Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Abstract

BackgroundMeta-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of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance.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is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.Methods and FindingsWe obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the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.ConclusionsDrug–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.

Optimizing randomized trial designs to distinguish which subpopulations benefit from treatment

“…Kirsch et al (2008) present suggestive, though not conclusive, evidence that certain commonly prescribed antidepressants may only be effective for those with severe, rather than moderate, depression at study baseline. With this in mind, it may be advantageous to incorporate the following preplanned interim analysis in one's trial of the new antidepressant: if it is observed that the treatment effect is sufficiently low among those with moderate baseline depression, one will enroll only those with severe baseline depression for the rest of the trial.…”

“…As described above, Kirsch et al (2008) present suggestive, but not conclusive, evidence from a meta-analysis that a class of commonly used antidepressants may not be superior to placebo for those with moderate pretreatment depression, while they are superior to placebo for those with severe pretreatment depression. We consider a method for designing a trial of a hypothetical new antidepressant with this in mind.…”

“…We present a particular design from the class D, and compare its power with that of two fixed designs under several scenarios. We continue to use the example introduced in § 3 of testing a hypothetical new antidepressant, motivated by the metaanalysis of Kirsch et al (2008). We let subpopulation 1 denote those with moderate pretreatment depression, and subpopulation 2 denote those with severe pretreatment depression.…”

“…For example, these could be subpopulations defined by a biomarker measured at baseline, such as human epidermal growth factor receptor-2 in studies of breast cancer therapies, as described by Baselga (2001) and Wang et al (2007, 846 M. ROSENBLUM AND M. J. VAN DER LAAN 2009), or defined by baseline factors such as initial severity of depression in studies of antidepressants as described by Kirsch et al (2008). In both examples, there is evidence that certain subpopulations may benefit more from certain treatments.…”

The neuroscience and context of adolescent depression

“…A meta-analysis has shown that SSRIs are less effective in paediatric than adult MDD, with minimal gains after four weeks of treatment (24). It is generally believed that the antidepressant efficacy of SSRIs increases as a function of baseline depression severity, but it is also hypothesised that this may be due to decreased responsiveness to the placebo effect of SSRIs, rather than to increased responsiveness to medication (25). It is notable that previously published data that supported the efficacy and safety of SSRIs in paediatric populations has shown to be incorrect when reanalysed (26).…”