Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis.

BACKGROUND: Antidepressant discontinuation symptoms are becoming an increasingly important part of clinical practice, but the incidence of antidepressant discontinuation symptoms has not been quantified. An estimate of antidepressant discontinuation symptoms incidence could inform patients and clinicians in the discontinuation of treatment, and provide useful information to researchers in antidepressant treatments. We aimed to assess the incidence of antidepressant discontinuation symptoms in patients discontinuing both antidepressants and placebo in the published literature. METHODS: We systematically searched Medline, EMBASE, and CENTRAL from database inception until Oct 13, 2022 for randomised controlled trials (RCTs), other controlled trials, and observational studies assessing the incidence of antidepressant discontinuation symptoms. To be included, studies must have investigated cessation or tapering of an established antidepressant drug (excluding antipsychotics, lithium, or thyroxine) or placebo in participants with any mental, behavioural, or neurodevelopmental disorder. We excluded studies in neonates, and those using antidepressants for physical conditions such as pain syndromes due to organic disease. After study selection, summary data extraction, and risk of bias evaluation, data were pooled in random-effects meta-analyses. The main outcome was the incidence of antidepressant discontinuation symptoms after discontinuation of antidepressants or placebo. We also analysed the incidence of severe discontinuation symptoms. Sensitivity and meta-regression analyses tested a selection of methodological variables. FINDINGS: From 6095 articles screened, 79 studies (44 RCTs and 35 observational studies) covering 21 002 patients were selected (72% female, 28% male, mean age 45 years [range 19·6-64·5]). Data on ethnicity were not consistently reported. 16 532 patients discontinued from an antidepressant, and 4470 patients discontinued from placebo. Incidence of at least one antidepressant discontinuation symptom was 0·31 (95% CI 0·27-0·35) in 62 study groups after discontinuation of antidepressants, and 0·17 (0·14-0·21) in 22 study groups after discontinuation of placebo. Between antidepressant and placebo groups of included RCTs, the summary difference in incidence was 0·08 [0·04-0·12]. The incidence of severe antidepressant discontinuation symptoms after discontinuation of an antidepressant was 0·028 (0·014-0·057) compared with 0·006 (0·002-0·013) after discontinuation of placebo. Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequencies of discontinuation symptoms, and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms. Heterogeneity of results was substantial. INTERPRETATION: Considering non-specific effects, as evidenced in placebo groups, the incidence of antidepressant discontinuation symptoms is approximately 15%, affecting one in six to seven patients who discontinue their medication. Subgroup analyses and heterogeneity figures point to factors not accounted for by diagnosis, medication, or trial-related characteristics, and might indicate subjective factors on the part of investigators, patients, or both. Residual or re-emerging psychopathology needs to be considered when interpreting the results, but our findings can inform clinicians and patients about the probable extent of antidepressant discontinuation symptoms without causing undue alarm. FUNDING: None.

Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis.

Importance: Placebo is the only substance systematically evaluated across common psychiatric diagnoses, but comprehensive cross-diagnostic comparisons are lacking. Objective: To compare changes in placebo groups in recent high-quality randomized clinical trials (RCTs) across a broad spectrum of psychiatric disorders in adult patients. Data Sources: MEDLINE and the Cochrane Database of Systematic Reviews were systematically searched in March 2022 for the latest systematic reviews meeting predetermined high-quality criteria for 9 major psychiatric diagnoses. Study Selection: Using these reviews, the top 10 highest-quality (ie, lowest risk of bias, according to the Cochrane Risk of Bias tool) and most recent placebo-controlled RCTs per diagnosis (totaling 90 RCTs) were selected, adhering to predetermined inclusion and exclusion criteria. Data Extraction and Synthesis: Following the Cochrane Handbook, 2 authors independently carried out the study search, selection, and data extraction. Cross-diagnosis comparisons were based on standardized pre-post effect sizes (mean change divided by its SD) for each placebo group. This study is reported following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main Outcome and Measure: The primary outcome, pooled pre-post placebo effect sizes (dav) with 95% CIs per diagnosis, was determined using random-effects meta-analyses. A Q test assessed statistical significance of differences across diagnoses. Heterogeneity and small-study effects were evaluated as appropriate. Results: A total of 90 RCTs with 9985 placebo-treated participants were included. Symptom severity improved with placebo in all diagnoses. Pooled pre-post placebo effect sizes differed across diagnoses (Q = 88.5; df = 8; P < .001), with major depressive disorder (dav = 1.40; 95% CI, 1.24-1.56) and generalized anxiety disorder (dav = 1.23; 95% CI, 1.06-1.41) exhibiting the largest dav. Panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, and mania showed dav between 0.68 and 0.92, followed by OCD (dav = 0.65; 95% CI, 0.51-0.78) and schizophrenia (dav = 0.59; 95% CI, 0.41-0.76). Conclusion and Relevance: This systematic review and meta-analysis found that symptom improvement with placebo treatment was substantial in all conditions but varied across the 9 included diagnoses. These findings may help in assessing the necessity and ethical justification of placebo controls, in evaluating treatment effects in uncontrolled studies, and in guiding patients in treatment decisions. These findings likely encompass the true placebo effect, natural disease course, and nonspecific effects.