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On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study.

ABSTRACT: BACKGROUND:The average treatment effect of antidepressants in major depression was found to be about 2 points on the 17-item Hamilton Depression Rating Scale, which lies below clinical relevance. Here, we searched for evidence of a relevant treatment effect heterogeneity that could justify the usage of antidepressants despite their low average treatment effect. METHODS:Bayesian meta-analysis of 169 randomized, controlled trials including 58,687 patients. We considered the effect sizes log variability ratio (lnVR) and log coefficient of variation ratio (lnCVR) to analyze the difference in variability of active and placebo response. We used Bayesian random-effects meta-analyses (REMA) for lnVR and lnCVR and fitted a random-effects meta-regression (REMR) model to estimate the treatment effect variability between antidepressants and placebo. RESULTS:The variability ratio was found to be very close to 1 in the best fitting models (REMR: 95% highest density interval (HDI) [0.98, 1.02], REMA: 95% HDI [1.00, 1.02]). The between-study standard deviation ? under the REMA with respect to lnVR was found to be low (95% HDI [0.00, 0.02]). Simulations showed that a large treatment effect heterogeneity is only compatible with the data if a strong correlation between placebo response and individual treatment effect is assumed. CONCLUSIONS:The published data from RCTs on antidepressants for the treatment of major depression is compatible with a near-constant treatment effect. Although it is impossible to rule out a substantial treatment effect heterogeneity, its existence seems rather unlikely. Since the average treatment effect of antidepressants falls short of clinical relevance, the current prescribing practice should be re-evaluated.

SUBMITTER: Volkmann C

PROVIDER: S-EPMC7657525 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study.

Volkmann Constantin C Volkmann Alexander A Müller Christian A CA

PloS one 20201111 11

<h4>Background</h4>The average treatment effect of antidepressants in major depression was found to be about 2 points on the 17-item Hamilton Depression Rating Scale, which lies below clinical relevance. Here, we searched for evidence of a relevant treatment effect heterogeneity that could justify the usage of antidepressants despite their low average treatment effect.<h4>Methods</h4>Bayesian meta-analysis of 169 randomized, controlled trials including 58,687 patients. We considered the effect s ...[more]

PMID: 33175895

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Project description:BackgroundThe observation that some patients appear to respond better to antidepressants for depression than others encourages the assumption that the effect of antidepressants differs between individuals and that treatment can be personalized.ObjectiveTo compare the outcome variance in patients receiving antidepressants with the outcome variance in patients receiving placebo in randomized controlled trials (RCTs) of adults with major depressive disorder (MDD) and to illustrate, using simulated data, components of variation of RCTs.MethodsFrom a dataset comprising 522 RCTs of antidepressants for adult MDD, we selected the placebo-controlled RCTs reporting outcomes on the 17 or 21 item Hamilton Depression Rating Scale or the Montgomery-Asberg Depression Rating Scale and extracted the means and SDs of raw endpoint scores or baseline to endpoint changes scores on eligible depression symptom rating scales. We conducted inverse variance random-effects meta-analysis with the variability ratio (VR), the ratio between the outcome variance in the group of patients receiving antidepressants and the outcome variance in the group receiving placebo, as the primary outcome. An increased variance in the antidepressant group would indicate individual differences in response to antidepressants.ResultsWe analysed 222 RCTs that investigated 19 different antidepressants compared with placebo in 345 comparisons, comprising a total of 61144 adults with an MDD diagnosis. Across all comparisons, the VR for raw endpoint scores was 0.98 (95% CI 0.96 to 1.00, I2 = 0%) and 1.00 (95% CI 0.99 to 1.02, I2 = 0%) for baseline-to-endpoint change scores.ConclusionBased on these data, we cannot reject the null hypothesis of equal variances in the antidepressant group and the placebo group. Given that RCTs cannot provide direct evidence for individual treatment effects, it may be most reasonable to assume that the average effect of antidepressants applies also to the individual patient.

Project description:BackgroundIntranasal esketamine has received regulatory approvals for the treatment of depression. Recently a large trial of repeated dose racemic ketamine also demonstrated efficacy in severe depression. However, uncertainties remain regarding comparative efficacy, dosage, and the time course of response.MethodsIn this systematic review and meta-analysis, we searched Embase, Medline, Pubmed, PsycINFO, and CENTRAL up to April 13, 2023, for randomised controlled trials (RCTs) investigating ketamine for depression. Two investigators independently assessed study eligibility and risk of bias and extracted the data on depression severity scores, response and remission rates, and all-cause dropouts. Multivariable mixed-effects meta-regressions incorporated drug formulation (racemic (Rac) or esketamine (Esket)) and dose (Low or High) as covariates. Treatment effects were assessed: immediately following the first dose, during further repeated dosing, and follow-up after the final dose of a treatment course. This study is registered with PROSPERO (CRD42021221157).FindingsThe systematic review identified 687 articles, of which 49 RCTs were eligible for analysis, comprising 3299 participants. Standardised mean differences (95% confidence intervals) immediately following the first/single treatment were moderate-high for all conditions (Rac-High: -0.73, -0.91 to -0.56; Esket-High: -0.48, -0.75 to -0.20; Rac-Low: -0.33, -0.54 to -0.12; Esket-Low: -0.55, -0.87 to -0.24). Ongoing effects during repeated dosing were significantly greater than the control for Rac-High (-0.61; -1.02 to -0.20) and Rac-Low (-0.55, -1.09 to -0.00), but not Esket-Low (-0.15, -0.49 to 0.19) or Esket-High (-0.22, -0.54 to 0.10). At follow-up effects remained significant for racemic ketamine (-0.65; -1.23 to -0.07) but not esketamine (-0.33; -0.96 to 0.31). All-cause dropout was similar between experiment and control conditions for both formulations combined (Odds Ratio = 1.18, 0.85-1.64). Overall heterogeneity varied from 5.7% to 87.6.InterpretationOur findings suggested that effect sizes for depression severity, as well as response and remission rates, were numerically greater for racemic ketamine than esketamine. Higher doses were more effective than low doses. Differences were evident in initial effects, ongoing treatment, and lasting effects after the final dose.FundingNone.

Project description:INTRODUCTION:Major depression is a leading cause of disability and has been associated with adverse effects in older persons. While many pharmacological and non-pharmacological interventions have been shown to be effective to address major depression in older persons, there has not been a meta-analysis that consolidates all the available interventions and compare the relative benefits of these available interventions. In this study, we aim to conduct a systematic review and network meta-analysis to compare the efficacy and acceptability of all the known pharmacological and non-pharmacological interventions for major depression in older persons. METHODS AND ANALYSIS:We will search Medline, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health, Cochrane Central Register of Controlled Trials and references of other review articles for articles related to the keywords of 'randomised trial', 'major depression', 'older persons' and 'treatments'. Two reviewers will independently select the eligible articles. For each included article, the two reviewers will independently extract the data and assess the risk of bias using the Cochrane revised tool for risk of bias. Bayesian network meta-analyses will be conducted to pool the depression scores (based on standardised mean difference) and the all-cause discontinuation across all included studies. The ranking probabilities for all interventions will be estimated and the hierarchy of each intervention will be summarised as surface under the cumulative ranking curve (SUCRA). Meta-regression and sub-group analyses will also be performed to evaluate the effect of study-level covariates. The quality of the evidence will be assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION:The results will be disseminated through conference presentations and peer-reviewed publications. They will provide the consolidated evidence to inform clinicians on the best choice of intervention to address major depression in older persons. PROSPERO REGISTRATION NUMBER:CRD42017075756.

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On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study.

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On the treatment effect heterogeneity of antidepressants in major depression: A Bayesian meta-analysis and simulation study.

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