Antidepressant Trials: Are the Diminishing Effect Sizes of Efficacy Trials Avoidable?

E scalating placebo response rates and diminishing effect sizes are principal causes of failure to detect efficacy in antidepressant drug (AD) trials, even for an approved AD used as the active control in a placebo-controlled study. Concerns regarding the therapeutic benefit of AD treatment in the past led several investigators to conduct meta-analyses of Food and Drug Administration (FDA) databases of New Drug Applications (NDAs) to assess treatment effect sizes for approved (marketed) ADs. Khan et al analyzed the magnitude of effect size based on the drug-placebo mean difference in Hamilton Depression Scale (HAM-D) or Montgomery-Asberg Depression Rating Scale for several NDA data sets submitted to the FDA for marketed ADs, finding positive, albeit modest, evidence of AD efficacy. Because NDAs include outcomes of all phase 2 and 3 placebo-controlled efficacy trials, whether a positive, negative, or failed trial, FDA data sets included in an NDA tend, if anything, to underestimate actual treatment effect sizes. Kirsch et al, however, in a similar type of analysis found lesser AD effect sizes and questioned the therapeutic value of AD treatment. This report elicited several responses disagreeing with their analysis and providing added support for established efficacy of antidepressant agents, even for dysthymia. Two research groups independently, one in Germany and one in England, reanalyzed the Kirsch data set using methodology both groups considered more appropriate, both confirming efficacy of ADs. The drug/placebo HAM-D mean difference score of 1.8 reported by Kirsch et al was recomputed to be 2.7. In addition, Kirsch et al failed to report that for 2 of the 4 NDA data sets, paroxetine and venlafaxine, the pooled drug/placebo difference exceeded 3.0, meeting the NICE criteria for clinical significance. All of these meta-analyses uniformly confirmed the finding that more severely depressed patients had greater drug/placebo differences due to lower placebo response rate. Because a preponderance of clinical trials confirm the value of marketed, FDA-approved ADs in major depressive disorder (MDD), in this commentary, the authors seek to explore reasons for this apparent trend for diminished AD effect sizes and the high incidence of failed trials in which even an approved AD-positive control does not differ significantly from placebo treatment. Fifteen years ago, Robinson and Rickels in an editorial, “Concerns about clinical drug trials,” offered recommendations to improve efficacy trial outcomes, including methodologies to minimize placebo response. Similarly, in their 30-year survey of antidepressant trial outcomes, Undurraga and Baldessarini concluded that capability to detect drug-placebo difference improved with fewer study sites, smaller sample sizes, and care in selecting study subjects. Regretfully, these recommendationswere largely ignored by pharmaceutical firms in designing and implementing multicenter efficacy trials. In 2003, Fava et al proposed a novel unbalanced, parallel group trial design with the intent of enhancing capability to detect AD efficacy employing smaller samples. And indeed, Fava’s group recently reported results of a positive AD augmentation trial with methylfolate in treatment-resistant depressed patients. Using a placebo-controlled, nonparallel group study design with only 75 patients and 6 sites, these investigators detected significant augmentation of AD treatment with methylfolate (mean pooled drug-placebo difference, 2.54; P <0.05, Cohen d = 0.385). This study design has not been approved as a pivotal clinical trial design by the FDA. A key factor in clinical trials conducted in the United States today is the widespread use of paid volunteers, mostly recruited via media advertising. Brody et al noted a gradual trend in the United States to enroll less severely depressed volunteer subjects, whom evidence shows are more likely to respond to placebo. These authors further disparage use of financial incentives to investigators for rapid enrollment, an unfortunate, yet common, practice to be avoided. Both Brody et al and Rutherford and Roose reported clinical trial subjects exaggerating their symptoms, often reiterating precise wording used in media advertisements. Exhibiting an overly keen interest in reimbursement ought to raise doubts about a subject’s suitability. Cases of fraudulent subjects, often going undetected, were documented, including deserting a trial for one with higher reimbursement, enrollment in the same study at two different sites,