The October edition of the Journal of World Psychiatry, the 3rd ranked journal of Psychiatry, will publish a reanalysis of antidepressant efficacy versus placebo in major depression. When the researchers, Arif Khan and Walter Brown, analyzed the data from the FDA archives for antidepressants approved between 1985 and 1997, “it was evident that the conventional wisdom of 70% response with antidepressants was at best an overestimate.” In fact, “the magnitude of symptom reduction was about 40% with antidepressants,” compared to “about 30% with placebo.”

“It quickly became apparent that many of the assumptions about the relative potency of antidepressants compared to placebo were not based on data from the contemporary trials but from an earlier era,” they wrote.

The researchers also compared clinical trial data about antidepressant effectiveness in major depression from non-pharmaceutical industry funded sources and industry trials submitted to the FDA. They did not, however, account for financial conflicts of interest among the authors of the “non-pharmaceutical industry” trials.

Nonetheless, the magnitude of symptom reduction for those in the placebo group was found to be higher in the “non-industry” trials. This is an important finding as a lower response to placebo in critical registration trials could inflate the drugs perceived efficacy.

When the researchers examined the difference in study designs between “non-industry” trials, they made another interesting discovery. In trials where the investigators and their staff were aware of the plan and the expectations of the study, the magnitude of symptom reduction “followed the pattern of accepted expectations.”

“Clearly, investigator and rater bias influences the magnitude of symptom reduction with all treatments, whether they are approved treatments, active controls, passive controls, sham treatments, treatment as usual, waiting list, or placebo,” they wrote.

When investigators remained “blinded” to the design and expectations of the study, however, “the symptom reduction with each treatment was of smaller magnitude and the differences among the various treatments and controls were also smaller.” In fact, under these circumstances, the depressed patients, no matter what treatment group they were in, reported symptom reductions that were not significantly different from placebo.

“In other words, when the level of blinding was high, and it was difficult for the investigators, their staff and depressed patients to guess treatment assignment, the differences between these treatments, controls, and placebo became quite small.”

The researchers conclude: “The effect size of current antidepressant trials that include patients with major depressive episode is approximately 0.30 (modest), and this fact needs to be heeded for future antidepressant trials.”

In a commentary to appear in the same journal, MIA author Joanna Moncrieff challenges that there are “no grounds to believe” that these drugs “have specific effects that would justify their classification as ‘antidepressants’.” She points out that the sedative effects of these drugs on their own are likely to have an impact on depression scales. For example, “changes in sleep alone can account for up to 6 points on the Hamilton Rating Scale for Depression.” But that does not necessarily mean that the drugs specifically target the symptoms of depression.

She also notes that the effects of the drugs can alert the research subjects that they are in an active treatment group, which “may create or exaggerate a difference between antidepressants and placebo.” “Unless the psychoactive effects of antidepressants are somehow discounted,” she writes, “differences between antidepressants and placebo cannot be interpreted as providing evidence that those drugs have a specific ‘antidepressant’ effect.”

Moncrieff concludes: “We need to recognize that antidepressants are psychoactive substances, we need more data on the nature of the varied psychoactive effects they produce, and we need to explore whether giving drugs that produce an artificially altered emotional state is a useful and acceptable intervention for people with depression.”

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Khan, A., & Brown, W. A. (2015). Antidepressants versus placebo in major depression: an overview. World Psychiatry, 14(3), 294-300. (Abstract)

Moncrieff, J. (2015). Antidepressants: misnamed and misrepresented. World Psychiatry, 14(3), 302-303. (Abstract)