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.
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.