Introduction and objective:
Treatment-resistant depression (TRD) remains a major clinical challenge affecting patients who fail to respond to at least two adequate antidepressant trials. The development of rapid-acting interventions targeting non-monoaminergic pathways has introduced new therapeutic possibilities. The aim of the review is to critically examine intranasal esketamine and psilocybin-assisted psychotherapy in TRD, comparing their mechanisms of action, clinical efficacy, durability of response, and safety profiles

Review methods:
A narrative review method consisting of a literature review was conducted using PubMed and Google Scholar databases. Randomized controlled trials, phase II-IV clinical trials, systematic reviews, and meta-analyses published primarily within the last eight years were analyzed. Case reports and preclinical studies were excluded.

Brief description of the state of knowledge:
Esketamine, an NMDA receptor antagonist, has demonstrated rapid antidepressant effects within hours and has received regulatory approval for TRD. While effect sizes are generally modest, relapse prevention has been shown in maintenance trials. Psilocybin, a 5-HT2A receptor agonist administered within a structured psychotherapeutic framework, has shown promising antidepressant effects in early-phase trials, including a large phase IIb study, with sustained improvement following limited dosing. However, its evidence base remains constrained by methodological challenges and limited long-term data

Summary:
Both agents converge on neuroplasticity-related mechanisms yet differ substantially in clinical implementation. Esketamine is an approved rapid-acting option for TRD, whereas psilocybin remains investigational. Further adequately powered trials and long-term safety data are required to define their roles within evolving treatment paradigms.