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Randomized Controlled Trial
. 2022 Aug 2:378:e067606.
doi: 10.1136/bmj-2021-067606.

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis

Marc B Stone  1 , Zimri S Yaseen  1 , Brian J Miller  2 , Kyle Richardville  3 , Shamir N Kalaria  4 , Irving Kirsch  5
Affiliations
Randomized Controlled Trial

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis

Marc B Stone et al. BMJ. .

Abstract

Objectives: To characterize individual participant level response distributions to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration from 1979 to 2016.

Design: Individual participant data analysis.

Population: 232 randomized, double blind, placebo controlled trials of drug monotherapy for major depressive disorder submitted by drug developers to the FDA between 1979 and 2016, comprising 73 388 adult and child participants meeting the inclusion criteria for efficacy studies on antidepressants.

Main outcome measures: Responses were converted to Hamilton Rating Scale for Depression (HAMD17) equivalent scores where other measures were used to assess efficacy. Multivariable analyses examined the effects of age, sex, baseline severity, and year of the study on improvements in depressive symptoms in the antidepressant and placebo groups. Response distributions were analyzed with finite mixture models.

Results: The random effects mean difference between drug and placebo favored drug (1.75 points, 95% confidence interval 1.63 to 1.86). Differences between drug and placebo increased significantly (P<0.001) with greater baseline severity. After controlling for participant characteristics at baseline, no trends in treatment effect or placebo response over time were found. The best fitting model of response distributions was three normal distributions, with mean improvements from baseline to end of treatment of 16.0, 8.9, and 1.7 points. These distributions were designated Large, Non-specific, and Minimal responses, respectively. Participants who were treated with a drug were more likely to have a Large response (24.5% v 9.6%) and less likely to have a Minimal response (12.2.% v 21.5%).

Conclusions: The trimodal response distributions suggests that about 15% of participants have a substantial antidepressant effect beyond a placebo effect in clinical trials, highlighting the need for predictors of meaningful responses specific to drug treatment.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years except for BJM who reports serving as a member of the CMS Medicare Evidence Development and Coverage Advisory Committee and receiving fees outside the related work from the Federal Trade Commission, the Health Resources and Services Administration, the Heritage Foundation, and Oxidien Pharmaceuticals; BJM was a medical officer at the FDA in the Division of Psychiatry from 2016 to 2017; no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Heatmaps showing predicted treatment responses (change from baseline) as a function of sex, age, and baseline severity on the Hamilton rating scale for depression (HAMD17)
Fig 2
Fig 2
(Top) Fit of the mixture model distributions (curves) for drug and placebo responses with the respective histograms for the observed drug and placebo responses. (Bottom) Overall finite mixture model and component normal distributions for drug and placebo. HAMD17=Hamilton rating scale for depression; SEM=standard error of the mean; SD=standard deviation
Fig 3
Fig 3
Estimated effect for each drug. Center line shows the overall (random effects) mean effect for active drug to show how each drug differs from the average. Placebo line is a reference for how the differences among drugs compare with the differences between drugs and placebo
See this image and copyright information in PMC

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