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Antidepressant Discontinuation Syndromes

Clinical Relevance, Prevention and Management

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Abstract

Discontinuation symptoms are recognised with tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and miscellaneous antidepressants. A wide variety of symptoms have been described, differing somewhat between antidepressant classes, and several symptom clusters or discontinuation syndromes appear to exist. A common feature is onset within a few days of stopping the antidepressant or, less commonly, reducing the dosage. Discontinuation syndromes are clinically relevant as they are common, can cause significant morbidity, can be misdiagnosed leading to inappropriate treatment and can adversely effect future antidepressant compliance.

Preventative strategies include tapering antidepressants prior to stoppage and educating patients and healthcare professionals to ensure that antidepressants are taken consistently and not stopped abruptly. Most reactions are mild and short-lived and require no treatment other than patient reassurance. Severe cases can be treated symptomatically or the antidepressant can be reinstated before being gradually withdrawn. Reinstatement usually leads to symptom resolution within 24 hours. Some individuals require very conservative tapering schedules to prevent the re-emergence of symptoms. With SSRIs and venlafaxine another strategy to consider is switching to fluoxetine, which may suppress the discontinuation symptoms, but which has little tendency to cause such symptoms itself. Neonatal discontinuation symptoms can follow maternal use of antidepressants during pregnancy and possibly breast feeding. The patient and doctor must take this into consideration when making prescribing decisions.

Discontinuation symptoms have received little systematic study with the result that most of the recommendations made here are based on anecdotal data or expert opinion. Research is needed to provide a firm evidence base for future recommendations.

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References

  1. Mann AM, MacPherson A. Clinical experience with imipramine (G22355) in the treatment of depression. Can Psychiatr Assoc J 1959; 4: 38–47

    PubMed  CAS  Google Scholar 

  2. Andersen H, Kristiansen ES. Tofranil treatment of endogenous depressions. Acta Psychiatr Scand 1959; 34: 387–97

    Article  PubMed  CAS  Google Scholar 

  3. Ceccherini-Nelli A, Bardellini L, Guazzalli M, et al. Antidepressant withdrawal phenomena: prospective findings [letter]. Am J Psychiatry 1993; 15(1): 165

    Google Scholar 

  4. Bialos D, Giller E, Jatlow P, et al. Recurrence of depression after discontinuation of amitriptyline. Am J Psychiatry 1982 139: 325–9

    PubMed  CAS  Google Scholar 

  5. Weller Jr RA, McKnelly WV. Case report of withdrawal dyskinesia associated with amoxapine. Am J Psychiatry 1983; 140(11): 1515–6

    PubMed  CAS  Google Scholar 

  6. Dilsaver SC. Antidepressant withdrawal syndromes: phenomenology and pathophysiology. Acta Psychiatr Scand 1989; 79: 113–7

    Article  PubMed  CAS  Google Scholar 

  7. Diamond BI, Borison RL, Katz R, et al. Rebound reactions due to clomipramine. Psychopharmacol Bull 1989; 2(2): 209–12

    Google Scholar 

  8. Nelson JC, Schottenfeld RS, Conrad ED. Hypomania after desipramine withdrawal. Am J Psychiatry 1983; 140: 624–5

    PubMed  CAS  Google Scholar 

  9. Santos AB, McCurdy L. Delirium after abrupt withdrawal from doxepin: case report. Am J Psychiatry 1980; 137: 239–40

    PubMed  Google Scholar 

  10. Law W, Petti TA, Kazdin A. Withdrawal symptoms after gradual cessation of imipramine in children. Am J Psychiatry 1981; 118: 647–50

    Google Scholar 

  11. Kramer JC, Klein DF, Fink M. Withdrawal symptoms following discontinuation of imipramine therapy. Am J Psychiatry 1961; 118: 549–50

    PubMed  CAS  Google Scholar 

  12. Geller B, Cooper TB, Carr LG. Prospective study of scheduled withdrawal from nortriptyline in children and adolescents. J Clin Psychopharmacol 1987; 7: 252–4

    PubMed  CAS  Google Scholar 

  13. Mirin SM, Schatzberg AF, Creasey DE. Hypomania and mania after withdrawal of tricyclic antidepressants. Am J Psychiatry 1981; 138: 87–9

    PubMed  CAS  Google Scholar 

  14. Otani K, Tanaka O, Kaneko S, et al. Mechanisms of the development of trazodone withdrawal symptoms. Int Clin Psychophamacol 1994; 9: 131–3

    Article  CAS  Google Scholar 

  15. Rothschild AJ. Mania after withdrawal of isocarboxazid. J Clin Psychopharmacol 1985; 5: 340–2

    PubMed  CAS  Google Scholar 

  16. Liskin B, Roose S, Walsh T. Acute psychosis following phenelzine discontinuation. J Clin Psychopharmacol 1984; 5: 46–7

    Google Scholar 

  17. Roth SD. More on psychosis following phenelzine discontinuation. J Clin Psychopharmacol 1985; 5: 360–1

    Article  Google Scholar 

  18. Tyrer P. Clinical effects of abrupt withdrawal from tricyclic antidepressants and monoamine oxidase inhibitors after long term treatment. J Affect Disord 1984; 6: 1–7

    Article  PubMed  CAS  Google Scholar 

  19. Halle MT, Dilsaver SC. Tranylcypromine withdrawal phenomena. J Psychiatry Neurosci 1993; 18(1): 49–50

    PubMed  CAS  Google Scholar 

  20. Le Gassicke J, Ashcroft GW, Eccleston D, et al. The clinical state, sleep and amine metabolism of a tranylcypromine (Parnate) addict. Br J Psychiatry 1965; 3: 357–64

    Article  Google Scholar 

  21. Vartzopulos D, Krull F. Dependence on monoamine oxidase inhibitors in high dose. Br J Psychiatry 1991; 158: 856–7

    Article  Google Scholar 

  22. Dilsaver SC, Feinberg M, Greden JF. Antidepressant withdrawal symptoms treated with anticholinergic agents. Am J Psychiatry 1983; 140(2): 249–51

    PubMed  CAS  Google Scholar 

  23. Dilsaver SC, Kronfol Z, Greden JF, et al. Antidepressant withdrawal syndromes: evidences supporting the cholinergic overdrive hypothesis. J Clin Psychopharmacol 1983; 3: 157–64

    PubMed  CAS  Google Scholar 

  24. Young AH, Currie A, Ashton CH. Antidepressant withdrawal syndrome [letter]. Br J Psychiatry 1997; 170: 288

    Article  PubMed  CAS  Google Scholar 

  25. Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomised clinical trial. Biol Psychiatry 1998; 44: 77–87

    Article  PubMed  CAS  Google Scholar 

  26. Einbinder E. Fluoxetine withdrawal [letter]? Am J Psychiatry 1995; 152(8): 1253

    Google Scholar 

  27. Black DW, Wesner R, Gabel J. The abrupt discontinuation of fluvoxamine in patients with panic disorder. J Clin Psychiatry 1993; 54(4): 146–9

    PubMed  CAS  Google Scholar 

  28. Oehrberg S, Christiansen PE, Behnke K, et al. Paroxetine in the treatment of panic disorder: a randomised, double-blind, placebo-controlled study. Br J Psychiatry 1995; 167: 374–9

    Article  PubMed  CAS  Google Scholar 

  29. Rosenstock HA. Sertraline withdrawal in two brothers: a case report. Int Clin Psychopharmacol 1996; 11(1): 58–9

    Article  PubMed  CAS  Google Scholar 

  30. Louie AK, Lannon RA, Kirsch MA, et al. Venlafaxine withdrawal reactions [letter]. Am J Psychiatry 1996; 153(12): 1652

    PubMed  CAS  Google Scholar 

  31. Fava M, Mulroy R, Alpert J, et al. Emergence of adverse effects following discontinuation of treatment with extended-release venlafaxine. Am J Psychiatry 1997; 154(12): 1760–2

    PubMed  CAS  Google Scholar 

  32. Giakas WJ, Davis SM. Intractable withdrawal from venlafaxine treated with fluoxetine. Psychiatric Ann 1997; 27(2): 85–6

    Google Scholar 

  33. Benazzi F. Nefazodone withdrawal symptoms. Can J Psychiatry 1998; 43(2): 194–5

    PubMed  CAS  Google Scholar 

  34. MacCall C, Callender J. Mirtazapine withdrawal causing hypomania. Br J Psychiatry 1999; 175: 390

    Article  PubMed  CAS  Google Scholar 

  35. Schatzberg AF, Haddad P, Kaplan EM, et al. Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. J Clin Psychiatry 1997; 58: 5–10

    PubMed  CAS  Google Scholar 

  36. Lader M. Benzodiazepine withdrawal states. In: Trimble MR, editor. Benzodiazepines divided. New York (NY): John Wiley & Sons, 1983; 17–31

    Google Scholar 

  37. Haddad P. The SSRI discontinuation syndrome. J Psychopharmacol 1998; 12(3): 305–13

    Article  PubMed  CAS  Google Scholar 

  38. Lejoyeux M, Ades J, Mourad I, et al. Antidepressant withdrawal syndrome: recognition, prevention and management. CNS Drugs 1996; 5(4): 278–92

    Article  CAS  Google Scholar 

  39. Sathananthan GL, Gershon S. Imipramine withdrawal: an akathisia-like syndrome. Am J Psychiatry 1973; 130: 1286–7

    PubMed  CAS  Google Scholar 

  40. Boisvert D, Chouinard G. Rebound cardiac arrhythmia after withdrawal from imipramine: a case report. Am J Psychiatry 1981; 138: 985–6

    PubMed  CAS  Google Scholar 

  41. Van Sweden B. Rebound antidepressant cardiac arrhythmia. Biol Psychiatry 1988; 24: 363–4

    Article  PubMed  Google Scholar 

  42. Gawin FH, Markoff RA. Panic anxiety after abrupt discontinuation of amitriptyline. Am J Psychiatry 1981; 138: 117–8

    PubMed  CAS  Google Scholar 

  43. D’Arcy PF. Dystonia and withdrawal symptoms with paroxetine [letter]. Int Pharm J 1993; 7: 140

    Google Scholar 

  44. Stoukides JA, Stoukides CA. Extrapyramidal symptoms upon discontinuation of fluoxetine [letter]. Am J Psychiatry 1991; 148(9): 1263

    PubMed  CAS  Google Scholar 

  45. Szabadi E. Fluvoxamine withdrawal syndrome. Br J Psychiatry 1992; 160: 283–4

    Article  PubMed  CAS  Google Scholar 

  46. Bloch M, Stager SV, Braun AR, et al. Severe psychiatric symptoms associated with paroxetine withdrawal [letter]. Lancet 1995; 346: 57

    Article  PubMed  CAS  Google Scholar 

  47. Landry P, Line R. Withdrawal hypomania associated with paroxetine. J Clin Psychopharmacol 1997; 17: 60–1

    Article  PubMed  CAS  Google Scholar 

  48. Kasantikul D. Reversible delirium after discontinuation of fluoxetine. J Med Assoc Thai 1995; 78(1): 53–4

    PubMed  CAS  Google Scholar 

  49. Parker G, Blennerhassett J. Withdrawal reactions associated with venlafaxine. Aust N Z J Psychiatry 1998; 32: 292–4

    Google Scholar 

  50. Agelink MW, Zitselsberger A, Kleiser E. Withdrawal symptoms after discontinuation of venlafaxine [letter]. Am J Psychiatry 1997; 154(10): 1473–4

    PubMed  CAS  Google Scholar 

  51. Wolfe RM. Antidepressant withdrawal reactions. Am Fam Physician 1997; 56(2): 452–62

    Google Scholar 

  52. Amsden GW, Georgian F. Orthostatic hypotension induced by sertraline withdrawal. Pharmacotherapy 1996; 16(4): 694–6

    Google Scholar 

  53. Coupland NJ, Bell CJ, Potokar JP. Serotonin reuptake inhibitor withdrawal. J Clin Psychopharmacol 1996; 16(3): 356–62

    Article  PubMed  CAS  Google Scholar 

  54. Price JS, Waller PC, Wood SM, et al. A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors, including the investigation of symptoms occurring, on withdrawal. Br J Clin Pharmacol 1996; 42: 757–63

    Article  PubMed  CAS  Google Scholar 

  55. Australian Adverse Drug Reactions Advisory Committee. SSRIs and withdrawal syndrome. Aust Adverse Drug Reactions Bull Nov 1996; 15 (1): 3

    Google Scholar 

  56. Stahl MMS, Lindquist M, Petterson M, et al. Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system. Eur J Clin Pharmacol 1997; 53: 163–9

    Article  PubMed  CAS  Google Scholar 

  57. Michelson D, Fava M, Amsterdam J, et al. Interruption of selective serotonin reuptake inhibitor treatment: double-blind, placebo controlled trial. Br J Psychiatry 2000; 176: 363–8

    Article  PubMed  CAS  Google Scholar 

  58. Zajecka J, Faweett J, Amsterdam J, et al. Safety of abrupt discontinuation of fluoxetine: a randomised, placebo-controlled study. J Clin Psychopharmacol 1998; 18: 193–7

    Article  PubMed  CAS  Google Scholar 

  59. Frost L, Lal S. Shock-like sensations after discontinuation of selective serotonin reuptake inhibitors [letter]. Am J Psychiatry 1995; 152(5): 810

    PubMed  CAS  Google Scholar 

  60. Keuthen NJ, Cyr P, Ricciardi JA, et al. Medication withdrawal symptoms in obsessive-compulsive disorder patients treated with paroxetine [letter]. J Clin Psychopharmacol 1994; 14(3): 206–7

    Article  PubMed  CAS  Google Scholar 

  61. Pacheco L, Malo P, Aragues E, et al. More cases of paroxetine withdrawal syndrome [letter]. Br J Psychiatry 1996; 169(3): 384

    Article  PubMed  CAS  Google Scholar 

  62. Haddad PM, Devarajan S, Dursun SM. Antidepressant discontinuation symptoms presenting as ‘stroke’. J Psychopharmacol. In press

  63. Haddad PM, Qureshi M. Misdiagnosis of antidepressant discontinuation symptoms. Acta Psychiatr Scand 2000; 102: 466–8

    Article  PubMed  CAS  Google Scholar 

  64. Young AH, Currie A. Physicians’ knowledge of antidepressant withdrawal effects: a survey. J Clin Psychiatry 1997; 58Suppl. 7: 28–30

    PubMed  Google Scholar 

  65. Donoghue J, Haddad P. Pharmacists lack knowledge of antidepressant discontinuation symptoms [letter]. J Clin Psychiatry 1999; 60: 124–5

    Article  PubMed  CAS  Google Scholar 

  66. Haddad P, Tylee A, Young A. P137 General practitioners’ knowledge of antidepressant discontinuation reactions [abstract]. J Psychopharmacol 1999; 13 (3) Suppl. A: A44

    Google Scholar 

  67. Demyttenaere K, Mesters P, Boulanger B, et al. Adherence to treatment regimen in depressed patients treated with amitriptyline or fluoxetine. J Affective Disorders. In press

  68. Kaplan HI, Sadock BJ, editors. Comprehensive textbook of psychiatry, VI. 6th ed. Baltimore (MD): Williams & Wilkins, 1995

    Google Scholar 

  69. Petti TA, Law W. Abrupt cessation of high-dose imipramine treatment in children. JAMA 1981; 246: 768–99

    Article  PubMed  CAS  Google Scholar 

  70. Stem SL, Mendels J. Withdrawal symptoms during the course of imipramine therapy. J Clin Psychiat 1980; 41: 66–7

    Google Scholar 

  71. Priest RG, Vize C, Roberts A, et al. Lay people’s attitudes to treatment of depression: result of opinion poll for Defeat Depression Campaign just before its launch. BMJ 1996; 313: 858–9

    Article  PubMed  CAS  Google Scholar 

  72. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders. Geneva: World Health Organization, 1992

  73. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Fourth edition. Washington, DC: American Psychiatric Association, 1994

  74. Haddad P, Anderson I. Antidepressants aren’t addictive: clinicians have depended on them for years. J Psychopharmacol 1999; 13(3): 291–2

    Article  PubMed  CAS  Google Scholar 

  75. Haddad P. Do antidepressants have any potential to cause addition? J Pychopharmacol 1999; 13(3): 300–7

    Article  CAS  Google Scholar 

  76. Routledge PA, Bialask MC. Adverse reactions to drug withdrawal. Adverse Drug React Bull 1997; 187: 711–4

    Article  Google Scholar 

  77. Kerr B, Myers P. Withdrawal syndrome following long-term administration of tamoxifen [letter]. J Psychopharmacol 1999; 13(4): 419

    Article  PubMed  CAS  Google Scholar 

  78. Keyser DL, Rodnitzky RL. Neuroleptic malignant syndrome in Parkinson’s disease after withdrawal or alteration of dopaminergic therapy. Arch Intern Med 1991; 151: 794–6

    Article  PubMed  CAS  Google Scholar 

  79. Gardos G, Cole JO, Tarsy D. Withdrawal syndromes associated with antipsychotic drugs. Am J Psychiatry 1978; 135: 1321–4

    PubMed  CAS  Google Scholar 

  80. Tranter R, Healy D. Neuroleptic discontinuation syndromes. J Psychopharmacol 1998; 12: 401–6

    Article  PubMed  CAS  Google Scholar 

  81. Mander AJ, Loudon JB. Rapid recurrence of mania following abrupt discontinuation of lithium. Lancet 1998; 339: 15–7

    Google Scholar 

  82. Dominguez RA, Goodnick W. Adverse events after the abrupt discontinuation of paroxetine. Pharmacotherapy 1995; 15(6): 778–80

    PubMed  CAS  Google Scholar 

  83. Benazzi F. Venlafaxine withdrawal symptoms. Can J Psychiatry 1996; 41: 487

    PubMed  CAS  Google Scholar 

  84. British National Formulary. British Medical Association & Royal Pharmaceutical Society of Great Britain. Section 4.3: Antidepressant drugs: withdrawal. London: The Pharmaceutical Press, 2000

  85. Drug and Therapeutics Bulletin. Withdrawing patients from antidepressants. Drug Ther Bull 1999; 37 (7): 49–52

  86. Rosenbaum JF, Zajecka J. Clinical management of antidepressant discontinuation. J Clin Psychiatry 1997; 58Suppl. 7: 37–40

    PubMed  CAS  Google Scholar 

  87. Schatzberg AF, Haddad P, Kaplan E, et al. Possible biological mechanisms of the serotonin reuptake inhibitor discontinuation syndrome. J Clin Psychiatry 1997; 58Suppl. 7: 23–7

    PubMed  CAS  Google Scholar 

  88. Koopowitz LF, Berk M. Paroxetine induced withdrawal effects. Human Psychopharmacol 1995; 10: 147–8

    Article  Google Scholar 

  89. Rosenblatt JE, Rosenblatt NC. Paroxetine withdrawal after slow dosage taper. Curr Affect Illness 1996; 15: 8–9

    Google Scholar 

  90. Rauch SL, O’Sullivan RL, Jenike MA. Open treatment of obsessive-compulsive disorder with venlafaxine: a series of ten cases [letter]. J Clin Psychopharmacol 1996; 16(1); 81–4

    Article  PubMed  CAS  Google Scholar 

  91. Phillips SD. A possible paroxetine withdrawal syndrome [letter]. Am J Psychiatry 1995; 152(4): 645–6

    PubMed  CAS  Google Scholar 

  92. Rothchild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry 1995; 152: 1514–6

    Google Scholar 

  93. Otto MW, Pollack MH, Sachs GS, et al. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioural therapy for patients with panic disorder. Am J Psychiatry 1993; 150: 1485–90

    PubMed  CAS  Google Scholar 

  94. Wisner KL, Perel M. Psychopharmacologic agents and electroconvulsive therapy during pregnancy and the puerperium. In: Cohen RL, editor. Psychiatric consultation in childbirth settings. New York: Plenum, 1988; 165–206

    Chapter  Google Scholar 

  95. Eggermont E, Raveschat J, Deneve V, et al. The adverse influence of imipramine on the adaptation of the newborn infant to extrauterine life. Acta Paediatr Belg 1972; 26: 197–204

    PubMed  CAS  Google Scholar 

  96. Cowe L, Lloyd DJ, Dawling S. Neonatal convulsion caused by withdrawal from maternal clomipramine. BMJ 1982; 284: 1837–8

    Article  PubMed  CAS  Google Scholar 

  97. Webster PA. Withdrawal symptoms in neonates associated with maternal antidepressant therapy. Lancet 1973; II: 318–9

    Article  Google Scholar 

  98. Australian Adverse Drug Reactions Advisory Committee. SSRIs and neonatal disorders: withdrawal reactions, breast milk transfer. Austral Adverse Drug Reactions Bull Nov 1997; 16 (4): 14

    Google Scholar 

  99. Dahl ML, Olhager E, Ahiner J. Paroxetine withdrawal syndrome in a neonate [letter]. Br J Psychiatry 1997; 171: 3 91–2

    Article  CAS  Google Scholar 

  100. Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Paediatrics 1993; 92: 721–2

    CAS  Google Scholar 

  101. Chambers CD, Johnson KA, Dick LM, et al. Birth outcomes in pregnant women taking fluoxetine. N Engl J Med 1996; 335: 1010–5

    Article  PubMed  CAS  Google Scholar 

  102. Briggs GG, Freeman RK, Yaffe SJ, editors. Drugs in pregnancy and lactation. 4th ed. Baltimore (MD): Williams and Wilkins, 1994: 192–5

    Google Scholar 

  103. Wisner KL, Gelenberg, AJ, Leonard H, et al. Pharmacologic treatment of depression during pregnancy. JAMA 1999; 282: 1264–9

    Article  PubMed  CAS  Google Scholar 

  104. Kent LSW, Laidlaw JDD. Suspected congenital sertraline dependence [letter]. Br J Psychiatry 1995; 167: 412–3

    Article  PubMed  CAS  Google Scholar 

  105. Buist A, Norman TR, Dennerstein L. Breast feeding and the use of psychotropic medication: a review. J Affect Disord 1990; 19: 197–206

    Article  PubMed  CAS  Google Scholar 

  106. Stowe ZN, Owens MJ, Landry JC, et al. Sertraline and desmethylsertraline in human breast milk and nursing infants. Am J Psychiatry 1997; 154: 1255–60

    PubMed  CAS  Google Scholar 

  107. Llewellyn A, Stowe ZN. Psychotropic medications in lactation. J Clin Psychiatry 1998; 59Suppl. 2: 41–52

    PubMed  Google Scholar 

  108. Stowe ZN, Cohen LS, Hostetter A, et al. Paroxetine in human breast milk and nursing infants. Am J Psychiatry 2000; 157: 185–9

    Article  PubMed  CAS  Google Scholar 

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Haddad, P.M. Antidepressant Discontinuation Syndromes. Drug-Safety 24, 183–197 (2001). https://doi.org/10.2165/00002018-200124030-00003

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