Comparative Efficacy and Functional Outcomes of Psychedelic-Assisted Therapies in Treatment-Resistant Depression: A Systematic Review of Recent Clinical Trials

Author: mycolabadmin
4/18/2025
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Summary

This systematic review examines how psychedelic-assisted therapies like ketamine and psilocybin help people with severe, treatment-resistant depression that doesn’t respond to standard antidepressants. The analysis of 10 recent clinical trials shows these therapies work quickly, often providing symptom relief within days rather than weeks, and importantly, they also help people return to work and daily functioning. These treatments are generally well-tolerated with minimal cognitive side effects, suggesting they could become important new options for patients who haven’t benefited from conventional depression treatments.

Background

Treatment-resistant depression (TRD) affects approximately 30% of individuals with major depressive disorder who fail to respond to standard antidepressant therapies. Conventional treatment modalities including pharmacotherapy, psychotherapy, and electroconvulsive therapy often yield limited results in this population. Psychedelic-assisted therapies, particularly ketamine, esketamine, and psilocybin, have emerged as promising alternatives with distinct mechanisms of action.

Objective

This systematic review aimed to assess and compare the comparative efficacy and functional outcomes of various psychedelic-assisted therapies in the management of treatment-resistant depression. The study sought to synthesize evidence on clinical efficacy and functional improvements across ketamine, esketamine, and psilocybin interventions in TRD populations.

Results

Ten RCTs were included, encompassing diverse psychedelic-assisted interventions with sample sizes ranging from 61 to 884 participants. Most studies demonstrated significant reductions in depressive symptom severity, with oral and intranasal esketamine and high-dose psilocybin showing sustained antidepressant effects. Functional improvements in workplace productivity and cognitive stability were reported in select trials, notably those involving esketamine nasal spray.

Conclusion

This review affirms the growing clinical relevance of psychedelic-assisted therapies as promising interventions for treatment-resistant depression, offering rapid symptom relief and emerging benefits in functional and cognitive domains. These therapies represent viable alternatives or adjuncts to conventional treatments, with generally favorable safety profiles, supporting continued clinical adoption and investigation for psychiatric care integration.

Published in:Cureus,
Study Type:Systematic Review,
Source: PMID: 40385821, DOI: 10.7759/cureus.82532