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Correspondence

Correspondence

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n engl j med
354;24
www.nejm.org june 1
5, 2006
2611
correspondence
Th
new england journal
of  
medicine
Depression — Augmentation or Switchafter Initial SSRI Treatment
To the Editor:
The report on the SequencedTreatment Alternatives to Relieve Depression(STAR*D) trial by Rush et al. (March 23 issue)
1
 advances the evidence base for the treatment of major depression. However, I believe it would beoverreaching and incorrect to characterize theresults of the study of drug treatment after initialtreatment with selective serotonin-reuptake in-hibitors (SSRIs) as definitive, owing to the sta-tistical underpowering of the design. This study seems to have the same shortcomings as do otherlarge studies, in that the authors incorrectly esti-mated the differences in remission among the various therapies that they tested. Rush et al.assumed that there would be a 15 percent differ-ence among treatments and designed the study accordingly.
2
Several studies sponsored by indus-try, independent investigators, and government have detected significant differences of 7 to 10percent.
3-5
Underpowering is a chronic problem in cur-rent study design that may lead many practition-ers to draw definitive but incorrect conclusionsthat affect patient care. For example, many reportsin the media have misrepresented the STAR*Dfinding that suggests — but does not conclu-sively demonstrate — that all treatments areequal. The investigators might have preventedthis problem if they had increased the number of participants in the study.
Norman Sussman, M.D.
New York University School of MedicineNew York, NY 10016sussman01@aol.com
Dr. Sussman reports having served as a consultant to Glaxo-SmithKline, Shire, and Wyeth and having received honorariafrom GlaxoSmithKline, Shire, Wyeth, and AstraZeneca.Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR,sertraline, or venlafaxine-XR after failure of SSRIs for depres-sion. N Engl J Med 2006;354:1231-42.
1.
Rush AJ, Fava M, Wisniewski SR, et al. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.Control Clin Trials 2004;25:119-42.Thase ME, Entsuah AR, Rudolph RL. Remission rates duringtreatment with venlafaxine or selective serotonin reuptake in-hibitors. Br J Psychiatry 2001;178:234-41.Baldomero EB, Ubago JG, Cercos CL, Ruiloba JV, Calvo CG,Lopez RP. Venlafaxine extended release versus conventional anti-depressants in the remission of depressive disorders after previ-ous antidepressant failure: ARGOS study. Depress Anxiety 2005;22:68-76.Cipriani A, Brambilla P, Furukawa T, et al. Fluoxetine versusother types of pharmacotherapy for depression. Cochrane Data-base Syst Rev 2005;4:CD004185.
To the Editor:
Trivedi et al. (March 23 issue)
1
 reported on patients’ use of sustained-release bu-propion or buspirone, in combination with cital-
2.3.4.5.
this week’s letters
2611
Depression — Augmentation or Switchafter Initial SSRI Treatment 
2613
Invariant Natural Killer T Cells in Bronchial Asthma
2616
ACAT Inhibition and the Progressionof Coronary Atherosclerosis
2617
Who Is at Greatest Risk for Receiving Poor-Quality Health Care?
2619
 
HER2
Mutation and Response to TrastuzumabTherapy in Non–Small-Cell Lung Cancer 
2621
Doxycycline Treatment for Lymphangioleio-myomatosis with Urinary Monitoring for MMPs
2623
Panniculitis during Dasatinib Therapyfor Imatinib-Resistant ChronicMyelogenous Leukemia
Downloaded from www.nejm.org on June 14, 2010 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.
 
Th
new england journal
of  
medicine
n engl j med
354;24
www.nejm.org june 1
5, 2006
2612
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.
2-5
 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 
1
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-
1.2.3.4.5.
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.
1
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.
2
 Second, patients reported numerous psychiatricand general medical coexisting conditions andlong durations of illness; most were chronically depressed. Third, remission rates are low in real-
1.
Downloaded from www.nejm.org on June 14, 2010 . Copyright © 2006 Massachusetts Medical Society. All rights reserved.

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