Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration

Abstract

Background: Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.

Methods and findings: We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug-placebo difference scores. Drug-placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups.

Conclusions: Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Conflict of interest statement

Competing Interests: IK has received consulting fees from Squibb and Pfizer. BJD, TBH, AS, TJM, and BTJ have no competing interests.

Figures

Figure 1. QUOROM Flow Chart

Figure 2. Mean Standardized Improvement as a Function of Initial Severity and Treatment Group

Drug improvement is portrayed as red triangles around their solid red regression line and placebo improvement as blue circles around their dashed blue regression line; the green shaded area indicates the point at which comparisons of drug versus placebo reach the NICE clinical significance criterion of d = 0.50. Plotted values are sized according to their weight in analyses.

Figure 3. Mean Standardized Improvement as a Function of Initial Severity and Treatment Group, Including Only Trials Whose Samples Had High Initial Severity

Drug improvement is portrayed as red triangles around their solid red regression line and placebo improvement as blue circles around their dashed blue regression line; the green shaded area indicates the point at which comparisons of drug versus placebo reach the NICE clinical significance criterion of d = 0.50. Plotted values are sized according to their weight in analyses.

Figure 4. Mean Drug–Placebo Difference Scores as a Function of Initial Severity

Plotted values are sized according to their sample sizes (n); the green line represents the NICE clinical significance criterion. The solid blue regression line represents the trend across all 35 trials; the dashed red line represents the trend excluding the left-most observation.