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This study evaluated the cost-effectiveness of PAT as a third-line treatment for major depressive disorder compared to standard of care (SOC). We used an individual-level, probabilistic simulation model that portrays representative US adults with TRD who receive SOC (pharmacotherapy, psychotherapy, electroconvulsive therapy, and esketamine nasal spray) and PAT over 12 months. We assumed the total cost of PAT was $5000, which we varied in sensitivity analyses ($3000\u201320,000). We calculated total costs, health effects (in terms of quality-adjusted life years [QALYs] gained), and incremental cost-effectiveness ratio (ICER) from limited healthcare and societal perspectives. PAT leads to an additional 0.031 QALYs and $3639 costs compared to SOC over 12 months, giving an ICER of $117,517 per QALY gained from a limited healthcare perspective. Using a $150,000 cost-effectiveness threshold, PAT had a 75% probability of being the cost-effective choice, and it was associated with a lower expected loss than SOC ($301 vs. $1307). Results were sensitive to uncertainty in model parameters, particularly the cost of PAT. PAT had a 1% probability of being cost-effective when its overall costs were $10,000 and 95% when its costs were $3000. This cost-effectiveness analysis found that when its costs are $5000 or less, PAT may offer economic value compared to available TRD treatments. Future studies can explore ways to reduce the cost of PAT and to understand its long-term effectiveness in maintaining remission and reducing the risk of relapse.<\/jats:p>","DOI":"10.1038\/s41398-025-03556-4","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T16:58:47Z","timestamp":1756486727000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Psilocybin-assisted therapy for treatment-resistant depression in the US: a model-based cost-effectiveness analysis"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4903-870X","authenticated-orcid":false,"given":"Anton L. 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