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A renewed, ethical defense of placebo-controlled trials of new treatments for major depression and anxiety disorders
  1. B W Dunlop1,
  2. J Banja2
  1. 1
    Emory University School of Medicine, Atlanta, Georgia, USA
  2. 2
    Atlanta Clinical and Translational Science Institute, Emory University School of Medicine, Atlanta, Georgia, USA
  1. Boadie W Dunlop, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1256 Briarcliff Road NE, Building A, 3rd Floor, Atlanta, GA 30322, USA; bdunlop{at}


The use of placebo as a control condition in clinical trials of major depressive disorder and anxiety disorders continues to be an area of ethical concern. Typically, opponents of placebo controls argue that they violate the beneficent-based, “best proven diagnostic and therapeutic method” that the original Helsinki Declaration of 1964 famously asserted participants are owed. A more consequentialist, oppositional argument is that participants receiving placebo might suffer enormously by being deprived of their usual medication(s). Nevertheless, recent findings of potential for suicidality in young people treated with antidepressants, along with meta-analyses suggesting that antidepressants add no significant clinical benefit over placebos, warrant a re-evaluation of the arguments against placebo. Furthermore, the nature of placebo treatment in short-term clinical trials is often not well understood, and lack of understanding can foster opposition to it. This paper will show how scientific justifications for placebo use are morally relevant. The fundamental ethical importance of placebo controls is discussed in relation to several aspects of clinical trials, including detection of adverse events, accurate assessment of clinical benefit, advancing understanding of the heterogeneity of depression and anxiety disorders and respecting informed consent requirements. Prohibiting the use of placebo controls is morally concerning in that such prohibitions allow for the possibility of serious adverse public health consequences. Moral worries that research participants receiving placebo are being unduly jeopardised will be shown to be exaggerated, especially in relation to the net benefits for end-users to be gained from the quality of data resulting from using placebo controls.

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  • Funding: Dr Dunlop is supported (in part) by a K12 grant from the National Institutes of Health National Center for Research Resources, K12 RR 017643 and 1KL2RR025009. Dr Banja is supported in part by the Atlanta Clinical and Translational Science Institute award UL1RR025008 from the National Institutes of Health.

  • Competing interests: Dr Dunlop receives research support from AstraZeneca, GSK, Novartis, ONO Pharmaceuticals and Takeda. He has served as a consultant to BMS and Wyeth and has received honoraria from BMS. Dr Banja reports no competing interests.

  • Provenance and Peer review: Not commissioned; externally peer reviewed

  • i Studies using an active comparator with which physicians are well experienced will often yield adverse-event profiles among participants that are characteristic of the drug and easily recognised. For example, in the case of selective serotonin reuptake inhibitors (SSRIs), the standard response profile of early reduction in irritability is often accompanied by nausea, headache or sexual dysfunction—thus providing information that can easily unblind the researcher. Therefore, for an experimental medication for which the adverse-event data are relatively sparse, and with which the investigator has no previous experience, blinding is stronger when the comparison is with placebo than with an active comparator.

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