A systematic review by the Canadian Network for Mood and Anxiety Treatments evaluated evidence for racemic ketamine in treatment-resistant depression. Single intravenous infusions have Level 1 evidence for efficacy in adults, while multiple or maintenance infusions have only Level 3 evidence. Adverse events include dissociative symptoms and hypertension. Non-IV formulations have Level 3 or 4 evidence. Single-dose IV racemic ketamine is a third-line recommendation; repeated use requires careful case-by-case risk-benefit assessment. Oral and other formulations should be limited to specialists with ketamine expertise at tertiary centers due to limited evidence and risk of misuse.
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).
Depression is the most common and disabling mood state in bipolar disorder, yet few effective treatments exist. This review covers emerging therapies, including new atypical antipsychotics lumateperone and cariprazine, which have shown efficacy in large placebo-controlled trials. Non-racemic amisulpride showed potential in one trial needing replication. Intravenous ketamine demonstrated rapid antidepressant and anti-suicidal effects after a single infusion in three small trials. Anti-inflammatory and mitochondrial modulators have inconsistent evidence. Zuranolone, psilocybin, and cannabidiol lack adequately powered trials. While novel agents are on the horizon, further validation and study of patient subgroups are needed.
A living systematic review with meta-analysis examined the efficacy, safety, and all-cause discontinuation of serotonergic psychedelics and MDMA for treating mental disorders. The review found that these substances show promise in reducing symptoms of conditions such as depression, anxiety, and post-traumatic stress disorder, with some evidence supporting their therapeutic potential. However, the authors note that the overall quality of evidence is limited by small sample sizes, short follow-up periods, and methodological concerns. Safety profiles varied, with most adverse events being mild to moderate, though serious adverse events were reported in some studies. The review emphasizes the need for larger, more rigorous trials to confirm these findings.