Kalfas, Michail, Tsapekos, Dimosthenis, Butler, Matthew, McCutcheon, Robert A., Pillinger, Toby, Strawbridge, Rebecca, Bhat, Bhagyashree Bhaskar, Haddad, Peter M., Cowen, Philip J., Howes, Oliver D., Joyce, Dan W., Nutt, David J., Baldwin, David S., Pariante, Carmine M., Lewis, Gemma, Young, Allan H., Lewis, Glyn, Hayes, Joseph F. and Jauhar, Sameer (2025) Incidence and nature of antidepressant discontinuation symptoms: a systematic review and meta-analysis. JAMA Psychiatry, 82 (9), 896-904. (doi:10.1001/jamapsychiatry.2025.1362).
Abstract
Importance: the incidence and nature of discontinuation symptoms following antidepressant cessation remain unclear.
Objective: to examine the presence of discontinuation symptoms using standardized scales (eg, Discontinuation-Emergent Signs and Symptoms [DESS]) and the incidence of individual discontinuation symptoms in individuals who stop taking antidepressants.
Data Sources: the databases Embase, PsycINFO, Ovid MEDLINE, and Cochrane Library were systematically searched from inception until November 7, 2023.
Study selection: randomized clinical trials (RCTs) reporting discontinuation symptoms using a standardized scale or individual symptoms (eg, adverse events) following antidepressant cessation were included.
Data extraction and synthesis : data extracted were cross-checked by 2 reviewers. Additional unpublished data from 11 RCTs were included. A random-effects meta-analysis was conducted to calculate standardized mean difference between individuals who discontinued an antidepressant vs those who continued an antidepressant or discontinued placebo. A proportion and odds ratio (OR) meta-analysis was performed to assess incidence of individual discontinuation symptoms compared to placebo. Subgroup analyses were conducted to compare different antidepressants. Data analysis was conducted between September 2024 and December 2024.
Main outcomes and measures: the primary outcomes were incidence and nature of antidepressant discontinuation symptoms measured using standardized or unstandardized scales.
Results: a total of 50 studies were included, 49 of which were included in meta-analyses. The 50 studies included 17 828 participants in total, with 66.9% female participants and mean participant age of 44 years. Follow-up was between 1 day and 52 weeks. The DESS meta-analysis indicated increased discontinuation symptoms at 1 week in participants stopping antidepressants (standardized mean difference, 0.31; 95% CI, 0.23-0.39; number of studies [k] = 11; n = 3915 participants) compared to those taking placebo or continuing antidepressants. The effect size was equivalent to 1 more symptom on the DESS. Discontinuation of antidepressants was associated with increased odds of dizziness (OR, 5.52; 95% CI, 3.81-8.01), nausea (OR, 3.16; 95% CI, 2.01-4.96), vertigo (OR, 6.40; 95% CI, 1.20-34.19), and nervousness (OR, 3.15; 95% CI, 1.29-7.64) compared to placebo discontinuation. Dizziness was the most prevalent discontinuation symptom (risk difference, 6.24%). Discontinuation was not associated with depression symptoms, despite being measured in people with major depressive disorder (k = 5).
Conclusions and relevance : this systematic review and meta-analysis indicated that the mean number of discontinuation symptoms at week 1 after stopping antidepressants was below the threshold for clinically significant discontinuation syndrome. Mood worsening was not associated with discontinuation; therefore, later presentation of depression after discontinuation is indicative of depression relapse.
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