We have made this page out of concern that the manuscript pasted below by Berger entitled, "Allocation Concealment: Requirement for Validity Claims in Psychotherapy Intervention Trials for Major Depressive Disorder" (MDD), was rejected for publication by the journal JAMA Psychiatry on the basis that the content would be embarrassing to JAMA Psychiatry editorial management. This rejection was in spite of the Berger paper being praised by independent reviewers provided by JAMA Psychiatry itself as "important", being scientifically correct, as well as calling for publication for the Berger paper. This situation has thus caused a concern about publication bias and academic nepotism, the details that we describe here (the positive reviewer comments and Berger paper are pasted below).

Background

The background of these concerns is as follows. JAMA Psychiatry published the following article by Hollon, et al., Effect of Cognitive Therapy With Antidepressant Medications vs Antidepressants Alone on the Rate of Recovery in Major Depressive Disorder A Randomized Clinical Trial. JAMA Psychiatry. 2014;71(10):1157-1164.

Hollon et al. concluded with the following positive comment on the efficacy of CT, "Combining CT with ADM (anti-depressant medication) enhanced the rate of recovery compared with ADM alone in a sample of patients with chronic or recurrent nonpsychotic MDD. The magnitude of this increment nearly doubled for patients with more severe depression or nonchronic MDD episodes, but there was little evidence of benefit for patients with less severe or chronic MDD."

The common affiliation (Same Dept., Same University) of Heckers (on the Editorial Board of JAMA Psychiatry and now Editor-in-Chief who then rejected the Berger critique of Hollon) and Hollon (JAMA Author) is an Editorial Ethics Infringement of the International Committee of Medical Journal Editors to which JAMA publications are a member; e.g., "An editor receives a submitted manuscript to review that has links to a company or organization in which the editor has some interest." (in this case critical of an author the editor has links and interest to) quoted from this Elseiver article on Editorial Ethics.

Note the same institution/same department affiliation of editor and author:
Stephan Heckers, MD, Editor-in-Chief, JAMA Psychiatry
Chair, Department of Psychiatry
Vanderbilt University School of Medicine, Nashville, Tennessee

Steven D. Hollon, PhD (JAMA Psychiatry Author)
Professor of Psychology and Human Development
Associate Professor of Psychiatry
Vanderbilt University, Nashville, Tennessee

In the same issue, JAMA Psychiatry also published this Editorial by Thase praising the Hollon study: Thase ME. Large-Scale Study Suggests Specific Indicators for Combined Cognitive Therapy and Pharmacotherapy in Major Depressive Disorder JAMA Psychiatry. 2014;71(10):1101-1102.

Thase went further in his editorial to praise the Hollon study stating, "the article by Hollon and colleagues in this issue of JAMA Psychiatry describes the main findings of one of the most important studies ever undertaken to evaluate the merits of combining psychotherapy and pharmacotherapy for treatment of major depressive disorder."

However, Thase and Hollon have previously worked together on the efficacy of medication and cognitive therapy in depression making publication of the editorial by Thase a clear conflict of interest and another Editorial ethics issue.

Ariticles previously co-authored by Thase and Hollon:
1. Thase ME, Friedman ES, Biggs MM, Wisniewski SR, Trivedi MH, Luther JF, Fava M, Nierenberg AA, McGrath PJ, Warden D, Niederehe G, Hollon SD, Rush AJ. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR-D report. Am J Psychiatry. 2007 May;164(5):739-52.
2. Hollon SD, Jarrett RB, Nierenberg AA, Thase ME, Trivedi M, Rush AJ. Psychotherapy and medication in the treatment of adult and geriatric depression: which monotherapy or combined treatment? J Clin Psychiatry. 2005 Apr;66(4):455-68. Review.

The opinion of the article by Berger which was rejected for publication by JAMA Psychiatry, was that the Hollon study was not robust because there was no double-blind (a standard and necessary measure in the evaluation of an intervention for an illness like MDD with subjective endpoints) in the design of the study (i.e, both therapists and subjects knew the type of therapy given), and that it was impossible to eliminate the element of hope and expectation on the part of the subjects. The double-blind problem was glossed-over in one line in the discussion by Hollon, and in spite of this crucial problem in the design of the study, both Hollon and Thase made the claims quoted above strongly suggesting confirmation of efficacy for the CT intervention.

We opine that JAMA Psychiatry should have:
1. ensured that Hollon et al. make a deeper discussion of the problems in their study.
2. limited the claims that Hollon et al. made in their paper regarding efficacy.
3. not allow publication of an Editorial like that of Thase which praised the Hollon article. Editorials can "chime-in" with a clinical trial under discussion further inflating any mistaken claims of efficacy.
3. not published the Editorial by Thase because of conflict of interest in having a prior co-author relationship with Hollon on the same topics.
4. published a nuanced critique once the problems with Hollon's paper and the conflict of interest between Hollon and Thase became apparent.

JAMA psychiatry rejected the Berger paper in spite of receiving many positive comments by the reviewers enlisted by JAMA Psychiatry themselves and listed below, including one calling for publication by stating, "Since this seems to be a general problem in the field of psychiatric research there are good reasons to publish the present study".

Dr. Howard Bauchner, the Editor-in-Chief of JAMA was contacted and asked to review the incident. He wrote us that Dr. Heckers was not the reviewing editor at the time of Hollon's submission, but completely skirted the issue that Heckers, as Editor-in-Chief, was also the reviewing editor of the Berger article that critiqued a paper in JAMA Psychiatry by a member of his staff Hollon. Heckers was protecting Hollon's paper and thus JAMA Psychiatry itself which would have to admit it published incorrect and misleading science in the Hollon paper.

Because of the above, we opine that the paper below was rejected on the basis that it would be embarrassing for JAMA Psychiatry to publish a critique of it's own problems in editing and policing exaggerated claims of efficacy of a psychotherapeutic intervention not born out by the study design the Hollon paper they published. It is also possible that the conflict of interest of Thase and Hollon having previously authored on the same topic together would have come to light further embarrassing JAMA Psychiatry.

We include the following reviewer comments and the rejected manuscript by Berger in order to publicly publish this important issue.

Independent Reviewers' Comments (Selected comments; Received on June 18, 2015):
1. "By and large the author's emphasis on problems in psychotherapy studies with blinding seems justified."

2. "The author points out that clinical trials for CBT cannot be carried-out under double blind conditions as would be required of pharmacotherapy or other somatic therapies and thus the rigor of CBT interventional studies would be quite different from those modalities that can be studied under double blinded conditions."

3. "This is an interesting study questioning the validity of the research in psychiatric issues where doubling blinding is impossible."

4."The study is important since there is a tendency to interpret the studies done in this field without the proper cautiousness needed due to the methodological obstacles."

5. "The present study gives a good example in how a recent study published in a respected journal could be overemphasizing the results obtained and how a large N in a biased study only emphasis the bias and not the true effect."

6. "Since this seems to be a general problem in the field of psychiatric research there are good reasons to publish the present study."

7. "The author criticizes (with good reason) that blinding of the assessor of symptoms is called 'single-blind.' "

Manuscript by Berger Rejected by Dr. Heckers of JAMA Psychiatry (decision received on June 18, 2015):

Allocation Concealment: Requirement for Validity Claims in Psychotherapy Intervention Trials for Major Depressive Disorder

Douglas M. Berger, M.D., Ph.D., Tokyo, Japan

The validity of Cognitive-Behavioral Therapy (CBT) efficacy for Major Depressive Disorder (MDD) is widely accepted and is based largely on clinical intervention studies of CBT in MDD. However, clinical trials for CBT can not be carried-out under double blind conditions as would be required of pharmacotherapy (or other somatic therapies), thus the rigor of CBT interventional studies is quite different from those modalities that can be studied under double blinded conditions.1,2 Treatment allocation can not be blinded in CBT studies because the subjects have to actively participate in cognitive restructuring tasks. More than just saying a study was “blinded”, absolute concealment of what treatment was allocated is crucial in order to avoid bias.3

CBT trials are sometimes stated to be,“single-blind” because the persons who rate the symptoms that subjects report are blind to the treatment allocation of the subject. The term “single-blind”, however, should be used with caution as single-blind is defined as the condition when subjects are blind, not the raters.4 Blind (or “masked) raters only record whatever bias may be in the subjective reports of the subjects that can be swayed by the unblinded conditions. Emphasizing that raters are blind in a CBT study can distract from the issue that subjects and treaters are not blind.

Allocation concealment is crucial for indications with subjective outcomes as in MDD.3 During a clinical trial, subjects with MDD report changes in the severity of subjective depressive symptoms that may be influenced by an expectation or hope for improvement.3 Only interventional studies for indications with objective endpoints can ignore potential bias from lack of blinding. For example, mortality rates, MI incidence, stroke, etc. where random error is small.1 In this line, a meta analysis of CBT trials that controlled for blinding found treatment effects to be small in MDD.5

However, studies continue to report positive results of unblinded trials without voicing strong caution on the validity of the results. Hollon et al. in the October 2014 issue of JAMA Psychiatry compared an Antidepressant medication only arm with a combined cognitive therapy/antidepressant arm.6 All the subjects who received antidepressants did so under unblinded conditions. The cognitive therapy subjects and their treaters were also unblind to the treatment given. The study concluded that the cognitive therapy/antidepressant combination enhanced the rate of recovery compared with antidepressant alone, and that the magnitude of this increment nearly doubled for patients with more severe depression with little evidence of benefit for patients with less severe MDD. Only one line at the end of the discussion noted the unblinded conditions could be a limitation.

An alternative conclusion could just as easily be that patients with greater severity MDD may have included more patients with a medication-responsive depression.7 For those subjects with greater severity, there could have been both antidepressant efficacy as well as more hope and expectation in the group who knew they had received combined cognitive therapy/medication leading to an erroneous conclusion of greater efficacy for the combined group. A large N as in this study is not necessarily a sign of robust results. A large N can create a significant finding on statistical testing as a small amount of bias in the subjects adds-up. Our alternative conclusion may also be incorrect, the important issue is that the lack of allocation concealment in the study design does not allow any valid conclusion to be made either way. The antidepressant in each arm of the study provides the same amount of hope and expectation; the CBT arm has the added potential for bias from hope and expectation.

In addition, mixing and comparing antidepressants that have market approval based on double-blinded placebo controlled outcome research with CBT, heretofore never studied under double-, or single-blinded conditions, in the same unblinded study is a serious problem. Handicapping one intervention group (antidepressants without the double-blinded placebo control needed for proof of efficacy), while providing advantage to another intervention group (unblinded CBT with no psychotherapy placebo which allows bias in one arm) which is then mixed with the handicapped group, confounds the study conditions and invalidates the design logic of a clinical trial.

Interventional studies for somatic therapies such as medications may also have elements of allocation non-concealment requiring caution in their interpretation. Exit analyses should be done and the results of any study in an indication with subjective endpoints such as MDD that has evidence of unblinding should be suspect to have bias. Whether medication, psychotherapy, or other intervention, no valid scientific assessment of efficacy can be made if a hurdle such as double blinding in the study design of an indication with subjective endpoints is not rigorously implemented.

Authors must state clearly when an intervention can not be studied with rigor, and conclusions need to be given with great caution when studies with subjective endpoints are unblinded. There is no regulatory authority like the FDA to review and approve a psychotherapeutic intervention for MDD, so that both professionals and society at large alike are dependent on the sound-bite conclusions made by authors and commentators on the results reported, many who are not disinterested to the topic studied.

The critical problem of the inability to double blind CBT clinical trials for MDD requires further evaluation by research groups who do not have a vested interest in CBT or related therapies. The validity of CBT (and its derivatives such as dialectical behavioral therapy) for indications other than MDD is part of a larger problem in the outcome studies for these interventions. Outcome studies for CBT in these other indications also require disinterested analysis and discussion on the crucial problem of allocation concealment when studying psychiatric conditions, the vast majority of which have subjective endpoints in their efficacy evaluations.

References
1. Piantadosi S. Clinical Trials: A Methodologic Perspective, Second Edition. New York: Wiley-Interscience; 2005.

2. 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).

3. Schulz, KF, Grimes DA, Blinding in Randomized Trials: hiding who got what. The Lancet, 2002:359; 696-700. February 23, 2002.

4. Friedman LM, Furgerg CD, DeMets DL. Fundamentals of Clinical Trials, Third Edition. Springer; 1998.

5. Lynch D, Laws, KR, McKenna PJ. Cognitive behavioral therapy for major psychiatric disorder: does it really work? A meta-analytical review of well-controlled trials. Psychol Med. 2010;40:9-24.

6. Hollon, SD, DeRubeis, RJ, Fawcett, J, et al., Effect of Cognitive Therapy With Antidepressant Medications vs Antidepressants Alone on the Rate of Recovery in Major Depressive Disorder A Randomized Clinical Trial. JAMA Psychiatry. 2014;71(10):1157-1164. doi:10.1001/jamapsychiatry.2014.1054.

7. 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.

This article was later published here in a slightly modified version:

Berger D. Double blinding requirement for validity claims in cognitive-behavioral therapy intervention trials for major depressive disorder [version 1; referees: 1 approved], F1000Research 2015, 4:639 (doi: 10.12688/f1000research.6954.1)

We would also like to note here this newer article where Stephan Heckers is again Editor-in-Chief of a journal that his faculty Steven D. Hollon has published an article as second author, another example of conflict of interest and nepotism at Vanderbilt University Dept. of Psychiatry:

Erica S. Weitz, MA; Steven D. Hollon, PhD; et al. Baseline Depression Severity as Moderator of Depression Outcomes Between Cognitive Behavioral Therapy vs Pharmacotherapy. An Individual Patient Data Meta-analysis. JAMA Psychiatry. Published online September 23, 2015. doi:10.1001/jamapsychiatry. 2015.1516.

Besides the conflict of interest issue, the logic of this meta-analysis that looked at studies that compared antidepressants with or without blinding, with unblinded CBT is not scientifically valid. Blinding antidepressants handicap them when compared to unblinded CBT, and unblinded antidepressants inmpairs their ability to show efficacy when blinded compared with placebo (and without a confounding unblinded CBT arm as in this study), which is another kind of handicap. Double-blind conditions are absolutely necessary in order to filter bias from the results of these outcome studies where the evaluation endpoints are subjective as they are in subjects with depression.