Abstract
Background: Selective serotonin reuptake inhibitors (SSRI) are widely used in medical practice. They have been associated with a broad range of symptoms, whose clinical meaning has not been fully appreciated. Methods: The PRISMA guidelines were followed to conduct a systematic review of the literature. Titles, abstracts, and topics were searched using the following terms: ‘withdrawal symptoms' OR ‘withdrawal syndrome' OR ‘discontinuation syndrome' OR ‘discontinuation symptoms', AND ‘SSRI' OR ‘serotonin' OR ‘antidepressant' OR ‘paroxetine' OR ‘fluoxetine' OR ‘sertraline' OR ‘fluvoxamine' OR ‘citalopram' OR ‘escitalopram'. The electronic research literature databases included CINAHL, the Cochrane Library, PubMed and Web-of-Science from inception of each database to July 2014. Results: There were 15 randomized controlled studies, 4 open trials, 4 retrospective investigations, and 38 case reports. The prevalence of the syndrome was variable, and its estimation was hindered by a lack of case identification in many studies. Symptoms typically occur within a few days from drug discontinuation and last a few weeks, also with gradual tapering. However, many variations are possible, including late onset and/or longer persistence of disturbances. Symptoms may be easily misidentified as signs of impending relapse. Conclusions: Clinicians need to add SSRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with benzodiazepines, barbiturates, and other psychotropic drugs. The term ‘discontinuation syndrome' that is currently used minimizes the potential vulnerabilities induced by SSRI and should be replaced by ‘withdrawal syndrome'.
References
1.
Stoukides J, Stoukides C: Extrapyramidal symptoms upon discontinuation of fluoxetine. Am J Psychiatry 1991;148:1263.
2.
Szabadi E: Fluvoxamine withdrawal syndrome. Br J Psychiatry 1992;160:283-284.
3.
Black D, Wesner R, Gabel J: The abrupt discontinuation of fluvoxamine in patients with panic disorder. J Clin Psychiatry 1993;54:146-149.
4.
Barr L, Goodman W, Price L: Physical symptoms associated with paroxetine discontinuation. Am J Psychiatry 1994;151:289.
5.
Einbinder E: Fluoxetine withdrawal? Am J Psychiatry 1995;152:1253.
6.
Debattista C, Schatzberg A: Physical symptoms associated with paroxetine withdrawal. Am J Psychiatry 1995;152:1235-1236.
7.
Dominguez R, Goodnick P: Adverse events after the abrupt discontinuation of paroxetine. Pharmacotherapy 1995;15:778-780.
8.
Bloch M, Stager S, Braun A, Rubinow D: Severe psychiatric symptoms associated with paroxetine withdrawal. Lancet 1995;346:57.
9.
Frost L, Lal S: Shock-like sensations after discontinuation of selective serotonin reuptake inhibitors. Am J Psychiatry 1995;152:810.
10.
Kasantikul D: Reversible delirium after discontinuation of fluoxetine. J Med Assoc Thai 1995;78:53-54.
11.
Phillips S: A possible paroxetine withdrawal syndrome. Am J Psychiatry 1995;152:645-646.
12.
Pyke R: Paroxetine withdrawal syndrome. Am J Psychiatry 1995;152:149-150.
13.
Fava G, Grandi S: Withdrawal syndromes after paroxetine and sertraline discontinuation. J Clin Psychopharmacol 1995;15:374-375.
14.
Leiter F, Nierenberg A, Sanders K, Stern T: Discontinuation reaction following sertraline. Biol Psychiatry 1995;38:694-695.
15.
Pacheco L, Malo P, Aragues E: More cases of paroxetine withdrawal syndrome. Br J Psychiatry 1996;169:384.
16.
Rosenstock H: Sertraline withdrawal in two brothers: a case report. Int Clin Psychopharmacol 1996;11:58-59.
17.
Zajecka J, Fawcett J, Amsterdam J: Safety of abrupt discontinuation of fluoxetine: a randomized, placebo-controlled study. J Clin Psychopharmacol 1998;18:193-197.
18.
Lejoyeux M, Adès J: Antidepressant discontinuation: a review of the literature. J Clin Psychiatry 1997;58:11-16.
19.
Medawar C: The antidepressant web. Int J Risk Safety Med 1997;10:75-126.
20.
Therrier F, Markowitz J: Selective serotonin reuptake inhibitors and withdrawal symptoms: a review of the literature. Hum Psychopharmacol 1997;12:309-323.
21.
Olver JS, Burrows GD, Norman TR: Discontinuation syndromes with selective serotonin reuptake inhibitors. CNS Drugs 1999;12:171-177.
22.
Rosenbaum J, Fava M, Hoog S, Ascroft R, Krebs W: Selective serotonin reuptake inhibitors discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87.
23.
Black K, Shea C, Dursun S, Kutcher S: Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. J Psychiatr Neurosci 2000;25:255-261.
24.
Shelton R: The nature of the discontinuation syndrome associated with antidepressant drugs. J Clin Psychiatry 2006;67:3-7.
25.
Warner C, Bobo W, Warner C, Reid S, Rachal J: Antidepressant discontinuation syndrome. Am Fam Physician 2006;74:449-456.
26.
Schatzberg AF, Blier P, Delgado P, Fava M, Haddad PM, Shelton RC: Antidepressant discontinuation syndrome. J Clin Psychiatry 2006;67:27-30.
27.
Nielsen M, Hansen E, Gotzsche P: What is the difference between dependence and withdrawal reactions? A comparison of benzodiazepines and selective serotonin re-uptake inhibitors. Addiction 2012;107:900-908.
28.
Renoir T: Selective serotonin reuptake inhibitor antidepressant treatment discontinuation syndrome: a review of the clinical evidence and the possible mechanisms involved. Front Pharmacol 2013;4:1-10.
29.
Moher D, Liberati A, Tetzlaff J, Altman DG: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;62:1006-1012.
30.
Belaise C, Gatti A, Chouinard VA, Chouinard G: Patient online report of selective serotonin reuptake inhibitor induced persistent post-withdrawal anxiety and mood disorders. Psychother Psychosom 2012;81:386-388.
31.
Chouinard G: Issues in the clinical use of benzodiazepines: potency, withdrawal and rebound. J Clin Psychiatry 2004;65 (suppl 5):7-12.
32.
Oehrberg S, Christiansen PE, Behnke K, Borup AL, Severin B, Soegaard J, Calberg H, Judge R, Ohrstrom JK, Manniche PM: Paroxetine in the treatment of panic disorder: a randomized, double-blind, placebo-controlled study. Br J Psychiatry 1995;167:374-379.
33.
Markowitz J, DaVane C, Liston H, Montgomery S: An assessment of selective serotonin reuptake inhibitor discontinuation symptoms with citalopram. Int Clin Psychopharmacol 2000;15:329-333.
34.
Robert P, Montgomery SA: Citalopram in doses of 20-60 mg is effective in depression relapse prevention: a placebo-controlled 6-month study. Int Clin Psychopharmacol 1995;10:29-35.
35.
Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K: The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand 1987;334:1-100.
36.
Montgomery S, Nil R, Durr-Pal N, Loft H, Boulenger J: A 24-week randomized, double-blind, placebo-controlled study of escitalopram for the prevention of generalized social anxiety disorder. J Clin Psychiatry 2005;66:1270-1278.
37.
Michelson D, Fava M, Amsterdam J, Apter J, Londborg P, Tamura R, Tepner R: Interruption of selective serotonin reuptake inhibitor treatment. Double-blind placebo-controlled trial. Br J Psychiatry 2000;176:363-368.
38.
Judge R, Parry M, Quail D, Jacobson J: Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetine treatment. Int Clin Psychopharmacol 2002;17:217-225.
39.
Montgomery S, Kennedy S, Lejoyeux M, Hindmarch I: Absence of discontinuation symptoms with agomelatine and occurrence of discontinuation symptoms with paroxetine: a randomized, double-blind, placebo-controlled discontinuation study. Int Clin Psychopharmacol 2004;19:271-280.
40.
Hindmarch I, Kimber S, Cocle S: Abrupt and brief discontinuation of antidepressant treatment: effects on cognitive function and psychomotor performance. Int Clin Psychopharmacol 2000;15:305-318.
41.
Montgomery S, Huusom A, Bothmer J: A randomised study comparing escitalopram with venlafaxine XR patients in primary care with major depressive disorder. Neuropsychobiology 2004;50:57-64.
42.
Sir A, D'Souza RF, Uguz S, George T, Vahip S, Hopwood M, Martin AJ, Lam W, Burt T: Randomized trial of sertraline versus venlafaxine XR in major depression: efficacy and discontinuation symptoms. J Clin Psychiatry 2005;66:1312-1320.
43.
Lader M, Stender K, Burger V, Nil R: Efficacy and tolerability of escitalopram in 12- and 24-week treatment of social anxiety disorder: a randomized, double-blind, placebo-controlled, fixed-dose study. Depress Anxiety 2004;19:241-248.
44.
Baldwin D, Huusom A, Maehlum E: Escitalopram and paroxetine in the treatment of generalised anxiety disorder: randomised placebo-controlled, double-blind study. Br J Psychiatry 2006;189:264-272.
45.
Baldwin D, Cooper J, Huusom A, Hindmarch I: A double-blind, randomized, parallel-group, flexible-dose study to evaluate the tolerability, efficacy and effects of treatment discontinuation with escitalopram and paroxetine in patients with major depressive disorder. Int Clin Psychopharmacol 2006;21:159-169.
46.
Tint A, Haddad P, Anderson I: The effect of rate of antidepressant tapering on the incidence of discontinuation symptoms: a randomized study. J Psychopharmacol 2008;22:330-332.
47.
Haddad P, Lejoyeux M, Young A: Antidepressant discontinuation reactions are preventable and simple to treat. BMJ 1998;316:1105-1106.
48.
Mallya G, White K, Gunderson C: Is there a serotoninergic withdrawal syndrome? Biol Psychiatry 1993;33:851-852.
49.
Bogetto F, Bellino S, Bonatto R, Patria L: Discontinuation syndrome in dysthymic patients treated with selective serotonin reuptake inhibitors: a clinical investigation. CNS Drugs 2002;16:273-283.
50.
Fava G, Bernardi M, Tomba E, Rafanelli C: Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia. Int J Neuropsychopharmacol 2007;10:835-838.
51.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, American Psychiatric Association, 1994.
52.
Coupland NJ, Bell C, Potokar JP: Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol 1996;16:356-362.
53.
Price J, Waller P, Wood S, Mackay A: A comparison of the post-marketing safety of four selective serotonin reuptake inhibitors including the investigation of symptoms occurring on withdrawal. Br J Clin Pharmacol 1996;42:757-763.
54.
Himei A, Okamura T: Discontinuation syndrome associated with paroxetine in depressed patients: a retrospective analysis of factor involved in the occurrence of the syndrome. CNS Drugs 2006;20:665-672.
55.
Van Geffen E, Hugtenburg J, Heerdink E, Van Hulten R, Egberts A: Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice: tapering versus abrupt discontinuation. Eur J Clin Psychopharmacol 2005;61:303-307.
56.
Cooper G: The safety of fluoxetine: an update. Br J Psychiatry 1988;153:77-86.
57.
Poryazova R, Siccoli M, Werth E, Bassetti C: Unusually prolonged rebound cataplexy after withdrawal of fluoxetine. Neurology 2005;65:967-968.
58.
Blum D, Maldonado J, Meyer E, Lanberg M: Delirium following abrupt discontinuation of fluoxetine. Clin Neurol Neurosurg 2008;110:69-70.
59.
Bhanji N, Chouinard G, Kolivakis T, Margolese H: Persistent tardive rebound panic disorder, rebound anxiety and insomnia following paroxetine withdrawal: a review of rebound withdrawal phenomena. Can J Clin Pharmacol 2006;13:69-74.
60.
Keuthen N, Cyr P, Ricciardi J: Medication withdrawal symptoms in obsessive-compulsive disorder patients treated with paroxetine. Int Clin Psychopharmacol 1994;14:206-207.
61.
Milliken C, Cooper S: Withdrawal symptoms from paroxetine. Hum Psychopharmacol 1998;13:217-219.
62.
Belaise C, Gatti A, Chouinard VA, Chouinard G: Persistent post-withdrawal disorders induced by paroxetine, a selective serotonin reuptake inhibitor, and treated with specific cognitive behavioral therapy. Psychother Psychosom 2014;83:247-248.
63.
Yasui-Furukori N, Kaneko S: Hallucination induced by paroxetine discontinuation in patients with major depressive disorders. Psychiatry Clin Neurosci 2011;65:384-385.
64.
Polimeni G, Grugno R, Cordici F, Vietta A, Caputi A, Bramanti P: Nocturnal enuresis after paroxetine abrupt discontinuation: a case report. J Clin Psychopharmacol 2008;28:589-591.
65.
Mazzatenta C, Peonia G, Martini P: Pruritus induced by interruption of paroxetine therapy. Br J Dermatol 2004;150:787.
66.
Landry P, Roy L: Withdrawal hypomania associated with paroxetine. J Clin Psychopharmacol 1997;17:60-61.
67.
Shoenberger D: Discontinuing paroxetine: a personal account. Psychother Psychosom 2002;71:237-238.
68.
Louie A, Lannon R, Ajari L: Withdrawal reaction after sertraline discontinuation. Am J Psychiatry 1994;151:450.
69.
Levenson J: Putative neuroleptic malignant syndrome associated with sertraline withdrawal. J Clin Psychopharmacol 2009;29:300-301.
70.
Benazzi F: Psychotic mania in bipolar II depression related to sertraline discontinuation. Can J Psychiatry 2002;47:584-585.
71.
Amsden G, Georgian F: Orthostatic hypotension induced by sertraline withdrawal. Pharmacotherapy 1996;16:684-686.
72.
Benazzi F: SSRI discontinuation syndrome related to fluvoxamine. Rev Psychiatr Neurosci 1998;23:94.
73.
Hirose S: Restlessness related to SSRI withdrawal. Psychiatry Clin Neurosci 2001;55:77-80.
74.
Benazzi F: Citalopram withdrawal symptoms. Eur Psychiatry 1998;13:219.
75.
Fernando A, Schwader P: A case of citalopram withdrawal. J Clin Psychopharmacol 2000;20:581-582.
76.
Adson D, Kotlyar M: Premature ejaculation associated with citalopram withdrawal. Ann Pharmacother 2003;37:1804-1806.
77.
Feth N, Cattapan-Ludewig K, Jaquenoud-Sirot E: Electric sensations: neglected symptom of escitalopram discontinuation. Am J Psychiatry 2006;163:160.
78.
Prakash O, Dhar V: Emergence of electric shock-like sensations on escitalopram discontinuation. J Clin Psychopharmacol 2008;28:359-360.
79.
Tomba E, Offidani E, Fava GA: Selective serotonin reuptake inhibitors withdrawal syndromes: new insights into pathophysiology and treatment; in Rees JP, Woodhouse OB (eds): Substance Withdrawal Syndrome. New York, Nova Science, 2009, pp 37-60.
80.
Bitter I, Filipovits D, Czobor P: Adverse reactions to duloxetine in depression. Expert Opin Drug Saf 2011;10:839-850.
81.
Dilsaver SC, Greden JF: Antidepressant withdrawal phenomena. Biol Psychiatry 1984;19:237-256.
82.
Blier P, Tremblay P: Physiologic mechanisms underlying the antidepressant discontinuation syndrome. J Clin Psychiatry 2006;67:8-13.
83.
Harvey BH, McEwen BS, Stein DJ: Neurobiology of antidepressant withdrawal: implications for longitudinal outcome of depression. Biol Psychiatry 2003;54:1105-1117.
84.
Murata Y, Kobayashi D, Imuta N, Haraguchi K, Ieiri I, Nishimura R, Koyama S, Mine K: Effects of serotonin 1A, 2A, 2C, 3A and 3B and serotonin transporter gene polymorphisms on the occurrence of paroxetine discontinuation syndrome. J Clin Psychopharmacol 2010;30:11-17.
85.
Fava GA, Offidani E: The mechanisms of tolerance in antidepressant action. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:1593-1602.
86.
Fava GA: Rational use of antidepressant drugs. Psychother Psychosom 2014;83:197-204.
87.
Offidani E, Guidi J, Tomba E, Fava GA: Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom 2013;82:355-362.
88.
Fava GA, Tomba E: The use of antidepressant drugs: some reasons for concern. Int J Risk Safety Med 1998;11:271-274.
89.
Fava GA, Tomba E, Tossani E: Innovative trends in the design of therapeutic trials in psychopharmacology and psychotherapy. Prog Neuropsychopharmacol Biol Psychiatry 2013;40:306-311.
90.
Offidani E, Fava GA, Sonino N: Iatrogenic comorbidity in childhood and adolescence: new insights from the use of antidepressant drugs. CNS Drugs 2014;28:769-774.
91.
Carvalho AF, Berk M, Hyphantis TN, McIntyre RS: The integrative management of treatment resistant depression. Psychother Psychosom 2014;83:70-88.
92.
Bergh S, Selbaek G, Engedal K: Discontinuation of antidepressants in people with dementia and neuropsychiatric symptoms (DESEP Study). BMJ 2012;344:1566.
93.
Cerovecki A, Musil R, Klimke A, Seemuller F, Haen E, Schennach R, Kuhn KU, Volz HP, Riedel M: Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics. CNS Drugs 2013;27:545-572.
94.
Rickels K: Should benozodiazepines be replaced by antidepressants in the treatment of anxiety disorders? Fact or fiction? Psychother Psychosom 2013;82:351-352.
95.
Balon R: Benzodiazepines revisited. Psychother Psychosom 2013;82:353-354.
96.
Kosten TR, O'Connor PG: Management of drug and alcohol withdrawal. N Engl J Med 2003;348:1786-1795.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
