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Original Investigation |

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

Steven D. Hollon, PhD1; Robert J. DeRubeis, PhD2; Jan Fawcett, MD3; Jay D. Amsterdam, MD4; Richard C. Shelton, MD5,6; John Zajecka, MD7; Paula R. Young, PhD7; Robert Gallop, PhD8
[+] 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.
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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.

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  Combined treatment enhanced the rate of recovery vs treatment with ADM alone (72.6% vs 62.5%; t451 = 2.45; P = .01; hazard ratio [HR], 1.33; 95% CI, 1.06-1.68; number needed to treat [NNT], 10; 95% CI, 5-72). This effect was conditioned on interactions with severity (t451 = 1.97; P = .05; NNT, 5) and chronicity (χ2 = 7.46; P = .02; NNT, 6) such that the advantage for combined treatment was limited to patients with severe, nonchronic MDD (81.3% vs 51.7%; n = 146; t145 = 3.96; P = .001; HR, 2.34; 95% CI, 1.54-3.57; NNT, 3; 95% CI, 2-5). Fewer patients dropped out of combined treatment vs ADM treatment alone (18.9% vs 26.8%; t451 = −2.04; P = .04; HR, 0.66; 95% CI, 0.45-0.98). 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 = .01). Patients who received combined treatment reported fewer serious adverse events than did patients who received ADMs alone (49 vs 71; P = .02), largely because they experienced less time in an MDD episode.

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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Figure 1.
Consolidated Standards for Reporting of Trials Diagram of Patient Flow Through the Study

MDD indicates major depressive disorder; SCID, Structured Clinical Interview for DSM-IV.15

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Figure 2.
Time to Recovery as a Function of Severity by Condition

Recovery was defined as 6 months without relapse following remission. A, Low-severity major depressive disorder (MDD), defined as an HRSD score of less than 22 at intake. B, High-severity MDD, defined as an HRSD score of 22 or greater at intake. ADM indicates antidepressant medication; CT+ ADM, cognitive therapy combined with ADM; HRSD, Hamilton Rating Scale for Depression; and dashed lines, median time to recovery (50th percentile).

aP < .001.

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Figure 3.
Time to Recovery as a Function of Chronicity by Condition Within High Severity

Recovery was defined as 6 months without relapse following remission. A, High-severity chronic major depressive disorder (MDD), defined as an HRSD score of greater than 22 at intake and episode duration of 2 years or more. B, High-severity nonchronic MDD, defined as an HRSD score of 22 or greater at intake and episode duration of less than 2 years. ADM indicates antidepressant medication; CT+ ADM, cognitive therapy combined with ADM; HRSD, Hamilton Rating Scale for Depression; and dashed lines, median time to recovery (50th percentile).

aP < .001.

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Cruciality of Blinding with Subjective Endpoints
Posted on April 8, 2015
Douglas M. Berger, M.D., Ph.D.
Meguro Counseling Center, Tokyo, Japan
Conflict of Interest: None Declared

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)



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