Exploratory Analyses of Efficacy Data From Major Depressive Disorder Trials Submitted to the US Food and Drug Administration in Support of New Drug Applications

Abstract

Treatment effect has declined over time in MDD trials, and there has been a high failure rate for these trials during the entire period, but the reasons for these findings remain elusive. Baseline disease severity seems to be a more important factor in study outcome than study duration, dosing regimen, sample size, time when studies were conducted, and regions where data were generated. Close attention is needed to a variety of factors in the design and conduct of these studies, including patient population, diagnostic considerations, patient assessment, and clinical practice differences. These considerations become increasingly important as globalization of clinical trials continues to increase.

Randomized, Placebo-Controlled Trials of Antidepressants for Acute Major Depression: Thirty-Year Meta-Analytic Review

“…The present findings are congruent with reviews discussed above indicating that antidepressant drug-vs-placebo differences in published reports of controlled trials are generally moderate (Baldessarini, 2005;Gartlehner et al, 2008;Kirsch et al, 2008;Tsapakis et al, 2008;Bridge et al, 2009;Wooley et al, 2009;Masi et al, 2010;Pigott et al, 2010;Khin et al, 2011). This conclusion was reached in the previous literature despite typical reliance on initial improvement on scale ratings rather than less readily achieved clinical remission, and despite growing evidence of publication bias toward underreporting of studies without significant drugplacebo differences (Ioannidis, 2008;Turner et al, 2008).…”

“…The present findings also support the broad consensus that drug-placebo differences have been declining for a variety of psychotropic drugs in recent decades, making it increasingly difficult to demonstrate efficacy (Khin et al, 2011;Yildiz et al, 2011a, b). This trend probably has encouraged increased reliance on larger trials (more subjects and collaborating sites) in order to maintain statistical power.…”

“…Moreover, there is little evidence that one antidepressant or pharmacological class of antidepressants is clearly and convincingly more effective than others (Anderson, 2001;Baldessarini, 2005Baldessarini, , 2012Cipriani et al, 2007;Papakostas et al, 2007;Gartlehner et al, 2008;Kirsch et al, 2008;Khin et al, 2011). In part, this lack of clear differentiation may arise from the modest drug-placebo differences in many controlled trials of antidepressants, which, in turn, may reflect broad clinical heterogeneity arising from the current broad concept of 'major depression' (Healy, 1997;Ghaemi, 2008).…”

“…The superiority of most clinically employed antidepressants over placebos in controlled trials has been modest in adult patients diagnosed with major depression, even lower in juvenile depressed patients, and probably has declined in recent years (Walsh et al, 2002;Baldessarini, 2005;Cipriani et al, 2007;Papakostas et al, 2007;Gartlehner et al, 2008;Kirsch et al, 2008;Tsapakis et al, 2008;Bridge et al, 2009;Wooley et al, 2009;Masi et al, 2010;Pigott et al, 2010;Khin et al, 2011). Evident decline in superiority of drugs over placebos has occurred despite evidence of selective reporting of positive findings of potential commercial interest from therapeutic trials (Ioannidis, 2008;Turner et al, 2008).…”

“…Possible differentiation of efficacy among antidepressants was a lively question soon after introduction of the SRIs and SNRIs (Healy, 1997;Baldessarini, 2005Baldessarini, , 2012. However, the popularity of most modern antidepressants owes far more to their perceived safety, relative ease of use, and broad clinical utility rather than to well-demonstrated superior efficacy in major depressive disorder compared with older agents (Baldessarini, 2005(Baldessarini, , 2012Cipriani et al, 2007;Papakostas et al, 2007;Wooley et al, 2009;Pigott et al, 2010;Khin et al, 2011).…”