Efficacy, Safety, and Tolerability of Psychedelics in Treatment-Resistant Depression (TRD).

About 30% of people with major depressive disorder do not respond to first-line treatment, leading to treatment-resistant depression (TRD), for which no consensus definition exists. Recent research has focused on two types of psychedelics: serotonergic (psilocybin, ayahuasca) and atypical glutamatergic (ketamine, esketamine). Both produce fast and long-lasting antidepressant effects that persist beyond the drug's presence in the body, suggesting downstream signaling cascades. Clinical development of psilocybin and esketamine for TRD is described, highlighting challenges with placebo due to psychotomimetic or dissociative effects. Intranasal esketamine has been approved for TRD, and psilocybin shows positive results. Adverse effects are generally acceptable. This development represents a breakthrough in psychiatry.

Study at a glance

Abstract

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, associated with substantial burden and large economical costs. Notwithstanding various conventional antidepressant treatment options, a large portion of depressed people (ca. 30%) fails to respond to first-line treatment, resulting in treatment-resistant depression (TRD). Although non-response to multiple antidepressant interventions is a common outcome, a consensus definition of TRD is not yet available. In practice, TRD is applied when two or more successive treatments with different antidepressants are not working. The last decade's intense research into new medicines for TRD has led to two developments, using typical or serotonergic (psilocybin, ayahuasca) and atypical (glutamatergic) psychedelics (ketamine, esketamine). Both approaches, although via different entrance mechanism, exhibit a fast onset but also long-lasting antidepressant effect far beyond the biological presence of the drug in the body, strongly indicating that downstream mechanisms activated by signaling cascades in the brain are involved. The present chapter describes the clinical development of psilocybin and esketamine for TRD and discusses the problems involved in the use of a proper placebo because of the psychotomimetic (psilocybin) or dissociative (ketamine) effects that interfere with performing "blind" studies. Nevertheless, intranasal esketamine was developed and approved for TRD, whereas psilocybin has shown positive results. Adverse effects and tolerability of both drugs in the dose ranges used are generally acceptable. The emergence of anti-TRD medicines for treatment of a very severe disease is a breakthrough in psychiatry.