A Meta-analysis of Factors Impacting Detection of Antidepressant Efficacy in Clinical Trials: The Importance of Academic Sites

Abstract

Variability in placebo response greatly complicates the design, conduct, and interpretation of clinical trials of antidepressant medications. To identify factors that impact detection of antidepressant-placebo differences, we conducted a meta-analysis of all relevant phase II-IV clinical trials for major depressive disorder conducted by the manufacturer of venlafaxine and desvenlafaxine completed by March 2011. We examined 15 factors potentially relevant to trial outcomes, using the standardized mean difference on the Hamilton Rating Scale for Depression (HAM-D₁₇) score as the primary outcome. Thirty trials comprising 8933 patients were included. In univariate analyses, antidepressant efficacy (ie, drug vs placebo difference) was predicted most strongly (β=3.74, p=0.0002) by the proportion of patients in the trial enrolled from academic sites. Other factors predicting larger drug-placebo differences included lower participant completion rate, fewer post-baseline study visits, earlier year of study, and study drug (venlafaxine>desvenlafaxine). In multivariate meta-regression modeling, only the proportion of patients from academic sites maintained statistical significance as a predictor of drug-placebo separation for both HAM-D₁₇ continuous score change (β=2.24, p=0.034) and response rate (β=2.26, p=0.035). Including a higher proportion of academic sites may increase the ability to detect differences between active drug and placebo in clinical trials of major depressive disorder.

Increasing placebo responses over time in U.S. clinical trials of neuropathic pain

“…In some of these meta-analyses, changing participant characteristics have been proposed to be responsible for the trend. 1,6,9,13,18,21 In general, this study did not uncover strong evidence that patient characteristics were related to placebo response magnitude. Meta-analyses of placebo responses in antidepressant and antipsychotic RCTs have also provided evidence that changing study characteristics drive trends in placebo response.…”

“…14 This, of course, could be due either to increases in the placebo response itself and/or diminishing efficacy of new drugs. Similar analyses of randomized controlled trials (RCTs) of antipsychotic 1,17,30,32 and antidepressant 6,9,21,28,36 drugs have shown statistically significant increases in placebo response over time.…”

“…16 Decreasing differential effects of drug vs placebo over time have been noted in clinical trials of antipsychotics, 19 antidepressants, 9,21 and statins. 14 This, of course, could be due either to increases in the placebo response itself and/or diminishing efficacy of new drugs.…”

A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of 2 Doses of Vortioxetine in Adults With Major Depressive Disorder

“…In a third analysis, 3 symptom severity was not a significant predictor of the difference between active treatment and placebo, whereas enrollment at academic sites was Interrupted, aborted, or preparatory acts or behavior 1 (0.6) 0 0 Actual attempt 0 0 0 Completed suicide 0 0 0 a A subject had a positive report at baseline or during study if the subject reported any of the following suicidal ideation or behavior: (1) active suicidal ideation with some intent to act, without specific plan; (2) active suicidal ideation with specific plan and intent; (3) interrupted, aborted, or preparatory acts or behavior; (4) actual attempt; (5) completed suicide (during study). Baseline is a combination of screening visit (lifetime assessment) and baseline visit assessment.…”

“…2 In a third analysis, symptom severity was not a significant predictor of the difference between active treatment and placebo, whereas enrollment at academic sites was strongly predictive of positive treatment effects. 3 This study suggested that raters in nonacademic settings may have a tendency to overestimate baseline scores that, in turn, could lead to higher placebo responses. Consistent with this observation, results of a study by Kobak et al 4 showed that site-based raters were more likely to assign higher 17-item Hamilton Depression Rating Scale scores at baseline than centralized raters who screened patients remotely.…”