A systematic review of five neuroimaging studies found that psilocybin therapy transiently increases global connectivity in major neural tracts and activates specific brain areas, and these changes are associated with antidepressant response in depressed patients. The pattern of functional brain changes resembles a 'brain reset' phenomenon and may serve as a predictor of psilocybin's antidepressant effects. Four of the studies were open-label, and one combined an open-label design with a randomized controlled trial. Three studies included psilocybin-assisted psychotherapy, and participants in most studies had treatment-resistant depression.
For 70 years depression treatment was limited by the monoamine hypothesis until the approval of the S-enantiomer of ketamine, an NMDA receptor blocker with rapid antidepressant and antisuicidal effects. Dextromethorphan, another NMDA receptor antagonist, has also been approved for depression in combination with bupropion. The GABA-A receptor modulator brexanolone has shown relatively rapid antidepressant efficacy. However, clinical utility is compromised by high drug costs, mandatory monitoring requirements, parenteral administration, lack of insurance coverage, COVID-19 effects on healthcare systems, and psychopharmacology training gaps. This narrative review analyzes the clinical pharmacology of recently approved antidepressants and barriers to bench-to-bedside translation. Overall, meaningful advances have not reached many depressed patients, including those with treatment-resistant depression who might benefit most.