A renewed, ethical defense of placebo-controlled trials of new treatments for major depression and anxiety disorders

Abstract

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.

Figure 1

Equivalency trial comparing a proven antidepressant (a selective serotonin reuptake inhibitor; SSRI) versus an investigational drug that acts through glutamate mechanisms (GLU-drug). (A) The sample of patients entering the study. Each octagon represents one person with depression. For simplicity, the figure supposes that there are two biological subtypes of depression (which cannot be clinically separated by any existing test): one due to altered serotonin signalling, identified by an “S” in the octagon, the other due to disrupted glutamate signaling, marked by a “G” in the octagon. Assume the serotonin form of depression is twice as common as the glutamate form. Also assume that SSRIs are fully effective in treating serotonin depressions and the GLU-drug is fully effective in treating glutamate depressions. (B) Through randomisation, equal proportions of each subtype of depression are assigned to treatment with the two drugs. (C) After 8 weeks of treatment, all serotonin-type depressions treated with SSRI have responded, and all glutamate-type depressions treated with GLU-drug have responded. Because the serotonin form of depression is more common than the glutamate form, there is a higher response rate in the SSRI treatment arm than the GLU-drug treatment arm. The conclusion from this equivalency trial design would be that the GLU-drug was ineffective, and it would not be approved, even though it is the better drug for the minority of patients who have the less common biological subtype of depression.