by Daniel Kriegman, PhD

Stone, MB, Yaseen, ZS, Miller, BJ, Richardville, K., Kalaria, SN & Kirsch, I. (2022). Response to acute monotherapy for major depressive disorder in randomized, placebo-controlled trials submitted to the United States Food and Drug Administration: analysis of individual participant data. BMJ, 378(e067606).

According to a meta-analysis of over 73,000 subjects in drug trials submitted by drug developers to the FDA, 15% of subjects who received an antidepressant appeared to experience a clinically significant decrease in the standard depression score used in studies of research.

Of those who received placebos, 69% experienced a 9-point decrease in their depression scores, which is a small “non-specific” response on this 52-point scale. An additional 10% of those who received placebos experienced a clinically significant “significant response” (a 16-point decrease). Of those who received the drugs, 25% had the big response. Thus, there was a 15% increase in significant responses (in about one in seven subjects) that appeared to be due to the drug.

The additional relief mechanism over the placebo effect for people with a large decrease in depression scores may have been the reduction in their reactivity to their worries and concerns and/or the effect of a psychoactive placebo. 15% of participants in drug trials may have benefited from drug-induced “responsiveness reduction” and/or the added impact of a psychoactive placebo which doubled the mean decrease in depression scores (eight points) produced by placebos alone.

As we can see from the graph, half of the large decrease in depression score (about eight points, which would not be considered a definite clinical improvement) was seen in the average subject who took a placebo. So, for those who experienced a “significant response,” their response was twice the average placebo effect. Even though the authors noted that half of this 16-point reduction was present in the mean placebo response, in practice any response seen after drug administration tends to be attributed to the drug. This misattribution of the total impact to the drug tends to occur despite the fact that “the power of suggestion” (the ordinary placebo alone) produced the same “great response” 40% as often as the drug. There was no comparison with a psychoactive a placebo, which we can be sure would produce the greatest benefit occasionally seen with the drug even more frequently.

Consider that, from the prescriber’s point of view, 25% of patients will show marked improvement. The prescriber’s experience, however, provides no information that would indicate that 10% would have had the same improvement with a placebo. Additionally, an additional 63%, on average, will appear to have a non-specific reduction (meaning it is somewhat positive but of uncertain clinical significance) in their depression scores. In clinical practice, these patients would probably appear unchanged or even slightly improved, although again the prescriber would have no way of knowing that an even larger group of patients (69%) would have had the same response if they had prescribed a placebo.


Mad in America hosts the blogs of a diverse group of writers. These posts are designed to serve as a public forum for discussion – broadly defined – about psychiatry and its treatments. The opinions expressed are those of the authors.