10007373 J Clin Psychiatry / Document Archive

Psychiatrist.com Home    Keyword Search

Close [X]

Search Our Sites

Enter search terms below (keywords, titles, authors, or subjects). Then select a category to search and press the Search button. All words are assumed to be required. To search for an exact phrase, put it in quotes. To exclude a term, precede it with a minus sign (-).

Keyword search:

Choose a category:

Choosing the appropriate category will greatly improve your chances of finding the best match.

All files at our sites: J Clin Psychiatry, Primary Care Companion, CME Institute, and MedFair

Search materials from our journals:

Abstracts from The Journal of Clinical Psychiatry, 1996–present, both regular issues and supplements

PDFs of the full text of The Journal of Clinical Psychiatry, 1996–present, both regular issues and supplements (Net Society Platinum [paid subscribers])

PDFs of the full text of The Primary Care Companion to The Journal of Clinical Psychiatry, 1999–present

Search CME offerings:

CME Institute, including CME from journals , supplements, and Web activities for instant CME credit (Net Society Gold [registered users]); also includes information about our CME program

CME activities from regular issues of The Journal of Clinical Psychiatry (Net Society Gold [registered users])

CME Supplements from The Journal of Clinical Psychiatry (Net Society Gold [registered users])


The article you requested is

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

J Clin Psychiatry 2011;72(4):464-472
Copyright 2011 Physicians Postgraduate Press, Inc.

To view this item, select one of the options below.

    1. Purchase this PDF for $40
      If you are not a paid subscriber, you may purchase the PDF.
      (You'll need the free Adobe Acrobat Reader.)
    2. Subscribe
      Receive immediate full-text access to JCP. You can subscribe to JCP print + online for $166 individual.
      JCP's 75th AnniversaryCelebrate!
      Celebrate JCP's 75th Anniversary with a special online-only subscription price of $75.
    1. Activate
      If you are a paid subscriber to JCP and do not yet have a username and password, activate your subscription now.
    2. Sign in
      As a paid subscriber who has activated your subscription, you have access to the HTML and PDF versions of this item.
  1. Did you forget your password?

Still can't log in? Contact the Circulation Department at 1-800-489-1001 x4 or send an email


Objective: There has been concern about a high rate of placebo response and a substantial failure rate in recent clinical trials in major depressive disorder (MDD). This report explores differences in efficacy data from placebo-controlled MDD trials submitted in support of new drug applications (NDAs) over a 25-year period.

Method: We compiled efficacy data from 81 randomized, double-blind clinical trials, with 21,611 evaluable patients, that were submitted to the US Food and Drug Administration as part of NDAs for an antidepressant claim between 1983 and 2008. Trial data were limited to completed, randomized, multicenter, double-blind, placebo-controlled clinical trials in adult patients diagnosed with MDD according to DSM-III or DSM-IV criteria. The database was further limited to patients who were involved in clinical trials for drugs widely viewed as effective antidepressants and for doses of these drugs also viewed as effective doses. Trials were rated as successful if they showed statistical superiority vs placebo for the investigational drug on change in Hamilton Depression Rating Scale (HDRS) score (last-observation-carried-forward data). (Trials with multiple investigational drug groups were successful if there was superiority in at least 1 drug group after adjustment for multiplicity.) In particular, we explored differences in effect size and success rate of these trials, based on when the studies were conducted, geographic location of the study sites (US vs non-US), trial duration, dosing regimen, study size, and baseline disease characteristics.

Results: Eighty-one percent of MDD patients were enrolled in US sites. Although the observed placebo and drug responses at non-US sites tended to be larger than at US sites, the treatment effect (drug-placebo difference) was similar (mean change from baseline of about –2.5 units in HDRS total score) in US and non-US trials. In both US and non-US trials, the placebo response showed a modest increase over the observation period (1983–2008). Treatment effect clearly diminished over this same period, at a similar rate for both US and non-US trials despite a marked increase in the sample size of the trials. Our analysis showed that 53% of all MDD trials in the last 25 years were successful. US trials had a higher success rate than non-US trials (58% vs 33%). Before 1995, the overall success rate was 55%, compared to 50% for trials in 1995 or later, and, in general, 6-week trials had a higher success rate than 8-week trials (55% vs 42%). It should be noted that the earlier trials were mostly 6 weeks, and the 6-week trials had higher mean baseline HDRS scores than the 8-week trials. Study size did not seem to influence trial success rates. Mean baseline HDRS total scores declined over the 25-year observation period for patients in both US and non-US trials, as did treatment effect in these trials, again, regardless of region. Fixed-dose trials had a numerically slightly greater success rate than flexible-dose trials (57% vs 51%), although on average treatment effect was numerically larger in the flexible-dose trials than in fixed-dose trials (mean of −2.9 vs −2.0 on HDRS units).

Conclusions: 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.

J Clin Psychiatry 2011;72(4):464–472

Submitted: April 22, 2010; accepted November 9, 2010 (doi:10.4088/JCP.10m06191).

Corresponding author: Ni A. Khin, MD, Division of Psychiatry Products, HFD-130, Food and Drug Administration, 10903 New Hampshire Ave, Bldg 22, Rm. 4110, Silver Spring, MD 20993-0002 (ni.khin@fda.hhs.gov).