Serotonergic psychedelics are being reconsidered as potential treatments for major depressive disorder. A Canadian task force systematically reviewed clinical trials from 1990 to 2021 and found that only psilocybin and ayahuasca have been tested in contemporary studies. Two pilot studies of single-dose ayahuasca for treatment-resistant depression showed preliminary positive effects (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy for major depressive disorder showed superiority to waitlist controls and comparable efficacy and safety to escitalopram with supportive psychotherapy, with additional trials showing efficacy in cancer-related depression (Level 3 evidence).
Lithium and clozapine are the only two somatic treatments with high-quality evidence of reducing suicide risk, in mood disorders and schizophrenia respectively; stopping lithium increases that risk. Ketamine and esketamine may offer a small, immediate antisuicide effect, though a disproportionate number of suicides occurred in esketamine-treated subjects versus placebo (3 vs. 0 among over 3500 subjects), requiring ongoing evaluation. The evidence for electroconvulsive therapy's antisuicide effect is low-quality. Antidepressants' effect is unclear: direct evidence shows they may increase suicidal ideation and risk in young people over the short term, while indirect evidence suggests they reduce risk over the long term. Clinicians have an expanding pharmacopeia, but some agents may also increase suicidality under specific circumstances.