美国食品和药物管理局提交的随机、安慰剂对照试验中治疗重度抑郁症急性单药治疗的反应：个体参与者数据分析。

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.

机构信息

Division of Psychiatry, Office of Neuroscience, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

Division of Hospital Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

出版信息

BMJ. 2022 Aug 2;378:e067606. doi: 10.1136/bmj-2021-067606.

DOI:10.1136/bmj-2021-067606

PMID:35918097

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9344377/

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% 9.6%) and less likely to have a Minimal response (12.2.% 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.

摘要

目的

描述 1979 年至 2016 年向美国食品和药物管理局提交的随机、安慰剂对照试验中，用于治疗重度抑郁症的单一疗法的个体参与者水平反应分布特征。

设计

个体参与者数据分析。

人群

1979 年至 2016 年，药物开发商向 FDA 提交的 232 项用于治疗重度抑郁症的药物单药随机、双盲、安慰剂对照试验，包括 73388 名符合抗抑郁药疗效研究纳入标准的成年和儿童参与者。

主要观察指标

使用 Hamilton 抑郁评定量表（HAMD17）等效评分转换反应，其中其他措施用于评估疗效。多变量分析检查了年龄、性别、基线严重程度和研究年份对抗抑郁药和安慰剂组改善抑郁症状的影响。使用有限混合模型分析反应分布。

结果

药物与安慰剂组之间的随机效应均值差异有利于药物（1.75 分，95%置信区间 1.63 至 1.86）。药物与安慰剂之间的差异随着基线严重程度的增加而显著增加（P<0.001）。在控制基线时参与者特征后，未发现治疗效果或安慰剂反应随时间的趋势。反应分布的最佳拟合模型是三个正态分布，从基线到治疗结束的平均改善分别为 16.0、8.9 和 1.7 分。这些分布分别指定为大、非特异性和最小反应。接受药物治疗的参与者更有可能出现大反应（24.5%（9.6%）），不太可能出现小反应（12.2%（21.5%））。