than pharma-
cological treatments, but in practice it is sometimes necessary to
continue pharmacological treatment, in patients with severe
anxiety disorders. The findings of a recent systematic review
indicate that antidepressant drugs are associated with increased
risk of spontaneous abortions, stillbirths, preterm deliveries, res-
piratory distress, endocrine and metabolic disturbance, with
some evidence of a discontinuation syndrome and of an increased
risk of cardiac defects; antipsychotics are associated with
increased gestational weight and diabetes and with increased
risk of preterm birth [I (M)] (Oyebode etal., 2012). However the
overall evidence on the balance of risks and benefits of psycho-
tropic drug treatment during pregnancy evolves over time and it
is wise to seek advice from respected information sources. The
BAP is producing guidance on the management of patients dur-
ing the perinatal period (McAllister-Williams etal., in
development).
Recommendations: women of child-bearing age
Remember that anxiety disorders are common among
women who wish to become pregnant [S]
Keep familiar with the changing evidence base about
the potential hazards of treatment of pregnant and
breast-feeding women with psychotropic drugs [S]
Consider carefully the anticipated benefits and risks of
pharmacological and psychological treatments of anxi-
ety disorders in pregnant women, including the poten-
tial relative and actual risks of harm to a developing
child [S]
23.4. Referral to secondary and tertiary care
mental health services
Despite the availability of many evidence-based pharmacologi-
cal and psychological treatments, a substantial proportion of
patients will not respond fully to initial treatments, provided in
primary medical care. The criteria for referral to secondary care
mental health services should be sufficiently flexible to ensure
that patients with disabling and treatment-resistant anxiety disor-
ders can have equitable access to mental health specialists.
Consensus between primary and secondary care about when
referral of patients with anxiety disorders is advisable should be
an explicit component of service commissioning procedures.
Potential criteria for referral to secondary care mental health ser-
vices include when the primary care practitioner feels insuffi-
ciently experienced to manage the patients condition; when two
or more attempts at treatment have not resulted in sustained
improvement; when there are severe coexisting depressive symp-
toms or a risk of suicide; when comorbid physical illness and
concomitantly prescribed treatments could interact with pre-
scribed psychotropic medication; and when proposed interven-
tions are not available within primary care services. Some
patients with complex, severe, enduring and treatment-resistant
anxiety disorders do not respond to the range of treatment options
delivered in secondary care mental health services, and these
patients should be referred to tertiary care specialist services for
patients with affective disorders.
Acknowledgements
The authors would like to thank Susan Chandler and Lynne Harmer of the
BAP office for organising the logistical aspects of the consensus meeting
and for their support during the subsequent consensus process. Secretarial
assistance for writing the consensus statement was provided by Magda
Nowak (University of Southampton)
The consensus group comprised Christer Allgulander, Ian Anderson,
Spilios Argyropoulos, David Baldwin, Borwin Bandelow, Alan Bateson,
David Christmas, Val Curran, Simon Davies, Hans den Boer, Lynne
Drummond, Rob Durham, Nicol Ferrier, Naomi Fineberg, Matt Garner,
Andrew Jones, Malcolm Lader, Alan Lenox-Smith, Glyn Lewis, Andrea
Malizia, Keith Matthews, Paul McCrone, Stuart Montgomery, Marcus
Munaf, David Nabarro, David Nutt, Catherine ONeill, Jan Scott, David
Taylor, Peter Tyrer, Nic van der Wee, Tom Watson, and Sue Wilson. The
patient organisations OCD Action and Anxiety UK were represented at the
meeting. Observers were also present from the Eli Lilly, Lundbeck, Pfizer
and Servier pharmaceutical companies.
26 Journal of Psychopharmacology
Conflict of interest
All participants were asked to provide information about potential con-
flict of interest at the time of the consensus meeting
Funding
This consensus statement received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
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 Journal of Anxiety Disorders 28 (2014) 537546

Contents lists available at ScienceDirect

Journal of Anxiety Disorders

Implicit associations in social anxiety disorder: The effects of

comorbid depression
Judy Wong a , Amanda S. Morrison a , Richard G. Heimberg a, ,
Philippe R. Goldin b , James J. Gross b
a
Adult Anxiety Clinic of Temple University, USA
b
Stanford University, USA

a r t i c l e i n f o a b s t r a c t

Article history: Implicit associations of the self to concepts like calm have been shown to be weaker in persons with
Received 31 August 2013 social anxiety than in non-anxious healthy controls. However, other implicit self associations, such as
Received in revised form 13 April 2014 those to acceptance or rejection, have been less studied in social anxiety, and none of this work has been
Accepted 19 May 2014
conducted with clinical samples. Furthermore, the importance of depression in these relationships has
Available online 14 June 2014
not been well investigated. We addressed these issues by administering two Implicit Association Tests
(IATs; Greenwald, McGhee, & Schwartz, 1998), one examining the implicit association of self/other to
Keywords:
anxiety/calmness and the other examining the association of self/other to rejection/acceptance, to indi-
Social anxiety disorder
Social phobia
viduals with generalized social anxiety disorder (SAD, n = 85), individuals with generalized SAD and a
Depression current or past diagnosis of major depressive disorder or current dysthymic disorder (n = 47), and non-
Implicit associations anxious, non-depressed healthy controls (n = 44). The SAD and SAD-depression groups showed weaker
Cognitive biases implicit self-calmness associations than healthy controls, with the comorbid group showing the weak-
est self-calmness associations. The SAD-depression group showed the weakest implicit self-acceptance
associations; no difference was found between non-depressed individuals with SAD and healthy controls.
Post hoc analyses revealed that differences appeared to be driven by those with current depression. The
SAD-only and SAD-depression groups did not differ in self-reported (explicit) social anxiety. The impli-
cations of these ndings for the understanding of SAD-depression comorbidity and for the treatment of
SAD are considered.
2014 Elsevier Ltd. All rights reserved.

1. Introduction to have a subsequent depressive disorder (Stein et al., 2001). In

Social anxiety disorder (SAD) and major depressive disorder
(MDD) are two of the most common mental disorders in the US
(Kessler, Chiu, Demler, Merikangas, & Walters, 2005), with 12-
month prevalence rates of 6.8% and 6.7%, respectively (Kessler,
Berglund, et al., 2005). SAD and MDD often occur together, and SAD
precedes MDD in approximately 70% of individuals with both dis-
orders (Kessler, Stang, Wittchen, Stein, & Walters, 1999; Schneier,
Johnson, Hornig, Liebowitz, & Weissman, 1992). In one study, indi-
viduals with SAD were at 3.5 times higher risk than those without
another study that followed adolescents into adulthood, the risk for
depression was 2-fold in individuals with SAD compared to those
without SAD and almost 3-fold compared to those with no anxiety
disorder (Beesdo et al., 2007). Increasing our knowledge of depres-
sion comorbidity among persons with SAD is important because
anxiety-depression comorbidity is associated with more chronic
distress, greater risk of relapse, and more impaired psychoso-
cial functioning than when the disorders present independently
(e.g., Brown, Schulberg, Madonia, Shear, & Houk, 1996; Lewinsohn,
Rohde, & Seeley, 1995; Reich et al., 1993; Ruscio et al., 2008). One
particular focus is understanding the role of information processing
biases in SAD with and without depression.

Portions of this paper were presented at the 2011 and 2012 meetings of the 1.1. Attentional biases in social anxiety disorder
Association for Behavioral and Cognitive Therapies.
Corresponding author at: Adult Anxiety Clinic, Department of Psychology, Weiss
Hall, Temple University, 1701 North 13th Street, Philadelphia, PA 19122-6085, USA.
Cognitive-behavioral models of SAD (e.g., Clark & Wells, 1995;
Tel.: +1 215 204 7489; fax: +1 215 204 5539. Heimberg, Brozovich, & Rapee, 2010; Hofmann, 2007; see Wong,
E-mail address: heimberg@temple.edu (R.G. Heimberg). Gordon, & Heimberg, 2014, for a review and comparison of

http://dx.doi.org/10.1016/j.janxdis.2014.05.008
0887-6185/ 2014 Elsevier Ltd. All rights reserved.
538 J. Wong et al. / Journal of Anxiety Disorders 28 (2014) 537546
cognitive-behavioral models of SAD) posit that dysfunctional infor-
mation processing contributes to the etiology and maintenance
of the disorder. In fact, a large body of research documents the
occurrence of one type of dysfunctional information processing,
attentional bias toward social threat stimuli, in SAD (for a review,
see Morrison & Heimberg, 2013; for a review of attentional bias
toward threat stimuli in the anxiety disorders more generally,
see Bar-Haim, Lamy, Pergamin, Bakermans-Kranenburg, & van
Ijzendoorn, 2007). However, limited research suggests that the
presence of depressive symptoms among individuals with social
anxiety/SAD may alter the nature of this response.
One study looked at the impact of depressive symptoms on
attentional bias among socially anxious individuals using an emo-
tional Stroop task (Grant & Beck, 2006). Socially anxious individuals
without depressive symptoms showed greater Stroop interference
for threat words relative to neutral and positive words. However,
the socially anxious-dysphoric group did not exhibit this bias. To
our knowledge, only two other studies have addressed this prob-
lem (LeMoult & Joormann, 2012; Musa, Lpine, Clark, Mansell, &
Ehlers, 2003). Both administered a dot-probe task to individuals
with SAD, SAD and a concurrent depressive disorder, and non-
patient controls. Musa et al. found results largely consistent with
Grant and Beck. Patients with SAD showed the expected bias (i.e.,
vigilance) toward social threat words. Patients with SAD and con-
current depression showed no such bias and appeared similar to
controls. In contrast to the 500 ms threat cue presentation dura-
tion employed by Musa et al., LeMoult and Joormann presented
threat cues for either 7 ms or 1000 ms. They found evidence of
attentional avoidance of angry faces in the depressed SAD group
compared to the non-depressed SAD group for the supraliminal
presentation. However, the meaning of these results is less than
clear, given that neither SAD group differed from controls on these
trials. In addition, no evidence of attentional bias, either vigilance
or avoidance, in either SAD group was detected for subliminally
presented angry face cues, nor for positive, sad, or disgust faces at
either presentation time.
Taken together, the pattern of results suggests that comorbid
depression may nullify, or at least dampen, attentional biases asso-
ciated with social anxiety at relatively brief exposures. When more
time is permitted for stimulus processing, biases may be observed
in the comorbid depression group, albeit in the opposite direction.
Indeed, Mathews and MacLoed (2005) have suggested that early
sensitivity to threat cues apparent in anxiety may by inhibited
in depression, in which biases toward mood-congruent informa-
tion are more commonly observed for stimuli that are presented
for longer durations, potentially due to slower, more strategi-
cally directed processes such as rumination. Therefore, it appears
prudent to consider whether concurrent depressive symptoms or
depressive disorder have similar effects on other automatic cogni-
tive biases in individuals with SAD.
1.2. Implicit associations and the Implicit Association Test (IAT)
Implicit associations are another important type of biased
cognitive processing that is receiving attention in research on
psychopathology. Implicit associations are thought to represent
stable memory constructs developed over time that contribute
to schemas about the self (Beevers, 2005; Haeffel et al., 2007).
The IAT, developed by Greenwald, McGhee, and Schwartz (1998),
examines implicit attitudes that someone holds regarding the rela-
tionship between a concept or category (e.g., owers) and an
attribute (e.g., goodness). The IAT has been widely used to exam-
ine attitudes regarding different racial groups, genders, and sexual
orientations (e.g., Devos & Banaji, 2005; Jellison, McConnell, &
Gabriel, 2004; Nosek, Banaji, & Greenwald, 2002). During the typi-
cal administration of the IAT, participants make a series of response
choices involving a concept discrimination (e.g., owers/insects)
and an attribute discrimination (e.g., good/bad). Participants are
instructed to respond rapidly with a right key press to items rep-
resenting one concept and one attribute (e.g., owers and good)
and with a left key press to items from the remaining two cate-
gories (e.g., insects and bad). Participants then complete a second
task in which key assignments for one of the pairs is switched.
IAT response latencies are interpreted in terms of relative associa-
tion strengths.1 It is assumed that responses are more rapid when
the concept and attribute mapped onto the same key are strongly
associated, whereas responses are assumed to be relatively slower
when the concept and attribute mapped on the same key are less
closely associated.
The use of implicit measures, such as the IAT, may be particularly
relevant with socially anxious individuals. Given that individuals
with SAD experience heightened self-presentational concerns and
fears of others evaluation, explicit self-report may yield an inaccu-
rate or incomplete picture of their experiences. For example, it is
a well-replicated phenomenon that persons with SAD report that
they perform more poorly on behavioral tests than do other infor-
mants (e.g., Rapee & Lim, 1992; Rodebaugh, Heimberg, Schultz, &
Blackmore, 2010; Rodebaugh & Rapee, 2005; Stopa & Clark, 1993).
Implicit measures like the IAT may minimize perhaps even cir-
cumvent self-presentational biases and effects.
1.3. Implicit associations in social anxiety and depression
Several studies have used the IAT to study implicit associations
in socially anxious individuals. de Jong (2002) administered the
IAT to female undergraduates high and low in social anxiety, using
concept categories of self (e.g., I, self) and other (e.g., their, them)
and attribute categories of low-esteem (e.g., bad, stupid) and high-
esteem (e.g., smart, valuable). Both high and low socially anxious
groups performed faster categorizing self with high-esteem words
than the reverse category pairings, although a signicant inter-
action effect suggested that this pattern was stronger in the low
socially anxious group. Similarly, another study found that high
social anxiety participants did not exhibit negative implicit self-
esteem; they responded more quickly to self-positive pairings than
to self-negative pairings (Tanner, Stopa, & De Houwer, 2006). How-
ever, they did respond more slowly to self-positive pairings than
those low in social anxiety. Notably, depressive symptoms did not
impact IAT performance.
Some researchers have also examined responses to an IAT in
which self or other is paired with rejection or acceptance, an area
of clear concern to persons with social anxiety. A self-rejection
IAT was used by Teachman and Allen (2007) in their study of
perceived peer acceptance/rejection and its relationship to implicit
and explicit fear of negative evaluation in adolescents. Adoles-
cents more easily associated the self with acceptance than with
rejection. Clerkin and Teachman (2010) examined the responses
to the same IAT of socially anxious undergraduates to whom they
provided training to modify implicit associations. Because all par-
ticipants were socially anxious, it was not possible to compare
their responses to those of a non-anxious sample, but similar to
the adolescent sample of Teachman and Allen (2007), they more
easily associated the self with acceptance than rejection. However,
trained participants demonstrated strengthened self-acceptance
1
As noted by Pinter and Greenwald (2005), it is important to keep in mind that
the standard interpretation of any IAT measure involves relative strengths of asso-
ciations of the two contrasted concept categories with the two contrasted attribute
categories (p. 75, italics added). Throughout this paper, we will refer to IAT results
using simplied descriptors (e.g., owers-good) to increase readability. However,
results are always referring to the relative strength of associations (e.g., owers-
good/insects-bad).
 J. Wong et al. / Journal of Anxiety Disorders 28 (2014) 537546
associations and were more likely to complete an impromptu
speech than students who had not received the implicit association
training.
Few studies of implicit attitudes in social anxiety have exam-
ined clinical samples. Gamer, Schmukle, Luka-Krausgrill, and
Egloff (2008) took a step in this direction when they recruited
socially anxious students who completed four weeks of cognitive-
behavioral group therapy at a university counseling center and
were administered the IAT before and after treatment. Their
responses were compared to non-anxious students who received
no treatment. Participants were asked to categorize self-other
words and anxiety-calmness words. Consistent with previous nd-
ings, socially anxious participants and non-anxious controls were
faster in the self-calm pairings than in the self-anxiety pairings on
both IAT administrations. However, socially anxious participants
had weaker self-calm implicit associations than non-anxious con-
trols at baseline. In addition, self-calm implicit associations had
strengthened following treatment, as socially anxious participants
no longer differed from controls.
To date, only one study has used the IAT to examine comor-
bid anxiety and depression in a diagnosed sample. Glashouwer
and de Jong (2010) compared implicit beliefs in a mixed anxi-
ety disorder group, those with a current diagnosis of MDD, those
with an anxiety disorder and comorbid MDD, and a healthy con-
trol group. Participants were part of the Netherlands Study of
Depression and Anxiety (Penninx et al., 2008). An IAT measured
implicit self-anxiety associations. As with previous IAT studies, all
groups exhibited faster reaction times on self-calm trials than on
self-anxiety trials. The anxious group showed weaker self-calm
associations than the depressed and control groups. The authors
made no hypotheses regarding the effect of comorbidity on IAT
scores, but the comorbid group had the weakest self-calm associ-
ations, although not signicantly different from the anxious group
(after Bonferroni correction).
Implicit associations have also been studied in relation to
depression. For example, in the study by Glashouwer and de Jong
(2010), an IAT was also administered in which self versus other
words were paired with words representing depression or ela-
tion. Although depressed participants exhibited faster reaction
times on self-elation trials than on self-depression trials, they
also demonstrated weaker self-elation associations than the anxi-
ety and control groups. Several additional studies have examined
the implicit associations of persons at cognitive risk for depres-
sion (e.g., Haeffel et al., 2007; Steinberg, Karpinski, & Alloy, 2007)
or previously depressed persons in reaction to a negative mood
induction (e.g., Gemar, Segal, Sagrati, & Kennedy, 2001; Meites,
Deveney, Steele, Holmes, & Pizzagalli, 2008). A full review of this
literature is beyond the scope of this paper, but see a meta-
analysis of implicit cognition in depression by Phillips, Hine, and
Thorsteinsson (2010). The general conclusion to be drawn from
these studies is that the implicit associations of self to positive
attributes of depressed/formerly depressed/at-risk-for-depression
persons are weaker than those of non-depressed persons. This is
important to the current research because it supports the idea that
comorbid depression may confer additional risk for cognitive bias
in socially anxious persons, unlike the somewhat mixed ndings
for attentional bias toward social threat.
1.4. Present study
Research has demonstrated the utility of the IAT and pro-
vided the groundwork for understanding implicit associations in
SAD. However, little is known about implicit associations in those
with SAD and comorbid depression. Furthermore, no studies have
examined implicit attitudes in a sample of clinically diagnosed,
treatment-seeking individuals with SAD and depression. Of the
539
studies reviewed above, the majority have been conducted with
analog samples, and only two have examined the impact of depres-
sive symptoms. Tanner et al. (2006) found no effect of depression
on the implicit associations of socially anxious persons. Glashouwer
and de Jong (2010) examined a mixed anxiety group and did not
focus specically on SAD. Given the high comorbidity of SAD and
MDD, and the impairment associated with this comorbidity, it is
crucial that we increase our understanding of the associated cog-
nitive processes so that we can expand our theoretical models and
enhance our treatment approaches.
One step toward this, and a goal of the current study, was to
examine implicit associations among treatment-seeking patients
with SAD and comorbid depression (i.e., MDD or dysthymia), com-
pared to patients with SAD but no history of depression, and to
healthy controls. We used two IATs, one measuring associations of
self/other with anxiety/calmness and the other measuring associ-
ations of self/other with rejection/acceptance.
Based on results from previous studies, we hypothesized that
individuals with SAD would exhibit weaker self-calm associations
than healthy controls. We also hypothesized that the comorbid
group would exhibit weaker self-calm associations than healthy
controls. Studies on implicit associations in depression suggest that
the comorbid group might have even weaker self-calm associations
than the SAD group, but the empirical support for this hypothesis
is not strong.
The self-rejection IAT used here was similar to the one used by
Clerkin and Teachman (2010) and Teachman and Allen (2007) and
has yet to be studied in a clinical sample of persons with SAD. Our
interest in this IAT comes in part from the literature on interper-
sonal rejection sensitivity (e.g., Downey & Feldman, 1996; Leary,
2006). Those with high levels of interpersonal rejection sensitiv-
ity are thought to have high expectations for rejection by others
and to place high value on being accepted (Downey & Feldman,
1996). Rejection sensitivity has been primarily studied as a risk
factor for depression (e.g., Ayduk, Downey, & Kim, 2001; Boyce &
Parker, 1989), but it may be an underlying personality trait in those
with social anxiety as well (Harb, Heimberg, Fresco, Schneier, &
Liebowitz, 2002). We sought to explore how a clinical sample would
perform on the self-rejection IAT, and whether there would be dif-
ferences between the SAD and SAD-depression groups, given the
potential importance of rejection sensitivity in both social anxiety
and depression.
2. Method
2.1. Participants
Participants were 136 individuals with a primary diagnosis
of generalized SAD and 44 healthy controls (HC group). Among
those with SAD, 47 individuals had a current or past diagnosis of
major depressive disorder (MDD) or current dysthymic disorder
(SAD + Dep group), and 85 individuals had no current or past diag-
nosis of depression (SAD group). Four individuals with SAD who
met criteria for a diagnosis of past dysthymic disorder were not
included in the current study due to poor inter-rater reliability on
the diagnostic measure (see Section 2.2). All participants with SAD
were enrolled in one of two randomized controlled trials for the
treatment of SAD. In one trial, participants (n = 74) were randomly
allocated to receive individually administered cognitive-behavioral
therapy (CBT) for SAD or to a waitlist control condition (see Goldin
et al., 2012). In the other trial, participants (n = 62) were randomly
assigned to complete either mindfulness-based stress reduction
(MBSR) or to an active comparison condition of aerobic exercise
(see Jazaieri, Goldin, Werner, Ziv, & Gross, 2012). Measures included
in the present analyses were administered prior to randomization.
540 J. Wong et al. / Journal of Anxiety Disorders 28 (2014) 537546
Participants were included in the treatment studies if they met
criteria for a principal diagnosis of generalized SAD according to the
Anxiety Disorders Interview Schedule for DSM-IV, Lifetime version
(ADIS-IV-L; Di Nardo, Brown, & Barlow, 1994; see below). Addi-
tional diagnoses, including MDD and dysthymia, were also assessed
with the ADIS-IV-L. Participants were excluded for current phar-
macotherapy or psychotherapy; history of medical disorders or
head trauma; and current psychiatric disorders other than gen-
eralized anxiety disorder, obsessive compulsive disorder (OCD),
agoraphobia without a history of panic attacks, specic phobia,
MDD, or dysthymic disorder. In Goldin et al. (2012), participants
were also excluded for current MDD or OCD, as well as previous
CBT treatment. In Jazaieri et al. (2012), participants were excluded
for previous completion of an MBSR course or regular meditation
practice or exercise regimen. With regard to depression diagnoses
in the SAD + Dep group, most met diagnostic criteria for past MDD
only (57.4%), current MDD only (21.3%), current MDD and current
dysthymia (10.6%), current dysthymia only (8.5%), or past MDD and
current dysthymia (2.1%).
HC participants had no history of any psychiatric problems
assessed by the ADIS-IV-L and were selected to match participants
with SAD in the Goldin et al. (2012) study in terms of sex, race, age,
and years of education. Participants were recruited via community
bulletin boards web-based community listings, and referrals from
mental health clinics and providers.
2.2. Materials
2.2.1. Anxiety Disorders Interview Schedule for DSM-IV, Lifetime
Version (ADIS-IV-L)
The ADIS-IV-L (Di Nardo et al., 1994) is a widely used, semi-
structured diagnostic interview that assesses current and past
episodes of anxiety and related disorders. For each diagnosis, the
interviewer provides a Clinicians Severity Rating (CSR), which is
a 9-point, Likert-type rating that ranges from 0 to 8; scores of 4
or greater indicate that the patient has met criteria for a DSM-
IV diagnosis. In a reliability study of a mixed diagnostic group,
the ADIS-IV-L indicated good to excellent inter-rater agreement
for current disorders (range of s = .67.86) and lifetime disorders
(range of s = .58.83), except dysthymia (e.g.,  = .36 as a lifetime
diagnosis; Brown, Di Nardo, Lehman, & Campbell, 2001). All indi-
viduals administering the ADIS-IV-L had satised training criteria
outlined by Brown et al. (2001) and were experienced clinicians
with at least masters-level training in clinical psychology.
2.2.2. Brief Fear of Negative Evaluation Scale (BFNE)
The BFNE (Leary, 1983) is a 12-item self-report measure that was
designed to assess the degree to which people experience appre-
hension at the prospect of being evaluated negatively. Participants
rate each item using a ve-point, Likert scale from 1 (Not at all char-
acteristic of me) to 5 (Extremely characteristic of me). Sample items
include I am afraid that people will nd fault with me and Some-
times I think I am too concerned with what other people think of
me. Research suggests that the reverse-scored items have inferior
validity and that only the eight straightforwardly worded items
be used (BFNE-S; Rodebaugh et al., 2004; Weeks et al., 2005). The
BFNE-S demonstrated excellent internal consistency in a sample
of patients with SAD ( = .92) and in a nonanxious control sample
( = .90; Weeks et al., 2005). The BFNE-S demonstrated adequate
internal consistency in all three of our groups (HC: = .92; SAD:
= .92; SAD + Dep: = .77).
2.2.3. Social Interaction Anxiety Scale (SIAS)
The SIAS (Mattick & Clarke, 1998) is a 20-item self-report scale
designed to measure fears of social interactions. Participants are
asked to rate each item using a Likert scale from 0 (not at all
characteristic or true of me) to 4 (extremely characteristic or true of
me). Sample items include I feel tense if I am alone with just one
person and I nd it difcult to disagree with anothers point of
view. The SIAS has been widely used in the assessment of social
anxiety and has shown good reliability and validity in a number
of studies (e.g., Brown et al., 1997; Mattick & Clarke, 1998; Safren,
Turk, & Heimberg, 1998). Rodebaugh, Woods, and Heimberg
(2007) have reported that the straightforward items of the SIAS
are more valid indicators of social interaction anxiety than the
reverse-scored items, which appear to be more strongly related to
the construct of extraversion, and therefore suggest utilizing only
the 17 straightforward items (SIAS-S) to calculate the total score.
In the current sample, internal consistency of the SIAS-S was good
in all three groups (HC: = .90; SAD: = .88; SAD + Dep: = .88).
2.2.4. Beck Depression Inventory II (BDI-II)
The BDI-II (Beck, Steer, Ball, & Ranieri, 1996; Beck, Steer, &
Brown, 1996) is a 21-item self-report instrument which assesses
the existence and severity of depressive symptoms. Participants
rate the severity of each symptom, such as sadness and loss of inter-
est, over the past two weeks on a 03 scale, with higher scores
indicating greater severity. The BDI-II has been used extensively
and has demonstrated good internal consistency in outpatient and
undergraduate populations (e.g., Beck, Steer, Ball, et al., 1996; Beck,
Steer, & Brown, 1996; Storch, Roberti, & Roth, 2004), as it did in
the three groups in the current sample (HC: = .73; SAD: = .91;
SAD + Dep: = .91).
2.2.5. Implicit Association Test
Participants completed two IATs administered via computer. In
both IATs, the concept discrimination was between self and other.
In one IAT, the attribute discrimination was between anxiety and
calmness, and in the other IAT, it was between acceptance and
rejection. Stimuli from the self category were I, own, my, me, and
self. Stimuli from the other category included them, others, you,
your, and they. Items from the anxiety category included afraid,
anxious, uncertain, nervous, and fearful, and items from the calm-
ness category included calm, restful, balanced, relaxed, and at ease.
Items representing the acceptance category were loved, welcomed,
admired, included, and respected, and items representing the rejec-
tion category included forgotten, alienated, deserted, shunned, and
disliked.
The IAT procedure was modeled after Egloff and Schmukles
(2002) IAT-Anxiety. Within each IAT, there were ve blocks of
trials. In the rst block, participants completed 20 practice tri-
als categorizing the concept discrimination (i.e., self/other). In the
second block, an additional 20 practice trials were completed for
categorizing the attribute stimuli. The fourth block was also a
practice block of 20 trials for categorizing self/other items with the
key assignment switched. The third and fth blocks were each com-
prised of 40 critical trials in which participants categorized items
into two combined categories. In the third block, items for self and
the positive attribute were to be categorized on the left and in the
fth block items for self and the negative attribute were to be cat-
egorized on the right. We chose not to counterbalance the order
of the pairings to remain consistent with the procedure of Egloff
and Schmukle (2002). They argue that the advantages of this type
of procedure may outweigh the disadvantages. Specically, they
suggest that, although we cannot interpret the IAT score in abso-
lute terms, this type of consistent ordering optimizes comparison
between participants and thus generates an ordering according to
the (relative) size of the IAT effect (p. 1443).
Participants were instructed that they would be asked to make
a series of category judgments. On each trial, a stimulus word was
presented in the center of the screen and category labels presented
in the upper left and right sides of the screen. Participants were
 J. Wong et al. / Journal of Anxiety Disorders 28 (2014) 537546
Table 1
Demographic information and self-report measures by diagnostic group.
Variable SAD
% female 52.9
% Caucasian 45.9
Age (SD) 33.8 (9.1)
Years education (SD) 16.9 (2.1)
BFNE-S (SD) 31.5 (5.6)
SIAS-S (SD) 46.5 (9.8)
BDI-II (SD) 11.4 (9.0)
Note. SAD social anxiety disorder; SAD + Dep SAD with current or past depression; % Caucasian proportion of individuals who self-identied as Caucasian versus non-
Caucasian; BFNE-S Brief Fear of Negative Evaluation Scale, straightforward item total; SIAS-S Social Interaction Anxiety Scale, straightforward item total; BDI-II Beck
Depression Inventory II.
*
p < .05.
**
p < .001.
instructed to use the Q key on the left side of the keyboard and
the P key on the right side of the keyboard for their responses. They
were told to keep their index ngers on the Q and P keys throughout
the task and to respond as quickly and accurately as possible. They
were also told that if they made an error they would see a red X
and that the task would continue. Each of the IATs exhibited excel-
lent reliability overall and within each group (anxiety/calmness
IAT: overall = .94, SAD + Dep = .94, SAD = .94, HC = .94; accep-
tance/rejection IAT: overall = .95, SAD + Dep = .96, SAD = .95,
HC = .95).
2.3. Procedure
Participants rst provided written informed consent. Diag-
nostic status was determined with the ADIS-IV-L. Participants
also completed a demographics questionnaire and the BDI-II at
this appointment. After leaving the laboratory, participants were
emailed a link to complete an online battery of self-report question-
naires, which included the social anxiety questionnaires reported
in the current study. At a later appointment, participants completed
the two versions of the IAT. Participants always completed the anx-
iety/calmness IAT prior to the acceptance/rejection IAT. The order
of the tasks was kept consistent across participants for the same
reason explained above regarding ordering of key assignments.
3. Results
3.1. Participant characteristics
See Table 1 for descriptive statistics and omnibus tests compar-
ing the three groups. Groups did not differ on age or sex; however,
there were signicant differences among the groups with regard to
years of education completed and ethnicity (i.e., Caucasian versus
non-Caucasian). Follow-up t-tests revealed the SAD + Dep group
reported fewer years of education than the HC group, t(81) = 2.60,
p = .01. The SAD group did not differ in years of education from
either of the other two groups, ps > .06. The omnibus chi-square
test for ethnicity approached signicance (p = .06), so we completed
follow-up tests, which revealed a greater proportion of Caucasian
than non-Caucasian individuals in the SAD + Dep group than the HC
group, 2 = 4.79, p = .04. The SAD group did not differ on ethnicity
compared with either the SAD + Dep group, 2 = 3.91, p = .07, or the
HC group, 2 = 0.29, p = .71.
With regard to symptom measures, omnibus tests were all sig-
nicant (see Table 1). In follow-up tests, the HC group reported
signicantly lower social anxiety and depression than both the
SAD group [BFNE-S: t(114) = 17.14, p < .001, SIAS-S: t(115) = 17.30,
p < .001; BDI-II: t(122) = 7.22, p < .001] and the SAD + Dep group
[BFNE-S: t(83) = 20.76, p < .001; SIAS-S: t(82) = 17.92, p < .001; BDI-
II: t(87) = 11.11, p < .001]. As expected, the SAD + Dep group
541
SAD + Dep Healthy controls Test statistic
40.4 54.5 2 = 2.4
63.8 40.9 2 = 5.6
32.7 (7.5) 33.5 (9.8) F = 0.2
16.2 (2.1) 17.3 (2.0) F = 3.4*
32.5 (3.8) 13.6 (4.6) F = 204.1**
48.6 (9.4) 16.4 (6.5) F = 173.9**
19.4 (10.4) 1.2 (1.8) F = 52.4**
endorsed greater depression than the SAD group [BDI-II:
t(127) = 4.57, p < .001]; however, they did not differ in self-reported
social anxiety [BFNE-S: t(121) = 1.10, p = .27; SIAS-S: t(121) = 1.12,
p = .26].
3.2. IAT data scoring and reduction
Response latencies from the IAT were scored according to the
algorithm developed by Greenwald, Nosek, and Banaji (2003).
Specically, trials with response latencies greater than 10,000 ms
were rst deleted. Participants for whom more than 10% of tri-
als had latencies less than 300 ms would then have been deleted,
but there were no such individuals in the sample. Then, each
error latency was replaced with an error penalty computed as the
mean latency of correct responses for that block + 600 ms. These
error penalty latencies were used from this point forward. Next,
inclusive standard deviations for all trials in the critical blocks
(i.e., blocks 3 and 5) were calculated. Then the mean latency for
responses in each of the critical blocks was calculated. A D score for
each IAT was calculated by subtracting the mean latency for self-
anxiety and self-rejection associations from the mean latency for
self-calmness and self-acceptance associations, respectively, and
then dividing this difference by the appropriate inclusive standard
deviation. This method of calculating a D score helps to account
for overall response latency as well as improve the psychomet-
ric properties of the IAT (Lane, Banaji, Nosek, & Greenwald, 2007).
Greater IAT scores indicate greater self-calmness or self-acceptance
associations.
3.3. IAT results
Within-group bivariate correlations between the two IATs and
between each of the IATs and self-reports of social anxiety (SIAS-S)
and depression (BDI-II) are shown in Table 2. The IAT scores cor-
related with each other within the SAD group and within the HC
group, but not within the SAD + Dep group (p = .06). Only three cor-
relations between IAT scores and self-report measures emerged as
signicant. In the SAD + Dep group, both IAT scores correlated with
depression, with greater self-calmness and greater self-acceptance
scores associated with lower depression. In the SAD group, greater
self-calmness associations were associated with lower social anxi-
ety.
See Fig. 1 for mean IAT scores for each task by group. Because
there was a signicant difference among the groups for years of
education and a near signicant difference in ethnicity (i.e., Cau-
casian versus non-Caucasian), we rst examined whether these
demographic characteristics were related to implicit associations
on either IAT, which would dictate whether they be included as
covariates in the IAT data analyses. Bivariate correlations revealed
that years of education was not signicantly related to either anx-
iety/calmness IAT scores, r = .09, p = .24, or acceptance/rejection
542 J. Wong et al. / Journal of Anxiety Disorders 28 (2014) 537546

Table 2 3.4. Post hoc analyses

Bivariate correlations of the IATs by diagnostic group.

Anxiety/Calmness Acceptance/Rejection Given that approximately half of the SAD + Dep group comprised
Implicit Association Test Implicit Association Test individuals with remitted depression (n = 27), we explored whether
Social anxiety disorder (SAD) the above results differed if the SAD + Dep group was split into its
A/R IAT .44*** two subgroups (i.e., SAD + Current Dep, SAD + Past Dep). A one-way
SIAS-S .25* .15 ANOVA comparing the four groups implicit self-calmness associ-
BDI-II .20 .07
ations was signicant, F(3, 172) = 5.43, p < .01, 2 = .09. Follow-up
Social anxiety disorder + Depression (SAD + DEP) t-tests were largely consistent with the previous analysis, in that
A/R IAT .28
both of the SAD + Dep groups exhibited weaker self-calmness asso-
SIAS-S .02 .23
BDI-II .45** .35*
ciations than the HC group, ps < .05. In addition, the two SAD + Dep
groups did not differ from one another, t(45) = 1.19, p = .24, Cohens
Healthy control (HC)
d = 0.35. However, whereas the SAD + Current Dep group continued
A/R IAT .66***
SIAS-S .04 .20 to exhibit weaker self-calmness associations than the SAD group,
BDI-II .19 .26 t(103) = 2.69, p < .01, Cohens d = 0.53, the SAD + Past Dep group did
Note. SIAS-S Social Interaction Anxiety Scale, straightforward item total; BDI-II
not differ from the SAD group, t(110) = 1.23, p = .22, Cohens d = 0.23.
Beck Depression Inventory II. Because of the use of listwise deletion, the sample This nal comparison suggests the previously observed differences
sizes differ from those reported for the primary analyses (SAD = 69, SAD + Dep = 44, between the SAD and SAD + Dep groups in self-calmness associa-
HC = 32). tions may be driven by those with current depression.
*
p < .05.
**
With regard to the acceptance/rejection IAT, the omnibus
p < .01.
***
p < .001.
ANOVA was again signicant, F(3, 172) = 3.70, p = .01, 2 = .06.
Follow-up t-tests revealed signicant divergences from previous
analyses. Here, the SAD + Current Dep group exhibited weaker self-
acceptance associations than the other three groups [compared
IAT scores, r = .11, p = .18, nor was ethnicity related to either anx-
to the SAD + Past Dep group: t(45) = 2.76, p < .01, Cohens d = 0.82;
iety/calmness IAT scores, r = .03, p = .74, or acceptance/rejection
compared to the SAD group, t(103) = 2.69, p < .01, Cohens d = 0.53;
IAT scores, r = .11, p = .16. Therefore, analyses did not control for
compared to the HC group, t(62) = 3.73, p < .01, Cohens d = 0.95].
either years of education or ethnicity. Likewise, we did not control
In contrast, the SAD + Past Dep group did not differ from the SAD
for self-reported social anxiety given that the two SAD groups did
group, t(110) = 0.30, p = .77, Cohens d = 0.06, or from the HC group,
not differ on either social anxiety self-report measure.
t(69) = 1.10, p = .28, Cohens d = 0.26. Given that the two SAD + Dep
A one-way analysis of variance (ANOVA) comparing the three
groups and the SAD group did not differ from one another on self-
groups on implicit self-calmness associations was signicant, F(2,
reported social anxiety as assessed with the SIAS-S, ps > .30, these
173) = 7.30, p < .01, 2 = 0.08. Follow-up t-tests revealed that the
results clearly suggest that current depression is driving the differ-
SAD + Dep group had the weakest self-calmness associations [com-
ence in self-acceptance associations observed previously.
pared to the HC group: t(89) = 3.76, p < .001, Cohens d = 0.80;
compared to the SAD group: t(130) = 2.37, p = .02, Cohens d = 0.44].
The SAD group also exhibited weaker self-calmness associations 4. Discussion
than the HC group, t(127) = 1.99, p < .05, Cohens d = 0.36.
Results for the acceptance/rejection IAT were similar but not The current study was the rst to examine implicit associations
identical. A one-way ANOVA comparing the three groups implicit of the self in a clinical, treatment-seeking sample of individuals
self-acceptance associations was signicant, F(2, 173) = 3.13, p < .05, with generalized SAD with and without comorbid depression. In
2 = 0.04. Levenes test for equality of variances was signi- line with hypotheses, a diagnosis of SAD was associated with the
cant, so reported follow-up t-tests were based on the test that strength of the anxiety-calmness IAT effect. Individuals with SAD
did not assume equal variances. Such t-tests revealed that the exhibited weaker self-calmness associations than non-anxious,
SAD + Dep group exhibited weaker self-acceptance associations non-depressed healthy controls. In addition, those with SAD and
than the HC group, t(86.54) = 2.75, p < .01, Cohens d = 0.59, and comorbid depression showed the weakest self-calmness associa-
the SAD group, t(118.52) = 1.98, p = .05, Cohens d = 0.35. The SAD tions compared to both individuals with SAD without a history of
group and HC group did not differ on self-acceptance associations, depression and healthy controls. When we looked more speci-
t(102.48) = 0.91, p = .36, Cohens d = 0.17. cally at the depression subgroups in post hoc analyses, both the

0.8
Self-Calmness/Acceptance IAT Scores

0.7

0.6

0.5

0.4 SAD

0.3 SAD+Dep

0.2 Healthy Controls

0.1

0
Calmness/Anxiety Acceptance/Rejecon
IAT

Fig. 1. Scores on two Implicit Association Tests (IATs) for individuals with social anxiety disorder (SAD), social anxiety disorder and a current and/or past diagnosis of
depression (SAD + Dep), and healthy controls (error bars are standard errors).
 J. Wong et al. / Journal of Anxiety Disorders 28 (2014) 537546
SAD-past depression and SAD-current depression groups showed
weaker self-calmness associations than the healthy controls. How-
ever, whereas the SAD-current depression group showed weaker
self-calmness associations than the SAD-only group, the SAD-past
depression group did not. On the self-rejection/acceptance IAT, the
SAD-current depression group showed the weakest self-acceptance
associations. However, in this analysis, self-acceptance associations
did not differ among individuals with SAD and remitted depression,
non-depressed individuals with SAD, and healthy controls. These
ndings suggest that current depression has a signicant effect
on both self-calmness and self-acceptance associations in socially
anxious individuals. Notably, self-reported (explicit) level of social
anxiety did not differ between the SAD-only and SAD-depression
groups.
Our ndings that individuals with SAD demonstrate weaker self-
calmness associations than non-anxious controls replicate results
from previous studies using non-clinical samples (e.g., Gamer
et al., 2008; Glashouwer & de Jong, 2010). The lack of signicant
difference between the SAD group and healthy controls on the self-
acceptance IAT was unexpected. This implicit association has been
far less examined in relation to social anxiety than has the self-
calmness association. Only two studies (Clerkin & Teachman, 2010;
Teachman & Allen, 2007) have utilized the self-acceptance IAT, but
the nature of these specic studies make predictions based upon
them somewhat difcult. Teachman and Allen examined implicit
self-acceptance associations among adolescents (ages 1318) as
part of a larger longitudinal investigation of adolescent social devel-
opment in familial and peer contexts (Allen, Porter, & McFarland,
2006), whereas Clerkin and Teachman focused on the utility of
training implicit associations in socially anxious college students.
Although the implicit self-acceptance associations of the socially
anxious participants improved with training, the authors did not
examine the implicit self-acceptance associations of socially anx-
ious participants versus healthy controls. Because fear of negative
evaluation and rejection are highly related to SAD (APA, 2013; Harb
et al., 2002), we expected to see this difference, which did not
appear. It is also of interest that recent research (Mallott, Maner,
DeWall, & Schmidt, 2009; Maner, DeWall, Baumeister, & Schaller,
2007) has demonstrated that non-anxious persons react to social
rejection with an increase in prosocial behavior and the desire to
afliate with others whereas those with high levels of social anxiety
do not show this pattern of response but rather are characterized by
social withdrawal in the face of social exclusion. Further research
on the implicit self-acceptance associations of persons with SAD
appears warranted.
4.1. The impact of comorbid depression
In our primary analyses, the SAD-depression group showed the
weakest self-calmness associations compared to non-depressed
SAD individuals and healthy controls. However, post hoc analyses
revealed that the difference between the SAD-depression and SAD-
only groups was driven by those with current depression; those
with remitted depression were no different from socially anxious
persons without a history of depression.
With regard to rejection/acceptance implicit associations, the
impact of current comorbid depressive was robust. Surprisingly,
the SAD-only, SAD-past depression, and healthy control groups did
not differ on self-acceptance associations. The SAD-current depres-
sion group had the weakest self-acceptance associations, weaker
than any of the other groups. That comorbid depression should
have an effect here follows from the literature on rejection sen-
sitivity as a risk factor for depression (Ayduk et al., 2001; Boyce &
Parker, 1989; Downey & Feldman, 1996), although it is unclear why
only those with current depression exhibited a difference from the
SAD-only group. It is possible that current depression may be more
543
closely linked with the expectation of negative outcomes, or at least
greater certainty about such outcomes, than social anxiety with or
without past depression, and that this was reected in our ndings.
More than two decades ago, Alloy, Kelly, Mineka, and Clements
(1990) proposed a cognitive explanation for when and why anxi-
ety and depression co-occur. They theorized that differing degrees
of certainty about ones ability to control important outcomes (i.e.,
helplessness) and negative-outcome expectancies (i.e., hopeless-
ness) resulted in a pure anxiety, mixed anxiety-depression, or
pure depression presentation. They argued that those who expe-
rience anxiety are uncertain of their helplessness. Those who are
certain of their helplessness and of negative outcomes primar-
ily experience depression. Those in a mixed depression-anxiety
state were theorized to be more certain of their helplessness but
uncertain about negative outcomes. If we apply this helpless-
hopelessness theory to explain the self-acceptance IAT results,
it could be argued that those with comorbid depression held
more negative outcome expectancies and were therefore more
likely to expect rejection. Non-depressed individuals with SAD,
in contrast, may have had relatively weaker negative outcome
expectancies.
Social anxiety-relevant implicit associations may be more neg-
ative and/or stable among socially anxious individuals when
depression is present. Like the attentional bias research reviewed
earlier (Grant & Beck, 2006; LeMoult & Joormann, 2012; Musa
et al., 2003), this suggests that the presence of depressive symp-
toms may modify maladaptive cognitive processes in those with
social anxiety. Similar to the arguments of Mathews and MacLoed
(2005) presented in the introduction, Musa et al. (2003) noted that
their ndings of nullied attention bias to threat at relatively brief
exposure durations suggests that anxiety and depression are asso-
ciated with biases at different stages of information processing
preattentive and selective attention processes are affected in
anxiety, and effortful, controlled processes are more likely to be
disrupted in depression. In the IAT, although the processes under
study are implicit in nature and thereby outside of conscious
awareness, stimuli are presented at durations sufcient for more
elaborative processing. As such, our ndings that individuals with
SAD with current comorbid depression exhibited less positive
implicit associations than individuals with SAD with no depres-
sion, who themselves exhibited less positive implicit associations
than healthy controls (at least in the case of self-calmness associ-
ations), appear to converge with this theory. Further, our results
suggest that SAD with current comorbid depression may represent
a more severe instantiation of social anxiety despite the fact that
this was not reected in our study on explicit self-report measures
of social anxiety, nor has it been consistently apparent in the studies
on attentional bias.
At present, it is unclear why those with SAD and remit-
ted depressed performed similarly to socially anxious individuals
without a history of depression, but not to those with current
depression, on both IAT tasks. Research on information processing
biases comparing currently to formerly depressed individuals is,
to our knowledge, scant. A handful of studies suggest that cur-
rently and formerly depressed individuals exhibit similar attention
biases (Fritzsche et al., 2010; Gupta & Kar, 2012; Joormann & Gotlib,
2007) and memory biases toward sad stimuli (Fritzsche et al., 2010;
Gupta & Kar, 2012). However, in the one study that has exam-
ined implicit associations found that on a self-esteem IAT, those
with remitted depression exhibited higher implicit self-esteem
than those with current depression and those without a history of
depression (Franck, De Raedt, & De Houwer, 2008). More research
is needed to investigate whether implicit biases associated with
depression are better characterized as a state marker of a depressive
episode, or a trait-like characteristic of people at risk for depres-
sion.
544 J. Wong et al. / Journal of Anxiety Disorders 28 (2014) 537546
4.2. Limitations and future directions
It should be noted that there are limitations in using the IAT as a
paradigm for examining implicit associations. As mentioned earlier,
the IAT was designed to measure relative association strengths and
was not meant to measure the difference in evaluative associations
with a single target concept (e.g., acceptance versus rejection asso-
ciations with the self). Karpinski (2004) points out that while some
target concepts have obvious and meaningful complementary pairs
(e.g., young-old), others do not (e.g., Santa Claus). He contends that
in many instances, the unspecied other is not a meaningful com-
plement to the self target concept for the research hypothesis being
tested. Pinter and Greenwald (2005) counter by arguing that the
other has been found to have a neutral valence. However, given
that the other may be perceived by socially anxious individuals as
a threatening stimulus, we would likely benet from examining
implicit self associations that are not tied to an other when studying
SAD.
As an alternative method, Karpinski and Steinman (2006) devel-
oped a Single Category IAT (SC-IAT) that eliminates the need for
a second contrast category. Preliminary examinations of the SC-
IAT suggest it shows acceptable reliability and validity (Karpinski
& Steinman, 2006). Therefore, a potential next step would be for
future studies of social anxiety and implicit associations to compare
the SC-IAT to traditional IAT measures.
In addition to limitations of the IAT, there were also some
methodological limitations to the current study. For one, other
stimuli, chosen to be consistent with previous studies, included the
words you and your. Respondents may have potentially con-
fused these words as belonging to the self category, thus adding
noise to the IAT results. Also, the order of administration of the IATs
used in the study was not counterbalanced, and the acceptance-
rejection IAT always followed the anxiety-calmness IAT. Practice
effects may have weakened the acceptance-rejection IAT effect.
In summary, the present results underscore the utility of exam-
ining implicit cognitions in our attempts to better understand and
treat SAD, alone and when it is comorbid with current depres-
sion. The self-calmness and self-acceptance IATs differentiated
among groups, but the specic patterns of results differed. Differ-
ences between the SAD-only and SAD-current depression groups
could reect differences in specic schema or provide an implicit
index of severity of social anxiety that might complement typ-
ically employed explicit measures. Future research should look
further into the malleability of maladaptive implicit associations
and examine the relationship between these associations and
behavior. Clerkin and Teachman (2010) demonstrated that self-
acceptance associations among socially anxious college students
could be strengthened by training and that trained participants
were more likely to complete an impromptu speech than untrained
participants. Replicating these ndings in a clinical sample of per-
sons with SAD could have important implications for treatment.
One interesting avenue to pursue would be to investigate whether
the addition of implicit association training to more commonly
applied cognitive behavioral treatments would be most benecial
for persons with SAD and comorbid depression.
Funding
This research was supported by NIMH Grant R01 MH076074
awarded to James J. Gross, Ph.D.
Conict of interest
None of the authors have any direct or indirect conicts of inter-
est, nancial or personal relationships or afliations to disclose.
The authors wish to thank Hooria Jazaieri and Faith Brozovich for
their assistance at various phases of data analysis and manuscript
preparation.
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Living
with
Anxiety
Understanding the role
and impact of anxiety
in our lives

Mental Health
Awareness Week 2014

1
The truth is that anxiety is at once a function
of biology and philosophy, body and mind,
instinct and reason, personality and culture.
Even as anxiety is experienced at a spiritual
and psychological level, it is scientifically
measurable at the molecular level and the
physiological level. It is produced by nature
and it is produced by nurture. Its a psychological
phenomenon and a sociological phenomenon.
In computer terms, its both a hardware problem
(Im wired badly) and a software problem
(I run faulty logic programs that make me
think anxious thoughts).1

1 1. Scott Stossell My Age of Anxiety.

Contents

05 Executive summary
08 Introduction
08 What is anxiety?
10 Anxiety and modernity
13 Living with Anxiety: Stephanie
15 Anxiety disorders in the UK
18 Living with anxiety: Ian
20 The state of the nation: Anxiety in the UK
28 Living with anxiety: Jane
30 Managing anxiety
36 A new age of anxiety?
40 Useful resources and information
42 References

Acknowledgements
This report was written by Paul Swift, Dr Eva
Cyhlarova, Isabella Goldie and Chris OSullivan.
Others who contributed to this report include
Paul Bristow, Joanna Carson, Hanna Biggs
2 and Jenny Edwards, CBE.
Foreword
We all experience anxiety; it is a natural human state and a vital part of
our lives. Anxiety helps us to identify and respond to danger in fight or flight
mode. It can motivate to us face up to dealing with difficult challenges. The
right amount of anxiety can help us perform better and stimulate action
and creativity.

But there is another side to anxiety. Persistent anxiety causes real emotional
distress and can lead to us becoming unwell and, at worst, developing
anxiety disorders such as panic attacks, phobias and obsessional behaviours.
Anxiety at this level can have a truly distressing and debilitating impact
on our lives and impact on our physical as well as our mental health.

Some commentators have described this as The Age of Anxiety. The

Mental Health Foundations survey, commissioned for this report, backs
up this sense of widespread heightened anxiety. Alarmingly, almost 1 in 5
people revealed that they feel anxious nearly all of the time or a lot of the
time. More than half of us have noticed that people are more anxious today
than they were 5 years ago. The survey highlights finance, money and debt
as the most common source of anxiety, perhaps reflecting the impact of
the recession and austerity on public mental health and well-being.

Anxiety is one of the most common mental health problems in the UK and
it is increasing. Yet it remains under-reported, under-diagnosed and under-
treated. A good ability to cope with anxiety is key to resilience in the face of
whatever life throws at us. However, experiencing it too much or too often
means we risk becoming overwhelmed, unable to find balance in our lives
or to relax and recover. Our ability to find some inner peace has never
been more important to our well-being.

This report is about framing anxiety as an essential aspect of our humanity

and part of the natural human emotional response to circumstances in our
lives. It is also about challenging the stigma that still gets in the way of our
reaching out for help and support when our levels of anxiety become a real
problem. As individuals and society we need to understand and engage with
anxiety better, recognising when it is helpfully alerting us to pay attention,
and ensuring we have coping strategies when its negative impact becomes
too great.

We need to recognise when the people around us, our friends, family
members and colleagues, are experiencing distressing levels of anxiety
or at risk of this because of life events and circumstances. Local public
health strategies need to identify the points at which people are most likely
to experience high anxiety and to offer a range of help that is simple, quick
to access and non-stigmatising. We encourage public health commissioners
to check the list of the most common sources of anxiety in this survey and

3
use them to help identify the best places and partnerships to reach out to
those 1 in 5 people who feel anxious nearly all the time or most of the time.

We consider there could be great benefit in public policy becoming anxiety

aware, adjusting its strategies and styles of interaction with the public in
order to prevent and reduce anxiety. If we truly recognised the mounting
costs of anxiety distress to people, their childrens futures, to communities
and employers, we would act now.

In todays Age of Apps where many people are livingdual lives, partly online,
then we can develop new and innovative digital approaches to living better
with anxiety, particularly to invest in the mental and emotional well-being of
our children and young people. We hope that this report will act as a catalyst
for a growth in self-help resources to enable us all to manage our response
to increasingly anxious thoughts.

Jenny Edwards CBE

Chief Executive
Mental Health Foundation

4
Executive summary
Anxiety is a familiar emotion because it is part
of everyones experience. Its natural function is to
alert us to potential threats, allowing us to evaluate
and respond to them in appropriate ways. This
heightened state of readiness can also help people
perform better and stimulate creative impulses.
Anxiety is often regarded as an artefact of modern
societies, one that is increasingly represented
in visual arts, music, literature and social media.
For some people anxiety triggers inappropriate
or disproportionate responses to perceived
threats, leading to persistent and intrusive
symptoms associated with anxiety disorders,
such as panic, phobias and obsessive behaviours, Agoraphobia affects between 1.5% and
which often have a debilitating effect on their
lives. Anxiety is one of the most prevalent mental
health problems in the UK and elsewhere, yet it is
still under-reported, under-diagnosed and under-
treated. This report explores the intersection
between popular perceptions of anxiety, the
experience of anxiety in peoples everyday
lives and the impact of anxiety disorders.
The experience of anxiety often involves
interconnected symptoms and disorders. It is
estimated that one in four people in the UK will
experience a mental health problem each year,
while one in six experience a neurotic disorder
such as anxiety or depression. Anxiety disorders
are also estimated to affect 3.3% of children and
young adults in the UK. The prevalence of the
most common forms of anxiety are given below.
People in their middle years (35 to 59) report
People in the older age groups tend to be
People with a disability are, on average, more
5
While 2.6% of the population experience
depression and 4.7% have anxiety problems,
as many as 9.7% suffer mixed depression
and anxiety, making it the most prevalent
mental health problem in the population
as a whole.
About 1.2% of the UK population experience
panic disorders, rising to 1.7% for those
experiencing it with or without agoraphobia.
Around 1.9% of British adults experience
a phobia of some description, and women
are twice as likely to be affected by this
problem as men.
3.5% of the general population in its fully
developed form; in a less severe form, up
to one in eight people experience this.
Post-Traumatic Stress Disorder (PTSD)
affects 2.6% of men and 3.3% of women.
Obsessive Compulsive Disorders (OCD)
affect around 23% of the population.
Generalised Anxiety Disorder affects
between 25% of the population, yet
accounts for as much as 30% of the
mental health problems seen by GPs.
Previous survey evidence suggests that:
Although, on average, women rate their life
satisfaction higher than men, their anxiety
levels are significantly higher than men.
the highest levels of anxiety compared to
other age groups.
happier and less anxious.
anxious than people without a disability.
 Unemployed people report significantly
higher anxiety levels than those in
employment.
People in the lowest income groups report
significantly higher anxiety levels than those
in the higher income groups.
On average, all ethnic groups report higher
levels of anxiety than people who describe
themselves as White British.
Young people aged 1624 are more likely to
report lower levels of anxiety compared with
adults generally.
Women and young adults aged 2029 are
the most likely to seek help for anxiety from
their GP.
Our specially commissioned survey of over 2,000
members of the public found that:
Almost one in five people feel anxious all
of the time or a lot of the time.
Only one in twenty people never feel anxious.
Women are more likely to feel anxious
than men.
The likelihood of feeling anxious reduces
with age.
Students and people not in employment are
more likely to feel anxious all of the time or
a lot of the time.
Financial issues are a cause of anxiety for
half of people, but this is less likely to be so
for older people.
Women and older people are more likely to
feel anxious about the welfare of loved ones.
Four in every ten employed people
experience anxiety about their work.
6
Around a fifth of people who are anxious
have a fear of unemployment.
Younger people are much more likely to feel
anxious about personal relationships.
Older people are more likely to be anxious
about growing old, the death of a loved one
and their own death.
The youngest people surveyed (aged 1824)
were twice as likely to be anxious about
being alone than the oldest people (aged
over 55 years).
One-fifth of people who have experienced
anxiety do nothing to cope with it.
The most commonly used coping strategies
are talking to a friend, going for a walk, and
physical exercise.
Comfort eating is used by a quarter of people
to cope with feelings of anxiety, and women
and young people are more likely to use this
as a way of coping.
A third of the students in the survey said
they cope by hiding themselves away from
the world.
People who are unemployed are more likely
to use coping strategies that are potentially
harmful, such as alcohol and cigarettes.
Fewer than one in ten people have sought
help from their GP to deal with anxiety,
although those who feel anxious more
frequently are much more likely to do this.
People are believed to be more anxious now
than they were five years ago.
There is a tendency to reject the notion that
having anxious feelings is stigmatising.
People who experience anxiety most
frequently tend to agree that it is stigmatising.
 Just under half of people get more anxious
these days than they used to and believe that
anxiety has stopped them from doing things
in their life.
Most people want to be less anxious in
their day-to-day lives.
Women and younger people are more
likely to say that anxiety has impacted
on their lives.
Surveys suggest we live in an age of anxiety
which reflects a shared mood about the defining
aspects of modern life: our work, the way we
raise children, our attitudes to people who are
disadvantaged, the future of public services,
the threat of terrorism, and so on. At another
level, there is evidence of the hidden impact of
more severe forms of anxiety upon the lives of a
significant number of people. Our understanding
of anxiety disorders has improved in recent
years due to research, the development of more
sophisticated diagnostics, effective treatments,
and the emergence of a genuine voice for people
living with anxiety. While these developments are
encouraging, our own work suggests that there
are still gaps that need to be addressed in
the provision of support for people who
experience anxiety.
7
We recommend a stepped care approach be
adopted to ensure that support for living with
anxiety is provided in the least stigmatising
and most inclusive way possible including:
Universal approaches to learning to
live well with anxiety should be built
into school curriculums from primary
1 onwards, including an understanding
of the role of anxiety in our lives, and
techniques for managing stresses
associated with school (such as peer
relationships, exams and transitions).
Peer-led approaches should be promoted
within universal settings such as
employment, schools and universities,
in recognition of the importance that young
people place on support from peers and the
unique level of empathetic understanding
that can be provided by those with a
common experience.
Access to good quality self-help approaches
should be made available across the UK
through quality-assured and co-designed
digital platforms to ensure they are fit for
purpose for those who choose not to use
face-to-face services (young people, people
in full time employment).
GP training and anxiety-related guidance
should be assessed for equalities impact and
adapted alongside groups of people who are
at highest risk of developing problematic
anxiety and least likely to have their needs
met by current service provision.
A sample of psychological services should be
audited to establish how well current referral
processes are working, who is accessing
these, and who is falling through the gaps.
This audit should include IAPT (Improving
Access to Psychological Therapies) in
England and Wales and initiatives to
improve access in Scotland.
 Agencies offering support to people with
anxiety should make greater use of peer
mentors and advice and information that
is explicitly based on the life experiences
of people who live with anxiety.

We also recommend that research be

commissioned to better understand:

The nature and understanding of anxiety

for different groups in society (women,
people with long-term conditions, older
people, people from black and minority
ethnic communities), and whether current
approaches and interventions can be found
to address specific needs.

The relationship between unemployment,

financial distress, and anxiety. The
Department of Work and Pensions should
develop strategies to prevent people who
are not working from becoming marginalised
from the workforce. Processes for accessing
social welfare for those unable to work due
to disability should be assessed for their
impact on anxiety levels.

The impact of technological advancements

in self-management for anxiety.

8
Introduction around us, or from professionals. However, as we
come to understand anxiety better, there is much
In this report we want to get deeper under the that we can do as individuals to take steps to
skin of anxiety, one of our most unwelcomed reduce its hold over us, and to learn to appreciate
emotional states, and understand the role that our full range of emotions without fear that they
it plays in our livesfor better and for worse. It will overtake us.
is not our intent to present the case for eradicating
anxiety, for being anxious is an important part of What is anxiety?
what it means to be human. We are often anxious
about those aspects of our lives that we care Everyone has feelings of anxiety at some point
most about: our health; our ability to clothe and in their life, whether it is about preparing for a job
feed ourselves and our family; and our ability to interview, meeting a partners family for the first
be connected and valued by others. Anxiety helps time, or the prospect of parenthood. While we
us to get up in the morning and motivates us to associate anxiety with alterations to our mental
step out of our comfort zone. state, experienced as worry or apprehension
perhaps, and physical symptoms such as raised
However, we often go to great lengths to avoid heart rate and adrenaline, we also understand
being anxious, feeling a sense of failure if we dont that it is likely to affect us only temporarily until
keep our worrying thoughts under tight control. the source of our anxiety has passed or we have
There may be times when these thoughts get learnt to cope with it. Anxiety is therefore one
away from us and begin to feel overwhelming. of a range of emotions that serves the positive
For some they may become habitual, leading function of alerting us to things we might need to
to regular uncomfortable, or even distressing, worry about: things that are potentially harmful.
physical symptoms. Patterns of avoidance may More importantly, these emotions help us to
build up, that can have a limiting effect on our lives. evaluate potential threats and respond to them
in an appropriate way, perhaps by quickening
Anxiety can also be exhilarating. Putting ourselves our reflexes or focusing our attention.
into situations that make us anxious can feel
like an ordeal at the time, but getting through to Fear, like anxiety, is a familiar emotion precisely
the other side can bring an incredible sense of because it is part of everyones experience
achievement. Our most important moments in life and we consider it an essential component
are usually not achieved without some sleepless of our humanity, yet it is also a psychological,
nights. Being a new parent, our wedding days, physiological and behavioural state we share
passing exams, and learning to drive bring great with animals when confronted by a threat to our
rewards, but it is unlikely that these were achieved wellbeing or survival. Fear increases the bodys
without some feelings of apprehension. arousal, expectancy, and neurobiological activity,
and triggers specific behaviour patterns designed
Anxiety is an emotional state that can work for to help us cope with an adverse or unexpected
us as well as against us. It is something we all situation. But how do we distinguish anxiety
have in common, but where we often differ is in from fear, given that the two are often
how we perceive these feelings of arousal and used interchangeably?
how we respond to them. Our life circumstances,
our upbringing and our personalities can all be
factors in why one persons exciting fairground ride
will leave another person in abject terror. Feeling
anxious isnt a sign of failure and there are times
when it is important to ask for help from those

9
If fear is fearful of something
particular and determinate,
then anxiety is anxious about
nothing in particular and is
indeterminate. If fear is directed
towards some distinct thing in
the world, spiders or whatever,
then anxiety is anxious about
being-in-the-world as such.
Anxiety is experienced in the
face of something completely
indefinite. It is, Heidegger
insists, nothing and nowhere
(Critchley, 2009).
10
While fear often has a specific, immediate context
which provokes classic fight or flight reflexes
the automatic fear response occurs faster than
conscious thought, releasing surges of adrenaline
which can subside quickly once the perceived
or actual threat has passedanxiety connotes
lingering apprehension, a chronic sense of worry,
tension or dread, the sources of which may be
unclear. It can be a vague, unpleasant emotion
experienced in anticipation of some ill-defined
misfortune. The committee charged with reviewing
the diagnostic criteria for the latest version of
the Diagnostic and Statistical Manual of Mental
Disorders (DSM)2 similarly distinguish anxiety as
a future-oriented mood state associated with
preparation for possible, upcoming negative
events from fear which is an alarm response to
present or imminent danger (real or perceived);
but add importantly, these descriptions represent
prototypes of fear and anxiety that lie at different
places upon a continuum of responding. Along
such a continuum, symptoms of fear vs. anxiety
are likely to diverge and converge to varying
degrees (Craske et al., 2009). Another writer,
expressing the distinction in less esoteric terms,
suggests the sudden re-arrangement of your guts
when an intruder holds a knife to your back (fear),
is different from the mild nausea, dizziness and
butterflies in your stomach as youre about
to make a difficult phone call (anxiety).3
This report is concerned with the way that different
types of anxiety, found at various points on the
continuum, are experienced by individuals and
how they are represented to the wider public.
It explores the everyday manifestations as well
as what happens when anxiety becomes more
than a temporary experience, and instead is
experienced as either a series of debilitating
episodes or a constant presence in someones
2. Published by the American Psychiatric Association, the DSM
offers standard criteria for the classification of mental disorders
for use by clinicians, researchers, pharmaceutical companies,
policymakers, etc. The latest version, DSM-V, was published in
May 2013.
3. From Harriet Lerner, The Dance of Connection blog October
11th 2009.
life. Anxiety disorders such as panic, phobias
and obsessive behaviours may be triggered by
traumatic memories, irrational hatred of specific
objects, proximity to particular situations or
physical locations, or a persistent worry that
something bad will happen in the future. A
defining characteristic of anxiety disorders is
that psychological symptoms, such as irritability,
difficulties concentrating and depression,
become persistent and intrusive. Many people
also experience physical symptoms, like heart
palpitations, sweating, tensions and pain, heavy
and rapid breathing, dizziness, fainting, indigestion,
stomach aches, sickness and diarrhoea; in acute
cases, people have described how it felt as though
they were dying. The lives of those with the most
severe forms of anxiety can become completely
dominated by their condition, meaning they find
it difficult to relax or achieve regular patterns
of sleep, becoming stuck in circular patterns
of thought that impair their ability to maintain
preferred lifestyles, hold down a job or sustain
personal relationships.
11
Anxiety and modernity
Although it is the most common sign of mental
distress in nearly every country in the world,
anxiety is often presented as an artefact of modern
Western societies; Norman Mailer, for example,
suggested that the natural role of twentieth-
century man [sic] is anxiety. The concept of
anxiety per se was first brought to prominence
as a philosophical and psychoanalytic concept in
the first part of the twentieth century. Freud was
a seminal figure in the development of Western
thinking about anxiety, which he conceived of as
a state of inner tension from which humans are
driven to escape. At a most basic level, anxiety is
a signal to the ego (the aspect of personality that
deals with reality) that something overwhelmingly
awful is about to happen and that it needs to
employ a defence mechanism in response.
Freud saw this as deriving from an infants
mental helplessness, which is a counterpart of
its biological helplessness. Humans learn to cope
with anxiety prompted by real threats, such as
fear of being bitten by a dog, either by avoiding
situations likely to contain the threat, or by
physically withdrawing from them.
Freuds typology also included neurotic anxiety
arising from an unconscious fear that we will
lose control of libidinal impulses, leading to
inappropriate behaviour, and moral anxiety, arising
from a fear of violating our own moral or societal
codes. Moral anxiety, he suggested, manifests
itself as guilt or shame. The task of psychoanalysis
is therefore to strengthen the ability of the ego to
find ways of coping with anxiety such as denial,
rationalisation, regression (to a childhood state)
or projection.
Within the existentialist philosophical tradition,
angst, from the German word for anxiety, is held
to be a negative feeling arising from the
experience of human freedom and responsibility
in a world where faith and traditional social
bonds have been undermined. Kierkegaards
classic example of existential angst is of a person
standing on the edge of a high cliff or building;
along with the fear of accidentally falling, the Freudian psychoanalysts would recognise as
person feels an irrational impulse to deliberately classical defence mechanisms: they learn to
fling themselves over the edge. The emotion the seal their anxiety off from public view. According
person feels upon realising that he or she has to Daniel Smith, they learn to cork their anxiety
this option is angst. Kierkegaard described the within themselves like acid in a vial. It isnt pleasant.
burden of making moral choices as a consequence The human mind isnt Pyrex, it can corrode. But
of free will the dizziness of freedom. Existential it works.6
psychology therefore proceeds from the
presumption that anxiety stems from a crisis in the Perhaps more significantly, the testimony of
exercise of free will, which might be manifested in people living with anxiety affords us a more
anxiety about ones mortality, the inevitability of rounded appreciation of the role that it plays in
loss, or about accepting personal responsibility shaping their lives; as Scott Stossel, author of My
for ones thoughts, feelings and actions. Age of Anxiety, puts it, anxiety can be a spur to
achievement as well as a barrier. Picture a bell
That anxiety somehow feels new may be4
curve with extreme anxiety on the far right and
explained partly by the fact that anxiety has been extreme lack of anxiety on the far left. If youre
the subject of significant scientific research for less too anxious to the point where its physically
than half a century, while the psychiatric profession and mentally debilitating, then your performance
first codified diagnostic criteria for all the different suffers. If youre not anxious enough, if youre not
disorders as recently as 1980, with the publication engaged and slightly activated by anxiety, as
of DSM-III. Subsequent advances in diagnostic it were, then your performance also suffers.7
techniques, coupled with the development
of effective pharmacological treatments and The voices of people living with the more acute
psychological therapies, have prompted primary forms of anxiety help us to conceive of anxiety
healthcare professionals to more readily identify as something more than simply a condition that
anxiety in their patients. requires diagnosis and treatment. How individuals
engage with their anxiety, how they manage it and
Anxiety is now recognised as one of the most represent it to the wider world lifts anxiety beyond
prevalent mental health problems in the UK, the realm of medicine and science and into
yet there is good evidence that it is still under- a broader sociological and cultural context.
reported, under-diagnosed and under-treated.
One reason may be that, unlike many other mental
health issues, people whose lives are affected
have not yet found a voice that articulates the
full range of experiences of anxiety, not just those
of people living with anxiety disorders. In recent
years, this has begun to change, as writers,
bloggers and campaigners have provided us
with an insight into Britains silent epidemic5
by describing the lived experience of anxiety, the
complexities and nuances of the various disorders,
the symptoms that are associated with them,
and the effect that anxiety has upon their lives.
For example, some people living with anxiety
describe feelings of shame and embarrassment
4. Rachel Cooke, The Observer, Sunday 15th September 2013.
at their physical symptoms, such as excessive
5. The Observer, Sunday 15th September 2013.
perspiration, which lead them to adopt what 6. From Monkey Mind: A Memoir of Anxiety by Daniel Smith, quoted
in The Observer, Sunday 15th September 2013.
12 7. Scott Stossel May Age of Anxiety.
For as long as I can remember
I have suffered from a deep
feeling of anxiety which I have
tried to express in my art.
Without anxiety and illness
I should have been like a ship
without a rudder
(Edvard Munch).
The representation of these more acute forms of
anxiety within the arts has long been established
as a powerful creative force in a way that fear
rarely is.8 From the dizziness of freedom has
flowed a rich artistic tradition since the beginning
of the twentieth century, starting with the close
relationship between early modernist artists
and psychoanalysis and the rise of art practices
within psychiatric hospitals, which in turn had
a significant impact on the development of art
history. Writers have also recognised anxiety
as a handmaiden to creativity,9 either as the
motivating spirit acknowledged by Graham
Greene, for example, or as the animating theme
of novels by Virginia Woolf, Franz Kafka and
Haruki Murakami. Most notably, the First World
War poets, many with the experience of early
psychiatric treatments for trauma, brought the
subjective experience of severe anxiety disorders
into the public realm. In another sphere, musicians
as diverse as Leonard Bernstein, Marvin Gaye
and Radiohead have represented anxiety in their
work, while The Kings Speech demonstrates that
a debilitating social anxiety can be the subject
matter of a commercially successful film as
well as a critically acclaimed one.
13
In 2009, the Mental Health Foundation published
In The Face of Fear, which addressed the questions
of how fear and anxiety affect our health and
society, and what we can do about it. At that time,
fear seemed a natural response to the dramatic
banking crisis of the previous year and the
potential socio-economic consequences that few
at the time could predict, except that it was likely to
be the deepest recession for a generation. Indeed,
research carried out for In The Face of Fear found
that people perceive our world as having become
more frightening and frightened. In 2014, five
years on, we are exploring whether and how that
mood of fear has translated into a more persistent
sense of apprehension and, taking a broader
perspective, how that fits into our historical
understanding of anxiety. We do this by asking:
do we live in age of anxiety? In doing so, we want
to draw attention to the way that anxiety affects
the lives of the people who live with it and consider
the contribution of anxiety to our culture.
This report explores the intersection between
popular perceptions of anxiety, the experience
of anxiety in peoples everyday lives, and the
impact of anxiety disorders. In doing so, we
have reviewed the research evidence on anxiety
disorders, commissioned a survey of public views,
and collected peoples stories about their own
experiences. The following chapters set out the
scale and nature of anxiety in the UK and how
it is currently managed, interspersed with case
studies describing what it is like to live with anxiety.
We hope that the report will contribute to a wider
understanding of the role that anxiety plays in
our lives and stimulate discussion about the
public health implications of learning to live
well with anxiety.
8. Later this year, the Anxiety Arts Festival will explore anxiety, its
causes, how it affects our lives and how it can act as a motivating
force for creativity.
9. Attributed to Aldous Huxley.
 Living with anxiety: Stephanie,
journalist, mid-20s
Your greatest strength is also your greatest
weakness. Ive always had a natural tendency
to be on edge, to be extremely aware of my
surroundings. Im alert all of the time and, although
a predisposition to being quite observant is great
for your career, it isnt always the best for your
personal relationships. As a writer, your job is to
see the things that other people dont necessarily
see. Its because of your ability to notice anything
and everything that you are able to draw
conclusions, notice trends or comment on various
social phenomena.

I had a brilliant upbringing and a really supportive

family. But Mum and Dad were in the process of
getting divorced when I went off to university, so
there I was, worried about putting on weight while
I had a lot going on at home. I started to spend
more and more time at the gym because exercise
was a great stress relief (and the endorphins didnt
hurt either). I started to see results in weight loss,
which made me want to do a bit more and then
a bit more. I guess, because Im a perfectionist, if
I was going to do something, I was going to do it
well!

My weight loss was drastic, but it never got to

the stage where I was hospitalised. But I was very
well aware that my behaviour was not normal;
even then I didnt lose that logical side of me.
Mum and Dad could see what was happening and
did encourage me to see a psychologist. It really
really helped. When I got the diagnosis (anorexia
nervosa/bulimia nervosa with mild anxiety
disorder), it was a shock. I was surprised to find out
that I had an anxiety disorder, and it was the eating
disorder that was the symptom, not the other way
around.

14
In my sessions with my psychologist, she used People deal with anxiety in different ways. For
CBT10. Good old CBT, it works every time! Im a some, its addiction; mine is an eating disorder.
big champion of it. The best techniques for me Your weight and your food intake is something that
are the ones that make me separate my emotions will never be out of your control, and thats why you
from the thoughts; to realise that what Im feeling find comfort with it. I know it will never completely
inside isnt necessarily an accurate representation go awayits part of my chemistrybut doing
of what the situation is. So, if Im feeling stressed CBT helped me and prevented me from going
out of my mind, I take a step back and notice that too far and over-thinking things. It helped me to
Im feeling stressed, then take another step back acknowledge that a thought is simply a thought
and notice that Im having the thought of feeling rather than the truth. Now I can gauge where I
stressed. That simple dissociation between I am in my overall wellbeing by my drive to watch
think, therefore I am really helps. what I eat or how I exercise. Now, if I have dessert,
thats okay. The more that food or weight is in the
The heightened anxiety I felt during my parents forefront of my mind, the more I know that I need
divorce lasted for about a year before I got into to change something in my life that is causing
CBT. Then, within six months I got back to being me that stress.
more like myself. I found that for me, the central
issue affecting my anxiety is control; more
specifically, the lack of control is what precipitates
my anxiety. It definitely flares up when Im stressed.
I used to repress everything to the point where
I would become overwhelmed with emotionI
would cut offbut that doesnt ever help because
you eventually explode; it has to come out at
some stage. Now I allow myself to feel stressed
or anxious for a little period because I know that
ultimately it will subside. I let it wash over me,
but then stop it because I know that the body
can only be in a state of stress for so long; it
ultimately calms itself down.

Ive had a couple of years now of being more

mindful and trying to observe myself from a birds-
eye perspective. I know what my limits are now.
Having recently moved to London, there were
definitely times last year when I fell back into my
old patterns of thinking because I was chronically
stressed about my job situation and repressed my
feelings of loneliness, missing creature comforts,
yet wanting to be this strong person. I was too
proud to acknowledge that I was having a tough
time. Id never really admit to friends how I was
feeling deep down, because that then meant Id
have to admit to myself that I had a problem again.
So, I went home and had a couple of booster
sessions with my counsellor.
10. Cognitive Behavioural Therapy (CBT): is one of a broad range of
psychotherapies or talking therapies that aims to change the way
15 that you think and behave.
Anxiety disorders in the UK
The best estimates suggest that: one in four
people in the UK will experience a mental health
problem each year; one in six will experience a
common mental health problem such as anxiety
or depression; and that these figures have steadily
increased over the past 20 years. Estimates of the
number of people who experience anxiety vary
because of the different methods for gathering
data and the different criteria used in identifying it.
Some surveys rely on self-reporting: peoples own
assessments of their emotional state. While the
results can help us appreciate the general mood
of a population and the distribution of anxiety
within a population, such surveys lack the
consistency of a diagnostic threshold. However,
reports based on service data will, by definition,
only include those willing and able to seek help
for their anxiety and rely on the correct
identification by professionals of the presence
of a problem. Estimating the prevalence of anxiety
problems is further complicated by the fact that,
in diagnostic terms, anxiety is the common thread
linking a range of disorders, from agoraphobia to
obsessive compulsive disorder. Some disorders
are linked (for example, agoraphobia and
panic disorders), while each displays particular
characteristics which themselves impact on
peoples lives.
16
What are the most common
anxiety disorders?
The experience of anxiety often involves a bundle
of interconnected symptoms and disorders
characterised by confusing circularity between
the triggers to anxiety and the responses that
it invokes. Scott Stossels bundle includes
emetophobia, a fear of vomiting (especially in
public), which is a condition that according to
Anxiety UK is not widely diagnosed even though
it is fairly prevalent. This is the aspect of his anxiety
that is most debilitating, he says, because it is
entwined with agoraphobia caused specifically
by a fear of being sick far from home as well
as nausea, a commonly experienced physical
symptom of many forms of anxiety. While the
separate elements to the bundle may not, in
themselves, have a decisive impact on his life,
the effects of their interaction can be devastating.
This can be seen more clearly in people diagnosed
with co-morbid depression and anxiety, which
often results from a downward spiral in which
anxiety leads to low mood which in turn intensifies
the anxiety. The most recent national survey of
mental health in the UK indicates that while 2.6%
of the population experience depression and
4.7% have anxiety problems, as many as 9.7%
suffer mixed depression and anxiety, making it
the most prevalent mental health problem among
the population as a whole (McManus et al., 2009).
Previous surveys conducted in 1993 and 2000
showed an increase in the prevalence of mixed
anxiety and depressive disorders, but only
small changes between 2000 and 2007 (Self
et al., 2012).
Panic is an exaggeration of the bodys normal
response to fear, stress or excitement. Panic
attacks are a period of intense fear in which
symptoms develop abruptly and peak rapidly.
Panic attacks have been described as a form
of emotional short-circuiting (Servian-Schreiber,
2005) whereby the limbic brain suddenly
takes over the bodys functioning, leading to
overwhelming sensations, which might include
a pounding heart, feeling faint, sweating, shaky developed form; in a less severe form up to one
limbs, nausea, chest pains, breathing discomfort in eight people, i.e. about 7 million in the UK, may
and feelings of losing control. Adrenaline be troubled by some agoraphobic symptoms.
overwhelms the cognitive functions that would
normally help the brain assess the real nature Post-Traumatic Stress Disorder (PTSD), or
of the threat to the body. The effects can be so syndrome, is a psychological reaction to a highly
severe that people experiencing panic attacks stressful event outside the range of everyday
believed they were dying. It is estimated that about experience, such as military combat, physical
1.2% of the UK population experience panic as violence, or a natural disaster. The symptoms
a separate disorder (Goodwin et al., 2005), rising usually include depression, anxiety, flashbacks,
to 1.7% for those experiencing it with agoraphobia recurrent nightmares, and avoidance of situations
(Skapinakis et al., 2011). that might trigger memories of the event. One
study of UK armed forces personnel deployed
A phobia is an intense and irrational fear of a to Afghanistan found that of 1,431 participants,
specific object or situation, such that it compels 2.7% were classified as having probable PTSD,
the person experiencing it to go to great lengths while a household survey of UK adults estimated
to avoid it. Phobias can be about harmful things a prevalence of 2.6% in men and 3.3% in women.
or situations that present a risk, but they can also Whilst a range of studies investigating the health
be of harmless situations, objects or sometimes challenges of asylum seekers and refugees
animals. Social phobia can include a fear of being have found that PTSD levels can be as much as
judged, scrutinised or humiliated in some way. It 10 times higher than the age-matched general
can show itself with a fear of doing certain things population (Fazel et al., 2005). A range of stressors
in front of others, such as public speaking. have been identified as impacting adversely on
According to the Office for National Statistics, mental health, including those experienced pre-
around 1.9% of British adults experience a phobia migration, such as torture, traumatic bereavement
of some description, and women are twice as and imprisonment, but also post-migration factors
likely as men to be affected by this problem. such as discrimination, detention, destitution
and delayed decision making in the asylum
Although agoraphobia is often associated with process (McColl et al., 2008). One study of women
a fear of open spaces, the main feature is intense asylum seekers in Scotland and Belgium found
anxiety triggering a panic response in situations that 57% were above the cut-point for PTSD
where escape is perceived as difficult or potentially symptomatology (Scottish Refugee Council
embarrassing, or where help may not be readily et al., 2009).
available; indeed, such crises often occur in
confined spaces. People with agoraphobia appear Obsessive Compulsive Disorder (OCD)
to experience two distinct types of anxiety affects around 23% of the population and is
panic, and the anticipatory anxiety related to fear characterised by unwanted, intrusive, persistent
of future panic attacks. Agoraphobia can have a or repetitive thoughts, feelings, ideas, sensations
dramatic limiting effect upon the lifestyle of people (obsessions), or behaviours that makes the
living with the condition, as they seek to avoid sufferer feel driven to do something (compulsions)
situations that make them anxious; for example, to get rid of the obsessive thoughts. This only
only using places where exit routes are known or provides temporary relief and not performing
staying close to exits. In extreme cases, individuals the obsessive rituals can cause great anxiety. A
are so fearful they become homebound altogether. persons level of OCD can be anywhere from mild
Onset of agoraphobia is usually between the to severe, but if severe and left untreated, it can
ages of 18 and 35 and affects between 1.5% destroy a persons capacity to function at work,
and 3.5% of the general population in its fully at school or even to lead a comfortable existence
in the home.
17
Generalised Anxiety Disorder (GAD) is the most lifestyle choices such as smoking, drinking too
commonly diagnosed anxiety disorder and usually much alcohol, and a poor diet (Mental Health
affects young adults. Women are more likely to be Foundation, 2009).
affected than men. While feelings of anxiety are
normal, people with GAD find it hard to control Children and young adults
them, to such an extent that it impinges upon their Anxiety disorders are estimated to affect 3.3%
daily life. It causes sufferers to feel anxious aboutof children and young adults in the UK (about
a wide range of situations and issues, rather than 290,000) and while we cannot be sure whether
one specific event. Unlike a phobia, which focuses children and young adults today are more
upon a specific object or situation, generalised anxious than previous generations, mental
anxiety is diffuse and pervades the sufferers daily health problems in young people are surprisingly
life. Although GAD is less intense than a panic common, disabling and run a chronic course
attack, its duration and the mental and physical (Cresswell et al., 2010; Hagell et al., 2013). Cohort
symptoms, such as irritability, poor concentration studies carried out from 1974 show significant
and the effects of disrupted sleep patterns, mean increases in emotional problems such as
that people with the disorder often find it difficultdepression and anxiety amongst young people,
and in 2004 it was estimated that 4% of children
to live the life they would prefer to live. GAD affects
25% of the population and has increased slightly and young people had an emotional disorder
since 1993 (Self et al., 2012), yet accounts for (anxiety or depression) (Green et al., 2005). The
as much as 30% of the mental health problems absence of similar research in the last eight years
in people seen by GPs, which explains why an means that it is difficult to assess the impact of the
analysis of people seeking help through primary financial crisis on levels of anxiety amongst young
care suggests a higher prevalence rate of 7.2% people. Nevertheless, in 2004, children and young
(Martin-Merino et al., 2010). people with emotional disorders were found
to be living in significantly poorer households
Anxiety and health compared to other children and were more likely
The true impact of anxiety can be masked when it to be educationally disadvantaged (Green et al.,
is the symptom of other more obvious or treatable 2005). One commentator has concluded that
physical problems which are likely to be prioritised such mental health problems have important
in any subsequent medical intervention. Anxiety implications for every aspect of young peoples
problems are common amongst cardiovascular lives including their ability to engage with
patients; for example, panic disorder is up to 10 education, make and keep friends, engage in
times more prevalent amongst people with chronic constructive family relationships and make their
obstructive pulmonary disease than in the general own way in the world (Hagell et al., 2013).
population (Livermore et al., 2010, cited by Naylor
et al., 2012). People with GAD have been found The results of a major study revealed that
to be at higher risk of coronary heart disease, children and adolescents with an autistic
while anxiety has also been linked to increased spectrum disorder were at particularly high risk
incidence of gastrointestinal problems, arthritis, of experiencing problematic levels of anxiety.
migraines, allergies, and thyroid disease. People Nearly 40% were estimated to have clinically
with anxiety disorders are four times as likely as elevated levels of anxiety or at least one anxiety
others to develop high blood pressure, and many disorder, with specific phobia most common
studies have shown a relationship between anxiety at nearly 30%, followed by OCD in 17%, social
and reduced white blood cell function, a sign of anxiety disorder and agoraphobia in nearly 17%
immune system weakness. There is also emerging and GAD in 15% (Van Steensel et al., 2011).
evidence of a link between stress and Alzheimers
disease. Anxiety is also associated with unhealthy

18
 Living with anxiety: Ian,
Environmental Trust Manager,
mid-30s

I heard a psychologist on the radio say that having

anxiety is like sticking your head above a trench
every day. Mine is not that severe; it is more like
getting ready for a job interview, a feeling that
I have to perform more highly than in reality I
actually have to. Some days it is worse than others,
but it is not often that Im away from thoughts that
distract me from letting go or having a good time;
there is always something at the back of my mind
saying youve got to sort this or that out.

What we are talking about is GAD. My head says

Im under attack and physically I feel like Im under
attack. I start holding my breath, shallow breathing,
my heart starts beating faster, pacing up and
down. I get shakingnot like my cup of tea would
go everywherebut more like a buzz, a readiness,
as though Im preparing for something. Maybe I
ramble on a bit; thats a product of it. Its energy-
sapping although I still manage to find energy.

Its only recently that Ive realised there is

something that needs to be explored a bit more
deeply. Im currently working with a CBT therapist,
talking about the time when I first noticed my
anxiety, trying to recognise whether it was a
particular incident that triggered it or whether
Ive had it from a younger age. My gut feeling
is that Ive always had a tendency to be anxious.
My grandmother was anxious and I wonder if
there is something genetic there. I was quite
shy and reserved at school but it became more
pronounced when I went to university. It was less
about the stress of moving away from home,
although that may have contributed to it, and more
uncertainty about me and my place in the world.

While I was at university my GP prescribed anti-

depressants, but I wasnt comfortable taking them.
I didnt have a diagnosis; I just used to think that
Im not quite hitting the right note, not quite getting
satisfaction from what I do, or that Im flawed in

19
some way. Having experienced life a bit more, I do think that sport is a great medicine. Id love
Ive noticed patterns of stress for which I sought to do 30 minutes of exercise a day, but the GAD
counselling. I didnt really nail down a diagnosis means that I feel I have to do X, Y and Z before I
and acceptance of GAD until about 3 years ago. can find time to do some exercise. Its a form of
That led to me to get involved with Anxiety UK perfectionism which means that you cant start
and they put me in touch with one of their something until youve lessened the anxious
cognitive behavioural therapists and Im currently feeling about these things that are pressing
looking at ways to change the way I think and because the world will blow up if you dont do
instil new behaviours and habits. It has taken those. Then you can think about exercising. Its
me a while to get to that point. difficult to get a well-rounded routine. I find that
taking on responsibilities helps. So Ive taken
Anxiety is always there, but it is heightened on the responsibility to take this seriously. I used
when there is a transition or anything new, so at to go out and drink and that didnt help, so now
a micro-level it could be a social situation I am not I dont drink, or very rarely.
entirely comfortable with. So there are different
levels of anxiety. When you hear the word anxiety, I havent ever stopped and that has been
classically you think of worry and you would be one of the problems. Constantly doing things
able to see it, but anxiety can be internalised as is something I feel is necessary as a way of
well. So when I am there with my family at a social preventing things going wrong. But that is actually
event, it might be the most natural, comfortable a negative thing because I havent been able to
thing in the world, but in my mind somewhere say, hang on Ian look at yourself a little bit more,
Ive got doubts and worries and anxieties that think some more positive thoughts because it
arent showing. has all been a bit of a rush. Even if GAD gives me
fear-fuelled oomph, Id definitely swap it for peace
My personality is positive by default; however, of mind, clarity, and the yearning to just be. Im
GAD interrupts my fun and placid temperament often left feeling sad, isolated and frustrated at
and replaces positivity with negative thoughts that the difficult task of simply enjoying life.
Im not good enough. Sometimes I wonder what
part of it is me and what part of it is GAD. I do get
a lot of things done, and then I think: is it good that
I have GAD? You know what they say: if you want
something done, give it to a busy person. Well, that
happens to me. But really I could use the energy
in much more productive ways. People have said
You need to learn to say no, but part of me on
the negative side goes, If I do say no then what
will people think of me? The other part of me says
I really want to get involved in this; Im going to
do it. And I know, because of the way I am, that
if I do agree to do something Ill worry about it.
So I agreed to put on the local carnival alongside
holding down my full-time job, as well as juggling
a social life. Im naturally an organised person and
I do have a passion for my local community, but my
worry about doing a bad job and worry about what
people will think of me spurred me on to put on
a good schedule of events.

20
The state of the nation: anxiety
in the UK
To get a picture of the extent and causes of anxiety
amongst the general population of Britain in early
April 2014, we commissioned a survey of 2,330
adults. The survey complements upon recent
11
large-scale survey evidence about anxiety, which
suggests that:
Although, on average, women rate their life
satisfaction higher than men, their anxiety
levels are significantly higher than men (Self People in the lowest income groups report
et al., 2012; the Office for National Statistics
(ONS), 2013).
People in the older age groups tend to be
happier and less anxious (Understanding
Society, 2013).
The anxiety levels of people with a disability
are higher, on average, than those of people
without a disability (ONS, 2013).
Unemployed people report significantly
higher anxiety levels than those in
employment (ONS, 2013).
significantly higher anxiety levels than those
in higher income groups (ONS, 2014).

People in their middle years (35 to 59) report On average, all ethnic groups reported higher
the highest levels of anxiety compared to levels of anxiety than people describing
other age groups (Self et al., 2012; ONS, 2013). themselves as White British (Hicks, 2013).

Young people aged 1624 are more likely to

report lower levels of anxiety compared with
adults generally (Potter-Collins & Beaumont,
2012; ONS, 2014).

Women and adults aged 2029 are most

likely to seek help from their GP for anxiety.
(Martin-Merino et al., 2010).

For the purposes of the survey, we defined

anxious as generally feeling worried, nervous, or
uneasy. The survey explored how often people feel
anxious, the causes of their anxiety, what they do
about it, and the impact of anxiety on their lives.
The findings presented an opportunity to map the
scale of anxiety across a representative sample
of the population, and analyse responses by age,
gender, social class and employment status.

11. Source: YouGov Plc. April 2014. Total sample size was 2,330
adults. Fieldwork was undertaken between 9th and 10th April 2014.
The survey was carried out online. The figures have been weighted
21 and are representative of all GB adults (aged 18+).
How often do people feel
anxious?
Almost one in five people feel anxious
nearly all of the time or a lot of the time.
Only one in twenty people say they never
feel anxious.
Women are more likely to feel anxious
than men.
The likelihood of feeling anxious tends
to decline with age.
In general which ONE, if any, of
the following statements do
you think BEST describes your
experience with anxiety in your
everyday life? (n=2,330)
I feel anxious nearly all of the time 4%
I feel anxious a lot of the time 14%
I feel anxious some of the time 41%
I rarely feel anxious 34%
I never feel anxious 5%
Dont know 1%

Students and people not in employment The frequency of anxious feelings decreased
are more likely than those who are working incrementally through the age groups of
or retired to feel anxious all of the time respondents, while the proportion of those saying
or a lot of the time. they rarely or never feel anxious increased with
age, from 25% of 1824 year olds at the lower
When asked to describe how frequently they end of the scale, to 49% of those aged 55 years
experience anxiety in their everyday life, our survey or older at the upper end. People not working for
found that 19% of people feel anxious either a lot other reasons than being unemployed (such as
of the time or all of the time. For this group, anxiety long-term disability) were three times more likely
is something that almost two-thirds (61%) of them (12%) to experience anxious feelings all of the
experience on a daily basis and a third (33%) time than the survey sample as a whole (4%).
experience it at least once a week. There was a Students (26%), people who are unemployed
marked difference between the experiences of (30%), and people not working for other reasons
men and women however, in that almost a quarter (33%) were more likely to feel anxious a lot of
of the women surveyed (22%) feel anxious a lot the time or all of the time compared to the
or all of the time, compared to 15% of the men. survey sample as a whole (19%).
A further 41% of people in the survey feel anxious
some of the time, meaning that six of every ten
respondents said they feel anxious at least some
of the time. Women were more likely to experience
this frequency of anxiety (68%) compared to men
(51%). Additionally, 47% of men said they are
either rarely or never anxious in their everyday
lives, compared to 31% of women.

22
What causes anxiety?
Nearly half of the people who said they
feel anxious in their everyday life said that
financial issues are a cause of anxiety, but
this is less likely to be so for older people
(those over 55 years).
Women and older people are more likely to
feel anxious about the welfare of loved ones.
Four in every ten people who are currently
employed said they experience anxiety
about issues to do with their work.
Around one-fifth of people who are anxious
have a fear of unemployment.
Younger people are more likely to feel
anxious about personal relationships.
Older people are more likely to be anxious
about growing old, the death of a loved one,
and their own death.
The youngest people surveyed (those aged
between 18 and 24) were twice as likely
to be anxious about being alone than the
oldest people (aged 55 and over).
23
We asked people to identify the causes of their
anxiety. Almost half of those surveyed (45%) said
that financial issues (i.e. money/finance/debt)
cause them to feel anxious. The survey highlighted
a marked decline in anxiety about finances
amongst people aged 55 years and older: nearly
one-third (32%) of this age group cited finances
as a cause compared to more than half for each
of the other age categories. Discounting people
who are retired (who are half as likely as others
to say financial issues are a cause of their anxiety),
this shows that not only are financial issues a
significant factor in anxiety for people of working
age, but also suggests that people in part-time
employment (53%), the unemployed (53%), and
people not working for other reasons (55%) are
slightly more likely to have anxious feelings about
money. The survey findings further suggest that
people in social grades C2D&E (49%) may be
more likely to feel anxious because of financial
issues than people in social grades AB&C1 (42%).
Work issues, such as long hours, were identified
by just over a quarter of people (27%) as a cause
of anxiety and 17% said that the fear of losing their
job or unemployment caused them to feel anxious.
Anxiety related to work appears to be consistent
across working life and then, as one might
expect, diminishes sharply as people approach
and enter retirement. Indeed, significantly higher
proportions of those in either full- or part-time
employment cited work issues (39%) and fear
of unemployment (22%) as a cause of anxiety
compared to the survey sample as a whole.
Which, if any, of the following
specifically cause you to feel
anxious in your everyday life?
(n=2,184)
Money/finance/debt 45%
Welfare of my loved ones/children 36%
Other work issues 27%
(e.g. long hours etc.)
Personal relationships 26%
Growing old 25%
Death of a loved one 22%
Fear of losing my job/unemployment 17%
Fear of being alone/isolation 16%
My own death 16%
Fear of crime/personal safety 14%
Other 14%
Dont know/cant recall 6%
24
Anxiety related to family and relationships featured
prominently in the survey. Personal relationships
were said to be a cause of anxious feelings for
26% of people who said they feel anxious in
everyday life, but significantly more so for people
aged 1824 (44%) and students (46%), and
significantly less so for people aged over 55
years (15%). Just over one-third of those surveyed
(36%) identified the welfare of a loved one or
children as a cause of anxiety, but significantly
more women (44%) than men (28%) cited this
as a cause, and the likelihood of citing it increased
with age so that almost half of people aged over
55 years (47%) said that this was a cause
of anxiety.
Age was also a factor in anxiety about growing
old, with 36% of those aged 55 years and above
saying they were anxious about this, compared
to just 15% of 1824 year olds. Similarly, 29% of
the people surveyed from the oldest age group
felt anxious about the death of a loved one,
compared to 13% from the youngest age group,
and twice as many from the oldest age group
(19%) were anxious about their own death,
compared to the youngest age group (10%).
However, the survey also threw up an interesting
anomaly around fear of being alone/isolation. We
might hypothesise that this would be a particular
source of anxiety for older people, yet young
people aged 1824 (28%) were twice as likely
to mention it than people in the 55 years and over
age group whose response (14%) was lower than
the survey sample as a whole (16%). This may be
suggestive of the importance placed on belonging
to a peer group by young people. Women (19%)
were slightly more likely than men (13%) to
mention this as a cause of feeling anxious, while
students (27%), people working part-time (23%)
and people not working for reasons other than
unemployment (23%) were also more likely to
have anxious feelings about being alone.
How do people cope with their Which, if any, of the following
anxiety? do you do/use to cope with
Nearly one-fifth of people who have
your feelings of anxiety in your
experienced anxiety do nothing to cope everyday life? (n=2,184)
with it.
Talk to a friend or relative 30%
The most commonly used coping strategies
Go for a walk 30%
included talking to a friend, going for a walk,
Comfort eating 24%
and physical exercise.
Physical activity/exercise 23%
Hide away from the world 18%
Comfort eating is used by a quarter of people
Alcohol 16%
(24%) to cope with feelings of anxiety and
Relaxation/meditation techniques 13%
women and young people are more likely
Cigarettes 10%
to use this as a way of coping.
Visit my GP 7%
Other 11%
Almost one-third of students in the survey
Dont know 2%
said they cope by hiding themselves away
from the world.
The most common coping strategy was talking
People who are unemployed are more likely to a friend or relative, used by 30% of people who
to use coping strategies that are potentially feel anxious in their everyday life, although women
harmful, such as alcohol and cigarettes, (38%) were more likely to do this than men (21%),
than those who are currently employed. and younger people (42%) were more likely to
do so than people in older age groups. This may
Fewer than one in ten people (7%) have also be an indication of the central role of peer
sought help from their GP to deal with relationships in the lives of young people.
anxiety, although those who feel anxious
more frequently are much more likely The survey explored peoples use of three active
to do this. approaches to coping with stress. Almost one-third
of all respondents (30%) said they would go for
We asked people who have experienced anxiety a walk to cope with anxiety, a little under a quarter
in their lives to identify the different ways they said they would undertake a physical activity or do
cope with it. Just under one in five (19%) do not some exercise (23%), while fewer (13%) would
do, or use, anything to cope with anxiety in their use relaxation or meditation. While these ways
everyday lives. The findings revealed an inverse of coping were employed fairly consistently across
relationship between the frequency with which all groups, the results suggest that people from
people experience anxiety and how active they social grades AB&C1 (27%) may be more likely
are in seeking ways to cope with it; so 32% of to undertake physical activities to deal with anxiety
people who rarely have anxious feelings said that than people from social grades C2D&E (19%).
they do nothing to cope with those feelings, while
only 6% of people who live with anxiety all the The survey also included four potentially harmful
time do nothing about it. The proportion of men coping strategies. Of these, comfort eating, was
not using coping strategies was higher (24%) employed by 24% of those surveyed and women
than for women (16%), and older people (28%) (29%) were more likely to cope in this way than
are less prone to using coping strategies than men (18%). People in the younger age groups
younger people. were much more likely to use comfort eating

25
than people in the older age groups. A similar
pattern across age and gender emerged in relation
to hiding away from the world, which was cited by
18% of respondents. Students were more likely
than other groups to hide themselves away; 31%
of students in the survey said they use this as a
coping strategy. The pattern of usage for alcohol
( just over one in six people) and cigarettes (one
in ten people) was not significantly different across
age groups or between men and women.

The findings suggest that unemployment may

be a factor in determining the types of strategies
that people use to cope with anxious feelings.
Unemployed people were more likely than other
groups to use potentially harmful strategies: about
a quarter (23%) said they would hide away from
the world, use alcohol (27%) and use cigarettes
(23%). In contrast, people who are retired are
much less likely than any of the other groups
to use any of these potentially harmful coping
strategies to cope with their anxiety.

Visiting a GP to deal with anxiety was an option

taken up by just 7% of respondents who had
reported anxious feeling at some point in their
lives, a proportion that was consistent across
gender and age groups. Yet those experiencing
anxiety most frequently were over five times more
likely to visit their GP than the survey sample as a
whole, while those experiencing anxiety a lot of the
time were more than twice as likely to visit their GP.

Despite this apparently low rate of self-referral

usage to GP services, 27% of those surveyed
agreed that a problem with anxiety is something
they would see a GP about. Agreement amongst
women was higher (31%) than amongst men
(23%), and more than half (56%) of those
experiencing anxiety nearly all of the time agreed
that anxiety is something they would visit their
GP about.

26
Perceptions of anxiety
People are believed to be more anxious now
than they were 5 years ago.
There is a tendency to reject the notion that
having anxious feelings is stigmatising.
People who experience anxiety most
frequently tend to agree that it is stigmatising.
The survey found strong agreement with the
proposition that people are more anxious now
than they were five years ago; as one might
expect, agreement is strongest amongst people
who experience anxiety most frequently (72%).
People were also asked to indicate the extent
of their agreement with statements addressing
aspects of stigma that may be attached to
anxiety. Just over a quarter of respondents
(26%) felt that feeling anxious is a sign of not
being able to cope, but almost twice as many
(50%) disagreed with this sentiment. Slightly
more people (29%) agreed that they would be
embarrassed to tell someone they have anxieties,
but again just under half (46%) indicated that
they would not be embarrassed. There was an
even stronger rejection of the notion that feeling
anxious is something to be ashamed of; just
10% of people agreed with this sentiment, while
nearly three-quarters (74%) of them disagreed.
However, people experiencing anxious feelings
most frequently were much more likely to
agree with these stigmatising views of anxiety,
while, conversely, respondents who had never
experienced anxious feelings were much more
likely to disagree with the proposition that they
would be embarrassed to tell someone they
have anxieties (57%).
27
The impact of anxiety
Just under half of people get anxious more
often these days than they used to and
believe that anxiety has stopped them
from doing things in their life.
Most people want to be less anxious in their
day-to-day lives.
Women and younger people are more likely
say that anxiety has impacted on their lives
in these ways.
We asked three questions of those people who
had experienced feelings of anxiety about the
impact it has upon their lives. More people agreed
(47%) than disagreed (31%) that they get more
anxious these days than they used to and there
were similar levels of agreement that feelings
of anxiety had stopped them from doing things
in their lives. There was a more clearly defined
tendency for people to agree (57%) than disagree
(14%) when asked if they would like to be less
anxious in their day-to-day lives. In each of these
domains, the tendency for agreement was larger
for women compared to men and for people in
the younger age groups compared to the older
age groups. People experiencing anxiety on a
frequent basis were also more likely to agree
than disagree with these statements.
The state of the nation
Our survey provides an important insight into
the impact that anxiety has upon peoples
everyday lives. The findings suggest that feelings
of anxiety are experienced widely and form part
of a familiar emotional landscape for people taking
part in the survey. The survey highlights those
areas of peoples lives most likely to generate
feelings of anxiety; stresses and worries about
families and personal relationships are a major
cause of anxiety, while financial issues and work-
related matters feature prominently in peoples
concerns. Overall, people believe that society
is more anxious than it was five years ago and
many of those who have experienced anxiety
in their own lives say that they are more anxious
than they used to be. However, the message
from people taking part in our survey is that
anxiety is not something to be ashamed of or
embarrassed about, or that anxious feelings
should be interpreted as a sign that someone is
unable to cope. This perhaps tells us something
about the level of awareness about anxiety that
now exists amongst the general public and their
potential receptiveness to initiatives to address
the problems posed by anxiety.
An important message to emerge from the survey
is that people find a variety of ways of coping
with feelings of anxiety that fall short of seeking
professional help. Although we made no attempt
to gauge the effectiveness of these strategies,
the preferences expressed for simple human
interaction and physical activity may suggest that
people deal with feelings of anxiety in ways that
have proved helpful with other emotional crises.
The survey also maps a less positive tendency
for some people to use potentially harmful
coping strategies, notably comfort eating or
social withdrawal.
28
The survey identifies discrete groups within the
populations for whom anxiety may be persistent
and at times debilitating, or for whom anxiety has
a disproportionate impact. It suggests that there
is a small but significant group of people for whom
anxious feelings are a constant presence that
may provoke a heightened sense of stigma, yet
they are also more active than most in seeking
ways to cope with them and are more likely to call
upon primary care services for help. This group
will include people who have a recognised anxiety
disorder, whether diagnosed or not, as well as
those at risk of experiencing acute episodes
of anxiety.
The survey suggests that gender, age and
employment status may be factors in shaping
the experience of anxiety in the UK. It reconfirms
that anxiety has a disproportionate effect upon
the lives of women compared to men in terms
of the frequency of anxious feelings, the source
of their anxiety and their preferences for coping
with it. Women are also more likely to report that
their anxiety has had a negative impact upon their
lives by, for example, stopping them doing things.
Similarly, younger people are more likely to be
affected by anxiety than people from older groups,
while people in the oldest age group (55 years and
over), and especially retired people, are markedly
less likely to be affected. Finally, the survey does
suggest that people who are not employed are
more likely to experience anxiety more frequently
than those in work, are more likely to be anxious
about financial matters, and be more likely to
cope in ways that are potentially harmful.
 Living with anxiety: Jane,
Volunteer, early 50s
I was probably considered a shy child, but I didnt
have any major problems in childhood. I had
one or two good friends although I wasnt really
comfortable in big groups and I did panic if I was
ever invited to parties or if there was a big group
thing in class. My anxiety has always been social
anxiety, so it has prevented me from doing a lot
of things. It really came to a head in my teenage
yearsthat traditional transition stage when I
was doing exams. That was when it really started
to kick in and I couldnt go to school, I couldnt
sit my exams, so I left and I got a job through
a relative. But I struggled with the work so I had
to leave. I tried college and had to leave that too.

I felt very ashamed and very embarrassed about

having anxiety and it was something I tried
desperately to cover up. Of course the more
I tried to cover it up, the more anxious I became.
I thought there was a real stigma around anxiety
at the time; I didnt realise that young people of my
age had similar experiences and feelings. I thought
it was just something that affected adults. My
father suffered with anxiety and it was something
he was ashamed of. He tried to cover it up and
wouldnt talk about it. So I picked up on that as
being something to be embarrassed about.

My GP diagnosed anxietyit wasnt social anxiety

then, it was just anxietyand he gave me valium;
I was about 17 at the time. I was also referred to
a psychologist at the local hospital, but I really
didnt understand what the psychologist or
psychiatrist was telling me; it was very unpleasant.
The tablets worked while I was taking them, but
once I stopped taking them, all the symptoms
came back and I still had all the very negative
frightening thoughtsit didnt help those. I had
a lot of physical symptoms, blushing and sweating
which people would comment on, so I became
more and more withdrawn. Eventually, I stopped
going out, so I lost friends, had no social life, no
relationships and became quite housebound. My
anxiety has meant that I havent been able to work

29
for a long time and even looking for a job is really
really difficult for me. I wanted to do something
because Im on benefits and I wanted to give
something back, also to feel better in myself,
to boost my own self-esteem.
I am a member of Anxiety UK and Ive been
working as a volunteer on their helpline for about
4 years now. I decided to do some volunteering
to help me practise my coping skills. I was always
terrified of doing it and then somebody gave me
a push and said Youve got to make an effort
now. I had a major panic attack the first day
I was here, but one of the staff took me outside
and had a chat with me; they said, Its OK, its
understandable, weve seen this before, its not
only you that this has happened to. Just hearing
thatthat it happens to other people as well
made all the difference. Everybody here has
experience of anxiety or, if they havent, they have
a special interest in it, so I dont have to hide it.
That was the biggest thing: not having to hide it.
I could have anxiety attacks with all the symptoms
and nobody would make any comments about it.
The people here have encouraged me and given
me support, and that has really helped me build
my self-esteem and confidence.
The biggest change has been coming here
because its such a supportive environment.
Peer support is the main thing that helps me cope,
but Ive also done an online CBT course. Ive seen
some therapists, but it may be part of my anxiety,
I just feel uncomfortable with therapists being
in the room; I feel trapped. I think its my social
anxiety. So Ive not been able to concentrate on
what they are saying because Ive been focused
on my anxiety and wanting to leave. Doing it online
there were no distractions and I really seemed to
take that in. Ive used those CBT techniques and
breathing control. There is some excellent self-help
online. So its been a combination of things.
30
Because it has been there for such a long time,
anxiety has taken root. Maybe I have an anxious
nature, so it is always going to be a part of my life.
But now I understand it a lot better, I know I am not
the only one who has itthat helps a lotand it
doesnt worry me as much because I have some
coping techniques and know what I can do to
reduce my anxiety.
Working here I can give people hope because
when they ring up they often think that anxiety
is going to ruin their lives and they are never going
to get better. I tell them, from my many years
experience, You can learn to manage it, it doesnt
have to control you, you can still get on with your
life. If you nip it in the bud when it starts, you have
a better chance of it not getting really bad. Dont
be frightened of it and dont bottle it up; share it
with someone you feel comfortable with. I also
contribute to a course at a local university, helping
to train therapists of the future. The fact that I
can use my anxiety in a positive way like this is
a massive thing for me because for so many years
I felt ashamed and embarrassed about it. So to be
able to talk about it openly and for my experience
to be embracedthey really want to hear itthats
been tremendous for me. And in general, I think it
makes you a more caring person, I really do.
Managing anxiety
A person cannot just simply decide not to be
anxious anymore (Anxiety Care UK).
Although anxiety can be a debilitating condition,
it is not an illness and therefore is no more
susceptible to being cured than other emotional
states that serve important functions as part of
the human survival kit. Our survey illustrates how
people experiencing anxiety in their everyday lives
often find the personal resources to cope through
simple remedies such as talking things through or
doing a physical activity, although the finding that
people from social grades C2D&E are less likely
to engage in a physical activity may suggest an
inequality in access to such resources. This gives
pause for thought when considering emerging
evidence on the benefits of this form of coping
strategy on wellbeing more generally (Mental
Health Foundation, 2013) and in managing stress
levels specifically (Gerber and Puhse, 2009).
These self-help strategies are less likely to work
for more acute disorders even though most are
highly treatable and full recovery is an achievable
goal. Medicines can ameliorate the worst
symptoms and aid the recovery process, but
are less useful in helping people to manage
the threat of relapse in the longer term. Lingering
symptoms, vulnerability to normal anxiety, and
stress-related intensification of symptoms and
anxiety contribute to a continuous risk of relapse,
but these are factors that are directly addressed
by psychological therapies which have been
shown to improve the long-term outcomes
for people who seek this type of help.
In 2010 it was estimated that there were 8.2
million diagnosed cases of anxiety disorder in
the UK (Fineberg et al., 2013) yet only about
one-third to half of sufferers receive treatment
(McCrone et al., 2008). One of the problems of
tackling anxiety disorders in the UK is the fact
that despite the incidence of anxiety symptoms
rising between 1998 and 2008, the incidence of
GP recorded anxiety diagnoses fell over the same
31
period (Walters et al., 2012). A number of reasons
for this apparent under-recording have been
suggested, including an increased preference by
GPs for recording the symptoms of anxiety rather
than specific diagnoses. Others have suggested
a preference for broad diagnostic labels, such as
anxiety states, which may reflect a lack of training,
a belief that the distinctions in anxiety states
are not meaningful in primary care practice,
or reluctance to use formal diagnoses which
may be perceived as stigmatising for patients
(Walters et al., 2012).
Others have pointed to structural problems in
the pathways that exist between primary and
specialist services following implementation of
the National Service Framework for Mental Health
(Cohen, 2008). This introduced the Improving
Access to Psychological Therapies (IAPT)
programme, which is designed to provide services
for those suffering from anxiety and depression
disorders; during the year 201213, more than
three-quarters of a million people in England were
referred to IAPT services nationally. Yet there is
evidence that only half of the people referred to
IAPT services go on to receive treatment, while
for those that remain, about half show significant
improvements or recover (Richards and Borglin,
2011). Somewhere along the line a great many
people who experience anxiety are either
not getting the treatment they require or are
choosing not to complete the course of therapy.
At the same time, the treatment of co-morbid
health and anxiety problems in acute patients
appears to be seriously under-developed.
For example, while 42% of patients with
cardiovascular disease are currently provided
with rehabilitation, only 16% of these programmes
have a psychological component, despite 31%
of these patients experiencing signicant anxiety
problems (Naylor et al., 2012). New collaborative
approaches involving a number of health
professionals working together with a patient
are likely to help and have been associated with
significant improvements in depression and
anxiety outcomes compared with usual care
(Archer et al., 2012).
Several different treatments are available to Health Foundation (2013) that exercise can be
ease the psychological and physical symptoms particularly effective in reducing the symptoms
of anxiety, including psychological therapies and of clinical anxiety when combined with CBT,
medication, as well as a range of guided self- although a review of 7 RCTs found no effect
help strategies and exercise on prescription. The for interventions comprising aerobic exercise
National Institute for Health and Care Excellence only (Bartley et al., 2013).
(NICE) recommends a stepped care approach to
treatment, starting with interventions that are the Media link: Gretchen Reynolds How Exercise Can
least intrusive of those likely to be effective (NICE, Calm Anxiety (New York Times).
2012). However, the evidence about the most
effective ways of treating anxiety is mixed and Cognitive Behavioural Therapy
we know little about the treatment preferences When someone is distressed or anxious, the way
of those seeking help with anxiety. This is worth they see and evaluate themselves can become
further exploration, as one American review negative. Cognitive behavioural therapy (CBT)
found evidence for enhanced outcomes for those helps people to understand the link between
receiving the treatment of their choosing and negative thoughts and mood and how altering
a marked preference for psychotherapeutic their behaviour can enable them to manage
support over other forms of treatment (McHugh anxiety and feel in control. It is the most effective
et al., 2013). non-pharmacological treatment for reducing
the symptoms of almost all mental health
Keeping active problems, but especially anxiety and depression
Studies on participation in leisure activities have (Stuhlmiller and Tolchard, 2009; Olatunji et al.,
shown improvements in self and life satisfaction, 2010), for people with anxieties about their health
which helps in reducing depression and anxiety (Tyrer et al., 2013), and leads to more general
and enhances a persons sense of wellbeing improvements in the quality of life of people
(Haworth, 2010), while the evidence about the experiencing anxiety (Hoffman et al., 2014).
effectiveness of exercise alone is mixed. According CBT has also been shown to be effective with
to Sport England, participation in physical activity children and young people, although it is not
and sport has been shown to be effective in yet clear whether it is more effective than other
reducing depression, anxiety, psychological treatments for these younger age groups
distress and emotional disturbance. Low to (James et al., 2013).
moderate physical exercise can reduce anxiety
and have both short and long-term beneficial One feature of CBT is that it is ashort-term therapy
effects on psychological health. Taking part in and, it is claimed, can be delivered effectively
sport and spectating can have a positive impact by primary care therapists either face-to-face
on the wellbeing and happiness of young people or as part of a self-help programme (Hifdt et
(ONS, 2014). A major limitation in the evidence al., 2011). There is evidence that CBT delivered
base is that while numerous studies and meta- in primary care settings has a moderate effect
analyses show that exercise is associated with on reducing symptoms of anxiety (Seekles et
reduced anxiety in clinical settings, not enough al., 2013). NICE therefore recommends CBT for
research has been done to map the effect of anxiety and panic disorders, and the availability
exercise on anxiety in real life (Anderson and of it has expanded rapidly in England under
Shivakumar, 2013). A recent systematic review the government-funded Improving Access to
of relevant Randomised Controlled Trials (RCTs) Psychological Therapies (IAPT) programme. The
concluded that exercise is effective in conjunction Scottish Mental Health Strategy (201215) has
with other treatments (Jayakody et al., 2014), also committed to improving and monitoring
confirming the conclusions of the Mental access to psychological therapies with an

32
important focus on older people, where there It may be helpful to think of
remains an equity issue across the UK despite
this approach in terms of a
an emerging evidence base of effectiveness
in treating anxiety and depression in later life radio. That is, imagine that the
(McMurchie et al., 2013). negative thoughts that drift
Media link: Jane Feinmann Coping with anxiety
into your mind are coming from
on the cheap (the Daily Telegraph). a loud radio that is tuned to a
station where the thoughts are
Mindfulness
Mindfulness is a variation of CBT in that it focuses very negative and seem to be
on changing the relationship between the shouting at you.
anxious person and his or her thoughts, rather
The skill in mindfulness is not
than changing the thoughts themselves. Using
meditation and similar techniques, it can help so much about trying to turn
people break out of the automatic pilot mode that the radio off, but changing the
leads to negative ways of thinking and responding.
Instead, it is about helping people to experience
way you listen to the radio. In
the world in the here and now. It does this by this way the volume of the radio
addressing the bodily symptoms experienced station can be reduced, and
when someone is anxious, but rather than avoiding
or withdrawing from these feelings, he or she therefore seem less disruptive
remains present and fully experiences them and and distressing.
in this way is able to observe their reactions in a
different way. One guide to mindfulness provides
a useful analogy:12

Reviews of studies into Mindfulness Behavioural

Therapy (MBT) have found the approach has a
strong positive effect upon mood and symptoms
of people with anxiety disorders (Hoffman et al.,
2010; Vollestad et al., 2012).

Media link: Julie Myerson How mindfulness based

cognitive behaviour therapy changed my life
(the Guardian).

33 12. From the Centre for Interventions information sheets.

Guided self-help
Guided self-help has become an increasingly
popular way of offering treatment because of
its low cost, adaptability to different forms of
digital and social media and its acceptability
to people who might otherwise not receive
treatment (Andrews et al., 2010) either for reasons
connected with their anxiety or because of time
pressure from commitments such as caring.
Most guided self-help is based on cognitive
behavioural approaches and aims to help the
person experiencing anxiety achieve a level of
recovery whereby they are able to understand
the nature of their anxiety and what is happening
physiologically to them. They are then helped
to develop the necessary skills to tolerate and
cope with it, by challenging unhelpful thinking,
evaluating their bodily symptoms realistically
and managing graded self-exposure to the
source of their anxiety.
Computerised CBT can be supported by reminders
from a non-clinical technician or practice nurse,
or guided by a clinician via telephone, email, live
links such as Skype, or posts on a private forum.
Many areas of the country also have self-help
groups that offer peer support. Andrews et al.
(2010) point out that a major advantage of this
form of CBT is the level of treatment fidelity that
can be achieved. Similarly, an evaluation of an
online mindfulness course has shown promising
results in terms of the acceptability of the means
of delivering help to people who might otherwise
not receive treatments and its ability to decrease
the anxiety experienced by course participants
(Krusche et al., 2013).
34
There is good evidence that guided self-help is
effective for:
Certain types of disorder, such as social
phobia and panic disorder (Vant Hof et al.,
2009; Lewis et al., 2012; Mayo-Wilson and
Montgomery, 2013).
Reducing the symptoms of some anxiety-
related conditions and improving quality of
life outcomes (Haug et al., 2013; Stubbings
et al., 2013).
Children with anxiety disorders
(Creswell et al., 2010).
People who are motivated (Newman et
al., 2011).
Those who have lower level anxiety problems
(Newman et al., 2011).
People who are not able or are not willing
to use other services for people with
anxiety disorders (Mayo-Wilson and
Montgomery, 2013).
There are doubts as to the long-term effectiveness
of these approaches compared to face-to-face
approaches (Coull and Morris, 2011; Haug et
al., 2013) and there is a lack of evidence of their
usefulness with older people or people with
more severe conditions (Newman et al., 2011).
Nevertheless, there are good reasons to believe
that where face-to-face CBT treatment is not
available or where individuals would choose
not to use such a service for reasons of control,
stigma or convenience, then it makes sense
to make self-help treatment widely available.
The range and diversity of self-help approaches
and methods of engagement means that
individuals have the ability to select those that
work best for their specific needs. As we engage
in more complex ways with technology then it
seems probable that we will see more innovation
develop in this field of support. More research is
needed, but a recent co-production project funded
by NHS Greater Glasgow and Clyde et al. found
that young people valued digital approaches to
self-help and peer support and recommended
increased development of digital assets aimed
specifically at and co-designed by young people
(NHS Greater Glasgow and Clyde et al., 2013).
For the past three years, The Mental Health
Foundation has worked with the Paul Hamlyn
Foundation, Comic Relief and Nominet Trust
to deliver the Innovation Labs programme,13
working with technology companies, mental
health organisations and young people to
co-design and deliver seven tools to support
young people address mental health concerns.
Throughout the process, the value of technology
to young people has been demonstrated, as
has their ability to manage risk and challenge
in online spaces.
Such developments recognise the new ways
that people want to access support, but also the
importance of providing a safe and quality assured
space to do so. At the same time it is critical that
digital spaces for mental health dont merely
replicate online what is available offline. A nuanced
understanding of the way different audiences
use technology is needed to best leverage
opportunities. Equally, digital services need to be
an opt in for those who are keen to use them, and
not an opportunity to remove or reframe existing
services by forcing people online when they arent
comfortable with that modality. In time this may
create cost-savings, but this should be a collateral
benefit and not a driver of digital innovation in
mental health.

We have also seen the development of scaled

technology-based tools for people to self-manage
mental ill health, including anxiety. A range of
products exist, with many health authorities in
the UK having engaged the services of companies
like Big White Wall14 to provide a validated, well
controlled online community for self-management
and self-exploration online. In Scotland, a different
approach is being developed with the Scottish
Government, NHS 24 and New Media Scotland
collaborating on the development of Project
Ginsberg. Ginsberg will provide a route for people
who use technology to gain insight into their
lives, using a range of apps and tools to better
self-manage distress. Ginsberg will provide an
online platform that will provide a selection of
digital products, including access to diagnostic,
treatment and monitoring tools that people can
access independently of face-to-face services.

13. www.innovationlabs.org.uk
35 14. www.bigwhitewall.com
Peer support
Peer support is a system of giving and receiving
help founded on key principles of respect, shared
responsibility, and mutual agreement of what
is helpful (Mead, 2003). The benefits of peer
support have been evidenced in a number of
studies in relation to supporting individuals
to self-manage their mental health problems
and for those whose mental health is most
at risk, such as isolated older people, people
with dementia and young carers. Identified key
benefits of peer support are the ability for the peer
mentor to provide support based on empathetic
understanding and from a position of having
previous experience of developing coping skills
for the particular set of problems encountered.
Most of the research regarding people
experiencing mental health problems has not
been specific to anxiety. However, there are
indications from work in relation to young people
during transitions and people adapting to life
with long-term conditions that peer support can
provide a helpful approach in learning to cope
with the anxiety that uncertainty brings.
UK Governments are recognising the benefits of
peer support and over recent years there has been pharmacological treatment options such as
a move to embed peer support approaches within second-generation antipsychotics (Depping et al.,
specialist mental health services as an additional
layer of support. The advancements in digital
technology may see further innovations in relation treat the physical symptoms without reducing
to peer support available online and is an area
worthy of fuller investigation in relation to anxiety.
For fuller consideration of the role of peer support,
see the Mental Health Foundations Need 2 Know
Peer Support Briefing available to download from
the Mental Health Foundation website.
36
Medication
Among patients diagnosed with anxiety,
approximately two-thirds are treated with
medication, anti-depressants accounting
for almost 80% of prescriptions made out
to this group (Martin-Merino et al., 2010).
Pharmacological interventions have been
found to be effective at improving quality of life
by reducing the symptoms of anxiety for some
patients (Hofmann et al., 2013), although not for
a significant number (Ravindran and Stein, 2010).
Medication is generally not as effective for older
adults as it is for younger adults (Wetherall et
al., 2013).
NICE suggests that for particular kinds of anxiety,
such as panic, social phobia and obsessions,
GPs should prescribe anti-depressants, especially
certain SSRIs (selective serotonin reuptake
inhibitors). SSRIs appear effective in treating
social phobia over the short term and the long
term (Stein et al., 2004), while augmentative
medications appear to be useful in the treatment
of GAD, which is a more chronic condition
(Chessick et al., 2006). Due to high rates of
treatment resistance, there is interest in new
2010). Additionally, beta-blockers and tranquilisers
are sometimes prescribed in the short term to
the psychological symptoms of anxiety.
The storm has died away,
and still we are restless,
uneasy, as if the storm were
about to break. Almost all
the affairs of men remain in
a terrible uncertainty. We think
of what has disappeared, and
we are almost destroyed by
what has been destroyed; we
do not know what will be born,
and we fear the future, not
without reason Doubt and
disorder are in us and with
us. There is no thinking man,
however shrewd or learned
he may be, who can hope
to dominate this anxiety, to
escape from this impression
of darkness
(Paul Valery, Crisis of the
Mind, 1919).
37
A new Age of Anxiety?
The term age of anxiety has been applied to
several periods in modern history and is taken
to mean a period of time marked by uncertainty
about how we make sense of life. It is often used
to refer to the period spanning the two world wars.
Previous generations, particularly in the West,
had believed that the trajectory of human society
was inexorably upwards, fuelled by the civilising
influences of faith, education and science in the
service of industry and commerce. The First World
War dealt a shattering blow to those old certainties
and the long period of economic and political
turmoil that followed is often characterised as
a time of despair and darkness. It was also marked
by a flowering of the visual arts, the emergence
of the social sciences as a discipline, and the
development of psychiatric medicine.
Are we living in similar times? The shock of the
recent economic crisis may have prompted fear
and anxiety in the short term, but some longer
term research suggests that the prevalence of
anxiety disorders is largely impervious to the
vicissitudes of the economy, suggesting instead
that social trends such as divorce and crime may
have greater explanatory validity (Twenge, 2000).
While the notion of anxiety disorders undoubtedly
relates to the individual human condition, is it
possible to speak more generally of anxiety as
a sociological phenomenon, a mood or emotion
that permeates a community of people? Can
an understanding of the state of the nations
mood give us an insight into the effects of
wider economic and social forces?
In 2010, the Government introduced a new
measure of wellbeing to broaden the indicators
of economic development in the UK. It is intended
that these indicators be used to inform the
public about the nations wellbeing and lead
to government policy that is more focussed not
just on the bottom line but on all those things
that make life worthwhile (Number10, 2010;
Hicks, 2011). One of the measures used in the
first of these wellbeing surveys relates to anxiety,
because being anxious is widely used as an
indicator of poor mental wellbeing, a widely
used generic measure of health status (Dolan
et al., 2011). This is important for the bottom
line because anxiety disorders are estimated
to cost the UK economy 10.1bn annually15
in direct medical costs as well as indirect costs
such as lost productivity due to absence from
work or early retirement (Fineberg et al., 2013).
For example, during 2011, around 27.4 million
working days were lost due to minor illnesses
such as coughs, colds and flu, while as many as
13.3 million working days were lost due to stress,
depression and anxiety. Moreover, the group of
people diagnosed with anxiety and depression
has one of the lowest rates of employment
(27.2%) of groups with a disability defined under
the Disability Discrimination Act. People suffering
anxiety are heavier users of primary care services
than other users of those services (Martin-Merino
et al., 2010) and the presence of an anxiety
disorder signicantly increases the costs
of providing care to people with long-term
conditions (Naylor et al., 2012).
Our survey showed that worries about money
and jobs are significant components of feelings
of anxiety and that employment status directly
effects how people assess their own anxiety;
working conditions, job satisfaction and job
security are known factors in peoples assessment
of their own anxiety levels (Bryan, 2012; Oguz et
al., 2013). The Office for National Statistics (ONS),
which is charged with collecting data to inform the
wellbeing indicator, has detected subtle changes
between 201112 and 201213: a small decrease
in people rating their lives as unsatisfactory
corresponding with a small decrease in the
same sample reporting high levels of anxiety.16
Yet the significant decrease in levels of anxiety
amongst people in employment was not shared
by people of working age who were unemployed
(ONS, 2013). This may reflect a shift in mood as
the worst of the recession passes, albeit short
of outright optimism about the future.
38
The age of anxiety narrative is attractive
because it appeals to our sense of zeitgeist,
a desire to find a shared mood about the defining
aspects of modern life; our work, the way we
raise children, our attitudes to people who are
disadvantaged, the future of public services, the
threat of terrorism and so on. But there is a danger
that in concentrating too much on the cultural
significance of anxiety, we miss the continuing
hidden impact of anxiety upon the lives of a great
many people. For those living with the chronic
forms of anxiety, it is more than a social index
that rises and falls over time. Even within the
last decade we have achieved a much better
appreciation of this, even though we still lack
definitive answers about the causes of anxiety
disorders. We know more about the complexity
of anxiety disorders, their symptomologies,
manifestations and the multiplicity of factors
that may be at play when someone experiences
anxiety. Our understanding has been enhanced
by a number of developments.
Firstly, a recognition by the medical and
scientific communities that anxiety is worthy
of attention. The collective clinical gaze has fallen
upon particular aspects of anxiety: developing
diagnostic consistency, the epidemiology of
the various conditions that fall within the
diagnostic criteria, causation and treatment.
New technologies have helped, so genetics
is now at the stage of suggesting heredity
as a possible factor in anxiety.
Secondly, the available options for managing
anxiety are now more sophisticated and nuanced
and we have a more robust evidence base for
assessing the effectiveness of treatments,
therapeutic interventions and coping strategies.
In particular, the utility of psychological
approaches, especially CBT, in managing anxiety
either through a therapeutic relationship or
as part of a self-help programme has been
established and there is still great scope
for expanding the availability of these.
15. At 2010 prices.
16. Both findings statistically significant at the 0.05 level.
Thirdly, the public profile of anxiety has been
raised as part of a wider public debate about
mental health and what we, as a society, need
to do about it. There are a number of strands
to this from campaigning and awareness-raising
by organisations such as Anxiety UK, to greater
interest from the news media and the emergence
of a distinctive voice for people who experience
anxiety through books and social media. These
have helped tackle perceptions of stigma that
have been associated with anxiety in the past.
While these developments are encouraging, our
own work suggests that there are still gaps that
need to be addressed in the provision of support
for people who experience anxiety. We know, for
example, that people approaching primary care
services do not always get the responses they
need, including accurate diagnosis and referral to
appropriate specialists, and too many people fail
to complete courses of treatment when they do.
39
Recommendations
We therefore make recommendations regarding
approaches to helping people with anxiety
and the research that is required to further
our understanding of the experience of living
with anxiety.
A stepped care approach should be adopted to
ensure that support to live with anxiety is provided
in the least stigmatising and most inclusive way
possible, including:
Universal approaches to learning to
live well with anxiety should be built into
school curriculums from primary 1 onwards,
including an understanding of the role
of anxiety in our lives and techniques
for managing stresses associated with
school (such as peer relationships,
exams and transitions).
Peer-led approaches should be
promoted within universal settings such
as employment, schools and universities,
in recognition of the importance that young
people place on support from peers and the
unique level of empathetic understanding
that can be provided by those with a
common experience.
Access to good quality self-help approaches
should be made available across the UK
through quality assured and co-designed
digital platforms to ensure they are fit for
purpose for those who choose not to use
face-to-face services (young people, people
in full time employment).
GP training and anxiety-related guidance
should be assessed for equalities impact
and adapted alongside groups of people
who are at highest risk of developing
problematic anxiety and least likely to have
their needs met by current service provision.
 A sample of psychological services should
be audited to establish how well referral
processes are working, who is accessing
these, and who is falling through the gaps.
This audit should include IAPT in England
and Wales and initiatives to improve access
in Scotland.
Agencies offering support to people with
anxiety should make greater use of peer
mentors and advice and information that
is explicitly based on the life experiences
of people who live with anxiety.
Research should be commissioned to
better understand:
The nature and understanding of anxiety
for different groups in society (women,
people with long-term conditions, older
people, people from black and minority
ethnic communities), and whether current
approaches and interventions can be
found to address specific needs.
The relationship between unemployment,
financial distress, and anxiety. The
Department of Work and Pensions should
develop strategies to prevent people
who are not working from becoming
marginalised from the workforce.
Processes for accessing social welfare
for those unable to work due to disability
should be assessed for their impact on
anxiety levels.
show how anxiety stems as much from concern
for family, friends and relationships as it does from
the demand of the outside world. Most people
instinctively seek solace and comfort in human
interaction when confronted with anxious thoughts
and feelings, and we know that these are the most
effective ways of dealing with them. But anxiety
can cause us to withdraw from society and
look for solutions in ways that may harm us.
We can glimpse in all of this the vital function that
anxiety plays in alerting us to threats to the things
that we hold most dear, as well as the material
things ( jobs, money, possessions) that we need
to sustain a modern existence. The testimony of
people living with anxiety demonstrates how they
cope and manage anxiety so that it remains a
vital component of who they are without coming
to define them. There remains a significant
amount of work to be done across society to
equip ourselves and bring our children up to live
with anxiety, not only focusing our attention on
the point where it becomes an identified problem,
but ensuring that we are able to get the most out
of life. Living to our full potential not limited by
the fear of anxiety.

The impact of technological advancements

in self-management for anxiety.

Perhaps the most important conclusion to

be drawn from this report is the importance
of framing anxiety as an essential aspect of our
humanity. All of us could trace a mental bell curve
like the one described by Scott Stossell to plot the
positive and negative uses to which we put our
stock of anxiety, both the creative impulses and
the destructive ones. The findings of our survey

40
Useful resources
and information
Books about the lived experience of anxiety
Scott Stossel (2014)
My Age of Anxiety: Fear, Hope, Dread, and the
Search for Peace of Mind published by Heinemann.
Daniel Smith (2013)
Monkey Mind: A Memoir of Anxiety published
by Simon & Schuster.
Blogs about living with anxiety
Claire Easthams Blog weallmadhere.
The time to change blog about anxiety.
The Anxiety No More website and a blog by
its founder Paul David.
41
Self-help guides
Northumberland Tyne and Wear NHS Foundation
Trust has a self-help guide that has been
commended by the BMA and has been well
reviewed by people accessing it online. For more
information and to download a copy, click here.
The NICE Guide to self-help resources for
generalised anxiety disorder is available to
download here.
Radio and television programmes and films
BBC Radio 4 Womans Hour Programme.
Psychological therapies
Directory of IAPT services.
The Counselling Directory has a number of articles
about anxiety.
An online mindfulness course is available at
Be Mindful Online.
Mental Health Foundation How to overcome fear
and anxiety.
A video about anxiety from the NHS
Choices website.
Anxiety Care UK website.
Tips on physical activity from the MIND website.
National organisations offering Samaritans24-hour helpline
help, advice and information 08457909090
email: jo@samaritans.org
Anxiety UK samaritans.org
08444 775 774 Emotional support for anyone feeling down,
anxietyuk.org.uk experiencing distress or struggling to cope.

Anxiety Care UK Council for Psychotherapy (UKCP)

anxietycare.org.uk 02070149955
psychotherapy.org.uk
British Association for Behavioural and Has a voluntary register of qualified
Cognitive Psychotherapies (BABCP) psychotherapists.
01617054304
babcp.com The Young Minds website has information
Can provide a list of qualified therapists. for parents concerned about a childs anxiety,
including a helpline (0808 802 5544)Monday
British Association for Counselling and to Friday 9.30am-4pm.
Psychotherapy (BACP)
01455 883300 YouthNet runs The Site which offers young adults
bacp.co.uk help with a range of problems, including anxiety.
Information about counselling and therapy.
See the itsgoodtotalk website for details of
local practitioners.

The British Psychological Society

01162549568
bps.org.uk
Produces a directory of chartered psychologists.

Mindfulness Based Cognitive Therapy

mbct.co.uk
Information about the therapy, classes in
Mindfulness and training.

NICE (National Institute for Health and Care

Excellence)
nice.org.uk
Information and guidelines on recommended
treatments for different disorders.

No Panic
Helpline 08001388889
nopanic.org.uk
Provides a helpline, step-by-step programmes,
and support for those with anxiety disorders.

42
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46
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 Magellans Clinical Practice Guideline
for the Assessment and Treatment of
Generalized Anxiety Disorder in Adults

2008-2014 Magellan Health, Inc. 7/14

This document is the proprietary information of Magellan Health, Inc. and its affiliates.
Magellan Clinical Practice Guideline Task Force

Thomas G. Carlton, M.D.

Nancy D. Donachie, M.D.
Kathleen Frampton, R.N., B.S.N., M.P.H.
Gary Henschen, M.D.
Pamela E. Kumar, R.N., B.S.N.
Kathryn Kvederis, M.D., D.F.A.P.A.
Louis A. Parrot, M.D., Ph.D.
Clifton A. Smith, D.O., M.S.
Fatimah A. Tahil, M.D., M.P.H.
Fred Waxenberg, Ph.D.

Table of Contents

Purpose of This Document .............................................................................. 3

Provider Feedback ........................................................................................... 3
Executive Summary ........................................................................................ 4
Generalized Anxiety Disorder in Adults
Assessment .............................................................................................. 9
Diagnosis and Treatment Planning.......................................................... 14
Patient and Family Education ................................................................. 14
Psychotherapy Treatments ...................................................................... 15
Pharmacology Treatments ....................................................................... 21
Combined Treatments ............................................................................. 36
Monitor Progress and Address Sub-optimal Recovery .............................. 38
References .................................................................................................... 40

2008-2014 Magellan Health, Inc. 2

This document is the proprietary information of Magellan Health, Inc. and its affiliates.
Purpose of This Document
Magellan Health (Magellan) has developed the Clinical Practice Guideline
Assessment and Treatment of Generalized Anxiety Disorders (GAD) in Adults for
use by providers working with Magellan members who may have these disorders. This
guideline is a research-based document that covers the psychiatric management of
adult patients with GAD. It reviews clinical features, epidemiology, assessment and
treatment planning including psychotherapy and pharmacotherapy. For detailed
information on the management of children and adolescents with GAD, see the
American Academy of Child and Adolescent Psychiatry (AACAP) Practice Parameter
for the Assessment and Treatment of Children and Adolescents with Anxiety
Disorders (2007).

The purpose of this document is to summarize recommendations from a literature

review conducted on GAD through April 2014. The rationale for this summary,
presented in table format, offers clinicians evidence- and consensus-based guidance
on assessment and treatment of GAD in one location for ease of use and reference.
However, clinicians also should become familiar with the content of the articles
referenced in the document.

As with all guidelines, this document is intended to augment, not replace, sound
clinical judgment. As a matter of good practice, providers should note clinically sound
exceptions to this practice guideline in the members treatment record, with
documentation of the clinical reasoning for making the exception. Magellan
periodically requests treatment records from providers in order to monitor compliance
with clinical practice guidelines. Additionally, this guideline does not supersede Food
and Drug Administration (FDA) determinations or other actions regarding withdrawal
or approval of specific medications or devices, and their uses. It is the responsibility of
the treating clinician to remain current on medication/device alerts and warnings that
are issued by the FDA and other regulatory and professional bodies, and to
incorporate such information in his or her treatment decisions.

Provider Feedback
Magellan welcomes feedback on our clinical practice guidelines. We take all
suggestions and recommendations into consideration in our ongoing review of the
guidelines. Comments may be submitted to:
Clinical Operations Coordinator
Re: CPG
Magellan Health
6950 Columbia Gateway Dr.
Columbia, Maryland 21046
CPG@MagellanHealth.com

2008-2014 Magellan Health, Inc. 3

This document is the proprietary information of Magellan Health, Inc. and its affiliates.
 Executive Summary
(A discussion of additions/changes in this updated guideline.)

This update to Magellans Clinical Practice Guideline for the Assessment and Treatment
of Generalized Anxiety Disorder (GAD) in Adults includes findings from peer reviewed
studies from November 2011 through April 2014. The new Diagnostic and Statistical
Manual of Mental Disorders Fifth Edition (DSM-5) reorganized the criteria for GAD
while leaving it virtually unchanged. The DSM-5 distinguishes GAD from non-
pathological anxiety indicating that worries associated with GAD are excessive and
usually interfere significantly with psychosocial functioning. Occurring even without
precipitants, they are more pervasive, distressing and pronounced with longer duration.
Worries are also more likely to be accompanied by physical symptoms, e.g.,
restlessness, being on edge. Patients with GAD may also have several psychic and
somatic symptoms including suicidality.

Assessment scales such as the Generalized Anxiety Disorder Severity Scale and the
Hamilton Anxiety Scale may be efficient tools for screening for GAD and assessing its
severity in clinical practice and research. Gibbons et al. reported that a new
computerized adaptive test for GAD, CAT-ANX, based on multidimensional item
response theory, allows the specific items administered and the number of items to vary
from individual to individual, leading to a decrease in the number of items required for a
fixed level of measurement uncertainty. Each patients items are selected from a large
bank of test items based on prior item responses.

The DSM-5 notes that childhood adversities and parental overprotection, although
associated with GAD, have not been identified as specific to GAD and are not sufficient
for making a diagnosis of GAD. Other associated factors include neuroticism, harm
avoidance, genetic factors and physiological factors. DSM-5 notes that one-third of the
risk of experiencing GAD is genetic.

According to the DSM-5, individuals diagnosed with GAD are most likely to have met the
criteria for other anxiety disorders and unipolar depressive disorders. A recent study by
Zbozinck et al. reviewed data from the Mini International Neuropsychiatric Interview
(MINI) to determine whether symptom overlap may inflate rates of co-morbidity between
GAD and major depressive disorders (MDD). Patients with GAD and MDD share
symptoms of difficulty sleeping, difficulty concentrating, being easily fatigued and
psychomotor agitation. Investigators found that the co-morbid GAD/MDD group
endorsed the overlapping symptoms more than a MDD group but not the GAD group. The
co-morbid group endorsed the overlapping symptoms more than the non-overlapping
symptoms. Zbozinck et al. suggested that rates of co-morbidity between GAD and MDD
may be inflated due to the symptom overlap.

The 2011 National Institute for Health and Clinical Excellence (NICE) guidelines stress
the importance of a comprehensive assessment of all patients suspected of having GAD,
considering not only the number, severity and duration of symptoms, but also the degree
of distress and functional impairment. The guidelines recommendations include active
monitoring of the individuals symptoms and functioning, indicating how active
monitoring may improve less severe presentation and avoid the need for additional
interventions.

2008-2014 Magellan Health, Inc. 4

This document is the proprietary information of Magellan Health, Inc. and its affiliates.
Psychotherapy Treatments
A recent randomized controlled trial by Norton et al. investigated the efficacy of a 12-
week transdiagnostic cognitive behavioral therapy (CBT) group treatment compared to a
12-week established diagnosis-specific group CBT treatment for panic disorder, social
anxiety disorder and GAD. Individuals with these disorders were randomized to the
transdiagnostic CBT group (received treatment deemphasizing diagnostic labels and
focusing on confronting feared stimulation including psychoeducation, cognitive
restructuring and exposure therapy) or the diagnosis-specific group (received treatment
specifically targeting the individual diagnosis). Results showed effects of transdiagnostic
CBT were as strong as those of diagnosis-specific CBT on outcome measures.
Researchers suggested that a single transdiagnostic CBT applicable to more than one
anxiety disorder may encourage more mental health practitioners to adopt CBT for the
treatment of all three disorders. Patel et al. have noted that CBT is the cornerstone for
treatment of adults with GAD, suggesting that if it is not effective, other therapies, e.g.,
relaxation training, worry exposure or exposure therapy, or short-term psychodynamic
psychotherapy, may augment or replace it.

A study by Paxling et al. addressed the content of therapist e-mails in therapist-guided

internet-based cognitive behavioral therapy (iCBT) for GAD. In this randomized trial,
three therapists delivered iCBT to participants diagnosed with GAD. Different therapist
behaviors had an impact on module completion. Allowing deadline flexibility was found
to be associated with negative outcome whereas task reinforcement was associated
with a positive outcome. Investigators suggested the need for larger studies addressing
the impact of e-mail support given in addition to traditional therapy. Bandelow has
suggested that internet-based CBT should not be recommended for the treatment of GAD
as trials have not compared it to traditional CBT in which the patient and therapist are
in personal contact.

A recent randomized controlled trial conducted by Bush et al. used the Pittsburgh Sleep
Quality Index (PSQL) as an outcome measure in a study examining the response to CBT
compared to enhanced usual care in older adults with GAD. Participants were
randomized to treatment with CBT (including psychoeducation, motivation interviewing,
relaxation training, cognitive restructuring, exposure, problem-solving skills training and
behavioral sleep management) or to enhanced usual care (including telephone
conversations with a therapist focusing on safety monitoring and providing support).
Outcomes measured by the PSQL administered at 3-months posttreatment and over a
12-month interval showed that participants who received CBT for anxiety experienced
improvement on scores of sleep quality, sleep latency and sleep disturbances than those
who received enhanced usual care. Researchers noted, however, that CBT did not
achieve improvement in sleep duration, daily functioning or the use of sleep medications.

Brenes et al. examined the effects of CBT delivered by telephone (CBT-T) to older
participants with GAD, panic disorder, combined GAD and panic disorder, or anxiety
disorder not otherwise specified. In this randomized controlled trial, participants were
randomized to CBT-T (including telephone therapy sessions and a treatment workbook,
a telephone therapy session and discussion with therapist) or to information-only
comparison (including written information on anxiety disorders and a list of referral
options). Findings of this study included: 1) participants receiving CBT-T demonstrated
greater improvement in self-report and clinician-rated worry and anxiety symptoms than
those in the information-only group; and 2) participants receiving CBT-T experienced
greater reductions in insomnia and anxiety than the information-only group. This effect
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did not continue six months after treatment completion. Researchers suggested a longer
intervention and also suggested that CBT-T may be helpful in a stepped-care to late-life
anxiety as older adults often prefer psychotherapy to pharmacotherapy. CBT-T does not
require attendance at regular face-to-face therapy sessions which older adults may not
be able to attend.

In another study, participants were randomized to an 8-week program of manualized

Mindfulness-Based Stress Reduction (MBSR) or to an attention control, Stress
Management Education (SME) to compare the effects of the two treatments. MBSR
included group in-class practices, e.g., breath-awareness, gentle Hatha yoga and Body-
Scan exercises, focusing on present experience and treating the body gently.
Participants were also instructed in present-focused awareness while eating, bathing or
cleaning. SME was taught in a didactic format comprising both class and home
activities, e.g., stress physiology, time management techniques, sleep physiology and
factors that buffer the impact of stress. Both MBSR and SME resulted in significant
reduction in anxiety symptoms as measured by the Hamilton Anxiety Scale, but MBSR
was associated with greater reduction in anxiety as measured by the Clinical Global
Impression of severity and Improvement and the Beck Anxiety Inventory compared to
SME. Researchers suggested that MBSR may result in greater resilience to stressful
psychological challenges and reduce anxiety symptoms in patients with GAD.

Pharmacology Treatments
Strongest evidence of clinical efficacy in the treatment of GAD has been found for the
first-line treatments for GAD: SSRIs escitalopram, paroxetine, sertraline; SNRIs
venlafaxine and duloxetine; and the calcium channel modulator - pregabalin. Second-
line treatment options include buspirone, benzodiazepines, i.e., alprazolam and
diazepam, and the antihistamine hydroxyzine. Quetiapine, an atypical antipsychotic, is
used as monotherapy in GAD and is reserved for treatment-refractory cases. Bandelow
et al., in a practical summary of the World Federation of Biological Psychiatry (WFSBP)
guidelines, advises that the benzodiazepines should only be used for long-term
treatment after other drugs or CBT have failed.

Berger et al. compared healthcare costs of patients with GAD who received treatment
with a benzodiazepine adjunctive to antidepressants to costs of patients who did not
receive concomitant therapy, finding that healthcare costs increased following
benzodiazepine treatment. Further, they noted that approximately half of the increase in
cost was associated with known sequelae of long-term treatment with benzodiazepines.
A later systematic review and meta-analysis performed by Offidani et al. analyzed
whether controlled comparisons support the current prescribing pattern favoring newer
antidepressants (SSRIs and SNRIs) over benzodiazepines. Researchers reported studies
showing no significant differences in response rates between patients receiving
benzodiazepines, venlafaxine XR, or placebo, although more adverse events (and
discontinuations of treatment) occurred in patients taking venlafaxine XR than in those
treated with benzodiazepines. Another study reviewed by Offidani et al. showed that
both lorazepam and paroxetine treatments were effective in reducing anxiety-related
psychiatric symptoms; however, somatic features improved significantly only in those
taking lorazepam. Researchers noted serious side effects of treatment with SSRIs, e.g.,
sexual dysfunction, weight gain, risk of osteoporosis, hyponatremia, gastrointestinal
bleeding and potential for drug interactions. They also noted a potential advantage of
SSRIs over benzodiazepines: the associated lower impairment in cognitive and
psychomotor skills. Nonetheless, they concluded that literature does not support the
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pattern favoring newer antidepressants over benzodiazepines in the treatment of
anxiety disorders. Bandelow et al. have reviewed literature demonstrating the efficacy
of escitalopram, paroxetine, and sertraaline, while also noting associated adverse
effects that may impair compliance. Researchers have suggested that SSRIs be taken in
the morning to avoid nocturnal restlessness and insomnia at the beginning of treatment.
Bandelow et al. have also reviewed literature reporting the results of randomized trials
demonstrating the efficacy of SNRIs, indicating that adverse effects may impair
compliance.

Mezhebovsky et al. conducted a large study to evaluate the efficacy and tolerability of
quetiapine XR monotherapy in older patients with GAD. Patients were randomized to
quetiapine XR or to placebo over a 9-week treatment period and a 2-week drug-
discontinuation period. Treatment was initiated at 50 mb/day with dose adjustment
made based on efficacy and tolerability. Results of this study showed significant
benefits over placebo (reduced anxiety symptoms at week 9 as measured by the
Hamilton anxiety Rating Scale). Additionally, significantly improvements were seen with
quetiapine XR as early as week 1, suggesting it may reduce anxiety symptoms within a
timeframe similar to benzodiazepines. Mezhebovsky et al. concluded that quetiapine XR
monotherapy is an effective, short-term treatment in older persons with GAD, improving
anxiety symptoms as well as quality of life. A small study by Chen et al., including
patients with an anxiety disorder or a mood disorder with anxiety symptoms who were
randomized to quetiapine XR as an adjunct to treatment with antidepressants
(escitalopram, paroxetine, venlafaxine, duloxetine and mirtazapine) or to a placebo plus
antidepressant, found a short-term benefit at 4-weeks in the group treated with
quetiapine XR as an adjunct to antidepressant treatment. At 8-weeks, there were no
significant differences between the two groups based on changes in anxiety symptoms.
Researchers suggested further studies are needed.

Pregabalins effect on sleep disturbance in patients with GAD was studied in a recent
review by Holsboer-Trachsler and Pieto). A review of the results of seven randomized
controlled trials found that treatment with pregabalin is associated with improvement in
sleep, functioning, and quality of life in patients with GAD. Adverse effects, including
sedation, were mild to moderate and limited to the first 2-3 weeks of treatment.

Levitan et al. reviewed two studies investigating the efficacy of the novel
antidepressant, agomelatine, for treatment-resistant GAD. The studies showed that
agomelatine demonstrated higher rates of response and anxiety remission than placebo
at 12 weeks, and patients randomized to continuing agomelatine after week 16 showed
a lower incidence of relapse than the placebo group. A more recent literature search and
review indicates that potential interactions with a number of compounds necessitate
caution when prescribing agomelatine. This updated guideline also discusses plant-
based medicines that show evidence for anxiolytic effects. Sarris et al. discuss the use
of these anxiolytics, cautioning that some may have mild and serious adverse effects.

Wetherell et al. examined whether sequenced treatment with escitalopram and CBT
boosts response and prevents relapse in older adults with GAD. Patients started on
escitalopram were randomized to one of four groups: 1) escitalopram augmented with
CBT followed by maintenance escitalopram; 2) escitalopram alone followed by
maintenance escitalopram; 3) escitalopram augmented with CBT followed by
maintenance placebo; and 4) escitalopram alone followed by maintenance placebo.
Findings showed that treatment with escitalopram followed by augmentation with CBT
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resulted in greater improvement in decreasing symptoms of worry measured by the
Penn State Worry Questionnaire than escitalopram alone. Patients receiving
maintenance escitalopram had a significantly lower relapse rate than those receiving
placebo. Among patient receiving maintenance placebo, those receiving escitalopram
augmented with CBT had lower rates of relapse than those who had escitalopram alone.
Wetherell et al. concluded that in older patients with GAD, antidepressant medication
augmented with CBT reduces pathological worrying and relapse, even when
antidepressant treatment is stopped after augmentation, noting that CBT could be an
option for older patients who prefer to discontinue antidepressants.

Bandelow et al. recommend that development of the treatment plan for GAD should be
affected by several conditions, e.g., preferences of patients, co-morbidity, severity of the
illness, substance use disorders, suicide risk and history of prior treatment.
Recommendations also include providing information and support to both individuals
with GAD, their families and their caregivers.

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Generalized Anxiety Disorder in Adults:

Recommendations Based on Recent Literature Review

Magellan conducted a review of the clinical literature on assessment and treatment of
GAD in adults. Key relevant recommendations from this literature are summarized
below. Magellan encourages providers to be familiar with this information and consult
the referenced research articles.

GENERALIZED ANXIETY DISORDER (GAD) IN ADULTS

PROCEDURE RECOMMENDATIONS
Assessment Generalized anxiety disorder (GAD) is a common condition with
a life-time prevalence 4.3%-5.9% and a 1-year prevalence of 0.2%-
4.3% (Bandelow et al., 2013; Kessler, Chiu, et al. 2005). In other
countries, the 12-month prevalence ranges from 0.4%-3.6%. (APA,
2013).The age of onset of GAD differs from that of other anxiety
disorders, with the majority of cases presenting between 35 to 45
years of age. Peaking in middle age, the prevalence of the diagnosis
declines across the later years of life, although GAD may be the
most common anxiety disorder among the older population (aged
55 to 85 years). Typically, symptoms fluctuate in intensity over
time, but GAD is usually a chronic condition where patients report
reduced quality of life related to general physical, mental and
social health and being unable to function as usual an average of
1.5 to 5.4 days per month (Collins et al., 2009; Baldwin, 2004).
GAD appears to be more common in primary care than in the
general population, suggesting that patients with GAD are high
users of primary care resources. GAD is diagnosed twice as often
in women as in men; in clinical settings, 55%-60% of those with
GAD are women (APA, 2013). Prevalence rates are higher in white
and Native American persons than in black, Asian and Hispanic
individuals (Newman et al., 2013). Although GAD does stand on
its own as a disorder with distinct onset, course, impairment and
prognosis it is one of the most highly co-morbid psychiatric
conditions (Hales et al., 2010, para. 2).

According to the Diagnostic and Statistical Manual of Mental

Disorders, Fifth Edition (DSM-5) published by the American
Psychiatric Association in 2013, GAD is an anxiety disorder
characterized by persistent, excessive and difficult-to-control
anxiety and worry about a number of activities or events (APA,
2013). The worry and anxiety are out of proportion to the actual
likelihood or impact of the anticipated events, its focus often
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 shifting from one concern to another during the course of the
disorder. Having difficulty in controlling the worry, the individuals
worrisome thoughts may interfere with attention to tasks at hand.
Worries may be about everyday, routine life circumstances, e.g.,
job responsibilities, health and finances, health of family
members, their childrens misfortunes or minor matters, e.g.,
chores around the house or tardiness in meeting appointments.

GAD is distinguished from non-pathological anxiety as worries

associated with GAD are excessive and usually interfere
significantly with psychosocial functioning. They may occur
without precipitants, and are more pervasive, distressing, and
pronounced with longer duration. Worries associated with GAD
are much more likely to be accompanied by physical symptoms,
e.g., restlessness or feeling keyed up or on edge. Constant worry
and related impairment in social, occupational or other important
areas of functioning lead to subjective stress (APA, 2013). GAD
may be accompanied by several psychic and somatic symptoms
including suicidality. Other features supporting diagnosis of GAD
include muscle tension, and somatic symptoms, e.g., nausea,
diarrhea, sweating, irritable bowel syndrome, headaches and
exaggerated startle response.

Clinical presentations often include somatic illness, pain, fatigue,

depression and problems with sleeping. Diagnosis of GAD must
meet the following DSM-5 criteria:
Persistent and excessive anxiety and worry about common
events or activities occur on more days than not, for six
months or more. Worry may focus on finances, marriage,
children, personal or family health, job performance or
security. The extent of anxiety is in excess of what might be
considered reasonable given the reality of the situation.
Difficulty controlling worry is associated with at least three of
the following six symptoms: restlessness or feeling keyed up or
on edge, easy fatigability, difficulty concentrating or mind
going blank, irritability, muscle tension and sleep disturbance
(difficulty falling or staying asleep, or restless unsatisfying
sleep).
Clinically significant distress or impairment in social,
occupational or other important areas of functioning are
caused by the anxiety, worry or physical symptoms. Diagnosis
of GAD should be made only when the focus of anxiety or
worry is unrelated to disorders, such as worry about entering
a social situation (social anxiety disorder) or as a response to
an identified stressor (adjustment disorder), having a panic
attack (as in panic disorder), gaining weight (as in anorexia
nervosa), being contaminated (as in obsessive-compulsive
disorder), having multiple physical complaints (as in
somatization disorder) or having a serious illness (as in
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 hypochondriasis). Also, in GAD, the worry does not occur
exclusively during post-traumatic stress disorder. Anxiety,
worry or physical symptoms cause clinically significant
distress or impairment in social, occupational or other
important area of function.
The disturbance is not due to the direct physiological effects of
a substance, e.g., a drug of abuse, a medication, or a general
medical condition, e.g., hyperthyroidism.
The disturbance is not better explained by another mental
disorder, e.g., panic disorder, social phobia, obsessive-
compulsive disorder, separation anxiety disorder,
posttraumatic stress disorder, body dysmorphic disorder,
illness anxiety disorder, schizophrenia or delusional disorder
(APA, 2013).
Patients with GAD may present with symptoms other than
anxiety, e.g., pain or sleep disturbance, leading to a misdiagnosis.

Assessment Scales Evidence from a criterion-standard study

found that the seven-item anxiety scale (GAD-7) has reliability,
criterion, construct, factorial and procedural validity, and may be
an efficient tool for screening for GAD and assessing its severity in
clinical practice and research (Spitzer, 2006; Kroenke et al., 2010).
Two other symptom severity measurement instruments have been
developed and tested for GAD. The Generalized Anxiety Disorder
Severity Scale (DGSS) is comprised of eight GAD symptoms for
assessment of frequency and intensity. The DGSS demonstrated
good internal reliability with the Hamilton Anxiety Scale (HAM-A)
and Clinical Global Impression Severity Scale (CGI-S) (Stein,
Fincham et al., 2009). The newly developed Daily Assessment of
Symptoms-Anxiety (DAS-A) scale was also shown to have validity
as a new instrument to assess onset of symptomatic improvement
in GAD (Feltner et al., 2009). A new computerized adaptive test for
GAD, CAT-ANX, based on multidimensional item response theory,
allows the specific items administered and the number of items to
vary from individual to individual, leading to a dramatic decrease
in the number of items required for a fixed level of measurement
uncertainty. Items are selected for each patient from a large bank
of test items based on prior item responses (Gibbons et al., 2013).

Epidemiological Data Data from the U.S. National Co-morbidity

Survey Replication (NCS-R) showed that GAD prevalence rates
changed when using a broader definition of episode from the
required 6 months. Community epidemiological data for the range
of 1-12 months showed that lifetime prevalence changed from 6.1%
to 4.2-12.7%; 12 month prevalence changed from 2.9% to 2.2-
5.5%; and 30 day prevalence changed from 1.8% to 1.6-2.6%.
Cases with episodes of 1-5 months did not differ greatly from those
with episodes greater than or equal to 6 months in onset,
persistence, impairment, co-morbidity, parental GAD or socio-
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 demographic correlates. These findings suggest that a large
number of people suffer from a GAD-like syndrome with episodes
of less than 6 months duration and question the basis for
excluding these people from a diagnosis of GAD (Kessler,
Brandenburg, et al. 2005). DSM-5 continues to include excessive
anxiety and worry (apprehensive expectation) occurring for at least
6 months as part of the diagnostic criteria for GAD (APA, 2013).

Risk Factors One study found that GAD (co-morbid or pure) was
associated with several risk factors across multiple domains of risk
during childhood: maternal internalizing symptoms, i.e., the
mothers symptoms of anxiety and depression manifesting as
insomnia, hopelessness, tension, somatic complaints, low
socioeconomic status, maltreatment, internalizing, conduct
problems and negative emotionality (Moffit, Caspi, et al. 2007).
Although childhood adversities and parental overprotection have
been shown to be associated with GAD, DSM-5 notes that these
factors have not been identified as specific to GAD and are not
sufficient for making a diagnosis of GAD (APA, 2013).
Temperamental factors, e.g., behavioral inhibition, neuroticism
and harm avoidance, are associated with GAD, as are genetic and
physiological factors. According to DSM-5, one-third of the risk of
experiencing GAD is genetic. Although there is cultural variation
in the expression of GAD, there is a lack of information about
whether the propensity for excessive worrying is related to culture
(APA, 2013).

Co-morbid Psychiatric Conditions Individuals meeting the

criteria for GAD are most likely to have met the criteria for other
anxiety disorders and unipolar depressive disorders which share
the same risk factors, although independent pathways are also
possible (APA. 2013). Other less common co-morbidities include
substance use, conduct, psychotic, neurodevelopmental and
neurocognitive disorders (APA, 2013). The co-morbidity rate with
major depression is about 59% and 56% with other anxiety
disorders (Hales et al., 2010; Canadian Psychiatric Association
Guideline, 2006). One study showed that the generalized anxiety
disorder major depression disorder (GAD-MDD) co-morbidity
may affect more of the adult population and constitute a greater
health burden than previously thought. Another study of the
association between GAD and MDD demonstrated that generalized
anxiety usually began before or concurrently in 37% of depression
cases, but depression began before or concurrently in 32% of
anxiety cases. Also, cumulatively, 72% of lifetime anxiety cases
had a history of depression, but 48% of lifetime depression cases
had anxiety. This study challenged the prevailing notion of a
predominant pattern in which generalized anxiety usually develops
into depression by showing that depression develops into
generalized anxiety almost as often (Moffitt, Harrington, et al.
2007). In addition, the co-occurrence of GAD and bipolar disorder
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 was reported from baseline data of the Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD) Study. The
investigation revealed that 18% of subjects with bipolar disorder
had a lifetime occurrence of GAD (somewhat higher for bipolar I
than for bipolar II disorder) and 51% of bipolar patients had at
least one type of lifetime anxiety disorder (Simon, 2009).
A more recent study addressed the symptom overlap of
participants (n=1218) meeting diagnostic criteria for GAD, MDD,
or both, to investigate whether co-morbidity may be explained by
overlapping diagnostic criteria. Data in the study included
symptom profiles of participants with GAD, MDD, and co-morbid
GAD/MDD. DSM-5 diagnostic criteria for GAD and MDD share
four symptoms: difficulty sleeping, difficulty concentrating, being
easily fatigued and psychomotor agitation. Authors reviewed data
from the Mini International Neuropsychiatric Interview (MINI) to
determine whether the co-morbid GAD/MDD group endorsed the
overlapping symptoms more than the non-overlapping symptoms,
and whether the co-morbid GAD/MDD group endorsed the
overlapping symptoms more than GAD only or MDD only groups.
Results showed that the GAD/MDD group endorsed the
overlapping symptoms more that the MDD group but not the GAD
group and the co-morbid group endorsed the overlapping
symptoms more than the non-overlapping symptoms. Findings
suggested that symptom overlap may inflate rates of co-morbidity
between GAD and MDD; alternatively it may represent the shared
psychopathology underlying the conditions (Zbozinek et al., 2012).

Co-morbid Physical Conditions Anxiety disorders have been

shown to be independently associated with several physical
conditions. Results from a large study, The German Health
Survey, revealed that after adjusting for socio-demographic factors
and other common mental disorders, the presence of an anxiety
disorder was significantly associated with thyroid disease,
respiratory disease, gastrointestinal disease, arthritis, migraine
headaches and allergic conditions. Co-morbidity was also shown
to be significantly associated with poor quality of life and disability
(Sareen, Jacobi, et al. 2006).

Suicide Ideation and Suicide Attempt Two studies demonstrated

that as a group of disorders, anxiety disorders were highly
prevalent among those with suicidal behavior in large community
samples. One study showed that anxiety disorders were
independent risk factors for suicidal behavior, even after adjusting
for co-morbidity with common mental disorders. Also, the
presence of an anxiety disorder in combination with a mood
disorder was associated with increased likelihood of suicidal
behavior, compared with those with mood disorder alone (Hawgood
et al., 2008; Sareen, Cox, et al. 2005). Another study of
adolescents and young adults aged 16-18, 19-21 and 21-25 years

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 showed that anxiety disorders were associated with moderate
increases in suicidal behavior and may account for approximately
7-10% of this populations rate of suicidal behaviors. There was
evidence to suggest that GAD was more strongly associated with
suicidal ideation, and that panic disorder was more strongly
associated with suicide attempts, than other anxiety disorders.
Also, the rates of suicidal behavior increased in proportion to the
number of anxiety disorders present (Boden, 2006). A more recent
study explored independent association between specific anxiety
disorders (including GAD) and suicide attempts and ideation using
a process that simulated a case-control study and made use of the
National Co-morbidity Survey Replication and the National
Epidemiologic Survey on Alcohol and Related Conditions. This
study presented evidence that each anxiety disorder, e.g., GAD, is
associated with suicide ideation and suicide attempts beyond the
effects of co-occurring mental disorders (Thibodeau et al., 2013).

Diagnosis and It is important to identify the diagnosis of GAD as early as possible

Planning in order to plan and begin treatment.

Patient and All patients who are suspected of having GAD should receive a
Family comprehensive assessment, not relying solely on the number,
Education severity and duration of symptoms, but also considering the
degree of distress and functional impairment (National Institute for
Health and Clinical excellence (NICE), 2011). Patients should
receive education from their physician about the nature of GAD,
options for treatment, and general prognosis. Physicians should
identify alleviating and aggravating factors as well as signs of
relapse for each patient. In addition, information on local self-help
and support groups, self-help reading material describing
evidence-based treatment strategies, and other resources such as
websites, may be helpful. To support informed decision-making,
patients should be informed about effectiveness, common side
effects of medications, probable duration of treatment, any costs
they might incur, and what to expect when treatment is
discontinued (Canadian Psychiatric Association Guideline, 2006).
Along with educating the patient, the individuals symptoms and
functioning should be actively monitored. Education and active
monitoring may have the effect of improving less severe
presentations and may avoid the need for further interventions
(NICE, 2011).
One study examined whether telephone-based collaborative
care for patients with panic disorder and/or GAD improves
clinical and functional outcomes more than the usual care
provided by primary care providers. Care managers called
patients at regular intervals and provided them with psycho-
education; assessed preferences for guideline-based care,
monitored treatment responses, and informed physicians of
their patients care preferences and progress via an electronic
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 medical record. Compared with the outcomes achieved by
primary care physicians usual care for panic and GAD, the
telephone-based collaborative intervention significantly
reduced anxiety and depressive symptoms, improved mental-
health related quality of life, and improved employment
patterns during the 12-month course of follow-up (Rollman,
2005).

Psychotherapy The efficacy of Cognitive Behavioral Treatments (CBT) for anxiety

Treatments in adults has been supported as a consistent and empirically
validated form of psychotherapy for GAD in the Consensus
Statement on Generalized Anxiety Disorder from the International
Consensus Group on Depression and Anxiety (Ballenger, 2001).
Additionally, the Canadian Psychiatric Association Clinical Practice
Guidelines on the Management of Anxiety Disorders (2006) notes
that CBT research demonstrates that it is more effective than no
treatment and non-specific psychological methods for GAD, and
that the magnitude of benefits is comparable to those reported in
studies of antidepressant drugs. In addition, these guidelines note
that CBT appears to be beneficial in both individual and group
settings where the benefits tend to be maintained during 6 months
to 2 years of follow-up. Several common problems have been
identified among individuals with GAD, including intolerance of
uncertainty, poor problem-solving approaches, and beliefs that
worry is a helpful way to deal with problems. The aforementioned
guidelines note that CBT interventions targeting these aspects
were effective in clinical trials (Canadian Psychiatric Association
Guideline, 2006).
Important research findings on psychotherapy for the treatment of
GAD include studies on CBT, Worry Exposure, Applied Relaxation,
Muscle Relaxation, Short-term Psychodynamic Psychotherapy and
Mindfulness-based Therapy summarized as follows:
One meta-analysis looking at the efficacy of CBT compared to
pharmacological therapy showed no significant differences in
their efficacy in the treatment of GAD. The attrition rates were
lower for CBT, which indicated that it was better tolerated by
patients. Also, because most comparisons of CBT treatments
were with the benzodiazepine drug class, more research is
needed to compare CBT to other psychotropic agents, i.e.,
Selective Serotonin Reuptake Inhibitors (SSRIs), Selective
Serotonin and Norepinephrine Re-uptake Inhibitors (SNRIs)
and buspirone (Mitte, 2005).
Another meta-analytic review of CBT in adults across all
anxiety disorders showed that cognitive therapy and exposure
therapy alone, in combination or combined with relaxation
training, were efficacious across the anxiety disorders with no
differential efficacy for any treatment components for any
specific diagnoses. When comparing across diagnoses,
outcomes for GAD and post-traumatic stress disorder (PTSD)
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 were superior to those for social anxiety disorder (Norton,
2007).
A large meta-analysis reviewed some 27 studies that examined
the efficacy of CBT versus placebo in the treatment of all adult
anxiety disorders. In comparing the average effect size
estimates of CBT, treatment efficacy for both anxiety
symptoms (Hedges g = 0.51) and depressive symptoms
(Hedges g = 0.38), GAD ranked among the lowest effect sizes
with the exception of panic disorder. The strongest effect size
estimates for CBT were for obsessive-compulsive disorder and
acute stress disorder (Hofman et al., 2008).
One study combined meta-analysis to determine overall effect
size of CBT in the treatment of both GAD and panic disorder
and meta-regression to determine the factors that had an
impact on this effect size. The study findings showed that CBT
is significantly less effective for patients with a severe form of
both disorders. Also, trials that compared CBT to a wait-list
control group found significantly larger effect sizes than those
comparing CBT to an attention placebo, but not to a pill
placebo. Also, these findings noted that most studies used
psychologists as providers and recommended that more
studies are needed with other professional groups as well as
other modes of administration, e.g., telephone, computer
(Haby, 2005).
Previous studies have suggested that transdiagnostic CBT for
anxiety disorders reduces symptoms of anxiety. A recent
randomized clinical trial by Norton and Barrera investigated
the efficacy of a 12-week transdiagnostic CBT group treatment
compared with a 12-week well-established diagnosis-specific
group CBT treatment for panic disorder, social anxiety
disorder, and GAD. Participants (n=46) with the above
disorders were randomized either to the transdiagnostic CBT
group or the diagnosis-specific CBT group. Participants in the
transdiagnostic CBT condition received treatment that
deemphasized diagnostic labels and focused on challenging
and confronting feared stimulation. It included
psychoeducation, cognitive restructuring and exposure
therapy. Participants in the diagnosis-specific CBT group
received group CBT treatment specifically targeting individual
diagnoses of panic disorder, social anxiety disorder and GAD.
The results of this trial showed effects of transdiagnostic CBT
at least as strong as those of diagnosis-specific CBT on most
outcome measures. Researchers noted the shared clinical
features and underlying processes among the anxiety
disorders and suggested that a single transdiagnostic CBT
applicable to more than one anxiety disorder may increase the
adoption rate of evidence-based CBT by mental health
practitioners. They concluded that the almost identical
outcomes across transdiagnostic and diagnosis-specific groups
provides preliminary evidence supporting the efficacy of
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 transdiagnostic CBT in the treatment of social anxiety
disorder, GAD and panic disorder, suggesting that
transdiagnostic treatments may be extended to include other
anxiety disorders (Norton et al., 2012).
CBT is considered the cornerstone of treatment of adults with
GAD with the goal of helping patients identify distressing/
dysfunctional beliefs and thought patterns with more rational
and realistic views (Patel et al., 2013). Authors noted other
nondrug therapies which can augment or replace CBT if it is
not effective, e.g., relaxation training, worry exposure or
exposure therapy, short-term psychodynamic psychotherapy.
Internet and computer-based CBT delivery formats continue to
be developed in an effort to increase patient access to this type
of therapy. One large meta-analysis studied the effects of 22
studies of computerized CBT models against a control
condition for patients with the following disorders: major
depression, panic disorder, social phobia or GAD. The mean
effect size superiority for the four diagnostic groups (Hedges g)
was 0.88 and specifically for GAD was 1.12 (2 studies; n=198)
showing short- and long-term benefits, good patient adherence
and satisfaction with computerized CBT despite decreased
clinician contact (Andrews et al., 2010). Similarly, a
randomized controlled trial of 8 week internet-delivered CBT
(n=89) consisting of a self-help program based on CBT
principles and applied relaxation along with therapist
guidance revealed significant improvement compared with the
control group on measures of worry, anxiety and depression at
both the 1- and 3-year follow up (Paxling et al., 2011).
An exploratory study addressed the content of therapist e-
mails in therapist-guided internet-based cognitive behavioural
therapy (iCBT) for GAD (Paxling et al., 2013). Authors
examined almost 500 e-mails from three therapists providing
support to patients (n=44) diagnosed with GAD in a
randomized controlled trial. Online text modules, e.g., applied
relaxation, worry exposure, problem solving, and cognitive
restructuring, communicated CBT strategies to the
participants in order to reduce problems related to excessive
worrying. Homework assignments were included and at the
end of each week the patient responded by providing
information about their progress and related problems. The
therapist replied to the e-mail with feedback and answers to
any patient questions. In this study, the therapist e-mails to
patients were analyzed and therapist behaviors were coded as
follows: deadline flexibility, task reinforcement, alliance
bolstering, task prompting, psychoeducation, self-disclosure,
self-efficacy shaping, and empathetic utterance. Investigators
indicated that distinct therapist behaviour exists in online
therapy. Lenience regarding deadlines was negatively
associated with treatment outcome, and task reinforcement
correlated with module completion and positive outcomes.
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 Investigators suggested further studies with a larger sample
size are needed along with studies addressing the impact of e-
mail support given in addition to traditional face-to-face
therapy (Paxling et al., 2013).Bandelow et al. suggested that
internet-based CBT should not be recommended for the
treatment of GAD as trials have not compared it to traditional
CBT in which the patient and therapist are in personal contact
(Bandelow et al., 2013).
A systematic review of 27 clinical trials (total n=2,373)
evaluating both pharmacological (14 studies using various
agents, i.e., antidepressants, anticonvulsants, buspirone,
piperazine/azapirone anxiolytic or quetiapine) and
psychotherapeutic interventions (13 studies 12 studies using
CBT in at least one study arm and one study comparing
community treatment vs. modular psychotherapy) for GAD in
adults aged 55 and over demonstrated that pooled treatment
effects were similar for either type of intervention and that
patients benefited from the active intervention when compared
to waiting list, usual care or minimal contact conditions. These
effects however, were lost for psychotherapeutic interventions
when other active conditions were employed as comparators,
i.e., discussion group, medical management, (Goncalves et al.,
2011).
There are emerging new approaches in the cognitive behavioral
treatment of GAD as it is a chronic condition that remains the
least-successfully treated of the anxiety disorders, i.e., client
returning to normative levels on key outcome measures. These
concerns have led to the development of new treatments that
expand CBT approaches in order to better target the function
of worry and the nature of GAD (Roemer, 2007). One meta-
analysis that focused specifically on the efficacy of CBT for
pathological worry among clients with GAD showed that CBT
is effective, with the largest treatment gains evidenced for
younger adults and for those who underwent individual CBT
treatment (Covin, 2007).
Stand-alone worry exposure therapy (WE) without further CBT
interventions was evaluated in a randomized controlled study
of 73 patients with GAD. Subjects were allocated to either WE
or applied relaxation (AR) for 15 sessions. Results showed that
patients in both groups exhibited distinct improvements on all
primary and secondary measures where symptoms of anxiety,
depression, excessive worrying, negative metacognitive
appraisal of worrying and thought suppression were reduced.
These treatment effects were stable at six month and one year
follow-up (Hoyer et al., 2009).
A randomized clinical trial of elderly patients (n=134)
examined the effect of CBT relative to enhanced usual care
(EUC) conducted in a primary care setting. Patients who
received EUC were telephoned biweekly during the first three
months of the study by the same therapist to provide support,
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 ensure patient safety and remind them to call staff if
symptoms worsened. Findings showed that patients receiving
CBT had greater improvement in worry severity, depressive
symptoms, and general mental health than those receiving
EUC. Mean change in GAD severity following CBT was
meaningful but not significantly than following EUC (Stanley
et al., 2008).
A later study examined the psychometric properties of the
Pittsburgh Sleep Quality Index (PSQI, a comprehensive self-
report measure of sleep quality and impairment, comparing
the component scores of older adults (n=134) with GAD to
those (n=82) without GAD (Bush et al, 2012). PSQI scores
showed that participants with GAD experienced greater sleep
difficulties than those without GAD. Researchers then used
the PSQI as an outcome measure in a trial examining the
response to CBT compared to enhanced usual care (EUC) in
older adults (n=134) with principal or co-principal GAD.
Participants were randomized to receive either CBT (consisting
of 10 individual sessions including psychoeducation,
motivational interviewing, relaxation training, cognitive
restructuring, exposure, problem-solving skills training and
behavioral sleep management) or EUC (consisting of biweekly
telephone conversations with a therapist, focusing on safety
monitoring and providing support). At posttreatment (3-
months) and over a 12 month interval, the Pittsburgh Sleep
Quality Index (PSQI), a comprehensive self-report measure of
sleep quality and impairment, was administered to each
group. Participants who received CBT for anxiety experienced
greater reductions (improvement) on scores of sleep quality,
sleep latency and sleep disturbances than those who received
enhanced usual care. Researchers noted that although CBT
for anxiety alleviated some aspects of sleep difficulty over time,
it did not improve improvement in sleep duration, daily
functioning or use of sleep medications (Bush et al., 2013).
Another study examined the effects of cognitive behavioral
therapy delivered by telephone (CBT-T) to older adults
diagnosed with a diagnosis of GAD, panic disorder, combined
GAD and panic disorder, or anxiety disorder not otherwise
specified (Brenes et al., 2012). Participants (n=60) were
randomized to CBT-T or information-only comparison. CBT-T
was comprised of telephone therapy sessions and a treatment
workbook. After the participant received a workbook chapter
addressing a specific topic, e.g., treatment rationale, relaxation
techniques, problem-solving, behavioral activation and relapse
prevention, a telephone therapy session was conducted during
which the content of the chapter was reviewed and the
participant could ask questions. Homework was reviewed and
discussed along with recommendations by the therapist.
Participants randomized to information-only received written
information on anxiety disorders and a list of referral options.
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 This study found that participants who received CBT
demonstrated greater improvement in self-report and clinician-
rated worry and anxiety symptoms than participants in
information only. They also experienced greater reductions in
insomnia and anxiety sensitivity. Follow-up data (6-months
after treatment completion) indicated no significant differences
in the reductions in anxiety sensitivity and insomnia between
the two conditions, suggesting that a longer intervention or
more intense follow-up may be needed. Researchers suggested
that CBT-T may be useful in a stepped care to late-life anxiety
as older adults often prefer psychotherapy to pharmacotherapy
and many are unable to attend regular face-to-face therapy
sessions. They also suggested that more follow-up sessions
should be integrated into telephone treatment (Brenes et al.,
2012).
A clinical review of muscle tension in GAD evaluated 13
controlled studies and found that muscle relaxation therapy
and CBT are the most effective treatments for GAD. The
investigators indicated that the efficacy of muscle relaxation
therapy for GAD lies primarily in its function of stress-
reduction and in helping to distract from excessive worry by
focusing on the muscles. Authors suggested that other
therapies using cognitive distraction should be developed and
studied for the treatment of GAD and muscle tension (Pluess
et al., 2009).
Short-term psychodynamic psychotherapy and CBT were
compared with regard to treatment outcome. Patients with
GAD were randomly assigned to receive either CBT (n=29) or
short-term psychotherapy (n=28) according to treatment
manuals on a weekly basis for 30 weeks. Results showed both
CBT and short-term psychodynamic psychotherapy yielded
significant, large and stable improvements using the primary
outcome measures symptoms of anxiety and depression. CBT
was superior in secondary measures of trait anxiety, worry
and depression. According to investigators, these findings
remained stable at the 12-month follow-up. Researchers noted
that outcomes in psychodynamic psychotherapy may be
optimized by employing a stronger focus on the process of
worrying as is the case in CBT (Salzer et al., 2010).
Investigators also proposed the conceptualization of worry in
psychodynamic psychotherapy as a mechanism of defense
that protects the subject from fantasies or feelings that are
even more threatening than the contents of his or her worries
(Salzer et al., 2010, p.5; Salzer et al. 2011).
Mindfulness-based therapy (MBT) was developed to help
individuals counter experiential avoidance strategies by use of
a mental state characterized by nonjudgmental awareness of
present moment experiences using techniques derived from
Buddhist meditation and traditional yoga practices (Hofmann
et al., 2010). A meta-analytic review of 39 studies of 1,140
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 patients was conducted on patients who received this
treatment (including both mindfulness-based cognitive therapy
and stress reduction) for a range of conditions, e.g., GAD,
cancer, depression and other medical or psychiatric disorders.
Overall findings showed that in patients with anxiety and
mood disorders, MBT was associated with effect sizes of 0.97
and 0.95 (Hedges g) for improving anxiety and mood
symptoms, respectively. Results from the 7 studies that
evaluated anxiety disorders specifically, i.e., GAD, GAD co-
morbid with panic disorder or social anxiety disorder)
significant treatment effects were found for reducing anxiety
symptoms (Hedges g=0.97) and depressive symptoms (Hedges
g=0.75) in those patients who demonstrated elevated level of
depressive symptoms at pre-treatment (Hofmann et al., 2010).
In a later trial, participants aged 18 or older (n=93) with GAD
were randomized to an 8-week program of manualized
Mindfulness-Based Stress Reduction (MBSR) or to an attention
control, Stress Management Education (SME) to compare the
effects of the two treatments (Hoge et al., 2013). MBSR was
comprised of group in class practices, e.g., breath-awareness,
gentle Hatha yoga and Body-Scan exercises, which focused on
present experience and treating the body gently. Participates
were also instructed in daily home practice, e.g., present-
focused awareness while eating, bathing or cleaning. SME,
which did not include any mindfulness components, was
taught in a didactic format comprising both class and home
activities, e.g., stress physiology, time management
techniques, sleep physiology, nutrition and factors that buffer
the impact of stress. Findings showed that both MBSR and
SME led to significant reductions in anxiety symptoms as
measured by the Hamilton Anxiety Scale (HAM-A). Anxiety
symptoms as measured by the Clinical Global Impression of
Severity and Improvement (CGI-S and CGI-I) the Beck Anxiety
Inventory (BAI), and the pre- and post-treatment Trier Social
Stress Tests were significantly reduced in the MBSR group
compared to the SME group. Researchers suggested that
MBSR, which may result in increased resilience to stressful
psychological challenges and reduce anxiety symptoms in
patients with GAD, should be studied further in larger trials
(Hoge et al., 2013).

Pharmacology In 2008, the World Federation of Societies of Biological Psychiatry

Treatments (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety,
Obsessive-Compulsive and Post-Traumatic Stress Disorders--
Revised were published to include treatment recommendations for
GAD (Bandelow et al., 2008). The WFSBP Task Force rank-ordered
clinical trials based on the quality of evidence for efficacy and
risk/benefit assessment. Strong evidence of clinical efficacy in the
treatment of GAD was found for first-line pharmacological
treatments for GAD, i.e., SSRIs escitalopram, paroxetine,
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 sertraline; SNRIs venlafaxine and duloxetine; and the calcium
channel modulator pregabalin. Second-line treatment options
include buspirone (for augmentation), benzodiazepines, i.e.,
alprazolam and diazepam, and the antihistamine hydroxyzine. An
atypical antipsychotic, i.e., quetiapine may be used as
monotherapy in GAD and is reserved for treatment-refractory
cases (Patel et al., 2013, Bandelow et al., 2012, Bandelow et al.,
2013). Only when all other drugs or CBT have failed,
benzodiazepines, i.e., diazepam and lorazepam, can be used for
long-term treatment (Allgulander 2010; Bandelow et al., 2008,
Bandelow et al., 2012).
The WFSBP Guidelines ranked the tricyclic antidepressant (TCA)
imipramine as a secondary drug of choice, despite its efficacy, due
to the higher toxicity and adverse event burden. In addition, these
guidelines cited strong evidence and recommended the
benzodiazepines, alprazolam and diazepam, for treatment-
resistant cases with no history of addiction and as adjuncts for
immediate relief of anxiety during the initiation of other agents and
for use in episodes of acute exacerbation. The WFSBP Guidelines
also indicated that the antihistamine, hydroxyzine, is effective but
has sedating properties. Lastly, these guidelines specified that in
treatment-refractory GAD patients, augmentation of SSRI
treatment with risperidone and olanzapine (SGAs) may be used
(Allgulander 2010; Bandelow et al., 2008).
An effect-size analysis of 21 double-blind placebo controlled trials
of pharmacologic treatments for GAD showed that mean effect
sizes (ES) by drug (or drug classes) were as follows: pregabalin
(0.50); antihistamines (0.45); SNRIs (0.42); benzodiazepines (0.38);
SSRIs (0.36) and azapirones (0.17) (Hidalgo et al., 2007). Moreover,
all of these drugs precipitate response (50% improvement in
symptom severity) in approximately two-thirds of patients and
remission (a reduction in symptom severity clinical measurement
scores to the normal range) in approximately one-half of the
responders, or one-third of total patients (Collins et al., 2009;
Hidalgo et al., 2007).
An earlier published summary of all peer-reviewed meta-analyses
and randomized placebo-controlled trials on the pharmacological
treatment of GAD concluded that trials with escitalopram,
paroxetine, sertraline and venlafaxine indicate that treatment with
Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective
Serotonin and Norepinephrine Re-uptake Inhibitors (SNRIs) can be
efficacious in the acute management of GAD. There was also some
evidence for the efficacy of certain benzodiazepines, buspirone,
imipramine, hydroxyzine and trifluoperazine (Baldwin, 2005).
Similarly, The International Consensus Group on Anxiety and
Depression recommends an SSRI, SNRI or non-sedating tricyclic
antidepressant (TCA) as the first-line pharmacotherapy for the
treatment of GAD (Rickels, 2006; Ballenger, 2001).
The U.S. Food and Drug Administration (FDA) approved the
following drugs in their respective classes for the treatment of
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 GAD: (1) azapirone anxiolytic buspirone, (2) SNRIs venlafaxine
and duloxetine, (3) SSRIs paroxetine and escitalopram, (4)
benzodiazepines diazepam, lorazepam and alprazolam, (5) first
generation antipsychotic (FGA) trifluoperazine, (6) antihistamine
hydroxyzine. Findings support pharmacological treatment for
patients with GAD for at least six months and up to a year (Collins
et al., 2009; Davidson 2009; Baldwin, 2005). In spite of some
convincing efficacy data, the Psychopharmacologic Drugs Advisory
Committee of the FDA voted against first-line treatment of GAD
with quetiapine due to the potential metabolic consequences of
maintenance treatment, the potential for extrapyramidal adverse
events and the risk of sudden death due to ventricular arrhythmia
(Allgulander, 2009).
In 2010, The International Psychopharmacology Algorithm Project
(IPAP) published a psychopharmacological treatment algorithm to
be used for all patients in the treatment of GAD. It addresses the
needs of patients who may achieve a good response, partial
response, non-response or loss of previous response (Davidson et
al., 2010). The IPAP consultants developing the algorithm
indicated that once the diagnosis of GAD has been established, an
evaluation for co-morbidities should be done at this point, and at
every subsequent point of assessment throughout the course of
treatment. This includes a careful evaluation for suicidality,
insomnia, substance abuse, non-compliance, childbearing
potential, elderly patient problems and cultural issues. They also
recommended that that stabilization of co-morbid disorders should
be attempted prior to treatment of GAD (Davidson et al., 2010).

Proposed Treatment Steps: Several conditions, e.g., patients

preference, severity of illness, co-morbidity, concomitant medical
illnesses, substance use disorders, risk of suicide, history of prior
treatments, cost issues and availability of types of treatment, may
affect the development of the treatment plan (Bandelow et al.,
2012). Information and support should be provided to individuals
with GAD, their families and caregivers.
The following summarizes important clinical information from the
decision points and action steps conveyed in the IPAP review and
treatment algorithm for GAD: (Davidson et al., 2010; IPAP GAD
Algorithm Flowchart, 2009).
Expert consensus indicates that an SSRI or SNRI monotherapy
may be the initial choice of medication of a treatment-naive
patient presenting with GAD. Other antidepressants, e.g.,
imipramine and trazodone, have shown efficacy, but are not
recommended as first-line treatments due to poor tolerability
and high risk of potential serious side effects.
If rapid response is warranted, or insomnia is predominant
symptom, a concomitant benzodiazepine may be used for a
short period of time in patients with no history of substance
abuse.
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 Response time to antidepressant drug treatment in GAD is
usually 4-12 weeks. A partial response should occur by the
initial evaluation point after 4-6 weeks with adequate dosing.
In cases where there is a good response after an adequate
trial, medications should be continued for at least one year, in
order to reduce the risk of relapse. Current state of knowledge
permits the prescriber to increase dose, augment, switch or
wait longer when there has been a partial response. A
switching strategy should be considered where adequate drug
trial has not elicited at least a 25% symptom improvement from
baseline using a valid clinical measurement scale.
Augmenting agents: atypical antipsychotics (risperidone
and olanzapine), benzodiazepines, antihistamine
(hydroxyzine), buspirone or anticonvulsant agent,
tiagabine (use with caution for patients with a history of
seizure disorder or predisposition).
Switching to another antidepressant within the same class
or to a different class e.g., SSRI to SNRI or SNRI to SSRI.
Psychotherapy may be added to the regimen.
Insomnia must also be addressed when evaluating a partial
response with the suggested use of hypnotic agents: non-
benzodiazepine GABAergic hypnotic drugs, benzodiazepines,
trazodone or mirtazapine. A sedating antihistamine may be
added. Patient should be counseled on possible lifestyle
changes.
If the patient has improved or achieves remission with these
new drugs, continue treatment for one year.
At this stage, if there is still a partial or non-response, the
clinician must evaluate for the presence of a significant co-
morbid disorder. Recommended drugs are as follows:
Co-morbid depression adequate dose of an
antidepressant or augmentation with bupropion,
buspirone, atypical antipsychotic, or the nutritional
supplement, chromium picolinate. Severe depression may
need ECT.
Co-morbid stable bipolar disorder add mood stabilizer,
anticonvulsant or atypical antipsychotic drug. May need
laboratory monitoring.
Co-morbid panic disorder add TCA or SSRI/SNRI or
benzodiazepine.
Co-morbid social anxiety disorder add benzodiazepine,
serotonin-reuptake inhibitor (SRI), atypical antipsychotic,
pregabalin or anticonvulsant agent, levetiracetam.
Co-morbid obsessive-compulsive disorder add SSRI or
clomipramine.
Co-morbid posttraumatic stress disorder add SSRI,
SNRI, atypical antipsychotic or sympatholytic drug,

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 prazosin.
If there is no co-morbid disorder, switch to another combination
that includes SSRI, SNRI, noradrenergic and specific serotonergic
antidepressant (NaSSa), or TCA or add a third drug of different
class from the other two. Psychotherapy may be added to the
regimen at this phase of treatment. Other important research
findings on recommended drugs to treat GAD are summarized
below:

Benzodiazepines Evidence-based reviews have demonstrated that

benzodiazepines are an effective and rapid treatment for many
patients with GAD (Baldwin, 2005; Mitte, 2005; Chessick, 2007).
However, the benzodiazepines have limited efficacy in the
treatment of GAD and co-morbid depression (Baldwin, 2005).
Baldwin et al. concluded that treatment with benzodiazepines
should be for a short-term duration (up to 4 weeks) in order to
avoid the risk of physical dependence and withdrawal resulting
from long-term usage. Other unwanted effects of benzodiazepines
may include sedation, memory disruption and psychomotor
impairment, with an associated increased risk of traffic accidents.
Other safety concerns with the use of benzodiazepines in the
elderly population have been noted due to the high incidence of
falls, hip fracture, withdrawal difficulties and increased risk of
cognitive impairment (Davidson et al., 2010; Collins et al., 2009:
Pollack et al., 2009; Baldwin, 2005; Mitte, 2005).
A recent study compared healthcare costs of patients with GAD
who received treatment with a benzodiazepine adjunctive to
antidepressants with costs of those who did not receive
concomitant therapy. Researchers found that healthcare costs
increased in patients following benzodiazepine treatment and
noted that approximately half of the increase in costs was
associated with known sequelae of long-term treatment with
benzodiazepines, e.g., care associated with accidents (Berger et al.,
2012).
In a later study, Offidani et al. performed a systematic review and
meta-analysis to analyze whether controlled comparisons support
the current prescribing pattern favoring newer antidepressants
(SSRIs, SNRIs) over benzodiazepines (Offidani et al., 2013). In one
study comparing the efficacy of benzodiazepines to venlafaxine XR
and placebo in patients with GAD (n=540), results showed no
significant differences in response rates between groups.
Discontinuations of treatment, due to adverse events, occurred
more often in patients taking venlafaxine XR than in those treated
with benzodiapepines. In another study, researchers evaluated the
efficacy of treatment with lorazepam, paroxetine or placebo in
patients with GAD (n=169) over four weeks. Results showed that
both lorazepam and paroxetine treatments were effective in
reducing anxiety-related psychiatric symptoms. Somatic features
improved significantly only in those taking lorazepam. Researchers

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 noted serious and bothersome side effects of treatment with SSRIs,
e.g., high rates of sexual dysfunction, weight gain, osteoporosis,
hyponatremia, gastrointestinal bleeding and potential for drug
interactions. Researchers suggested that the only potential
advantage of SSRI versus benzodiazepines is the associated lower
impairment in cognitive and psychomotor skills. They concluded
that literature lends no support to the pattern favoring newer
antidepressants over benzodiazepines in the treatment of anxiety
disorders (Offidani et al., 2013).

Azapirones Two meta-analyses have shown that buspirone (an

azapirone anxiolytic with partial agonist properties at 5-HT1A
receptors) has comparable efficacy to benzodiazepines in the
treatment of GAD and seems to be a suitable alternative for long-
term treatment of the condition with side effects that are mild and
non-serious (Baldwin, 2005; Mitte, 2005). Another meta-analytic
review showed that buspirone appears to be useful in the
treatment of GAD, particularly for those patients who had not
been on a benzodiazepine, because it may be less effective than
benzodiazepines. Also, these findings were inconclusive about
buspirones long-term efficacy and its superiority to
antidepressants, psychotherapy or kava (Chessick, 2007).
Currently, buspirone is rarely used as monotherapy in GAD but is
more frequently used as augmentation to first-line agents due to
its slow onset of action, variable tolerability and overall lack of
benefit against other co-morbid disorders (Davidson et al., 2010;
Pollack, 2009).

Selective Serotonin Reuptake Inhibitors (SSRIs) Several SSRI

antidepressant drugs are currently used in the treatment of GAD.
Efficacy findings with the best levels of evidence support
escitalopram, paroxetine-immediate release and sertraline. The
IPAP consultants noted that of these three aforementioned agents,
sertraline has the best safety data in pregnancy and lactation (
Davidson et al., 2010; Bandelow et al., 2008). Studies have been
conducted to determine whether some of the SSRIs have more
advantages than the others:
A published review of research findings from paroxetine
clinical trials (3 short-term and 1 long-term relapse study)
showed that it is an effective short- and long-term
treatment agent for GAD, demonstrating substantial
patient improvement in family, social and work
functionality, achieving remission, and in relapse
prevention. Researchers note that paroxetine has
demonstrated efficacy in depression and in several anxiety
disorders (e.g., panic, OCD, social anxiety and PTSD)
making it a favorable option to treat core symptoms of GAD
along with disorders that are commonly co-morbid with it
(Rickels, 2006).

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 Study findings support the clinical efficacy of short-term
treatment with sertraline, resulting in significant
improvement in both psychic and somatic anxiety
symptoms, including quality of life and work productivity
(Allgulander, 2004).
A study comparing the efficacy of sertraline and paroxetine
in the treatment of GAD showed no difference in
therapeutic efficacy or tolerability (Ball, 2005). Another
study showed there were no differences in efficacy between
escitalopram (10-20 mg./day) and paroxetine (20-50
mg./day) in the treatment of GAD. However, patients
treated with paroxetine reported significantly more side
effects (e.g., insomnia, constipation, sexual dysfunction,
weight gain) than with escitalopram (Bielski, 2005).
A randomized, single-blind trial comparing sertraline (50-
100mg./day) and buspirone (10-15 mg./day) in elderly
patients (n=46) showed that they were both efficacious and
well tolerated for the treatment of GAD in this population
(Mokhber et al., 2010).
GAD patients who were treatment responders were
prescribed escitalopram for 24-76 weeks. Findings showed
that escitalopram (20 mg./day) significantly reduced the
risk of relapse in these patients risk of relapse was 4.04
times higher in the placebo group (Allgulander, 2005).
A randomized controlled study of 177 adults, aged 60 years
and older, evaluated the use of escitalopram 10 to 20
mg./day against placebo during 12 weeks in the treatment
of GAD. Researchers found a statistically significant
difference in the mean cumulative response rate (i.e.,
decrease in anxiety symptoms and improvement in role
functioning) for escitalopram (69%) compared with placebo
(51%). Response rates were not significantly different when
using an intention-to-treat (ITT) analysis. Further study is
necessary to assess safety and efficacy compared to longer
term treatment (Lenze et al., 2009).
In a recent review of literature, Bandelow et al. reported the
results of randomized trials including various treatments of
GAD. They reported a number of controlled trials
demonstrating the efficacy of the SSRIs escitalopram,
paroxetine, and sertraline. Although SSRIs are generally
well tolerated they noted adverse effects that may impair
compliance and suggested that they should be taken in the
morning to avoid nocturnal restlessness and insomnia at
beginning of treatment (Bandelow et al., 2013).

Selective Serotonin and Norepinephrine Re-uptake Inhibitors

(SNRIs) Venlafaxine extended release (XR) was the first SNRI
antidepressant to receive FDA approval for the treatment of GAD
followed by duloxetine (Collins et al., 2009; Davidson 2009;
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 Baldwin, 2005).
An open trial demonstrated equal efficacy and tolerability
during 8 weeks in patients with GAD who received
venlafaxine XR or paroxetine. Double-blind, placebo-
controlled, comparison studies are needed to draw
definitive conclusions (Kim, 2006).
A trial of duloxetine showed its superiority to placebo in the
short-term management of GAD with its demonstrated
efficacy, safety and tolerability leading to improvement in
symptom severity and functioning. The adverse effects most
frequently associated with duloxetine were nausea,
dizziness and somnolence. Another study, which pooled
data from two multi-center trials, evaluated the efficacy of
duloxetine (60-120 mg./day) in patients with GAD and
significant pain symptoms. It showed that the drug is
effective in reducing anxiety symptoms, pain severity and
in improving patient functioning (Rynn, 2007).
Retrospectively derived pooled data from five studies
reported efficacy of venlafaxine XR in patients with GAD
who are age 65 and older, but there were findings of
intolerance in frail elderly subjects (Davidson et al., 2010).
Further post hoc analysis of previous duloxetine clinical
trial data assessed painful physical symptoms in patients
with GAD using two 9-10 week efficacy trials (n=840) and
one relapse prevention trial (n=887) comprising both a 26-
week open-label treatment phase and a 26-week double-
blind, placebo-controlled treatment continuation phase.
Findings showed that both short- and long-tern duloxetine
treatments were associated with improvement in painful
physical symptoms in GAD. Additionally, patients who
responded to duloxetine treatment and subsequently
discontinued treatment experienced a worsening of painful
symptoms (Beesdo et al., 2009). Another large (n=668)
clinical trial of adult patients treated with duloxetine
compared to placebo (n=495) showed an almost 2:1 rate of
substantial return to normative functioning and quality of
life, i.e., global role functioning, subjective well-being and
perceived health (Pollack et al., 2007).
A non-inferiority comparison of duloxetine 60-mg./day and
venlafaxine extended-release (XR) 75-227 mg./day for the
treatment of adults with GAD pooled data from nearly
identical 10-week, multicenter, randomized, placebo-
controlled, double-blind studies. Non-inferiority trials are
designed to analyze the amount of drug/placebo difference
between two treatments. An independent expert consensus
panel determined the statistical and clinical criteria for
non-inferiority and clinical response (i.e., > 50% reduction
in HAMA Rating Scale total score). Findings showed that
duloxetine 60-120 mg./day met all of the criteria for non-
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 inferiority and exhibited a similar safety and tolerability
profile compared with venlafaxine XR 75-225 mg./day
(Allgulander et al., 2008).
A systematic review of studies in the use of duloxetine
substantiated the drugs effectiveness for anxiety disorders
with or without concomitant major depression. Specifically,
the GAD studies confirmed duloxetines short-term
effectiveness, long-term efficacy, early response to
treatment at first and second weeks of therapy and
efficacy/tolerability in the elderly (Mancini et al., 2010).
A recent review of literature reported the results of
randomized trials demonstrating the efficacy of SNRIs
(Bandelow et al., 2013). In all but one trial, venlafaxine was
effective against GAD. Duloxetine was also found to be
effective against GAD in controlled trials. Researchers
cautioned that adverse effects, e.g., nausea, sleep
problems, agitation, may impair compliance (Bandelow et
al., 2013).

Tricyclics (TCAs) In a 2003 Cochrane review of antidepressants

used to treat GAD, Kapczynski et al. noted that the tricyclic
antidepressant, imipramine, has been studied as early as 1988 for
its comparative effectiveness against alprazolam, and in a later
study (1993) compared to trazodone, diazepam and placebo.
Published results of these early studies demonstrated that
imipramine was effective in alleviating such symptoms as
dysphoria, anticipatory negative thinking, apprehension and
worry. This Cochrane meta-analytic review concluded that
available evidence suggests that imipramine, venlafaxine and
paroxetine are superior to placebo in treating GAD in adults.
Sertraline had been shown to be superior to placebo in treating
GAD in children and adolescents. This study was not able to
assess the differences in efficacy between imipramine and
venlafaxine, or venlafaxine and paroxetine, as there were no direct
comparisons of these agents in this review. This review also noted
findings suggesting that paroxetine and imipramine are similar in
terms of efficacy and tolerability (Kapczinski, 2003). While
imipramine is effective in the treatment of GAD, it is currently
considered a second-line option due to its lower tolerability profile
and potential lethality in overdose (Davidson et al., 2010;
Bandelow et al., 2008).

Noradrenergic and specific serotonergic antidepressant (NaSSA)

Findings from a trial of mirtazapine (fixed dose 30 mg. for 12
weeks) supported its efficacy and tolerability for the treatment of
GAD. Further randomized placebo-controlled studies are needed to
explore the utility of this agent in the treatment of anxiety
disorders (Gambi, 2005). Mirtazapine may be considered to treat
insomnia in patients with GAD who have had an otherwise good
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 response to SRI drugs (Davidson et al., 2010).

Antipsychotics A published literature review on the efficacy of

typical and atypical antipsychotics for primary and co-morbid
anxiety symptoms or disorders noted that there is fair evidence
that typical antipsychotics, especially trifluoperazine, were
effective in the short-term treatment of GAD (Gao, 2006).Using
annual data from the 1996-2007 National Ambulatory Medical
Care Survey, a study reported that across this 12-year period,
antipsychotic prescriptions in visits for anxiety disorders increased
from 10.6% to 21.3% particularly among new patients (Comer et
al., 2011). The investigators noted the availability of SGA drugs
with improved anxiolytic prosperities and fewer short-term
anticholinergic and extrapyramidal effects than first generation
agents while offering less sedation have contributed to this trend.
In addition, authors reported that across drug classes,
antipsychotic medications ranked near the top in off-label use,
drug safety concerns and inadequate supporting evidence (p.
1064, Comer et al., 2011).
Data from a small (N=30) open-label, flexible-dose study of
adjunctive risperidone suggest that augmentation of an
adequate dose of an SSRI, SNRI or benzodiazepine, with
low-dose risperidone initiated at least eight weeks prior to
the study, may be a useful option for patients with GAD,
panic disorder and social anxiety disorder refractory to
adequate initial pharmacotherapy. Results showed
significant reduction in anxiety symptoms, and while two
patients reported mild akathisia (one was persistent), no
patients developed dystonias (Simon, 2006).
Olanzapine, risperidone and quetiapine immediate-release
(IR) have all been studied as adjunctive agents to
antidepressants and/or anxiolytics in the treatment of
refractory GAD with inconsistent results (Gao et al., 2009).
However, quetiapine extended-release (XR) 150 mg./day
monotherapy yielded consistent anxiolytic effects across
three studies that were superior to placebo and as effective
as paroxetine 20 mg./day and escitalopram 10 mg./day
but with an earlier onset of action. Also, in a 52-week
treatment of GAD, quetiapine-XR was superior to placebo
in the prevention of anxiety relapses (Gao et al., 2009;
Bandelow et al., 2008).
One study investigated the efficacy of atypical antipsychotic
monotherapy in mood disorders co-morbid with GAD.
Patients (n=111) with bipolar disorder co-morbid with GAD
(88%) or panic disorder (59%) were randomly assigned to
receive risperidone 0.5 mg.-4 mg./day or placebo
monotherapy for 8 weeks. Out of the 63 patients who
completed the study, there were no statistically significant
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 differences between risperidone or placebo on the primary
outcome measure for anxiety or secondary outcome
measures for panic depression, mania and disability (Gao
et al., 2009).
A more recent meta-analysis on the treatment of GAD with
atypical antipsychotics (SGAs) suggests that existing data
do not support their usage as augmentation therapy for
refractory GAD. Five studies (n=912) demonstrated that
SGA augmentation (using olanzapine, risperidone or
quetiapine) did not demonstrate superiority against placebo
for clinical response or remission and showed that these
patients were 43% more likely to discontinue treatment.
Conversely, four studies (n=1383) that examined
quetiapine XR monotherapy (150 mg.) demonstrated that
patients were 31% more likely to respond, and 44% more
likely to achieve remission than the placebo group. In
addition, patients in the quetiapine group were 30% more
likely to leave the study before completion. Investigators
stressed that while quetiapine monotherapy may be
efficacious, issues with adverse effects and tolerability
must be considered in clinical practice (Lalonde et al.
2011). In addition, two other systematic reviews on the use
of SGAs for the treatment of refractory GAD emphasized
the need for both larger and more rigorous clinical trials on
safety and efficacy in order to recommend their usage
(Samuel et al, 2010; Lorenz et al., 2010).
With a lifetime prevalence of 6% in older patients, GAD is
both undertreated and under investigated (Mezhebovsky et
al., 2012). In a recent, large study, researchers evaluated
the efficacy and tolerability of quetiapine XR monotherapy
in older patients (n=450), aged 66 and greater) with GAD.
Patients were randomized to quetiapine XR (50-300
mg/day) or placebo over a 9-week treatment period and a
2-week drug-discontinuation period. Treatment was
initiated at 50 mg/day with dose adjustment made on the
basis of efficacy and/or tolerability. Efficacy evaluations
were based on the changes in the Hamilton Anxiety Rating
Scale (HAM-A), Clinical Global Impressions-Severity of
Illness (CGI-S), and the Montgomery Asberg Depression
Rating Scale (MADRS). Results showed significantly
reduced HAM-A scores at week 9 with quetiapine XR
versus placebo. Significant improvements were also seen
with quetiapine XR as early as week 1, suggesting the
reduction of anxiety symptoms within a timeframe similar
to benzodiazepines. In patient-reported outcomes,
quetiapine XR was associated with significant
improvements versus placebo. Researcher concluded that
quetiapine XR monotherapy is an effective short-term
treatment in older patients with GAD, improving anxiety
symptoms, psychic and somatic symptoms, health-related
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 quality of life, sleep quality and pain versus placebo
(Mezhebovsky et al., 2013).
A small study evaluated the feasibility of augmenting
antidepressant treatment with quetiapine XR in patients
with either a primary anxiety disorder or a mood disorder
with co-morbid anxiety symptoms (Chen et al., 2012).
Patients receiving treatment with an antidepressant, i.e.,
escitalopram, paroxetin, venlafaxine, duloxetine, and
mirtazapine, were randomized to quetiapine (50-300
mg/day) or placebo for 8 weeks. Although efficacy
evaluations based on changes in the HAM-A and CGI-S
showed no significant differences between the quetiapine
XR and placebo groups at 8 weeks, treatment with
quetiapine XR as an adjunct to treatment with an
antidepressant provided a short-term benefit at 4 weeks.
Researchers cautioned that the results should be
considered preliminary due to the small sample size,
recommending further studies (Chen et al., 2012).

As noted in the Assessment section, GAD may be the most

common anxiety disorder in the elderly. Clinicians should be
aware of a FDA Alert that was issued notifying health care
professionals that both conventional and atypical antipsychotics
are associated with an increased risk of mortality in elderly
patients treated for dementia-related psychosis (FDA Alert
6/16/08).

Non-benzodiazepine hypnotics Zolpidem extended-release co-

administered with escitalopram in patients insomnia and co-
morbid GAD was studied in a multicenter, double-blind, parallel-
group trial. Patients (n=383) received open-label escitalopram
10mg./day and were randomized to either adjunctive zolpidem
extended-release 12.5 mg. or placebo. Findings showed that
combination zolpidem and escitalopram improved all measures of
sleep to a significantly greater degree than escitalopram and
placebo. Improvements were also seen in many measures of
daytime functioning and quality of life. Zolpidem extended-release
did not significantly augment the anxiolytic effects of the
escitalopram and there was no associated rebound upon
withdrawal of therapy (Fava et al., 2009).

Anticonvulsants As noted earlier, the World Federation of

Societies of Biological Psychiatry (WFSBP) Guidelines for the
Pharmacological Treatment of Anxiety, Obsessive-Compulsive and
Post-Traumatic Stress Disorders-Revised classify pregabalin as a
first-line treatment for GAD. Conversely, the IPAP pharmacological
algorithm consultants do not yet support the position of
pregabalin due to a relative lack of clinical experience in use for
treatment of GAD to date and a deficiency of data to establish
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 efficacy for co-morbid conditions (Davidson et al., 2009). While
pregabalin is not indicated for treatment of GAD in the United
States, it is indicated for this use in Europe (Pollack, 2009).
A study compared pregabalin (300 mg./day, 450 mg./day
and 600 mg./day) to alprazolam 1.5 mg./day and placebo.
The pregabalin treatment was associated with significant
end-point improvement on the Hamilton Anxiety Rating
Scale (HAM-A), which was comparable to alprazolam at all
three doses at the end of four weeks of treatment and two
follow-up visits during drug discontinuation (Rickels, 2005).
A recent literature review of the evidence on the role of
anticonvulsant drugs in the treatment of anxiety disorders
showed that the strongest evidence (level 1 meta-analysis
and replicated randomized controlled trials) was for
pregabalin in GAD with or without co-morbidity (Mula,
2007).
Pooled data were analyzed from six double-blind, placebo-
controlled trials where response to treatment for GAD was
evaluated for three fixed-dose pregabalin groups (150, 300-
450, 600 mg./day) and for a benzodiazepine group. In the
high-insomnia subgroup, the anxiolytic efficacy of
pregabalin 300-600 mg. was comparable with
alprazolam/lorazepam. Whereas the 150 mg. dose of
pregabalin was associated with improvement in anxiety
measurement scores, it did not have a significant effect on
insomnia symptoms (Montgomery et al., 2009).
Another pooled analysis of the same six trials (above)
examined the efficacy of pregabalin in depressive symptoms
associated with GAD through a post-hoc analysis of the
existing clinical trial database. Findings showed that in
patients with GAD, pregabalin reduced associated
symptoms of depression in the 150, 300-450 and 600
mg./day groups where pregabalin 300-450 mg./day dosage
demonstrated the most beneficial response (Stein, Baldwin
et al., 2009).
A more recent meta-analysis examined 7 trials of GAD
patients (n=1,352) using pregabalin compared to placebo
and calculated an overall effect size of 0.364 (Hedges g), an
effect size of 0.349 on psychic anxiety symptoms, and 0.239
on somatic anxiety symptoms. Investigators concluded that
while pregabalin is an effective treatment for GAD, they also
noted these effect sizes are smaller than earlier studies even
though their findings were based on participants taking the
largest doses of the drug during the clinical trial (Boschen
2011).
A recent review summarized the results of clinical trials and
pooled analyses providing data on pregabalins effect on
sleep disturbance in patients with GAD (Holsboer-Trachsler
and Prieto, 2013). Sleep disturbance, i.e., difficulty falling or
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 staying asleep, or restless, unsatisfying sleep, is a symptom
of GAD in DSM-5. Hiksbier-Trachsler and Prieto noted that
insomnia, associated with impairment in both functioning
and quality of life, is an important target for effective
treatment of GAD. A review of the results of seven
randomized controlled trials found that treatment with
pregabalin is associated with improvement in sleep among
patients with GAD as well as improved functioning and
quality of life. Adverse events were mild to moderate and
limited to the first 2-3 weeks of treatment. One of these,
sedation, occurs in some patients but the incidence is lower
compared to benzodiazepines. Authors concluded that
pregabalin is a treatment option for patients with GAD who
present with insomnia (Holsboer-Trachsler and Prieto,
2013).
Tiagabine is a selective gamma-aminobutyric acid (GABA)
reuptake inhibitor that increases synaptic GABA
availability. Study conclusions were mixed. While tiagabine
demonstrated efficacy in one randomized controlled trial, it
did not show benefit in subsequent combined analysis of
three additional trials (Davidson et al., 2010; Pollack, 2009).

Novel Agents - Antidepressants may have many shortcomings in

the treatment of anxiety states in that they do not work quickly,
may have significant side effects, e.g., nausea, agitation, sexual
dysfunction, and may be associated with distressing symptoms
upon discontinuation. Therefore, the search for novel
pharmacological agents for GAD continues (Starcevic, 2007).
Riluzole, a presynaptic glutamate release inhibitor used in the
treatment of amyotrophic lateral sclerosis (ALS), has demonstrated
very promising results in reducing symptoms of anxiety in GAD
patients in a recent clinical trial. An 8-week, open-label, fixed-dose
trial of riluzole in 18 outpatients with GAD resulted in a significant
reduction in anxiety symptoms where 67% of patients responded
and 44% entered remission by the end of the study (Pollack, 2009;
Gao et al., 2009). Another novel agent, the corticotropin-releasing
factor receptor-1 antagonist (CRF), pexacerfont (100mg./day) was
studied in patients (n=294) with GAD (after receiving a one week
loading dose of 300 mg./day) in a randomized trial comparing it to
placebo or escitalopram (20 mg./day) in a 2:2:1 ratio, i.e., a half-
powered comparator arm. Response rates for pexacerfont, placebo
and escitalopram were 42, 42, and 53% respectively, leading
researchers to conclude that the novel agent did not demonstrate
anxiolytic properties (Coric et al., 2010).
The novel antidepressant, agomelatine, which has both a
serotonergic and a melatonergic mechanism of action (Stein,
2012), has been considered to be a promising option for treatment-
resistant GAD. Authors reviewed two studies that investigated the
efficacy of agomelatine in the treatment of GAD. In a 12-week,
randomized, controlled trial examining the efficacy of agomelatine
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 in patients (n=121) with GAD, researchers found that in a 12-week
treatment period, agomelatine demonstrated higher rates of
response and anxiety remission than placebo. Another trial
evaluating the efficacy of agomelatine in preventing relapses in
patients with GAD over six months, found that patients
randomized to continue agomelatine after week 16 showed a lower
incidence of relapse at the endpoint than the placebo group
(Levitan et al., 2012). A more recent literature search and review
noted that although preliminary data indicate agomelatine as a
promising option for both acute and long-term treatment of GAD,
caution is needed when prescribing and using it in patients with
psychiatric or medical co-morbidities, due to potential interactions
with a number of compounds. They suggest studies are needed,
especially in special populations such as elderly patient with GAD
(Buoli et al., 2014).
Complementary and Alternative Medicine (CAM) At the present
time, Piper methysticum (kava), has been the most widely used and
studied herbal medicine for the treatment of GAD and other
anxiety disorders. Reported meta-analytic findings of 11
randomized controlled trials of kava monopreparations (60-280
mg.) demonstrated significant anxiolytic activity compared to
placebo in all but one trial (Sarris et al., 2009). Kava is currently
restricted from use in the United Kingdom, Canada and the
European Union due to concerns about hepatoxicity reported in
some 93 cases resulting in the call for removing kava from over-
the-counter public use to prescription only (Sarris et al., 2009).
The first randomized, double-blind, placebo-controlled
efficacy and tolerability trial of Matricaria recutita
(Chamomile extract) was conducted using 57 outpatients
with mild to moderate GAD where 28 patients received
chamomile and 29 patients received placebo. Chamomile
(220 mg) or placebo therapy was initiated daily at week 1
and increased to 2 tablets daily during the second week.
Patients with a 50% reduction or less in HAM-A scores from
baseline were increased 1 tablet each week up to week 5 if
they still continued to have a 50% reduction or less in
symptom improvement (up to 5 capsules daily during week
5-8 of therapy). Results showed that patients had a
significantly greater reduction in mean total HAM-A scores
with chamomile versus placebo treatment (Amsterdam et
al., 2009).
A more recent comprehensive review of plant-based
medicines assessed in human clinical trials revealed
evidence for anxiolytic effects for 21 plants (Sarris et al.,
2013). This review reported evidence supporting the use of
the following plant-based anxiolytics: piper methysticum
(kava), matricaria recutita (chamomile), ginkgo biloba,
scutellaria lateriflora (skullcap), silybum marianum (milk
thistle), passiflora incarnata (passionflower), withania
somniferum (ashwaghanda), galphimia glauca (galphimia),
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 centella asiatica (gotu cola), rhodiola rosea (roseroot),
echinacea spp (purple cone flower), melissa officinalis
(lemon balm), and echium amoenum (Iranian borage). In
one 15-week, controlled, double blind randomized trial,
patients (n=191) with GAD were randomized to one of the
following treatments: 1) 2-4 capsules of dried galphimia
(350 or 700 mg/day) or 2) lorazepam in capsule form (1 -2
mg). Anxiety scores on Hamilton Anxiety Scale were
significantly reduced for galphimia treatment compared
with lorazepam over the course of the 15 week period.
Authors cautioned that some anxiolytic plants may have
mild adverse effects, e.g., digestive disturbance, headaches
and skin reactions. Serious adverse effects may include liver
toxicity associated with kava (Sarris et al., 2013).

Combined Both the Canadian Psychiatric Association Clinical Practice

Treatments Guidelines on the Management of Anxiety Disorders (2006) and The
International Psychopharmacology Algorithm Project (IPAP) report
and psychopharmacological treatment algorithm indicated that
there is no current evidence to support the routine combination of
CBT and pharmacology in the treatment of GAD. Pharmacological
or psychological treatments have broadly similar efficacy in the
acute treatment of GAD, but the comparative efficacy of combined
drug and psychological approaches for a long-term period is not
established. Both the IPAP report/algorithm and the Canadian
Guideline recommend that as in other anxiety disorders, when
patients with GAD do not benefit from CBT or have a limited
response, a trial of pharmacotherapy is advisable. Similarly,
patients who show limited benefit from pharmacotherapy may
benefit from CBT. The Canadian Guideline also emphasizes that
studies are required to evaluate whether CBT reduces the rate of
relapse when pharmacologic treatment is discontinued (Davidson
et al., 2009; IPAP GAD Algorithm Flowchart, 2009; Canadian
Psychiatric Association, 2006).
A later study assessed the efficacy of combined treatment
including CBT and venlafaxine XR in patients with GAD. Patients
(n=117) were randomly offered or not offered an option of adding
CBT (12-weeks) in addition to venlafaxine XR (Crits-Christoph et
al., 2011). Only one-third of those offered CBT chose to receive the
therapy including techniques such as applied relaxation/self-
control desensitization; training in self monitoring of
environmental, somatic, affective, imaginal and thought cues;
slowed diaphragmatic breathing; and development of coping self-
statement to respond to cues. Results of the study showed no
evidence of additional benefit for the combined CBT and
venlafaxine XR compared to venlafaxine XR alone in treating
patients with GAD (Crits-Christoph et al., 2011).
An area of emerging interest and research is the sequential
treatment of pharmacotherapy and CBT as a two-staged intensive

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 approach to the treatment of anxiety disorders and mood disorders
(Pull, 2007). In reviewing published studies of sequential use of
pharmacotherapy and psychotherapy in mood and anxiety
disorders, Fava et al. noted that available studies on anxiety
disorders (panic disorder and obsessive-compulsive disorder) do
not substantiate long-term benefits from the sequential
combination of pharmacotherapy and psychotherapy as was
demonstrated for recurrent unipolar depression (Fava, 2005).
Since the sequential approach has not yet been applied to GAD,
social phobia and post-traumatic stress disorder, Fava suggests
the need for such research in the treatment of these conditions.
A trial evaluated the specific effectiveness of CBT combined
with medication tapering, i.e., benzodiazepine discontinuation,
among GAD patients compared to GAD patients receiving non-
specific psychological therapy with medication tapering. Those
patients receiving CBT had a markedly better benzodiazepine
cessation rate (75% to 37%), with this groups discontinuation
rate being twice as high. The number of patients who no longer
met GAD criteria was also greater in the CBT group. The
addition of specific CBT components targeting manifestations
of the disorder, apprehension related to ending medication,
and behavioral and cognitive factors involved in the
maintenance of excessive worry may facilitate benzodiazepine
cessation among patients suffering from GAD (Gosselin, 2006).
A large randomized controlled trial (n=1004) of adults being
treated in 17 primary care clinics for anxiety disorders (panic,
generalized anxiety, social anxiety, and posttraumatic stress
disorder) were treated with Coordinated Anxiety Learning and
Management (CALM) or usual care (UC) for three to 12
months. Usual care consisted of treatment by a patients
physician with limited familiarity with evidenced-based
psychotherapy, or referral to a mental health specialist. The
CALM intervention was designed to allow patient choice of
CBT, medication or both; it also included real-time web-based
outcomes monitoring to optimize treatment decisions and care
management to promote medication adherence. Investigators
reported that CALM compared with UC resulted in greater
improvement in anxiety symptoms, depression symptoms,
functional disability and quality of care during the 18 months
of follow-up (Roy-Byrne et al, 2010).
A recent study examined sequenced treatment with
escitalopram and CBT to learn whether this treatment boosts
acute response and prevents relapse in adults aged 60 and
older with GAD (Wetherell et al., 2013). Participants with GAD
(n=73) were treated with escitalopram over 12 weeks followed
by randomization to one of four conditions: 1) 16 weeks of
escitalopram (10-20 mg/day) combined with 16 sessions of
CBT followed by 28 weeks of maintenance escitalopram, 2) 16
weeks of escitalopram (10-20 mg/day) alone followed by 28
weeks of maintenance escitalopram, 3) 16 weeks of
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 escitalopram (10-20 mg/day) combined with 16 sessions of
CBT followed by 28 weeks of pill placebo, or 4)16 weeks of
escitalopram (10-20 mg/day) alone followed by 28 weeks of pill
placebo. This study showed that a sequence of escitalopram
followed by augmentation with CBT resulted in greater
improvement in pathological worry as measured by the Penn
State Worry Questionnaire than those on escitalopram alone.
However, escitalopram followed by augmentation with CBT did
not lead to higher rates of response on a measure of anxiety
symptoms. Participants receiving maintenance escitalopram
had a significantly lower relapse rate than those receiving
placebo. In addition, among participants taking maintenance
placebo, those who received escitalopram augmented with CBT
had lower rates of relapse than those who had escitalopram
without CBT. Researchers concluded that antidepressant
medication augmented with CBT reduces pathological
worrying and relapse risk in older patients with GAD, even
when antidepressant treatment is stopped after augmentation.
They suggested that for older patients who prefer to
discontinue antidepressants, CBT could be an option. Further
they noted that CBT could be an alternative to augmentation
with antipsychotic medications which are increasingly used in
treating anxiety disorders (Wetherell et al., 2013).

Monitor 1. Psychiatric Co-morbidity and Recovery/Recurrence Findings

Progress and from a 12-year prospective study that examined the long-term
Address course of GAD showed that it is a chronic anxiety disorder
Sub-optimal with low probability (0.58) of achieving recovery. After 12
Recovery years, 42% of GAD patients remained in their intake episode.
Of those who did recover, nearly one-half subsequently had a
recurrence. Researchers noted that these results are clearly
inconsistent with earlier assumptions, reflected in the DSM-III
criteria, that GAD is a residual and innocuous condition that
usually does not lead to significant impairment. Rather, the
long-term course appears to be chronic in nature, with more
recent studies showing significant impairment across multiple
domains. For those patients suffering with major depressive
disorder co-morbid with anxiety disorder, the likelihood of
recovering from the depression is reduced (Bruce, 2005).
2. Pharmacology and Relapse One of the main problems with
the pharmacotherapy of anxiety states is a high rate of relapse
upon discontinuation of the medication. Strategies have been
proposed to improve this situation longer pharmacological
treatment in order for remission to occur (Starcevic, 2007).
Also, there is evidence to suggest that early lack of
improvement (at weeks 1 and 2) on a drug may be a strong
negative predictor of improvement at the 8th week. These
findings were demonstrated for all three agents in a
comparative trial of placebo, diazepam and a serotonin

2008-2014 Magellan Health, Inc. 38

This document is the proprietary information of Magellan Health, Inc. and its affiliates.
 receptor (5HT-1A) partial agonist (Rynn, 2006). (N.B. Refer to
previous discussion of the WFSBP Guidelines on page 9 and
summarization of the IPAP psychopharmacological treatment
algorithm on page 10,11 for strategies to manage treatment
resistance and more recent meta-analysis findings on SGA
augmentation efficacy for refractory GAD on page 15).
3. Standard Tools to Assess Response The Canadian Psychiatric
Associations Clinical Practice Guidelines on the Management of
Anxiety Disorders (2006) notes that the 14-item Hamilton
Anxiety Rating Scale (HARS) can be used by clinicians to
assess GAD illness severity and response to therapy. Self-rated
tools may also be appropriate for GAD, such as the Penn State
Worry Questionnaire and the Generalized Anxiety Disorder
Questionnaire-IV. The Canadian guideline also notes that
response to clinical trials of pharmacotherapy is often defined
as a Clinical Global Improvement (CGI) score of < 2 (very much
or much improved) or a 50% reduction in the HARS score.
Remission is usually defined as a HARS score < 7 (no or
minimal anxiety), and full recovery in GAD should be defined
as no longer meeting the diagnostic criteria for the disorder
(symptom resolution), as well as a return to pre-morbid
functioning in all aspects of life (Canadian Psychiatric
Association Guideline, 2006).

2008-2014 Magellan Health, Inc. 39

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Curr Psychiatry Rep (2015) 17:531
DOI 10.1007/s11920-014-0531-3
ANXIETY DISORDERS (A PELISSOLO, SECTION EDITOR)
The Role of Emotion and Emotion Regulation in Social Anxiety
Disorder
Hooria Jazaieri & Amanda S. Morrison &
Philippe R. Goldin & James J. Gross
# Springer Science+Business Media New York 2014
Abstract Many psychiatric disorders involve problematic
patterns of emotional reactivity and regulation. In this review,
we consider recent findings regarding emotion and emotion
regulation in the context of social anxiety disorder (SAD). We
first describe key features of SAD which suggest altered
emotional and self-related processing difficulties. Next, we
lay the conceptual foundation for a discussion of emotion and
emotion regulation and present a common framework for
understanding emotion regulation, the process model of emo-
tion regulation. Using the process model, we evaluate the
recent empirical literature spanning self-report, observational,
behavioral, and physiological methods across five specific
families of emotion regulation processessituation selection,
situation modification, attentional deployment, cognitive
change, and response modulation. Next, we examine the em-
pirical evidence behind two psychosocial interventions for
SAD: cognitive behavioral therapy (CBT) and mindfulness-
based stress reduction (MBSR). Throughout, we present sug-
gestions for future directions in the continued examination of
emotion and emotion regulation in SAD.
Keywords Emotion . Emotion regulation . Emotion
dysregulation . Process model . Social anxiety disorder (SAD)
This article is part of the Topical Collection on Anxiety Disorders
H. Jazaieri (*)
Department of Psychology, Institute of Personality and Social
Research, University of California, Berkeley, 4152 Tolman Hall,
Berkeley, CA 94720-1650, USA
e-mail: hooria@berkeley.edu
A. S. Morrison : J. J. Gross
Department of Psychology, Stanford University, Stanford, CA, USA
P. R. Goldin
Betty Irene Moore School of Nursing Science, University of
California, Davis, Sacramento, CA, USA
Introduction
Social anxiety disorder (SAD) is associated with severe
impairments in nearly every realm of the patients life [1],
making it the fifth most disabling psychiatric disorder [2].
Although prevalent [3] and chronic [4], SAD is often
undertreated [5]. Current estimates suggest that as many
as 80 % of individuals meeting diagnostic criteria for
SAD will receive no treatment over the course of their
lifetimes, while those who eventually pursue treatment do
so in their late 20s, which is typically more than a decade
after symptom onset [6].
According to the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5; pp. 202203), a diagnosis of
SAD is warranted when the following key features are pres-
ent: a marked and persistent fear of social and performance
situations (criterion A); the individual fears that behaviors or
anxiety symptoms will be negatively evaluated by others
(criterion B); social situations almost always provoke fear or
anxiety within the individual (criterion C); feared situations
are avoided and, when not avoided, endured with intense fear
or anxiety (criterion D); the fear or anxiety experienced by the
individual is out of proportion to the actual threat posed by the
social situation (criterion E); the fear, anxiety, or avoidance is
persistentlasting for 6 months or longer (criterion F); and
the fear, anxiety, or avoidance causes clinically significant
distress or impairment in social, occupational, or other impor-
tant areas of functioning (criterion G) [7].
Many have posited that SAD involves emotion dysregula-
tion or difficulties with emotion regulation [8, 9]. The diag-
nostic criteria for SAD suggest altered emotional and self-
related processing difficulties; however, the DSM criteria for
SAD do not specifically point to regulatory difficulties. Only
recently has clinical research focused on emotion and emotion
regulation in SAD and how treatments can facilitate adaptive
emotion regulation efforts.
531, Page 2 of 9
In this review, we first provide a conceptual and theoretical
foundation for examining emotion and emotion regulation,
introducing the process model of emotion regulation, which
we utilize as a framework for understanding the occurrence of
emotion dysregulation in SAD. We then evaluate two psycho-
social interventions, which are designed to promote adaptive
emotion regulation. Throughout, we highlight studies that use
a variety of measures, including patient self-reports,
observational/behavioral data, and physiological indices.
Where possible, we also highlight areas for continued
research.
Emotion and Emotion Regulation
One of the most difficult questions facing the field of affective
science is defining exactly what an emotion is and what it is
not [10]. Emotions are one type of affective response among
many, including moods and stress responses [11]. They are
briefer than moods and include a broader set of responses than
are typically included within stress responses. There are sev-
eral core features of emotions that are worth noting [12]. First,
emotions include situational antecedents or an internal or
external activating event. Second, emotions require conscious
or preconscious attention to the activating event. Third, there
is implicit or explicit subjective appraisal of whether an emo-
tion is useful (or not) in achieving the present goal(s). Fourth,
emotions unfold over time and promote relevant action urges,
physiological activation (central and peripheral), and, in some
cases, expressive behaviors.
Emotion regulation refers to efforts made to influence the
particular emotions one has, when one has them, and how
these emotions are (or, in some cases, are not) experienced
and/or expressed [13]. In contrast, emotion dysregulation is
conceptualized as a state in which despite ones best efforts,
emotion-regulatory attempts fail to achieve emotion-related
goal(s), and the person is unable to make the necessary cor-
rections to achieve the emotion-related goal(s) [12]. Emotion
dysregulation has been closely tied to psychopathology, espe-
cially mood and anxiety disorders [14].
Three core features of emotion regulation are important to
note [12]. First, although theories and research tend to empha-
size downregulation of negative emotions, positive emotion
regulation, that is, influencing the intensity and/or duration of
positive emotions, is also relevant to consider. Second, emo-
tion regulation can be a conscious, intentional, effortful pro-
cess or it can be a process that occurs without conscious
awareness. Third, emotion-regulatory processes must be eval-
uated within their specific contexts and in light of ones
regulatory goal(s) to determine whether they are adaptive
or maladaptive.
Emotion-regulatory processes can be organized into groups
based on when they have their primary impact on the emotion-
Curr Psychiatry Rep (2015) 17:531
generative process [15]. The most common framework for
understanding emotion regulation is the process model of
emotion regulation (see Fig. 1), which includes five specific
families of emotion regulation processessituation selection,
situation modification, attentional deployment, cognitive
change, and response modulation. Situation selection refers
to efforts made to influence emotion by either increasing or
decreasing the likelihood of encountering a given situation
where particular emotions are likely elicited. Situation
modification refers to efforts made to alter ones emotions
by changing external, physical features in the environment.
Attentional deployment refers to efforts made to alter ones
emotions by directing ones attention in a particular way in a
given situation. Cognitive change refers to efforts made to
alter ones emotions by modifying the subjective meaning of
the situation. Lastly, response modulation refers to efforts
made to alter physiological, experiential, or behavioral re-
sponses in a situation. Table 1 depicts a maladaptive and
adaptive example of each of these five strategies.
It bears emphasizing that emotion-regulatory strategies are
neither adaptive nor maladaptive but must be considered
within the context and goal(s) operative in a given situation
[16]. A recent meta-analysis highlighted considerable varia-
tion both between and within families of emotion regulation
processes [17]. Relatedly, although much less is known
about this empirically, presumably in most situations, individ-
uals are using multiple strategies in a single situation, either in
sequence or simultaneously. Research suggests that being able
to apply a variety of emotion-regulatory strategies in a flexible
manner is what constitutes adaptive emotion regulation and
promotes health and well-being [18, 19].
Emotion and Emotion Regulation in SAD
Emotion regulation difficulties in SAD have been documented
on both intra- and interpersonal levels. Individuals with SAD
exhibit a limited repertoire of strategies and are thought to
have deficits that are relevant to specific aspects of SAD [20].
However, some researchers have suggested a more general
disturbance in emotion-regulatory neural circuits in SAD [21].
In the sections that follow, we use the process model of
emotion regulation [15] as a framework for understanding
emotion dysregulation in SAD.
Situation Selection
Situation selection refers to the decision to approach or avoid a
specific context that may generate unwanted emotional re-
sponses. In SAD, situation selection involves the avoidance of
feared social and performance situations. Often, patients pre-
dict that future situations and related emotional responses will
be negative. Compared to those without SAD, patients
Curr Psychiatry Rep (2015) 17:531 Page 3 of 9, 531

Fig. 1 The process model of

emotion regulation. Reprinted
with permission from Guilford
Press

interpret social situations as being more threatening and arrive
at more catastrophic conclusions [8]. These distorted interpre-
tations lead to avoidance of social and performance situations.
One study that examined memories of autobiographical social
situations in patients with SAD and healthy controls found
that patients demonstrated greater avoidance of present situa-
tions that resemble situations they have encountered in the
past [22].
When compared to healthy controls, patients with SAD
self-report greater use of situation selection when recalling
past social anxiety-evoking situations [23]. Research suggests
that social isolation and limited approach behavior, particular-
ly of activities or situations where positive emotions may be
generated [24], are characteristic of SAD. Clinically, aside
from rare circumstances where the patient is caught off guard
by the situation or the potential consequences for avoiding the
situation are very high (e.g., giving a presentation at work or
risk getting fired), patients craft their daily lives to strategically
select the situations they wish to avoid.
Avoidance works because it creates immediate, short-
term relief from having to encounter the feared stimuli. Ac-
cordingly, patients judge the avoidance of the situation as a
success since the situation and emotion (fear/anxiety) are
avoided; yet the maladaptive avoidance behavioral pattern is
reinforced. The utilization of situation selection not only
avoids the feared environment, but it also avoids experiencing
the feared emotion of anxiety. Consequently, the patient does
not have the opportunity to increase tolerance to the seemingly
intolerable situation/emotion.
Situation Modification
Once a patient has entered a social or performance situation,
situation modification can become operative. Situation mod-
ification refers to modifying the situation to influence which
emotions will or will not occur. Maladaptive situation modi-
fication can take several forms in SAD, the most common of
which is engaging in safety behaviors. These are covert or
overt behaviors employed with the intention of reducing
threatening emotional states and maintaining a sense of safety.
Safety behaviors include a broad range of behaviors and are
common in anxiety disorders more generally. There are a
variety of subtypes of safety behaviors in SAD, for example,
behaviors that involve avoidance or impression management
[25] and attempts to reduce the likelihood of negative evalu-
ation from others [8]. Cognitive models of SAD posit that
safety behaviors contribute to the maintenance of anxiety and
negative beliefs about social situations. A recent study showed
that as concerns about public exposure and scrutiny of neg-
ative self-attributes increased, so did safety behaviors [26].
While safety behaviors may make situations less threatening
or awkward for the patient, these behaviors can be problematic

Table 1 Maladaptive and adaptive emotion regulation in social anxiety disorder

Situation selection Situation modification Attentional deployment Cognitive change Response modulation

Maladaptive ER Avoid going to the Enter the meeting Browse the Internet on ones Use cognitive Inhibit and push away
meeting in order to room and move a laptop/smartphone to reappraisal skills to ones anxious thoughts,
avoid feeling anxious chair to the corner avoid engaging with others convince oneself feelings, and physical
during the meeting and sit away from before the meeting begins that this job does sensations
others not matter
Adaptive ER Go to the meeting in order Enter the meeting Look at objects in the Use cognitive Inhibit the urge to act on
to feel satisfaction for room, open a bottle meeting roompictures reappraisal skills to the emotion of anger
participating in ones job of cold water, and on the walls, colors, and actively challenge when the manager
start drinking to textures in environment to distorted, anxious starts the meeting
cool down help feel more comfortable thoughts 15 min late, again
before the meeting begins
531, Page 4 of 9
and perceived as unskillful. They can inadvertently increase
anxiety and cause patients to appear less appealing to others,
thus providing more evidence for the patients catastrophic
beliefs and predictions [27, 28]. Situation modification or
safety behaviors are valiant efforts to regulate uncomfortable
emotions but are coupled with consequences that perpetuate
affective disturbance.
Encouragingly, research suggests that when instructed to
reduce safety behaviors, patients with SAD perceived and
actually received more positive responses in a social interac-
tion then when not instructed to reduce safety behaviors [29].
Research has also demonstrated that patients instructed to
eliminate the use of safety behaviors during cognitive behav-
ioral therapy (CBT) had greater reductions in social anxiety
symptoms following treatment compared to those who con-
tinued with safety behaviors [30]. Taken together, these find-
ings suggest that when instructed, patients can reduce safety
behaviors, resulting in both intra- and interpersonal benefits.
Attentional Deployment
Once in a social situation, an individual may direct attention in
a particular way to influence emotions. There are many
choices in terms of where an individual can place his or her
attentione.g., the immediate environment (social or non-
social objects) versus the self (e.g., internal sensations).
Meta-analyses indicate that biased attention toward threat is
characteristic of anxiety disorders in general [31] and specific
information processing biases have been documented in SAD
[32]. For example, SAD has been associated with general
(rather than specific) biases in emotion recognition [33], in-
creased self-focused attention, and atypical self-referential
processing [34]. The attentional bias to negative information
observed in SAD has been implicated in enhancing maladap-
tive emotion regulation and may increase emotional vulnera-
bility and potential for psychopathology [35].
Although attentional bias toward threat causally contrib-
utes to impaired emotion regulation in SAD, not all forms of
attentional deployment in the context of threat are problemat-
ic. For example, in a laboratory induction of deliberate atten-
tional avoidance of negative information, emotional responses
to a speech stressor were adaptively regulated and socially
anxious participants displayed beneficial behavioral conse-
quences as a result during the speech performance [36]. By
attending to non-threatening cues, reductions in self-reported,
behavioral, and physiological measures of anxiety are possible
[37]. This suggests selective attention to information can be an
adaptive form of emotion regulation in some circumstances, at
least in the short term. Difficulty disengaging attention
from threatening aspects of a situation may maintain SAD
[38]. However, it may be possible to retrain attentional bias
from negative information in SAD [39], thereby reducing
social anxiety symptoms [40, 41]. Furthermore, CBT is also
Curr Psychiatry Rep (2015) 17:531
beneficial for patients who are slower to disengage from
negative stimuli [42]. The role of various forms of maladap-
tive and adaptive attentional deployment in SAD is an impor-
tant area for continued research.
Cognitive Change
Cognitive change is one of the main targets of CBT for SAD
[43]. It involves utilizing cognitive skills (e.g., perspective
taking, reframing the meaning of thoughts and situations,
challenging interpretations) to modify the meaning of stimuli
that generate emotional reactions. Cognitive reappraisal is the
most researched form of cognitive change and is largely
considered to be an adaptive emotion-regulatory strategy.
When employed appropriately, cognitive reappraisal can mod-
ify emotional reactions to anxiety-provoking situations and
enhance psychological flexibility and emotional well-being
[11]. On the other hand, difficulty employing reappraisal is
considered a core mechanism in the maintenance of psycho-
pathology in individuals with anxiety and mood disorders
[44]. Compared to healthy adults, patients with SAD report
being less skillful at using cognitive change strategies [23].
Neuroimaging studies have begun to elucidate specific
brain circuit deficits during cognitive reappraisal in patients
with SAD. Compared to healthy adults, patients with SAD
have difficulty recruiting cognitive control prefrontal cortex
(PFC) brain networks when reappraising reactivity to harsh
facial expressions [45]. Specifically, there can be delayed re-
cruitment of PFC regions and lesser inverse PFC-amygdala
functional connectivity when reappraising negative self-
beliefs [46]. However, a recent study found that CBT can
modify these deficits by increasing brain signal magnitude,
timing, and functional connectivity of the PFC-amygdala dur-
ing cognitive reappraisal [47]. These results suggest deficient
cognitive reappraisal processes in SAD can be restored when
appropriate training is employed [46, 45].
Current models suggest that self-focused appraisal can be a
successful emotion regulation strategy for patients with SAD
[48]. However, one recent study suggests that ones beliefs
about being negatively evaluated (rather than self-focused
attention) produce changes in behavior that results in poor
social performance and subsequent rejection [49]. Thus,
examining the exact nature of the patients distorted beliefs
(e.g., beliefs of being negatively evaluated rather than
distorted self-focused beliefs more generally) may be a fruitful
area of continued research.
In another recent study utilizing a 2-week daily diary to
examine emotions, social events, and emotion regulation
in social anxiety, the use of cognitive reappraisal to reduce
distress resulted in fewer negative social events on the
following day for participants with lower social anxiety
but did not influence the daily lives of participants with
high social anxiety [50]. This suggests that there may be
Curr Psychiatry Rep (2015) 17:531
important subgroups of indiviudals who will benefit from
the use of cognitive reappraisal. Additionally, the timing of
acquisition of reappraisal skills during CBT appears to be an
important marker of treatment response [51]. Additional
research is needed to understand whether introducing
reappraisal earlier in treatment can be beneficial for patients
with SAD. A more fine-grained analysis of the type of belief
and subsequent reappraisal, patient symptom severity, and the
timing of reappraisal skill acquisition are areas for future
research.
Response Modulation
After an emotion occurs, response modulation refers to strat-
egies to modify one or more components of the emotional
response (e.g., experience, behavior, physiology). One form
of response modulation is expressive suppression, whereby
the individual inhibits outward expressions of the emotion,
such as facial behavior. Another form of response modulation
is experiential avoidance, which involves altering, avoiding,
or concealing anxious thoughts and feelings, and is common
in patients with SAD [52]. When compared to healthy con-
trols, patients with SAD report greater use of expressive
suppression and less skill in employing response modulation
in social situations [23]. Research suggests that patients with
SAD engage in response modulation to both negative [53] and
positive [54] emotions, perhaps due to the underlying fear of
negative or positive evaluation.
In experience sampling studies, patients with SAD report
fewer positive experiences on days they reported engaging in
more experiential avoidance [24]. Similarly, patients report
fewer positive social events and less positive emotion on days
following the use of greater positive emotion suppression
[50]. Non-acceptance of emotional responses has been asso-
ciated with social interaction and social performance anxiety
[20]. Suppression often leads to less warm and outgoing
behavior, which may in turn elicit less friendly behaviors
(even rejection) from others, which subsequently generates
negative emotions [8]. However, the use of emotion suppres-
sion strategies during CBT is not a marker of treatment re-
sponse in patients with SAD [51] and CBT has been shown
to be beneficial even for patients endorsing particularly high
levels of experiential avoidance [55, 56].
Clinical Perspective
The emphasis on emotions in psychological treatments is not a
new idea [57, 58]. To date, many formal treatment programs
and clinical interventions have been developed to address
emotion dysregulation [5965], and there is evidence for the
usefulness of emotion regulation training in psychotherapy for
Page 5 of 9, 531
SAD [21]. Here, we focus on two distinct psychosocial
interventions for SAD: CBT and mindfulness-based stress
reduction (MBSR).
Cognitive Behavioral Therapy
Based on Aaron Becks pioneering work [66, 67], CBT
utilizes cognitive and behavioral strategies to break the
maladaptive cycle that exists among distorted thoughts,
emotions, and behaviors. CBT includes training in cogni-
tive restructuring of maladaptive beliefs (cognitive change)
and behavioral strategies such as exposure to avoided
situations (situation selection) and is an effective treatment
for many types of psychological problems. To a lesser
degree, CBT also works toward modifying maladaptive
patterns of situation modification, attentional deployment
[68], and response modulation emotion-regulatory strategies.
CBT is the gold-standard intervention for SAD [43].
Emotion regulation strategies have been shown to predict,
moderate, and mediate treatment response to CBT. This
should inspire clinicians to consider matching treatments to
people with different emotion regulation difficulties or to
enhance the efficacy of existing treatments by capitalizing
on the specific emotion regulation strategies that appear to
show the largest and most consistent effects. While research
has demonstrated that patients with SAD endorse more neg-
ative and fewer positive self-views and emotions when com-
pared to healthy controls, CBT can modify this pattern. Mod-
erator analyses show that CBT works quite well for patients
who endorse lower psychological flexibility [55]. Mediator
analyses have begun to identify specific mediators of the
impact of CBT for SAD on social anxiety symptom reduction.
A recent randomized controlled trial of CBT for SAD has
shown that reductions of maladaptive interpersonal beliefs
[69] as well as increases in cognitive reappraisal self-
efficacy [70] and positive self-views [71] during treatment
mediate reductions in social anxiety symptoms. Importantly,
increases in cognitive reappraisal self-efficacy [70] and pos-
itive self-views [71] also predict reduction of social anxiety
symptoms 1-year post-CBT.
A more nuanced analysis examined weekly change across
16 sessions of individual CBT and found that weekly social
anxiety decreases were associated with decreases in utilizing
suppression and increases in using cognitive reappraisal suc-
cessfully during treatment and that weekly increases in using
cognitive reappraisal successfully predicted post-CBT reduc-
tion in social anxiety symptom severity [72]. Neurally, studies
have shown that CBT reduces negative emotion experience
and allows for greater and quicker recruitment of reappraisal-
related brain regions [47]. Furthermore, there is some evi-
dence that CBT may be mediated by top-down regulation
and decreased emotional reactivity [73].
531, Page 6 of 9
This growing body of literature on CBT for SAD is en-
couraging and yet there is still much to be donefor example,
some initial research suggests that there may be an interesting
relationship between the specific treatment phases of CBT
(e.g., cognitive vs. cognitive+behavioral exposures) and the
use of maladaptive versus adaptive emotion-regulatory strat-
egies in patients with SAD [74]. A more detailed examination
of phases of CBT and the interaction between maladaptive and
adaptive emotion-regulatory strategies is warranted. Further-
more, as the field of psychology moves toward transdiagnostic
treatments, continued research examining blends of adaptive
components across existing interventions will be needed.
Cognitive behavioral conceptualizations of SAD may benefit
from integrating constructs aligned with alternative treat-
ments. For example, researchers have begun to examine the
role of trait mindfulness in CBT for SAD [75]. One study
found that cognitive restructuring and mindfulness strategies
together reduced post-event processing, a ruminative and
anxiety-maintaining cognitive process common among indi-
viduals with SAD, and improved affect [76]. Others have
begun to directly compare CBT to alternative mindfulness-
based treatments for SAD [56, 55].
Mindfulness-Based Stress Reduction
MBSR was originally developed by Jon Kabat-Zinn, Ph.D.,
for adults suffering from chronic pain [MBSR; 77] and has
since become a widely accepted and empirically supported
intervention for many psychological and medical disorders
[78]. In MBSR, individuals cultivate the mental quality of
mindfulnessa non-judgmental, flexible, and present-
moment attentional focus. Through training and practice, the
exercises taught in MBSR are thought to reduce the habitual
tendency to automatically and compulsively engage in and
react to mental states and external environments [79].
Several meta-analyses have shown that MBSR reliably
decreases symptoms of stress, anxiety, and depression and
increases well-being across clinical and non-clinical samples
[8082] and is associated with increased positive and de-
creased negative affective states [78, 83, 84]. MBSR yields
symptom improvement in mixed samples of individuals with
anxiety disorders [85], though only a few studies have
targeted a specific anxiety disorder [86, 87], and even fewer
have focused specifically on SAD. Mindfulness-based ap-
proaches and interventions for SAD improve mood, function-
ality, and quality of life and reductions in fear of negative
evaluation [88, 89]. A recent study found that in patients with
generalized SAD, MBSR decreased social anxiety and depres-
sive symptoms, decreased perceived stress and loneliness, and
increased self-esteem and satisfaction with life [90]. As noted
above, in an effort to address treatment non-responders or
those who will not participate in traditional treatments, re-
searchers are increasingly interested in examining the role of
Curr Psychiatry Rep (2015) 17:531
trait mindfulness in patients with SAD and comparing
mindfulness-based interventions to the current gold-standard
treatment of CBT for SAD. Interestingly, in one trial of MBSR
for SAD, patients did not achieve the rate of response on core
symptoms of SAD when compared to group CBT, though
MBSR was as efficacious as CBT in improving subjective
well-being, mood, and overall functioning [91].
Neuroimaging data have begun to illuminate the neural
mechanisms through which MBSR influences emotion regu-
lation in SAD. Following MBSR, patients with SAD reported
decreased negative emotion experience in addition to reduced
amygdala activity and increased activity in attentional deploy-
ment brain regions [92]. These findings suggest that MBSR
may reduce emotional reactivity and enhance emotion regu-
lation in patients with SAD. Additionally, in a recent random-
ized controlled trial comparing MBSR to an aerobic exercise
(AE) stress reduction program, MBSR resulted in greater
reductions in negative emotions when patients were asked to
engage in present-moment focused meta-cognitive attention
regulation in the context of negative self-beliefs embedded in
autobiographical, anxiety-provoking social situations. Inter-
estingly, more meditation practice during MBSR was associ-
ated with greater decreases in negative emotion and social
anxiety symptom severity, as well as increases in attention-
related regions when implementing the attention regulation
strategy [93]. This suggests that mindfulness meditation train-
ing may improve clinical symptoms and emotion reactivity
through augmentation of meta-cognitive attention regulation
ability in patients with SAD. In a related analysis [94], results
indicated that during a self-referential processing experimen-
tal task, compared to AE, MBSR yielded greater reductions in
self-endorsement of negative self-views which in turn was
related to a reduction in social anxiety symptom severity.
Neurally, the MBSR group displayed an increased attention-
related posterior cingulate cortex/precuneus response. These
findings suggest that MBSR may train adaptive self-referential
processing in patients with SAD.
Conclusion
From our review, it is apparent that emotion dysregulation
exists in SAD. Without intervention, clinical symptoms and
difficulties persist and significantly impact the individuals
life. Fortunately, treatments for SAD exist which include
components that address difficulties with emotion regulation.
Despite these interventions, treatment non-responders and
those who are unable or unwilling to participate in traditional
forms of treatment still exist. Future research must develop
alternative interventions and refine existing interventions to
improve the efficacy and acceptability of treatments for indi-
viduals with SAD. Given the emerging research we have
Curr Psychiatry Rep (2015) 17:531
reviewed, it appears that investigating the role of emotion and
emotion dysregulation in SAD has much to offer in this area.
Compliance with Ethics Guidelines
Conflict of Interest Hooria Jazaieri, Amanda S. Morrison, Philippe R.
Goldin, and James J. Gross declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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