Vol 4 n° 4 - Drug Development
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Challenges in the development of clinical trials for major depressive disorder: lessons learned from trials in minor depression Mark H. Rapaport, MD; Rachel E. Maddux, BA ver the last decade, there has been increasing attention  focused  on  the  inadequacy  of  the  current methodology  employed  in  randomized  clinical  trials involving new antidepressant medications. The primary focus of this concern has centered on the need to ade- quately differentiate the effectiveness of new treatments from the placebo condition.There has been considerable consternation because of the increasing rate of placebo response seen in all types of trials in psychiatry, particu- larly trials of mood and anxiety disorders.1-3 This growing awareness has led to a variety of different efforts that have begun to address concerns about trial design and method- ology.4-6 These include an ongoing series of workshops sponsored by the National Institute of Mental Health (NIMH)  and  the  New  Clinical  Drug  Evaluation  Unit (NCDEU).7 The NIMH has also hosted a series of con- sensus conferences over the last few years in an attempt to begin to focus attention on these concerns. Such confer- ences  have  investigated  issues  including  placebo  and placebo response and the development of new instru- ments for the assessment of mood and anxiety disorders. There has also been a series of international meetings, including a symposium held in Rhodes, Greece in 2000, which brought together international experts in method- ology with senior staff from the NIMH and the Food and Drug Administration (FDA). The culmination of these concerted efforts was a consensus statement that was pub- lished in Neuropsychopharmacology in 2002.8 The Rhodes panel identified 4 critical problem areas: (i) the nature of the patient sample; (ii) the limitations of behavioral meth- ods and analyses used for assessing treatment-related improvement and recovery; (iii) the lack of consensus about standards for determining speed of onset and action for medications; and (iv) the failure to integrate advances into our knowledge about depression in antidepressant Keywords:  clinical  trial  design;  clinical  methodology;  antidepressant;  major depressive disorder; depression; minor depression Author  affiliations:  Department  of  Psychiatry,  Cedars-Sinai  Medical  Center, Los   Angeles,   Calif,   USA (Mark   H. Rapaport);   Department   of   Psychiatry, University  of  California,  Los  Angeles,  Los  Angeles,  Calif,  USA  (Mark  H. Rapaport, Rachel E. Maddux)Address   for   correspondence:Mark H. Rapaport,   MD, Department   of Psychiatry,  Cedars-Sinai  Medical  Center,  8730  Alden  Drive,  Thalians,  Room C301, Los Angeles, CA 90048, USA
(e-mail: Mark.rapaport@cshs.org) C l i n i c a l   r e s e a r c h 4 0 2 O This paper reviews some of the challenges faced by indi- viduals who design and implement clinical trials of poten- tial antidepressant medications. Particular emphasis is placed on questioning the validity of some of the theo- retical assumptions that form the underpinnings of most conventional trials. Work from our group developing clin- ical trial methodology for minor depression is used as an example of how alternate constructs may be helpful to differentiate drug-placebo differences. Dialogues Clin Neurosci. 2002;4:402-407.