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

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

Chiara Gastaldon #  1 , Georgios Schoretsanitis #  2   3   4 , Elena Arzenton  5 , Emanuel Raschi  6 , Davide Papola  7 , Giovanni Ostuzzi  7 , Ugo Moretti  5 , Erich Seifritz  4 , John M Kane  2   3   8 , Gianluca Trifirò  5 , Corrado Barbui  7
Affiliations

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

Chiara Gastaldon et al. Drug Saf. 2022 Dec.

Abstract

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.

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Conflict of interest statement

Drs. Gastaldon, Arzenton, Papola, Ostuzzi, Raschi, Moretti, and Barbui have nothing to disclose. Dr. Schoretsanitis has served as a consultant for HLS Therapeutics. Dr. Seifritz has received educational grants, consulting fees and lecture honoraria from Janssen Cilag, Lundbeck, Angelini, Otsuka, Servier, Ricordati, Vifor, Sunovion, Schwabe and Mepha. Dr. Kane has been a consultant and/or advisor for or has received honoraria from Alkermes, Allergan, LB Pharmaceuticals, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson and Johnson, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Reviva, Roche, Sumitomo Dainippon, Sunovion, Takeda, Teva and UpToDate and is a shareholder in LB Pharmaceuticals and Vanguard Research Group. Dr. Trifirò has served in the last three years on advisory boards/seminars funded by SANOFI, Eli Lilly, AstraZeneca, Abbvie, Servier, Mylan, Gilead, Amgen; he was the scientific director of a Master program on pharmacovigilance, pharmacoepidemiology and real-world evidence which has received non-conditional grant from various pharmaceutical companies; he coordinated a pharmacoepidemiology team at the University of Messina until October 2020, which has received funding for conducting observational studies from various pharmaceutical companies (Boehringer Ingelheim, Daichii Sankyo, PTC Pharmaceuticals). He is also scientific coordinator of the academic spin-off "INSPIRE srl" which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.). All the above-mentioned activities are not related to the topic of the manuscript.

Figures

Fig. 1
Fig. 1
Reporting odds ratios (RORs) and 95% confidence intervals (CI) for each antidepressant (ROR > 1 indicates an increased withdrawal risk associated with antidepressants) – all other drugs were considered as comparators
Fig. 2
Fig. 2
Clinical classification and prioritisation of relevant signals of disproportionate reporting. Red: strong association with withdrawal syndrome, yellow: moderate association with withdrawal syndrome; green: weak association with withdrawal syndrome
See this image and copyright information in PMC

References

    1. Kramer JC, Klein DF, Fink M. Withdrawal symptoms following dicontinuation of imipramine therapy. Am J Psychiatry. 1961;118:549–550. doi: 10.1176/ajp.118.6.549. - DOI - PubMed
    1. Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: are guidelines evidence-based? Addict Behav. 2019;97:111–121. doi: 10.1016/j.addbeh.2018.08.027. - DOI - PubMed
    1. Davies J, et al. Clinical guidelines on antidepressant withdrawal urgently need updating. BMJ. 2019;365:l2238. doi: 10.1136/bmj.l2238. - DOI - PubMed
    1. Fava GA, et al. Withdrawal symptoms after serotonin-noradrenaline reuptake inhibitor discontinuation: systematic review. Psychother Psychosom. 2018;87(4):195–203. doi: 10.1159/000491524. - DOI - PubMed
    1. Fava GA, et al. Withdrawal symptoms after selective serotonin reuptake inhibitor discontinuation: a systematic review. Psychother Psychosom. 2015;84(2):72–81. doi: 10.1159/000370338. - DOI - PubMed

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