Is MDD the right target for early-stage psychedelic-assisted therapy trials?

Major depressive disorder (MDD) is a poor target for early psychedelic research aiming at FDA approval, according to this critique of a recent Phase II trial comparing psilocybin-assisted therapy with escitalopram. The psychiatric category of MDD is heterogeneous, vaguely defined, and overdiagnosed, making it difficult to detect a reliable signal with any intervention, especially in non-severe cases. Current rating scales like QIDS and HAM-D fail to capture functional status, quality of life, and well-being—outcomes more relevant to psychedelic interventions. Additionally, psychedelic experiences often foster acceptance or equanimity toward suffering, which may be orthogonal to symptom reduction as measured by these scales. The authors argue for alternative research directions.

Study at a glance

Abstract

Abstract The recently published Imperial College study of a Phase II, double-blind, randomized, controlled trial comparing psilocybin-assisted therapy to a six-week titration of escitalopram for Major Depressive Disorder (MDD) should raise concerns for this illness category as a target of early psychedelic research given a goal of FDA approval. There are three reasons why MDD is the wrong target at this stage of research development. Firstly, the psychiatric category of MDD is heterogeneous, vaguely-defined, and overdiagnosed in a way that will problematize finding a reliable signal with psychedelic interventions (or any intervention), particularly within non-severe cases. Secondly, current rating scales for MDD (QIDS used in the Imperial College trial, but also HAM-D) are limited in approximating the kinds of things we ultimately care most about with depressive states, namely functional status, quality of life, and well-being: measures that seem more salient for psychedelic interventions and which are not adequately captured by these rating scales used in a majority of clinical trials. And thirdly, there are inherent conflicts between psychiatric conceptualizations of MDD (and its symptom amelioration) and the kinds of perspectives on one’s suffering often occasioned by psychedelic experiences themselves: while these kinds of psychedelic-catalyzed openings may lead to a form of acceptance or equanimity with regards to one’s life circumstances this could be in many ways orthogonal to reductions in HAM-D scores. We argue that for these reasons MDD is a non-ideal target at this stage of the science and propose alternative directions.