Background: One-third of Veterans with major depressive disorder suffer from treatment-resistant depression (TRD). This is the first study to evaluate the long-term outcomes of psilocybin in Veterans with severe TRD.

Methods: This paper presents 12-month results from an open-label pilot study assessing the effects of 25 mg psilocybin in Veterans with severe TRD, defined as a major depressive episode failing to respond to ≥5 treatments, or lasting >2 years. 10 out of 15 participants completed the 12-month follow-up. Depression severity was measured by Montgomery-Åsberg Depression Rating scale (MADRS) at 6, 9, and 12 months posttreatment. Response was defined as ≥50 % reduction in MADRS, and remission as ≤10 MADRS score.

Results: Depression scores show significant reductions from baseline across all timepoints. However, there was an increase in MADRS scores from short-term timepoints (Weeks 3 and 12) to Month 12. Of 10 participants, at Month 6, 80 % met response and 50 % met remission criteria for the MADRS. At Month 9, acute responses began to wane. At Month 12, 40 % maintained response and 30 % maintained remission.

Limitations: Limitations include the small sample size and its uncontrolled, unblinded design.

Conclusions: In this first-of-kind study on long-term effects of psilocybin for Veterans with severe TRD, depression scores showed significant sustained reductions up to 12-months. However, the antidepressant effects began to wane at 6 months, and then more substantially after 9 months, although these increases in MADRS did not reach statistical significance. Further research is needed.

Trial registration: ClinicalTrials.gov Identifier: NCT04433858.

Keywords: Depression; Long-term outcomes; Psilocybin; Psychedelics; Treatment-resistant depression; Veterans.

Copyright © 2025. Published by Elsevier B.V.

背景： 三分之一患有重度抑郁症的退伍军人遭受治疗抵抗性抑郁（TRD）。这是首次评估在严重 TRD 的退伍军人中使用裸盖菇素长期效果的研究。

方法： 本文报告了一项开放标签试点研究的12个月结果，该研究评估了对≥5种治疗无效或持续时间超过两年的重大抑郁发作期的严重 TRD 退伍军人使用25毫克裸盖菇素的效果。在15名参与者中，有10人完成了12个月的随访。通过蒙哥马利-阿斯伯格抑郁量表（MADRS）测量了6、9和12个月时的抑郁症严重程度。反应定义为 MADRS 分数降低≥50%，缓解定义为 MADRS 分数≤10。

结果： 抑郁症评分在所有时间点上相对于基线均显示出显著下降，但在短期时间点（第3周和第12周）到第12个月时，MADRS 评分有所增加。在10名参与者中，在第6个月时，80% 的人达到了 MADRS 反应标准，50% 达到了缓解标准。在第9个月时，急性反应开始减弱。在第12个月时，40% 的人维持了反应状态，30% 维持了缓解状态。

局限性： 研究的局限性包括样本量小和未控制、未设盲的设计。

结论： 在这项首次针对长期使用裸盖菇素治疗严重 TRD 退伍军人效果的研究中，抑郁症评分显示，在12个月内有显著持续降低。然而，抗抑郁效果在6个月时开始减弱，并且在9个月后进一步减弱，尽管 MADRS 分数增加并未达到统计学意义。需要进行更多的研究。

试验注册： ClinicalTrials.gov 编号：NCT04433858。

关键词： 抑郁症；长期效果；裸盖菇素；致幻剂；治疗抵抗性抑郁；退伍军人。