Original Article| Volume 62, ISSUE 1, P65-71, July 01, 2007

Relationship Between Depression Severity Entry Criteria and Antidepressant Clinical Trial Outcomes

Published:December 06, 2006DOI:


      We assessed whether increasing the minimum prerandomization Hamilton Depression Rating Scale (HAM-D) score to enrich the severity of the depressed sample affects antidepressant trial outcome.


      Using the Food and Drug Administration Summary Basis of Approval reports, we examined outcome data from 51 clinical trials (11,270 depressed patients) evaluating 10 investigational antidepressants.


      Using four categories of trials with increasing minimum HAM-D entry trial criteria, we found no statistically significant relationship between prerandomization categories and trial outcome overall. Although there were minor differences in trial outcome among the three categories with the lowest entry criteria (mean 49%, range, 44.4%–50.0%), the antidepressant trials requiring the highest prerandomization HAM-D score (≥ 20 HAM-D 17) had the lowest frequency of positive outcomes (20%), χ2 = 4.04, df =1, p = .04. Paradoxically, high entry criteria requirements failed to increase reliably actual mean total prerandomization HAM-D scores, although mean total prerandomization HAM-D scores and use of flexible dosing were associated with higher rates of positive outcome. A greater placebo response was seen in trials requiring higher prerandomization depressive symptoms.


      In summary, requiring higher prerandomization depressive symptoms was not associated with an increased rate of favorable outcomes among these 51 antidepressant trials.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bollini P.
        • Pampallona S.
        • Tibaldi G.
        • Kupelnick B.
        • Munizza C.
        Effectiveness of antidepressants.
        Br J Psychiatry. 1999; 174: 297-303
        • Brown W.A.
        Predictors of placebo response in depression.
        Psychopharmacol Bull. 1988; 24: 14-17
        • Dworkin R.H.
        • Katz J.
        • Gitlin M.J.
        Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain.
        Neurology. 2005; 65: S7-S19
        • Elkin E.
        • Shea T.
        • Watkins J.T.
        • Imber S.D.
        • Sotsky S.M.
        • Collins J.F.
        • et al.
        General effectiveness of treatments.
        Arch Gen Psychiatry. 1989; 46: 971-982
        • Gram L.F.
        Inadequate dosing and pharmacokinetic variability as confounding factors in assessment of efficacy of antidepressants.
        Clin Neuropharmacol. 1990; 3: S35-S44
        • Greist J.H.
        • Mundt J.C.
        • Kobak K.
        Factors contributing to failed trials of new agents: Can technology prevent some problems?.
        J Clin Psychiatry. 2002; 63: 8-13
        • Gunnell D.
        • Saperia J.
        • Ashby D.
        Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: Meta-analysis of drug company data from placebo controlled, randomized controlled trials submitted to the MHRA’s safety review.
        BMJ. 2005; 330: 385-389
        • Joffe R.
        • Sokolov S.
        • Streiner D.
        Antidepressant treatment of depression: A meta-analysis.
        Can J Psychiatry. 1996; 41: 613-616
        • Joyce P.R.
        • Paykel E.S.
        Predictors of drug response in depression.
        Arch Gen Psychiatry. 1989; 46: 89-99
        • Kasper S.
        • Fuger J.
        • Moller H.J.
        Comparative efficacy of antidepressants.
        Drugs. 1992; 42: 11-23
        • Khan A.
        • Brodhead A.E.
        • Kolts R.L.
        • Brown W.A.
        Severity of depressive symptoms and response to antidepressants and placebo in antidepressant trials.
        J Psychiatr Res. 2005; 39: 145-150
        • Khan A.
        • Khan S.
        • Brown W.A.
        Are placebo controls necessary to test new antidepressants and anxiolytics?.
        Int J Neuropsychopharmacol. 2002; 5: 193-197
        • Khan A.
        • Khan S.R.
        • Walens G.
        • Kolts R.
        • Giller E.L.
        Frequency of positive studies among fixed and flexible dose antidepressant clinical trials: An analysis of the Food and Drug Administration Summary Basis of Approval Reports.
        Neuropsychopharmacology. 2003; 28: 552-557
        • Khan A.
        • Kolts R.L.
        • Thase M.E.
        • Krishnan K.R.R.
        • Brown W.
        Research design features and patient characteristics associated with the outcome of antidepressant clinical trials.
        Am J Psychiatry. 2004; 161: 2045-2049
        • Khan A.
        • Leventhal R.M.
        • Khan S.R.
        • Brown W.A.
        Severity of depression and response to antidepressants and placebo: An analysis of the Food and Drug Administration Database.
        J Clin Psychopharmacol. 2002; 22: 40-45
        • Khan A.
        • Schwartz K.
        Study designs and outcomes in antidepressant clinical trials.
        Essent Psychopharmacol. 2005; 6: 221-226
        • Leon A.C.
        Are two antidepressant mechanisms better than one?.
        J Clin Psychiatry. 2004; 65: 31-36
        • Morris J.B.
        • Beck A.T.
        The efficacy of antidepressant drugs.
        Arch Gen Psychiatry. 1974; 31: 33-41
        • Quitkin F.M.
        • Rabkin J.F.
        • Markowitz J.M.
        • Stewart J.W.
        • McGrath P.G.
        • Harrison W.
        Use of pattern analysis to identify true drug response: A replication.
        Arch Gen Psychiatry. 1987; 44: 259-264
        • Schatzberg A.F.
        Dosing strategies for antidepressant agents.
        J Clin Psychiatry. 1991; 52: 14-20
        • Thase M.E.
        Studying new antidepressants: If there were a light at the end of the tunnel, could we see it?.
        J Clin Psychiatry. 2002; 63: 24-28
        • Walsh B.T.
        • Seidman S.N.
        • Sysko R.
        • Gould M.
        Placebo response in studies of major depression: Variable, substantial, and growing.
        JAMA. 2002; 287: 1840-1847
        • Wilcox C.S.
        • Cohn J.B.
        • Linden R.D.
        • Heiser J.F.
        • Lucas P.B.
        • Morgan D.L.
        • et al.
        Predictors of placebo response: A retrospective analysis.
        Psychopharmacol Bull. 1992; 28: 157-162
        • Yang H.
        • Cusin C.
        • Fava M.
        Is there a placebo problem in antidepressant trials?.
        Curr Top Med Chem. 2005; 5: 1077-1086