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Original Investigation
February 19, 2020

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

Author Affiliations
  • 1Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  • 2Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
  • 3Department of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine, School of Public Health, Yoshida-Konoe, Sakyo, Kyoto, Japan
  • 4Department of Clinical Epidemiology, Kyoto University Graduate School of Medicine, Kyoto University School of Public Health, Yoshida-Konoe, Sakyo, Kyoto, Japan
  • 5Department of Psychiatry, University of Oxford, Oxford, United Kingdom
  • 6Warneford Hospital, Oxford Health National Health Service Foundation Trust, Oxford, United Kingdom
  • 7Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Ontario, Canada
JAMA Psychiatry. 2020;77(6):607-617. doi:10.1001/jamapsychiatry.2019.4815
Key Points

Question  Is there evidence that response to antidepressants varies systematically based on individual differences?

Findings  In a meta-analysis of 87 randomized clinical trials (17 540 unique participants) on the use of antidepressants in individuals with major depression, there was 14% more variability in response to antidepressants than to placebo. Baseline severity of depression did not moderate this variability, but variability in response to noradrenergic agents was higher than that of selective serotonin reuptake inhibitors and antidepressants classified as other; variability also tended to be lower in studies published more recently.

Meaning  Response to antidepressants may include individual differences, which are associated with variability beyond nonspecific random or statistical factors, with some evidence that antidepressant class and publication year are associated with variability.


Importance  Antidepressants are commonly used worldwide to treat major depressive disorder. Symptomatic response to antidepressants can vary depending on differences between individuals; however, this variability may reflect nonspecific or random factors.

Objectives  To investigate the assumption of systematic variability in symptomatic response to antidepressants and to assess whether this variability is associated with severity of major depressive disorder, antidepressant class, or year of study publication.

Data Sources  Data used were from a recent network meta-analysis of acute treatment with licensed antidepressants in adults with major depressive disorder. The following databases were searched from inception to January 8, 2016: the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, and PsycINFO. Additional sources were international trial registries, drug approval agency websites, and key scientific journals.

Study Selection  Analysis was restricted to double-blind, randomized placebo-controlled trials with available data at the study’s end point.

Data Extraction and Synthesis  Baseline and end point means, SDs, number of participants in each group, antidepressant class, and publication year were extracted. The data were analyzed between August 14 and November 18, 2019.

Main Outcomes and Measures  With the use of validated methods, coefficients of variation were derived for antidepressants and placebo, and their ratios were calculated to compare outcome variability between antidepressant and placebo. Ratios were entered into a random-effects model, with the expectation that response to antidepressants would be more variable than response to placebo. Analysis was repeated after stratifying by baseline severity of depression, antidepressant class (selective serotonin reuptake inhibitors: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and vilazodone; serotonin and norepinephrine reuptake inhibitors: desvenlafaxine and venlafaxine; norepinephrine-dopamine reuptake inhibitor: bupropion; noradrenergic agents: amitriptyline and reboxetine; and other antidepressants: agomelatine, mirtazapine, and trazodone), and publication year.

Results  In the 87 eligible randomized placebo-controlled trials (17 540 unique participants), there was significantly more variability in response to antidepressants than to placebo (coefficients of variation ratio, 1.14; 95% CI, 1.11-1.17; P < .001). Baseline severity of depression did not moderate variability in response to antidepressants. Variability in response to selective serotonin reuptake inhibitors was lower than variability in response to noradrenergic agents (coefficients of variation ratio, 0.88; 95% CI, 0.80-0.97; P = .01), as was the variability in response to other antidepressants compared with noradrenergic agents (coefficients of variation ratio, 0.87; 95% CI, 0.79-0.97; P = .001). Variability also tended to be lower in studies that were published more recently, with coefficients of variation changing by a value of 0.005 (95% CI, 0.002-0.008; P = .003) for every year a study is more recent.

Conclusions and Relevance  Individual differences may be systematically associated with responses to antidepressants in major depressive disorder beyond placebo effects or statistical factors. This study provides empirical support for identifying moderators and personalizing antidepressant treatment.

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