Withdrawal Syndrome Following Discontinuation of 28 Antidepressants: Pharmacovigilance Analysis of 31,688 Reports from the WHO Spontaneous Reporting Database

Drug Saf. 2022 Dec;45(12):1539-1549. doi: 10.1007/s40264-022-01246-4. Epub 2022 Nov 18.


Introduction: Evidence is lacking on withdrawal syndrome related to individual antidepressants and relevant risk factors for severe reactions.

Objective: To ascertain whether antidepressants are associated with an increased reporting of withdrawal syndrome as compared with other medications, and to investigate risk factors for severe reactions.

Methods: This is a case/non-case pharmacovigilance study, based on the VigiBase®, the WHO global database of individual case safety reports of suspected adverse drug reactions. We performed a disproportionality analysis of reports of antidepressant-related withdrawal syndrome (calculating reporting odds ratio [ROR] and Bayesian information component [IC]). We compared antidepressants to all other drugs, to buprenorphine (positive control), and to each other within each class of antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclics and other antidepressants). Antidepressants with significant disproportionate reporting were ranked in terms of clinical priority. Serious versus non-serious reactions were compared.

Results: There were 31,688 reports of antidepressant-related withdrawal syndrome were found. A disproportionate reporting was detected for 23 antidepressants. The estimated ROR for antidepressants altogether, compared to all other drugs, was 14.26 (95% CI 14.08-14.45), 17.01 for other antidepressants (95% CI 16.73-17.29), 13.65 for SSRIs (95% CI 13.41-13.90) and 2.8 for tricyclics (95% CI 2.59-3.02). Based on clinical priority ranking, the strongest disproportionate reporting was found for paroxetine, duloxetine, venlafaxine and desvenlafaxine, being comparable to buprenorphine. Withdrawal syndrome was reported as severe more often in males, adolescents, persons in polypharmacy, and with a longer antidepressant treatment duration (p < 0.05).

Conclusions: Antidepressants are associated with an increased reporting of withdrawal syndrome compared with other drug classes. When prescribing and discontinuing antidepressants, clinicians should be aware of the potentially different proclivity of withdrawal syndrome across individual antidepressants, and the liability to experience more severe withdrawal symptoms in relation to specific patient characteristics.

MeSH terms

  • Adolescent
  • Antidepressive Agents / adverse effects
  • Bayes Theorem
  • Buprenorphine*
  • Humans
  • Male
  • Pharmacovigilance
  • Selective Serotonin Reuptake Inhibitors / adverse effects
  • Substance Withdrawal Syndrome* / epidemiology
  • World Health Organization


  • Antidepressive Agents
  • Serotonin Uptake Inhibitors
  • Buprenorphine