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Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression

  • Andrew F. Leuchter (a1), Aimee M. Hunter (a1), Molly Tartter (a2) and Ian A. Cook (a3)



Pill-taking, expectations and therapeutic alliance may account for much of the benefit of medication and placebo treatment for major depressive disorder (MDD).


To examine the effects of medication, placebo and supportive care on treatment outcome, and the relationships of expectations and therapeutic alliance to improvement.


A total of 88 participants were randomised to 8 weeks of treatment with supportive care alone or combined with double-blind treatment with placebo or antidepressant medication. Expectations of medication effectiveness, general treatment effectiveness and therapeutic alliance were measured (trial registration at NCT00200902).


Medication or placebo plus supportive care were not significantly different but had significantly better outcome than supportive care alone. Therapeutic alliance predicted response to medication and placebo; expectations of medication effectiveness at enrolment predicted only placebo response.


Pill treatment yielded better outcome than supportive care alone. Medication expectations uniquely predicted placebo treatment outcome and were formed by time of enrolment, suggesting that they were shaped by prior experiences outside the clinical trial.

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Corresponding author

Andrew F. Leuchter, MD, Laboratory of Brain, Behavior, and Pharmacology, Semel Institute for Neuroscience and Human Behavior at UCLA, 760 Westwood Plaza, Los Angeles, CA 90024, USA. Email:


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Research support for this study was received from the National Center for Complementary and Alternative Medicine of the National Institutes of Health (grant number R01 AT002479), Eli Lilly and Company and Wyeth Pharmaceuticals (now a wholly owned subsidiary of Pfizer).

Declaration of interest

A.F.L, within the past 5 years, has received research support from the National Institutes of Health, Wyeth Pharmaceuticals, Novartis Pharmaceuticals, Seaside Therapeutics, Genentech, Shire Pharmaceuticals, Neuronetics, Eli Lilly and Company, and Neurosigma. He has served as a consultant to NeoSync Inc., Brain Cells, Inc., Taisho Pharmaceuticals, Eli Lilly and Company, and Aspect Medical Systems/Covidien. He is Chief Scientific Officer of Brain Biomarker Analytics LLC (BBA). He owns stock options in NeoSync, Inc. and has equity interest in BBA. I.A.C., within the past 5 years, has received research support from Aspect Medical Systems/Covidien, National Institutes of Health, Neuronetics and Shire; he has been on the speakers' bureau for Neuronetics and the Medical Education Speakers Network; he has been an advisor/consultant/reviewer for Allergan, Covidien, Pfizer, Neuronetics, NeuroSigma, NIH (ITVS), US Department of Defense, US Department of Justice, VA (DSMB); his biomedical intellectual property is assigned to the Regents of the University of California, and he owns stock options in NeuroSigma.



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Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression

  • Andrew F. Leuchter (a1), Aimee M. Hunter (a1), Molly Tartter (a2) and Ian A. Cook (a3)
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Response to Corbyn and Kripalani 02.24.15

Please see attachments for Author's Response, copyright transfer and publication agreements, and disclosure form.

Conflict of interest: Please see disclosure statement attached.

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Are conclusions overstated for placebo response?

Bryony R, Corbyn, Psychiatry Ct3
06 February 2015

We read Leuchter et al's study(1) with great interest. The implications of their research not only have the potential tofurther understanding of placebo responses in clinical trials, but also brings into question the pharmacological advantage of antidepressant medication over placebo in clinical outcomes for depression. Their findings warrant full evaluation so that they can be considered within thecontext of the wider research base. However, an accurate appraisal is currently limited by a lack of clarity in the methodology presented. We suggest several areas in which further clarification couldassist critical appraisal.

Firstly, the use of the HRSD as a measure of depression severity warrants discussion. A 2004 literature review failed to find evidence to support its use, describing it as irretrievably flawed. Interestingly, many scale items were not found to sufficiently contribute to the measure of depression severity.(2) Without a valid measure of severity, can we be assured that participants met criteria for at least moderate depressive symptoms at baseline? Any failure to exclude those with milder symptoms could also account for the similar outcomes demonstrated between pill-taking groups. NICE advocate for the avoidance of antidepressant prescription in those with less than moderate depressive symptoms, due to the poor risk benefit ratio.(3)

In terms of the study design, the sample size appears to be lower than one would anticipate. This is not helped by the significant loss to follow up of 24%. Given that the report does not reference a power calculation, are the authors able to provide clarity regarding their choice of sample size?

The process of recruitment also requires clarification. Recruitment via advertisement can be prone to selection bias and account for loss of external validity within studies.(4) We suggest that advertisement recruitment may have attracted participants particularly keen to seek active treatment, possibly in order to avoid health care expenditure. Of those recruited, it is understood that randomisation was undertaken. Further clarification regarding this process would be helpful.

It is understood that research co-ordinators were blinded during supportive care interactions. Double blinding is clearly essential in a study which involves a subjective outcome measure. Given that these research co-ordinators were often trained nurses, we raise the concern that they may have recognized relevant side effects and unintentionally deduced a participant's group assignment. With loss of their impartiality,clinicians form expectations and these have the power to significantly influence outcomes.(5) As trained nurses, it is also likely that their interactions may have provided therapeutic input aside from those considered to be consistent with 'supportive care'. Were certain professionals more likely to report improvements in the placebo group?

Of further interest, we cannot find evidence to rule out suicidal behaviour as another potential confounder in this study. Participants' response to antidepressant medication may have been influenced by differences in serotonergic functioning, which has been linked to having ahistory of suicidal acts.(6)

With the above concerns in mind, we suggest that further consideration of the risk of type II error may be of value. We would be interested in the extent to which the authors have explored the potential for type II error and welcome their response.

1. Leuchter A, Hunter A, Tartter M, Cook I. Role of pill-taking, expectation and therapeutic alliance in the placebo response in clinical trials for major depression. British Journal of Psychiatry 2014; 205: 443-449.

2 Bagby M, Ryder A, Schuller D, Marshall M. The Hamilton Depression Rating Scale: Has the gold standard become a lead weight? American psychiatric association 2014; 161: 2163-2177.

3 National Institute of Health and Care Excellence. Depression in adults: The treatment and management of depression in adults. National Institute of Health and Care Excellence, 2009.

4 Fransen G, van Marrewijk C, Mujakovic S, Muris J, Laheij R, Numans M et al. Pragmatic trials in primary care. Methodological challenges and solutions demonstrated by the DIAMOND-study. BMC Medical Research Methodology 2007; 7: 16.

5 Even C, Siobud-Dorocant E, Dardennes R. Critical approach to antidepressant trials. Blindness protection is necessary, feasible and measurable. British Journal Psychiatry 2000; 177: 47-51.

6 Sullivan G, Oquendo M, Milak M, Miller J, Burke A, Ogden R et al. Positron Emission Tomography Quantification of Serotonin1A Receptor Binding in Suicide Attempters With Major Depressive Disorder. JAMA Psychiatry, Published on line 30th December 2014.

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