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    Cruciality of Blinding with Subjective Endpoints
    Douglas M. Berger, M.D., Ph.D. | Meguro Counseling Center, Tokyo, Japan




    This study by Hollon et al., was not double blind, i.e., neither the subjects nor treaters were blind to the treatment(s) given. Unfortunately, no psychotherapy study, and in particular no CBT study where treaters and patients have to undergo cognitive and behavioral exercises, can be double-, or single-, blinded. Raters were “masked”, but this does not make the study single blind because single blind is defined as when the subjects are blind (1). Masked raters only record the report that comes out of the subject-treater system, biased or not. Calling raters “blind” instead of “masked” could be true, however, this nomenclature still does not make the study single-blinded, misleading readers into thinking the study was blinded and/or well-controlled.

    Blinding is a crucial point in understanding the design of a trial of depression with subjective endpoints. Full allocation blinding of a treatment in a clinical trial is critical for a study of Major Depression where endpoints are subjective (2). The elements of expectation and hope in an unblinded study with subjective endpoints can easily bias subjects’ statements of depressive symptom changes to the raters, and a large N as in this study can easily validate a biased outcome to “statistical significance.” Some researchers may voice the objection that medications may also be unmasked because of certain side-effects noticed by the subjects. This can be true with some medications, but not every trial would be unmasked to subjects as is necessarily the case for CBT, and trials showing significant unmasking should be invalidated whether drug or psychotherapy.

    Blinding may not be required when studying certain conditions that have strongly objective endpoints, i.e., stroke incidence, bone fracture incidence, death rate, etc. where the intervention’s efficacy would be great compared with random error and bias (3); unfortunately random error and bias is very large in the subjective endpoints studied in depression. 

    The results obtained by Hollon et al. could also be interpreted as that subjects with milder depression included more patients who did not have a medically-responsive depression (4), while for those with greater severity, there was both drug efficacy as well as hope and expectation in the cognitive therapy group biasing the results to the combination therapy. This interpretation is just as plausible as the conclusion that combination therapy is more effective for severe depression. The study design of this clinical trial without double blinding in subjective endpoints is too limited to make any conclusions of superior efficacy for combination therapy. 

    As a final note, it is not a valid study design to mix and compare study arms that have different levels of bias control (i.e., double-blinded drug therapy with unblinded psychotherapy) without being clear this is a severe limitation. This type of research could be called “observation of community treatment”, but it should not be termed a “clinical trial” because that would put unblinded studies with subjective endpoints at the same level of validity as clinical trials with strong double-blinding (5). 

    (1) Friedman LM, Furgerg CD, DeMets DL. Fundamentals of Clinical Trials, Third Edition. Springer; 1998 (or internet search for:“definition of single-blind”). 

    (2) Schulz, KF, Grimes DA, Blinding in Randomised Trials: hiding who got what. The Lancet, 2002:359; 696-700. Feburary 23, 2002. 

    (3) Piantadosi S. Clinical Trials: A Methodologic Perspective, 2nd ed. New York: Wiley-Interscience; 2005. 

    (4) Khan A, Leventhal R, Khan SR, Brown WA. 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

    (5) Hanrahan C, New JP. Antidepressant Medications: The FDA-Approval Process and the Need for Updates. Ment Health Clin. 2014;4(1):45. Available at: http://mhc.cpnp.org/doi/full/10.9740/mhc.n186950 (accessed April 8th 2015)







    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    October 2014

    Effect of Cognitive Therapy With Antidepressant Medications vs Antidepressants Alone on the Rate of Recovery in Major Depressive Disorder: A Randomized Clinical Trial

    Author Affiliations
    • 1Department of Psychology, Vanderbilt University, Nashville, Tennessee
    • 2Department of Psychology, University of Pennsylvania, Philadelphia
    • 3Department of Psychiatry, University of New Mexico, Albuquerque
    • 4Department of Psychiatry, University of Pennsylvania, Philadelphia
    • 5Department of Psychiatry, Vanderbilt University, Nashville, Tennessee
    • 6currently at the Department of Psychiatry, University of Alabama, Birmingham
    • 7Department of Psychiatry, Rush University, Chicago, Illinois
    • 8Department of Mathematics and Applied Statistics, West Chester University, West Chester, Pennsylvania
    JAMA Psychiatry. 2014;71(10):1157-1164. doi:10.1001/jamapsychiatry.2014.1054
    Abstract

    Importance  Antidepressant medication (ADM) is efficacious in the treatment of depression, but not all patients achieve remission and fewer still achieve recovery with ADM alone.

    Objective  To determine the effects of combining cognitive therapy (CT) with ADM vs ADM alone on remission and recovery in major depressive disorder (MDD).

    Design, Setting, and Participants  A total of 452 adult outpatients with chronic or recurrent MDD participated in a trial conducted in research clinics at 3 university medical centers in the United States. The patients were randomly assigned to ADM treatment alone or CT combined with ADM treatment. Treatment was continued for up to 42 months until recovery was achieved. Survival analyses based on subdistribution hazard models were used to model treatment outcomes.

    Interventions  Antidepressant medication with or without CT.

    Main Outcomes and Measures  Blind evaluations of recovery with a modified version of the 17-item Hamilton Rating Scale for Depression and the Longitudinal Interval Follow-up Evaluation.

    Results  Of the 452 participants, 227 were randomized to the CT combined with ADM treatment group, and 225 to the ADM treatment alone group. Combined treatment enhanced the rate of recovery vs treatment with ADM alone (75.2% vs 65.6%; t451 = 2.44; P = .02; hazard ratio [HR], 1.32; 95% CI, 1.06-1.65; number needed to treat [NNT], 11; 95% CI, 6-91). This effect was conditioned on a statistically nonsignificant interaction with severity (t451 = 1.67; P = .09; NNT, 6) and a significant interaction with chronicity (χ2 = 7.66; P = .02; NNT, 6) such that the advantage for combined treatment was limited to patients with severe, nonchronic MDD (84.7% vs 57.7%; n = 147; t146 = 3.88; P = .001; HR, 2.21; 95% CI, 1.48-3.31; NNT, 4; 95% CI, 2-8). There was no difference in the number of patients who dropped out of combined treatment vs ADM treatment alone (18.1% vs 24.8%; t451 = −1.77; P = .08; HR, 0.70; 95% CI, 0.47-1.04). Remission rates did not differ significantly either as a main effect of treatment or as an interaction with severity or chronicity. Patients with comorbid Axis II disorders took longer to recover than did patients without comorbid Axis II disorders regardless of the condition (P = .001). There were no statistically significant differences in the numbers of serious adverse events in the 2 groups (41 in the ADM plus CT group vs 52 in the ADM-alone group; χ1 = 1.76; P = .18).

    Conclusions and Relevance  Cognitive therapy combined with ADM treatment enhances the rates of recovery from MDD relative to ADMs alone, with the effect limited to patients with severe, nonchronic depression.

    Trial Registration  clinicaltrials.gov Identifier: NCT00057577

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