Individual Differences in Response to Antidepressants A Meta-analysis of Placebo-Controlled Randomized Clinical Trials

IMPORTANCE Antidepressants are commonly used to treat major depressive disorder (MDD). Antidepressant outcomes can vary based on individual differences; however, it is unclear whether specific factors determine this variability or whether it is at random. OBJECTIVE To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether variability is associated with MDD severity, antidepressant class, or study publication year. DATA SOURCES Data used were updated from a network meta-analysis of treatment with licensed antidepressants in adults with MDD. The Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycInfo were searched from inception to March 21, 2019. Additional sources were international trial registries and sponsors, drug companies and regulatory agencies' websites, and reference lists of published articles. Data were analyzed between June 8, 2020, and June 13, 2020. STUDY SELECTION Analysis was restricted to double-blind, randomized placebo-controlled trials with depression scores available at the study's end point. DATA EXTRACTION AND SYNTHESIS Baseline means, number of participants, end point means and SDs of total depression scores, antidepressant type, and publication year were extracted. MAIN OUTCOMES AND MEASURES Log SDs (b(ln) sigma) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in b(ln) sigma between treatment groups while controlling for end point mean. Secondary models determined whether differences in variability between groups were associated with baseline MDD severity; antidepressant class (selective serotonin reuptake inhibitors and other related drugs; serotonin and norepinephrine reuptake inhibitors; norepinephrine-dopamine reuptake inhibitors; noradrenergic agents; or other antidepressants); and publication year. RESULTS In the 91 eligible trials (18 965 participants), variability in response did not differ significantly between antidepressants and placebo (b(ln) sigma, 1.02; 95% CI, 0.99-1.05; P = .19). This finding is consistent with a range of treatment effect SDs (up to 16.10), depending on the association between the antidepressant and placebo effects. Variability was not associated with baseline MDD severity or publication year. Responses to noradrenergic agents were 11% more variable than responses to selective serotonin reuptake inhibitors (b(ln) sigma, 1.11; 95% CI, 1.01-1.21; P = .02). CONCLUSIONS AND RELEVANCE Although this study cannot rule out the possibility of treatment effect heterogeneity, it does not provide empirical support for personalizing antidepressant treatment based solely on total depression scores. Future studies should explore whether individual symptom scores or biomarkers are associated with variability in response to antidepressants.

Automated summary

The study investigated the variability in symptomatic response to antidepressants, finding no significant difference in response variability between different antidepressants and placebo, as well as no association with disease severity or publication year. However, responses to noradrenergic agents were found to be more variable than responses to selective serotonin reuptake inhibitors.