Psychedelics: Future Therapeutics in Major Depression?

Major depressive disorder, including treatment-resistant depression, affects many people and carries high costs. About 30% of patients do not respond to first-line antidepressants like SSRIs and SNRIs. Research over the past two decades has produced two new drug classes: typical serotonergic psychedelics (psilocybin, ayahuasca) and atypical glutamatergic/NMDA psychedelics (ketamine, esketamine). Both provide fast, long-lasting antidepressant effects that outlast the drug's presence in the brain, though they cause short-lived side effects like psychotomimetic or dissociative symptoms. These developments represent a breakthrough, but the acute effects complicate blinded studies and placebo control. The field is now advancing new research methods and exploring underlying mechanisms.

Study at a glance

Abstract

Major depressive disorder (MDD), including treatment-resistant depression (TRD), is a highly prevalent psychiatric disorder. MDD is associated with severe suffering, burden and large economical costs. Although various conventional antidepressant treatments are available, a large portion of depressed people does not or not adequately respond to the first-line treatments (mostly SSRIs and SNRIs) and a substantial part (ca, 30%) completely fails to respond, leading to TRD. The last two decades of intense research into new drugs for major depression and TRD has led to two lines of development, namely, Typical (or serotonergic) psychedelics (psilocybin, ayahuasca) and atypical (glutamatergic/NMDA) psychedelics (ketamine, esketamine). Both approaches, via a different entrance mechanism, have a fast (immediate) onset, combined with a long-lasting antidepressant action, which cannot be explained by long-term biological presence of the drug in the brain. The psychedelic drugs acutely initiate short-lasting CNS-induced side effects but also lead to activation of downstream cortical processes that underlie the 'lasting' antidepressant effects. In the present chapter, the clinical developments that have led to the marketing of psilocybin and esketamine for major depression disorders has been described. The emergence of fast onset antidepressants for major depression and treatment-resistant depression is a huge step forward in treating major psychiatric disorders. The acute psychotomimetic (psilocybin) or dissociative (esketamine) effects heavily interfere with performing of 'blind' studies, making proper placebo effects challenging. The development of new medicines that are acutely effective in depressive disorders is, however, a real breakthrough in psychiatry, but has also led to a spur of new research activities into new mechanisms involved, and also in developing new research techniques involved in designing proper research methodologies to bring this exciting field into adulthood.