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Original Investigation
February 17, 2021

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, England
  • 6Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, England
  • 7Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, Ontario, Canada
  • 8Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany
  • 9Institute of Psychiatry, Psychology and Neuroscience, Department of Psychosis Studies, King’s College of London, London, England
  • 10Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China
JAMA Psychiatry. Published online February 17, 2021. doi:10.1001/jamapsychiatry.2020.4564
Key Points

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

Findings  In this meta-analysis of 91 randomized clinical trials (18 965 participants) on the use of antidepressants in major depression, no evidence was found of more variability in response to antidepressants than to placebo. Variability was not associated with baseline depression severity or study year, but variability in response to noradrenergic agents was higher than that of selective serotonin reuptake inhibitors.

Meaning  Individual differences may not underlie variability in the association between total depression scores and antidepressant treatment; future efforts toward personalization should focus on individual symptoms or biomarkers.


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 (bln σ̂) were derived for treatment groups (ie, antidepressant and placebo). A random-slope mixed-effects model was conducted to estimate the difference in bln σ̂ 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 (bln σ̂, 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 (bln σ̂, 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.

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    2 Comments for this article
    Multiple testing correction ?
    Roland Dardennes, MD | Université de Paris
    Dear Sir,
    We read with Great interest this new article from the Meta-analytic Oxford Team. We have one question: did. the authors adjust their résults from multiple-testing fallacy? As an example, a p-value of .02 between the variability of response between noradrenergic and sérotoninergic antidepressant would not be of any significance if no multiple-testing adjustment was performed.
    Best wishes
    Pr. Roland Dardennes and Mrs Nebal Alanbar, PhD
    Noradrenergic antidepressants and larger response variability
    Takeshi Terao, MD, PhD | Department of Psychiatry, , Oita University Faculty of Medicine
    To the Editor: I read with great interest the article by Maslej et al1 in which they showed that the responses to noradrenergic antidepressants (NAs) were significantly more variable than those to selective serotonin reuptake inhibitors (SSRIs). Although the authors mentioned that antidepressants primarily affecting noradrenaline may have a greater effect than those exclusively affecting synaptic serotonin, they do not address the potential causes underlying the greater response variation of NAs compared with SSRIs. Moreover, the authors mentioned that functional unblinding during randomized clinical trials (RCTs) involving NAs might explain this finding because dropout rates due to adverse effects of NAs are generally higher than those for SSRIs, suggesting that observers are not blinded to treatment allocation in some RCTs. Furthermore, there is insufficient justification provided for the final statement of the article in which the authors suggest that NAs may be the most suitable therapy for personalized treatment. I would like to elaborate on this topic.

    It is well-known that noradrenaline triggers a manic switch in patients with depression.2 Furthermore, imipramine and serotonin–norepinephrine reuptake inhibitors (SNRIs) have induced a manic switch significantly more often than placebo in 40 observational studies, unlike SSRIs.3 According to the Diagnostic and Statistical Manual of Mental Disorders (5th Edition),4 full-manic or full-hypomanic episodes occurring during antidepressant treatment, which persist at a fully syndromal level beyond the physiological effect of the treatment, are strongly suggestive of a manic or hypomanic episode, respectively. Therefore, patients displaying a manic or hypomanic switch during NA treatment would have been diagnosed with bipolar I and bipolar II disorder, respectively. The former may have dropped out from the RCT with low scores of intention-to-treat analyses, while the latter completed the RCT with high scores. The patients with true depression responded to NAs normally. Therefore, responses to NAs may have been highly variable because the cohort included patients with true depression, bipolar I disorder, and bipolar II disorder. It is noteworthy to mention that a substantial portion of patients with unipolar depression present manic and/or hypomanic episodes, resulting in a change of diagnosis to bipolar disorder.5 Considering the diagnostic heterogeneity underlying the variable responses to NAs, clinicians should change pharmacotherapeutic NAs to mood stabilizers when appropriate, and thus adopt a personalized treatment approach.

    1. Maslej MM, Furukawa TA, Cipriani A, Andrews PW, Sanches M, Tomlinson A, et al. Individual differences in response to antidepressants: a meta-analysis of placebo-controlled randomized clinical trials. Published online [February 17, 2021]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2020.4564
    2. Bunney WE Jr, Murphy DL, Goodwin FK, Borge GF. The switch process from depression to mania: relationship to drugs which alter brain amines. Lancet. 1970;1(7655):1022-1027.
    3. Allain N, Leven C, Falissard B, Allain JS, Batail JM, Polard E, et al. Manic switches induced by antidepressants: an umbrella review comparing randomized controlled trials and observational studies. Acta Psychiatr Scand. 2017;135(2):106-116.
    4. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC; 2013.
    5. Terao T, Ishii N, Hirakawa H. A specific group of patients with diagnostic conversion from depression to bipolar disorder