Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression (EPIsoDE): 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial

Of 144 randomised participants, 142 received at least one intervention dose and post-treatment assessment, and 126 completed at least one six- or twelve-month follow-up and were included in the follow-up analyses. Baseline characteristics were broadly balanced across groups. Mean age was 42.4 years, 41% were female, and the sample was reported as 98% white. By twelve months, 40 participants (32%) had started antidepressant pharmacotherapy, 32 (25%) had used a classical psychedelic, and 86 (68%) had attended the integration group at least once. On the primary outcome, HAMD17 scores improved significantly over time across groups. The estimated mean change from baseline was -7.93 points at six months and -7.74 points at twelve months, both with adjusted p<0.0001. There were no significant differences between treatment groups. When follow-up antidepressant and psychedelic use were added to the model, the pattern remained essentially unchanged. Antidepressant pharmacotherapy during follow-up was associated with worse HAMD17 outcomes (β=3.79, 95% CI 1.98 to 5.60), whereas psychedelic use was not clearly associated with outcome. Secondary BDI-II results were consistent with the clinician-rated findings. Mean change from baseline was -9.51 points at six months and -11.11 points at twelve months, both significant, with no significant group differences. In models adjusting for follow-up drug use, the improvements remained significant and the between-group pattern was again null. Logistic regression showed no significant between-group differences in response or sustained response at either follow-up. Remission data were described but not emphasised as showing clear group differences. Post-hoc analyses suggested larger and more consistent HAMD17 reductions in males. Suicidal behaviours during follow-up were uncommon: two events at six months and four at twelve months, mostly preparatory actions, with one suicide attempt. Suicidal ideation on the CSSRS did not change clearly from baseline, while HAMD item 3 suggested a strong anti-suicidal effect at all post-baseline assessments.

Mertens and colleagues interpret the findings as showing stable and clinically meaningful antidepressant benefit lasting up to twelve months after one or two 25 mg psilocybin doses with adjunct psychotherapy in TRD. They describe the average HAMD17 improvement of roughly 8 points and the response rates at follow-up as evidence of durable benefit, while noting that the observational design means the results should be interpreted cautiously. The authors state that there was no clear evidence that a second 25 mg dose added benefit over regimens that included only one 25 mg dose, although they note that the 25 mg-25 mg group showed numerically higher response rates and that retreatment remains a plausible hypothesis for future study. They say the BDI-II findings aligned with the clinician-rated results, supporting a consistent antidepressant effect across measurement types. They also argue that spontaneous recovery is unlikely to fully explain the findings, given the chronicity of TRD, although they acknowledge that it cannot be ruled out in a naturalistic follow-up without a control condition. In comparing their results with earlier studies, the authors suggest that long-term outcomes here were more modest than those reported in some major depression studies, which they attribute partly to the TRD population and to design differences such as enriched follow-up in other work. They suggest that the durability of benefit may relate to extended psychotherapeutic support, including preparatory, dosing, integration, and post-trial group sessions. They also note that antidepressant pharmacotherapy after the trial was associated with poorer outcomes, which they interpret as likely reflecting greater residual illness among those needing medication again, and that post-trial psychedelic use was not associated with better depression outcomes. The paper highlights several limitations: the psychotherapeutic component was not experimentally separated from psilocybin, so the relative contribution of drug versus psychotherapy is unknown; follow-up was naturalistic and lacked a placebo arm; some participants were unblinded during follow-up; other therapies were not systematically captured; the sample was relatively homogeneous and potentially self-selected; and the study was not powered to test all follow-up comparisons. The authors also note that new adverse events were not systematically collected during follow-up, limiting conclusions about long-term safety. They argue that future research should use larger head-to-head trials, examine retreatment, compare dosing and psychotherapy approaches, and include cost-effectiveness work if psilocybin-assisted therapy is to be evaluated for implementation in healthcare systems.

The authors conclude that this naturalistic follow-up provides the first demonstration of sustained antidepressant efficacy of 25 mg psilocybin with adjunct psychotherapy over twelve months in a large TRD cohort. They say the findings support the clinical potential of one or two doses while also showing the need for better methods to evaluate long-term outcomes of psychedelic therapies. They further suggest that, if confirmed, psilocybin with psychotherapy could represent a shift towards an integrated pharmacological-psychotherapeutic model of care rather than chronic symptom management alone.