PANIC DISORDER Panic disorder is defined by the presence of recurrent and unpredictable panic attacks, which are distinct

episodes of intense fear and discomfort associated with a variety of physical symptoms, including palpitations, sweating, trembling, shortness of breath, chest pain, dizziness, and a fear of impending doom or deathParesthesias, gastrointestinal distress, and feelings of unreality are also common. Panic attacks have a sudden onset, developing within 10 min and usually resolving over the course of an hour, and they occur in an unexpected fashion. The frequency and severity of panic attacks vary, ranging from once a week to clusters of attacks separated by months of well-being. The first attack is usually outside the home, and onset is typically in late adolescence to early adulthood Etiology and Pathophysiology of panic disorders The etiology of panic disorder is unknown but appears to involve a genetic predisposition, altered autonomic responsivity, and social learning. Panic disorder shows familial aggregation; the disorder is concordant in 30 to 45% of monozygotic twins, and genome-wide screens have identified suggestive risk loci on 1q, 7p15, 10q, 11p, and 13q. Acute panic attacks appear to be associated with increased noradrenergic discharges in the locus coeruleus. Intravenous infusion of sodium lactate evokes an attack in two-thirds of panic disorder patients, as do the 2-adrenergic antagonist yohimbine, cholecystokinin tetrapeptide (CCK-4), and carbon dioxide inhalation. It is hypothesized that each of these stimuli activates a pathway involving noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe. Agents that block serotonin reuptake can prevent attacks. It is theorized that panic-disorder patients have a heightened sensitivity to somatic symptoms, which triggers increasing arousal, setting off the panic attack. Accordingly, therapeutic intervention involves altering the patient's cognitive interpretation of anxiety-producing experiences as well as preventing the attack itself. GENERALIZED ANXIETY DISORDER Patients with generalized anxiety disorder (GAD) have persistent, excessive, and/or unrealistic worry associated with muscle tension, impaired concentration, autonomic arousal, feeling on edge or restless, and insomnia. Onset is usually before age 20, and a history of childhood fears and social inhibition may be present. Etiology and Pathophysiology Experimental work suggests that anxiogenic agents share in common the property of altering the binding of benzodiazepines to the -aminobutyric acid (GABA)A receptor/chloride ion channel complex. Benzodiazepines are thought to bind two separate GABAA receptor sites: type I, which has a broad neuroanatomic distribution, and type II, which is concentrated in the hippocampus, striatum, and neocortex. The antianxiety effects of the various benzodiazepines and side effects such as sedation and memory impairment are influenced by their relative binding to type I and type II receptor sites. Serotonin [5-hydroxytryptamine (5HT)]; also appears to have a role in anxiety, and buspirone, a partial 5HT1A receptor agonist, and certain 5HT2A and 5HT2C receptor antagonists (e.g., nefazodone) may have beneficial effects. STRESS DISORDERS Patients may develop anxiety after exposure to extreme traumatic events such as the threat of personal death or injury or the death of a loved one. The reaction may occur shortly after the trauma (acute stress disorder) or be delayed and subject to recurrence

(PTSD). The patient may feel depersonalized and unable to recall specific aspects of the trauma, though typically it is reexperienced through intrusions in thought, dreams, or flashbacks, particularly when cues of the original event are present. Patients often actively avoid stimuli that precipitate recollections of the trauma and demonstrate a resulting increase in vigilance, arousal, and startle response. Etiology and Pathophysiology It is hypothesized that in PTSD there are excessive release of norepinephrine from the locus coeruleus in response to stress and increased noradrenergic activity at projection sites in the hippocampus and amygdala. These changes theoretically facilitate the encoding of fear-based memories. Greater sympathetic responses to cues associated with the traumatic event occur in PTSD, although pituitary adrenal responses are blunted. OBSESSIVE-COMPULSIVE DISORDER Obsessive-compulsive disorder (OCD) is characterized by obsessive thoughts and compulsive behaviors that impair everyday functioning. Onset is usually gradual, beginning in early adulthood, but childhood onset is not rare. The disorder usually has a waxing and waning course, but some cases may show a steady deterioration in psychosocial functioning. Etiology and Pathophysiology A genetic contribution to OCD is suggested by twin studies. Family studies show an aggregation with Tourette's disorder. OCD is also more common in males and in firstborn children. The anatomy of obsessive-compulsive behavior is thought to involve the orbital frontal cortex, caudate nucleus, and globus pallidus. The caudate nucleus appears to be involved in the acquisition and maintenance of habit and skill learning, and interventions that are successful in reducing obsessive-compulsive behaviors also decrease metabolic activity measured in the caudate.

Anxiety Disorders
Introduction
Anxiety disorders are a group of syndromes (see Table 1) characterised by symptoms of excessive worrying, intense fears, hypervigilance and/or somatic symptoms, in the absence of a dangerous situation.

Table 1: The Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) Definition of 'Anxiety Disorders"

Panic disorder, with and without agoraphobia Agoraphobia, without a history of panic disorder Social anxiety disorder (SAD) Specific phobia Obsessive-compulsive disorder (OCD) Post-traumatic stress disorder (PTSD) Acute stress disorder Generalised anxiety disorder (GAD) Anxiety disorder due to a general medical condition Substance-induced anxiety disorder Anxiety disorder not otherwise specified

Anxiety disorders are the most common of all the psychiatric disorders (Robins et al, 1984), and recent crosscountry studies indicate that they are highly prevalent. In addition, two anxiety disorders are among the four most common medical illnesses in the USA; the other two are also closely associated with anxiety. Phobias are the most common anxiety disorder, followed by depression, substance abuse and OCD (Karno et al, 1988). Pharmaco-economic research suggests that one-third of all costs related to mental illness are incurred because of anxiety disorders (Dupont et al, 1997), and the economic burden of disorders such as SAD (Schneier et al, 1992b) and OCD (Hollander, 1997; Dupont et al, 1995) is extremely high. The treatment of anxiety disorders has changed substantially over the past decade, mainly because of the development of safer, non-benzodiazepine agents, in particular the selective serotonin re-uptake inhibitors (SSRIs). SSRIs were originally developed for the treatment for depression, and they have subsequently showed efficacy in the treatment of anxiety due to their serotonergic activity. Read more about the treatment of anxiety disorders. This area of the Brain Explorer offers an overview of the causes ofand treatment foranxiety disorders, with no particular emphasis on any disorder. However, more detailed information about panic disorder can also be found on this website.

Aetiology
Anxiety disorders can be triggered by a number of factors, including life experiences and psychological traits. In particular, increased stress and inadequate coping mechanisms may contribute to anxiety. Family history and genetics have also been implicated in the aetiology of anxiety disorders. Studies show that there is a link between anxiety disorders and specific areas of the brain, and that an imbalance in the brain that regulate anxiety, such as noradrenaline, serotonin and Gammain certain neurotransmitters aminobutyric acid (GABA), may contribute to the symptoms of the disease.

The forebrain is the area most affected in people with anxiety disorders. The limbic system , which is involved in storing memories and creating emotions, is also thought to play a central role in processing all and the dorsal raphe project to the septohippocampal anxiety-related information. Both the locus coeruleus and circuit, which in turn projects to other areas of the limbic system that mediate anxiety. The hippocampus amygdala are of particular importance, as they are interconnected and also project to both subcortical and cortical nuclei. Interestingly, in some people with post-traumatic stress disorder (PTSD), the hippocampus in this part of the brain, which is appears to be smaller. This may be because of degeneration of dendrites thought to be caused by a stress-induced increase in the concentrations of glucocoticoids. Other brain structures involved in controlling emotion, such as the hypothalamus , may also be involved in the pathogenesis of anxiety disorders. People with obsessive-compulsive disorder (OCD) often show increased , in particular the striatum and other frontal lobe areas of the forebrain. activity in the basal nuclei

Serotonin Hypothesis
The serotoninergic systems are involved in controlling anxiety and are almost certainly involved in the pathogenesis of anxiety disorders. Although there has been much research into the role of serotonin in the brain, , a full understanding of its function, particularly in in particular its function and influence in the synaptic cleft disease, is yet to be found (Fuller and Wong, 1997). However, the discovery that selective serotonin reuptake inhibitors (SSRIs), which enhance serotonin-mediated neurotransmission in the brain, are useful in treating mood and anxiety disorders led to the hypothesis that serotonin dysfunction is important in the aetiology of these disorders. The fact that at least some antidepressant agents, such as the SSRIs, appear to relieve anxiety symptoms suggests that both anxiety disorders and depression share some common aetiopathological mechanisms (Boulenger et al, 1997). This is further illustrated by twin studies showing a common genetic susceptibility between anxiety and depression (Kendler et al, 1987, 1992). The discovery of a common biological basis for anxiety disorders and depression would simplify and improve the treatment of these related disorders (Stahl, 1997). There are various theories linking the function of serotonin and its receptors to the actions of both anxiolytic and antidepressant drugs. Pharmacological manipulation to enhance serotonin concentration in the brain increases anxiety, and a reduction in serotonin concentrations is associated with reduced anxiety. This suggests that anxiety is caused by abnormally increased serotonin concentrations and depression due to abnormally decreased serotonin concentrations. However, this is an oversimplification of the issue and it has been hypothesised that serotonin receptors actually adapt to the increased concentrations of serotonin and there is a down-regulation of inhibitory 5-HT1A receptors leading to excessive neuronal impulse flow (Stahl, 1997). Animal models of anxiety have been used to clarify the precise involvement of serotonergic mechanisms in antagonist, ritanserin, the partial 5-HT1A anxiety disorders (Snchez, 1993). The 5-HT2A/2C receptor receptor agonists, buspirone and ipsapirone, and the 5-HT3 receptor antagonists, zacopride and ondansetron, have all shown anxiolytic effects in a variety of animal test models (Snchez, 1993). In addition, creating an overall increase in serotonergic activity, using the SSRI citalopram and the serotonin-releasing agent, fenfluramine, relieved symptoms of anxiety in mice. Furthermore, the panic- and anxiety-inducing effects of mCPP, a serotonin receptor agonist, are well documented (Eriksson et al, 1991).