Professional Documents
Culture Documents
Emanuela Offidani c
a
Affective Disorders Program, Department of Psychology, University of Bologna, Bologna, Italy; b Department of
Psychiatry, State University of New York at Buffalo, Buffalo, N.Y., and c Center for Complementary and Integrative
Key Words syndrome was variable, and its estimation was hindered by
Withdrawal symptoms · Selective serotonin reuptake a lack of case identification in many studies. Symptoms typ-
inhibitors · Adverse events · Side effects · Discontinuation ically occur within a few days from drug discontinuation and
syndrome · Tolerance · Antidepressive agents · Depression · last a few weeks, also with gradual tapering. However, many
Anxiety variations are possible, including late onset and/or longer
persistence of disturbances. Symptoms may be easily mis-
identified as signs of impending relapse. Conclusions: Clini-
Abstract cians need to add SSRI to the list of drugs potentially induc-
Background: Selective serotonin reuptake inhibitors (SSRI) ing withdrawal symptoms upon discontinuation, together
are widely used in medical practice. They have been associ- with benzodiazepines, barbiturates, and other psychotropic
ated with a broad range of symptoms, whose clinical mean- drugs. The term ‘discontinuation syndrome’ that is currently
ing has not been fully appreciated. Methods: The PRISMA used minimizes the potential vulnerabilities induced by SSRI
guidelines were followed to conduct a systematic review of and should be replaced by ‘withdrawal syndrome’.
the literature. Titles, abstracts, and topics were searched us- © 2015 S. Karger AG, Basel
ing the following terms: ‘withdrawal symptoms’ OR ‘with-
drawal syndrome’ OR ‘discontinuation syndrome’ OR ‘dis-
continuation symptoms’, AND ‘SSRI’ OR ‘serotonin’ OR ‘anti- Introduction
depressant’ OR ‘paroxetine’ OR ‘fluoxetine’ OR ‘sertraline’ OR
‘fluvoxamine’ OR ‘citalopram’ OR ‘escitalopram’. The elec- In the 1990s, case reports [1–16] started documenting
tronic research literature databases included CINAHL, the withdrawal reactions following the discontinuation of se-
Cochrane Library, PubMed and Web-of-Science from incep- lective serotonin reuptake inhibitors (SSRI). As the vol-
tion of each database to July 2014. Results: There were 15 ume of the literature grew, one of the earliest reviews [17]
randomized controlled studies, 4 open trials, 4 retrospective suggested that a discontinuation syndrome consisting of
investigations, and 38 case reports. The prevalence of the a cluster of somatic and psychological symptoms could
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E-Mail karger@karger.com
IT–40127 Bologna (Italy)
www.karger.com/pps
E-Mail giovanniandrea.fava @ unibo.it
indeed occur. The clinical data suggested that the syn- SSRI. We restricted our search to SSRI drugs. Due to the impor-
drome could last up to 3 weeks and could be improved by tance of serendipitous observations, we included studies of various
designs: randomized controlled trials (RCT), open investigations,
restarting the same or a similar antidepressant drug (AD). retrospective studies, and single case reports. We excluded studies
Even though discontinuation symptoms were mostly re- if they were conducted in nonclinical samples and settings and/or
ported after abrupt suspension, they were found to occur were based on the exploration of patients’ websites [30].
also after gradual tapering [17–19] and to differ in preva-
lence according to the pharmacological profile of SSRI Data Extraction
Data were independently extracted by both reviewers with the
[20, 21]. use of a precoded form. The following data were extracted from
In 1998, a specific index for the withdrawal symptom- studies meeting the criteria for inclusion in the systematic review:
atology, the Discontinuation Emergent Signs and Symp- age, gender distribution, study design, type of SSRI, number of pa-
toms (DESS) checklist [22], was developed. Diagnostic tients, group comparisons, treatment duration and assessment
criteria, such as those developed by Black et al. [23], were times, and methods used to assess withdrawal symptoms. The
terms ‘relapse/recurrence’, ‘rebound’, and ‘withdrawal’ were used
proposed. Such criteria encompassed both somatic (diz- according to Chouinard’s definitions [31]: recurrent symptoms
ziness, light-headedness, vertigo, shock-like sensations, are a gradual return of the patient’s original symptoms with the
paresthesias, fatigue, headache, nausea, tremor, diarrhea, same rate of intensity as before treatment; rebound symptoms are
and visual disturbances) and psychological (anxiety, in- a rapid return of the original symptoms but worse than before
somnia, and irritability) symptoms and required signifi- treatment, and withdrawal symptoms are new symptoms that were
not part of the patient’s illness before treatment and are associated
cant distress to be associated with them [23]. with specific classes of psychotropic drugs. The terms ‘withdrawal
The term ‘discontinuation syndrome’ has progressive- syndromes’ and ‘discontinuation syndromes’ were considered to
ly replaced ‘withdrawal syndrome’ or ‘reactions’ [24]. In be equivalent. Particularly in case reports, adherence to the proto-
the past decade, few studies assessed the presence of dis- type description of SSRI discontinuation syndromes [23] was
continuation symptoms, and the topic has attracted lim- checked but was not considered to be a requisite.
ited attention also as to literature reviews [25–28]. To the Data Synthesis
best of our knowledge, in the English language there has In view of the highly heterogeneous patient populations and
been no systematic review on the clinical aspects of SSRI differences in the design of RCT, a meta-analysis was not deemed
discontinuation according to established criteria [29]. to be appropriate.
Yet, such knowledge is important because of the wide-
spread use of SSRI in medical practice.
Results
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et al. [40], in 87 patients suffering from depression who drugs, paroxetine produced significantly more discontin-
had their maintenance therapy with paroxetine, fluox- uation symptoms than escitalopram did (5 or 10 mg, p <
etine, sertraline, and citalopram interrupted for 4–7 days, 0.001) [44].
reported that, although DESS scores increased in all treat- Baldwin et al. [45] evaluated the difference between
ment groups, paroxetine caused significantly more dis- abrupt and tapered discontinuation when using parox-
continuation symptoms than other SSRI did (p < 0.05). etine or escitalopram in patients with MDD. Discontinu-
Two RCT examined the onset of withdrawal symp- ation-emergent effects were assessed in two separate dou-
toms following treatment with escitalopram [41] or ser- ble-blind periods. First, patients were randomized to one
traline [42]. When escitalopram was compared to venla- of two treatment interruption periods (placebo substitu-
faxine XR in MDD patients, significantly more venlafax- tion for 3–5 days), and then they were randomized to a
ine-treated patients than escitalopram-treated ones 1- to 2-week tapered withdrawal period. During the short
reported a DESS score >4 in a 1-week runout period (p < placebo substitution, there were no significant differenc-
0.01) [41]. Increased dreaming, trouble sleeping, ner- es. In the tapered condition, results showed that the
vousness or anxiety, irritability, and sudden worsening of changes in the total DESS score were significantly greater
mood occurred with an incidence >10% in the escitalo- for paroxetine than escitalopram after 1 week of alter-
pram group. Sir et al. [42] systematically evaluated the nate-day dosing (p < 0.01) and a subsequent (posttreat-
presence of withdrawal reactions by using the Antide- ment) week with placebo (p < 0.01). In order to examine
pressant Discontinuation Scale (ADDS) [42] in an 8-week two different tapering strategies, Tint et al. [46] random-
multicenter randomized trial comparing sertraline and ized 28 patients treated with different SSRI or venlafaxine
venlafaxine XR in 163 patients with MDD. After a tapered to a short (3 days) or long (14 days) taper. Results showed
discontinuation, 34.3% of patients treated with sertraline that 46% of subjects reported discontinuation symptoms
experienced a discontinuation syndrome from moderate and that the incidence was similar in both conditions (47
to severe; 23.9% of them experienced a mild discontinu- vs. 46% in the short vs. long taper groups).
ation reaction, while 23.9% reported a minimal one. Sub- In conclusion, among patients with MDD, the average
jects taking venlafaxine XR also reported discontinuation mean DESS score was 5.7 (SD = 7.36) for those who dis-
symptoms from minimal to very severe (minimal = 17.7%; continued treatment with paroxetine [22, 38, 39, 45],
mild = 27.4%; moderate = 38.7%; severe = 3.2%; very se- whereas for escitalopram [41, 45] it ranged from 2.4 to
vere = 1.6%). The authors reported only ADDS symp- 3.2, and in both studies investigating fluoxetine discon-
toms that occurred in more than 10% of patients, showing tinuation [22, 38], it was 0.2 (SD = 3.86). In patients with
no differences between those who received sertraline SAD, rates of discontinuation symptoms after treatment
compared to venlafaxine XR. Dizziness (33.3%), vivid with escitalopram (10–20 mg/day) ranged from 17 to 27%
dreams (26.4%), fatigue (22.2%), vertigo (5.6%), rapid [36, 43]. However, only a few studies used either a defini-
changing mood (6.9%), and tachycardia (4.2%) were the tion of withdrawal reaction based on specific criteria [23,
most frequently reported symptoms [42]. 47] or a cutoff score of the DESS [36, 40, 43, 46] to deter-
Paroxetine was observed to cause discontinuation mine the occurrence of withdrawal symptoms.
symptoms also in patients with anxiety disorders. In SAD
patients, 28.4% of those who were treated with paroxetine Withdrawal Symptoms in Open Trials
had a total DESS score ≥4, compared to 15.1, 17.1, and Two open trials of fluvoxamine involving respectively
21.7% of patients treated with escitalopram (5, 10, and 15 17 obsessive-compulsive disorder [48] and 14 panic dis-
mg, respectively) and 1.9% of patients assigned to placebo order [3] patients systematically reported the emergence
(p < 0.001 vs. placebo) [43]. Similar results emerged in of withdrawal syndromes. In both reports, patients expe-
patients suffering from generalized anxiety disorder. Af- rienced withdrawal reactions as assessed by using the 90-
ter a 12-week randomized placebo-controlled trial of es- item Hopkins Symptom Checklist (HSCI-90) [48] or re-
citalopram (5, 10, or 20 mg, respectively) and paroxetine, lying on spontaneous reports [3]. Twenty-three percent
generalized anxiety disorder patients underwent a wash- of obsessive-compulsive disorder patients [48] and 85.7%
out period of 2 weeks [44]. At discontinuation, while pa- of PD patients [3] experienced dizziness, nausea, head-
tients treated with escitalopram did not differ in terms of ache, confusion, low energy, and weakness that abated in
adverse events from placebo controls, those who discon- about 2–3 weeks.
tinued paroxetine showed a significantly higher mean Bogetto et al. [49] examined the discontinuation syn-
DESS score compared to controls (p < 0.001). As to active drome in 97 patients with dysthymic disorder treated
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Table 1. Signs and symptoms of withdrawal from SSRI
all reports, withdrawal reactions appeared within 1–5 anxiety, and irritability. One subject also experienced hy-
days following either abrupt [68, 69] or tapered [9, 14, 13, persensitivity of the genitals and premature ejaculation
16, 70, 71] discontinuation and lasted from 1–2 weeks [76].
[13, 14, 69, 70] to 6 weeks [16] or even longer (13–14
weeks) [9, 68]. In most cases, symptoms disappeared Escitalopram
spontaneously, except for 2 reports in which sertraline Case reports of escitalopram discontinuation syn-
25–50 mg/day was reintroduced [68, 71] and another 2 in drome involved 2 patients [77, 78]. One subject gradually
which a combination of psychotropic drugs was pre- reduced escitalopram (over 3 weeks) [77], while the other
scribed [69, 70]. Fatigue, instability, vertigo, and flu-like first missed a few doses and then reduced the drug very
symptoms were the more frequently reported adverse re- gradually (over 9 months) [78]. Both experienced elec-
actions. Extrapyramidal symptoms and electric-shock tric-shock sensations a few days after drug stoppage,
sensations were also reported [9, 70]. Furthermore, 1 pa- which lasted from 5 days [77] to 4 weeks [78].
tient experienced orthostatic hypotension [71].
Fluvoxamine Discussion
Three case reports of fluvoxamine discontinuation
syndrome were also published [2, 72, 73]. Even though Despite the limited literature available, the results of
one patient gradually discontinued fluvoxamine [72] and this systematic review indicate that withdrawal symp-
another missed only few doses [73], they both experi- toms may occur with any type of SSRI (citalopram, esci-
enced withdrawal symptoms such as dizziness, nausea, talopram, fluoxetine, fluvoxamine, paroxetine, and ser-
paresthesia, loss of concentration, restless feelings, and traline), even though they are exceedingly more frequent
agitation. Symptoms were managed with fluvoxamine re- with paroxetine. Symptoms when paroxetine was discon-
sumption [2, 73] or treated with clonazepam [72]. tinued were significantly superior to placebo in most of
the RCT that were performed [22, 32, 37–40, 43–45]. The
Citalopram duration of treatment might be as short as 2 months [33,
Three clinical cases reporting withdrawal reactions in 39, 42]. The prevalence of the syndrome was variable, and
patients receiving citalopram were also found [74–76]. its estimation was hindered by a lack of case identification
All subjects showing withdrawal syndromes gradually in many studies. Gradual tapering does not eliminate the
discontinued citalopram. Symptoms appeared within risk of withdrawal reactions. Indeed, a significant advan-
1–5 days after the last dose and lasted from 1 week [74] tage of gradual tapering compared to abrupt discontinu-
to 2 months [76]. Common symptoms were dizziness, ation did not emerge [45, 46]. A wide range of clinical
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The term ‘discontinuation syndrome’ has progressive- dications (e.g., AD are to be preferred to benzodiazepines
ly replaced ‘withdrawal syndrome’ in the SSRI literature. in anxiety disorders due to a lack of dependence) [94, 95].
This shift was heavily supported by the pharmaceutical Clinicians are familiar with the withdrawal phenom-
industry [27, 88] and was aimed at emphasizing that SSRI ena that may occur from alcohol, benzodiazepines, bar-
do not cause addiction or dependence, and symptoms are biturates, opioids, and stimulants [96]. The results of this
substantially different from the phenomena that take review indicate that they need to add SSRI to the list of
place with benzodiazepines [24]. However, Nielsen et al. drugs potentially inducing withdrawal phenomena. The
[27] have demonstrated that there are impressive simi- term ‘discontinuation syndrome’ minimizes the vulner-
larities between SSRI and benzodiazepines in this respect. abilities induced by SSRI and should be replaced by ‘with-
Defining ‘withdrawal syndromes’ as those pertaining to drawal syndrome’.
benzodiazepines [27], antipsychotic drugs [93], and tri-
cyclic antidepressants [80] and ‘discontinuation syn-
dromes’ as those of SSRI does not appear to reflect the
Disclosure Statement
evidence in the literature. Indeed, the use of this latter
term has minimized the potential vulnerabilities induced No author has financial arrangements that might represent po-
by SSRI and has provided the ground for misleading in- tential conflicts of interest for the findings presented.
References
1 Stoukides J, Stoukides C: Extrapyramidal 14 Leiter F, Nierenberg A, Sanders K, Stern T: 25 Warner C, Bobo W, Warner C, Reid S, Rachal
symptoms upon discontinuation of fluox- Discontinuation reaction following sertra- J: Antidepressant discontinuation syndrome.
etine. Am J Psychiatry 1991;148:1263. line. Biol Psychiatry 1995;38:694–695. Am Fam Physician 2006;74:449–456.
2 Szabadi E: Fluvoxamine withdrawal syn- 15 Pacheco L, Malo P, Aragues E: More cases of 26 Schatzberg AF, Blier P, Delgado P, Fava M,
drome. Br J Psychiatry 1992;160:283–284. paroxetine withdrawal syndrome. Br J Psy- Haddad PM, Shelton RC: Antidepressant dis-
3 Black D, Wesner R, Gabel J: The abrupt dis- chiatry 1996;169:384. continuation syndrome. J Clin Psychiatry
continuation of fluvoxamine in patients with 16 Rosenstock H: Sertraline withdrawal in two 2006;67:27–30.
panic disorder. J Clin Psychiatry 1993; 54: brothers: a case report. Int Clin Psychophar- 27 Nielsen M, Hansen E, Gotzsche P: What is the
146–149. macol 1996;11:58–59. difference between dependence and with-
4 Barr L, Goodman W, Price L: Physical symp- 17 Zajecka J, Fawcett J, Amsterdam J: Safety of drawal reactions? A comparison of benzodi-
toms associated with paroxetine discontinua- abrupt discontinuation of fluoxetine: a ran- azepines and selective serotonin re-uptake in-
tion. Am J Psychiatry 1994;151:289. domized, placebo-controlled study. J Clin hibitors. Addiction 2012;107:900–908.
5 Einbinder E: Fluoxetine withdrawal? Am J Psychopharmacol 1998;18:193–197. 28 Renoir T: Selective serotonin reuptake inhibi-
Psychiatry 1995;152:1253. 18 Lejoyeux M, Adès J: Antidepressant discon- tor antidepressant treatment discontinuation
6 Debattista C, Schatzberg A: Physical symp- tinuation: a review of the literature. J Clin Psy- syndrome: a review of the clinical evidence
toms associated with paroxetine withdrawal. chiatry 1997;58:11–16. and the possible mechanisms involved. Front
Am J Psychiatry 1995;152:1235–1236. 19 Medawar C: The antidepressant web. Int J Pharmacol 2013;4:1–10.
7 Dominguez R, Goodnick P: Adverse events Risk Safety Med 1997;10:75–126. 29 Moher D, Liberati A, Tetzlaff J, Altman DG:
after the abrupt discontinuation of parox- 20 Therrier F, Markowitz J: Selective serotonin Preferred reporting items for systematic re-
etine. Pharmacotherapy 1995;15:778–780. reuptake inhibitors and withdrawal symp- views and meta-analyses: the PRISMA state-
8 Bloch M, Stager S, Braun A, Rubinow D: Se- toms: a review of the literature. Hum Psycho- ment. J Clin Epidemiol 2009;62:1006–1012.
vere psychiatric symptoms associated with pharmacol 1997;12:309–323. 30 Belaise C, Gatti A, Chouinard VA, Chouinard
paroxetine withdrawal. Lancet 1995;346:57. 21 Olver JS, Burrows GD, Norman TR: Discon- G: Patient online report of selective serotonin
9 Frost L, Lal S: Shock-like sensations after dis- tinuation syndromes with selective serotonin reuptake inhibitor induced persistent post-
continuation of selective serotonin reuptake reuptake inhibitors. CNS Drugs 1999;12:171– withdrawal anxiety and mood disorders. Psy-
inhibitors. Am J Psychiatry 1995;152:810. 177. chother Psychosom 2012;81:386–388.
10 Kasantikul D: Reversible delirium after dis- 22 Rosenbaum J, Fava M, Hoog S, Ascroft R, 31 Chouinard G: Issues in the clinical use of ben-
continuation of fluoxetine. J Med Assoc Thai Krebs W: Selective serotonin reuptake inhibi- zodiazepines: potency, withdrawal and re-
1995;78:53–54. tors discontinuation syndrome: a random- bound. J Clin Psychiatry 2004; 65 (suppl 5):
11 Phillips S: A possible paroxetine withdrawal ized clinical trial. Biol Psychiatry 1998;44:77– 7–12.
syndrome. Am J Psychiatry 1995; 152: 645– 87. 32 Oehrberg S, Christiansen PE, Behnke K,
646. 23 Black K, Shea C, Dursun S, Kutcher S: Selec- Borup AL, Severin B, Soegaard J, Calberg H,
12 Pyke R: Paroxetine withdrawal syndrome. tive serotonin reuptake inhibitor discontinu- Judge R, Ohrstrom JK, Manniche PM: Parox-
Am J Psychiatry 1995;152:149–150. ation syndrome: proposed diagnostic criteria. etine in the treatment of panic disorder: a ran-
13 Fava G, Grandi S: Withdrawal syndromes af- J Psychiatr Neurosci 2000;25:255–261. domized, double-blind, placebo-controlled
ter paroxetine and sertraline discontinuation. 24 Shelton R: The nature of the discontinuation study. Br J Psychiatry 1995;167:374–379.
J Clin Psychopharmacol 1995;15:374–375. syndrome associated with antidepressant
drugs. J Clin Psychiatry 2006;67:3–7.
198.143.56.1 - 11/18/2015 4:08:39 PM
DOI: 10.1159/000370338
Downloaded by:
78 Prakash O, Dhar V: Emergence of electric 84 Murata Y, Kobayashi D, Imuta N, Haraguchi 90 Offidani E, Fava GA, Sonino N: Iatrogenic co-
shock-like sensations on escitalopram dis- K, Ieiri I, Nishimura R, Koyama S, Mine K: morbidity in childhood and adolescence: new
continuation. J Clin Psychopharmacol 2008; Effects of serotonin 1A, 2A, 2C, 3A and 3B insights from the use of antidepressant drugs.
28:359–360. and serotonin transporter gene polymor- CNS Drugs 2014;28:769–774.
79 Tomba E, Offidani E, Fava GA: Selective sero- phisms on the occurrence of paroxetine dis- 91 Carvalho AF, Berk M, Hyphantis TN, McIn-
tonin reuptake inhibitors withdrawal syn- continuation syndrome. J Clin Psychophar- tyre RS: The integrative management of treat-
dromes: new insights into pathophysiology macol 2010;30:11–17. ment resistant depression. Psychother Psy-
and treatment; in Rees JP, Woodhouse OB 85 Fava GA, Offidani E: The mechanisms of tol- chosom 2014;83:70–88.
(eds): Substance Withdrawal Syndrome. New erance in antidepressant action. Prog Neuro- 92 Bergh S, Selbaek G, Engedal K: Discontinua-
York, Nova Science, 2009, pp 37–60. psychopharmacol Biol Psychiatry 2011; 35: tion of antidepressants in people with demen-
80 Bitter I, Filipovits D, Czobor P: Adverse reac- 1593–1602. tia and neuropsychiatric symptoms (DESEP
tions to duloxetine in depression. Expert 86 Fava GA: Rational use of antidepressant Study). BMJ 2012;344:1566.
Opin Drug Saf 2011;10:839–850. drugs. Psychother Psychosom 2014; 83: 197– 93 Cerovecki A, Musil R, Klimke A, Seemuller F,
81 Dilsaver SC, Greden JF: Antidepressant with- 204. Haen E, Schennach R, Kuhn KU, Volz HP,
drawal phenomena. Biol Psychiatry 1984; 19: 87 Offidani E, Guidi J, Tomba E, Fava GA: Effi- Riedel M: Withdrawal symptoms and re-
237–256. cacy and tolerability of benzodiazepines ver- bound syndromes associated with switching
82 Blier P, Tremblay P: Physiologic mechanisms sus antidepressants in anxiety disorders: a and discontinuing atypical antipsychotics.
underlying the antidepressant discontinua- systematic review and meta-analysis. Psycho- CNS Drugs 2013;27:545–572.
tion syndrome. J Clin Psychiatry 2006; 67: 8– ther Psychosom 2013;82:355–362. 94 Rickels K: Should benozodiazepines be re-
13. 88 Fava GA, Tomba E: The use of antidepressant placed by antidepressants in the treatment of
83 Harvey BH, McEwen BS, Stein DJ: Neurobiol- drugs: some reasons for concern. Int J Risk anxiety disorders? Fact or fiction? Psychother
ogy of antidepressant withdrawal: implica- Safety Med 1998;11:271–274. Psychosom 2013;82:351–352.
tions for longitudinal outcome of depression. 89 Fava GA, Tomba E, Tossani E: Innovative 95 Balon R: Benzodiazepines revisited. Psycho-
Biol Psychiatry 2003;54:1105–1117. trends in the design of therapeutic trials in ther Psychosom 2013;82:353–354.
psychopharmacology and psychotherapy. 96 Kosten TR, O’Connor PG: Management of
Prog Neuropsychopharmacol Biol Psychiatry drug and alcohol withdrawal. N Engl J Med
2013;40:306–311. 2003;348:1786–1795.