new england journal
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opram, after citalopram alone was ineffective inan initial trial. Approximately 30 percent of pa-tients had a remission, as measured by the 17-itemHamilton Rating Scale for Depression — a figureconsistent with the placebo effects reported inother studies of the treatment of depression.
Indeed, the authors noted that the study designdid not include a placebo control and, therefore,did “not allow us to exclude spontaneous remis-sion, the nonspecific effects of treatment, or theextended use of citalopram alone as the likely ex-planation for the present findings.” Nevertheless,they concluded in their very next paragraph that “augmentation of SSRIs with either agent will re-sult in symptom remission.” They also ponderedthe adoption of such drug combinations as “first-line treatment in an attempt to achieve greaterremission rates sooner in more patients than withSSRIs alone.” Similar conclusions describing theclinical usefulness and advantages of the drugsappear in the study abstract (without mentioninglimitations). Given the study design, these con-clusions seem unsupportable.
Scott C. Williams, Psy.D.
736 Tanager Ln.Geneva, IL 60134
Trivedi MH, Fava M, Wisniewski SR, et al. Medication aug-mentation after the failure of SSRIs for depression. N Engl J Med2006;354:1243-52.Elkin I, Shea MT, Watkins JT, et al. National Institute of Mental Health Treatment of Depression Collaborative ResearchProgram: general effectiveness of treatments. Arch Gen Psychia-try 1989;46:971-82.Walsh BT, Seidman SN, Sysko R, Gould M. Placebo responsein studies of major depression: variable, substantial, and grow-ing. JAMA 2002;287:1840-7.Moncrieff J. The antidepressant debate. Br J Psychiatry 2002;180:193-4.Wampold BE, Minami T, Tierney SC, Baskin TW, Bhati KS.The placebo is powerful: estimating placebo effects in medicineand psychotherapy from randomized clinical trials. J Clin Psy-chol 2005;61:835-54.
To the Editor:
In his editorial accompanyingthe two STAR*D articles, Rubinow
emphasizesthat medications with various mechanisms of ac-tion were all roughly equivalent in efficacy andasks what one can possibly infer about the patho-physiology of major depression. In our view, Ru-binow puts his finger in an open wound of psy-chiatry — that is, its insufficient and purely descriptive classification. If we lump together allpatients with major depressive syndromes, regard-less of whether there is a family history of schizo-
phrenia, unipolar or bipolar depression, a coex-isting attention deficit–hyperactivity disorder orborderline personality disorder, or discrete abnor-malities on electroencephalography or magneticresonance imaging, we end up with a mixed bagas a study sample. Such study groups necessarily produce mixed results in etiologic and therapeu-tic research. We need a more specific and cause-dependent classification system in psychiatry if we want to progress to more specific therapeuticrationales in psychiatric disorders.
Ludger Tebartz van Elst, M.D.Dieter Ebert, M.D.Bernd Hesslinger, M.D.
University Clinic Freiburg79104 Freiburg, Germanytebartzvanelst@uniklinik-freiburg.de
Rubinow DR. Treatment strategies after SSRI failure — goodnews and bad news. N Engl J Med 2006;354:1305-7.
The authors reply:
Sussman raises the impor-tant question of whether the results would haverevealed significant differences had the samplebeen larger, despite the fact that this is the larg-est second-step clinical trial ever conducted. Werespectfully disagree with the notion that ourfindings are the result of an underpowered study.Given the three-group design, the study had 80percent power to detect an effect size of 0.12 inremission rates, which is considered to be a smalleffect.
The translation of the effect size into adetectable difference in a three-group trial is not as straightforward as in a two-group trial. If one were conducting a two-group trial with a similarsample size, there would be 80 percent power todetect a difference of approximately 10 percent in remission rates. Although one can argue that more modest differences are clinically important, we believe that a difference of 10 percent or lessin remission rates is probably not clinically mean-ingful.Williams asks whether the 30 percent rate of remission in our study may be due to the pla-cebo effect, as in efficacy trials. The STAR*Dremission rate is probably not due to placebo forseveral reasons. First, patients in step 2 of STAR*Dhad already undergone a full trial with an SSRI.
Second, patients reported numerous psychiatricand general medical coexisting conditions andlong durations of illness; most were chronically depressed. Third, remission rates are low in real-
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