A comparison between psilocybin and esketamine in treatment-resistant depression using number needed to treat (NNT): A systematic review
This systematic review (s=5) of randomised controlled trials (RCTs) compares oral psilocybin (25mg) and intranasal esketamine (56-84mg) with an oral antidepressant in adults with depression (TRD). The review showed significant depressive symptom reduction with psilocybin (Number Needed to Treat; NNT=5) and esketamine (NNT=7). Psilocybin has a Number Needed to Harm (NNH) of 5 for nausea, while esketamine induces mild side effects (NNH<10).
Authors
- Roger McIntyre
- Jonathan Rosenblat
- Shokouh Meshkat
Published
Abstract
Background
Inadequate outcomes with monoamine-based treatments in depressive disorders are common and provide the impetus for mechanistically-novel treatments. Esketamine is a proven treatment recently approved for adults with Treatment-Resistant Depression (TRD) while psilocybin is an investigational treatment. Translation of the clinical meaningfulness for these foregoing agents in adults with TRD is required. Herein we evaluate the Number Needed to Treat (NNT) and Harm (NNH) of esketamine and psilocybin in adults with TRD.
Methods
We conducted a systematic review of randomized controlled trials, comparing the clinical efficacy of oral psilocybin to the co-commencement of intranasal esketamine with an oral antidepressant in adults with TRD.
Results
25 mg psilocybin had a significant reduction in depressive symptoms at 21-days post-dose, the NNT was 5 [95 % CI = 3.1, 18.5]. Psilocybin-induced nausea had a significant NNH = 5. Fixed-dosed esketamine at 56 mg and 84 mg had a significant effect at 28-days post-dose, (NNT of 7 [95 % CI56mg = 3.5, 46.7], [95 % CI84mg = 3.6, 142.2]). Esketamine-induced headache, nausea, dizziness, and dissociation had NNHs <10.
Limitations
The preliminary results may only reflect a small portion of the patient population. These results require replication and longer term studies investigating maintenance therapy.
Conclusion
Relatively few pharmacologic agents are proven safe and effective in adults with TRD. NNT estimates for investigational psilocybin and esketamine in TRD indicate clinical meaningfulness. The NNH profile for both aforementioned agents is clinically acceptable. Our results underscore the clinical relevance of these treatment options in adults with TRD.
Research Summary of 'A comparison between psilocybin and esketamine in treatment-resistant depression using number needed to treat (NNT): A systematic review'
Introduction
Major Depressive Disorder (MDD) is common and often fails to respond to standard monoamine-based treatments, producing rates of treatment-resistant depression (TRD) estimated at 30–60%. Clinical definitions from regulatory agencies require failure of at least two adequate antidepressant trials for a diagnosis of TRD. Because TRD is associated with substantial disability and healthcare costs, there is interest in mechanistically novel treatments. Esketamine, an NMDA receptor antagonist, is an approved glutamate-based therapy for TRD, while psilocybin, a 5-HT2A agonist, is investigational. Preliminary studies suggest both agents produce rapid antidepressant effects that may converge on pathways involved in synaptogenesis and cellular plasticity (for example, BDNF/mTOR signalling), but direct head-to-head comparisons are lacking. Wong and colleagues set out to compare the clinical meaningfulness of psilocybin and esketamine for adults with TRD using Number Needed to Treat (NNT) and Number Needed to Harm (NNH) metrics. In the absence of randomized head-to-head trials, the authors performed a systematic review of randomized controlled trials (RCTs) that used the Montgomery–Åsberg Depression Rating Scale (MADRS) to quantify depressive symptoms, and then derived NNTs and NNHs from the included placebo-controlled studies to inform relative efficacy and tolerability.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Study Details
- Study Typemeta
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Wong, S., Kwan, A. T., Teopiz, K. M., Le, G. H., Meshkat, S., Ho, R., d'Andrea, G., Cao, B., Di Vincenzo, J. D., Rosenblat, J. D., & McIntyre, R. S. (2024). A comparison between psilocybin and esketamine in treatment-resistant depression using number needed to treat (NNT): A systematic review. Journal of Affective Disorders, 350, 698-705. https://doi.org/10.1016/j.jad.2024.01.142
References (6)
Papers cited by this study that are also in Blossom
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Chen, X., Hou, X., Bai, D. et al. · American Journal of Psychiatry (2019)
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)
Mcintyre, R. S., Rosenblat, J. D., Nemeroff, C. B. et al. · American Journal of Psychiatry (2021)
Moliner, R., Girych, M., Brunello, C. A. et al. · Nature Neuroscience (2023)
Nikolin, S., Rodgers, A., Schwaab, A. et al. · EClinicalMedicine (2023)
Cited By (4)
Papers in Blossom that reference this study
Roberts, C., Seynaeve, M., Ermakova, A. O. et al. · Journal of Psychopharmacology (2026)
Brudner, R. M., Kaczmarek, E., Blainey, M. G. et al. · Journal of Psychopharmacology (2025)
Chisamore, N., Kaczmarek, E. S., Doyle, Z. et al. · Canadian Journal of Psychiatry (2025)
Fountoulakis, K. N., Saitis, A., Schatzberg, A. F. · American Journal of Psychiatry (2025)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.