Sex-Specific Effects of Psilocybin Versus Escitalopram on Anxiety and Anhedonia: A Bayesian Reanalysis of Antidepressant Treatment Outcomes

Major depressive disorder is described as a common and disabling condition with substantial sex differences in prevalence, symptom expression, and clinical course. The authors note that women are often underrepresented in antidepressant and psychedelic trials, and that earlier studies have rarely examined whether treatment responses differ by sex. They also argue that this matters because psilocybin and escitalopram act on the serotonin system through different mechanisms, and ovarian hormones may influence serotonergic signalling, stress responsivity, and antidepressant effects. Frick and colleagues therefore set out to reanalyse data from a randomised controlled trial comparing psilocybin with escitalopram in people with moderate-to-severe major depressive disorder, focusing on whether sex-by-treatment interactions were present across several psychological domains. Their aim was to test whether men and women differed in post-treatment outcomes for depression, anxiety, anhedonia, thought suppression, well-being, and sexual dysfunction, and whether any differences appeared clinically meaningful. They frame the work as a retrospective Bayesian reanalysis intended to generate more nuanced and conservative evidence from a small existing trial.

The paper is a retrospective Bayesian reanalysis of a six-week, double-blind randomised controlled trial in adults with moderate-to-severe major depressive disorder. Fifty-nine participants were included, of whom 20 were female; 30 were allocated to psilocybin and 29 to escitalopram. The authors state that participants met a depression severity threshold at entry and that all provided written informed consent for the original trial. Because this was a secondary analysis of previously collected data, separate consent for the reanalysis was not required. The original intervention involved two dosing visits spaced three weeks apart. Participants in the psilocybin group received 25 mg psilocybin, while those in the escitalopram group received 1 mg psilocybin as an active low-dose control intended to preserve expectancy and procedural similarity. Between dosing sessions, participants took daily oral capsules, with the number increased from one to two after three weeks. Trained clinicians provided psychological support before, during, and after dosing, including integration therapy at intermediate visits, and optional follow-up support was available after the final visit. Outcomes were assessed at baseline and after six weeks using validated scales for depressive symptoms (MADRS, QIDS-SR-16, BDI), anxiety (STAI), anhedonia (SHAPS), thought suppression (WBSI), and well-being (WEMWBS). Sexual dysfunction was measured with PRSexDQ-SALSEX only at the six-week follow-up, so it was analysed separately as an ordinal outcome. The main continuous outcomes were modelled as post-treatment scores adjusted for baseline severity. For the seven continuous measures, the authors fitted Bayesian linear regression models with treatment condition, sex, and their interaction as predictors, along with baseline score as a covariate. They used sceptical priors that shrink estimates towards zero, and repeated the analyses with wider priors as a sensitivity analysis. Evidence was summarised with posterior means, 95% credible intervals, and Bayes factors for whether effects were non-zero, clinically meaningful, or negligible. The sexual dysfunction outcome was analysed using cumulative link ordinal regression, followed by within-arm Mann-Whitney U tests. Missing data were handled by complete case analysis, and participants were analysed according to their randomised assignment.

Across the depression scales, sex-related effects were small and uncertain. For MADRS, BDI, and QIDS-SR-16, the posterior estimates for female-versus-male differences within each treatment arm, and for the sex-by-treatment interactions, all had wide credible intervals that included zero. Bayes factors were generally weak or inconclusive, indicating no clear evidence for meaningful sex differences or for strict equivalence. The QIDS-SR-16 showed the most attenuated pattern of the three depression measures. The clearest finding was for anxiety. On the STAI, women in the psilocybin group showed substantially lower post-treatment anxiety than men, with a posterior mean female-male contrast of -10.5 and a 95% credible interval from -17.5 to -3.29. The corresponding contrast in the escitalopram group was smaller and uncertain, and the sex-by-treatment interaction also trended in the same direction. The Bayes factor suggested strong evidence that the female advantage under psilocybin exceeded a minimally clinically important difference. Anhedonia also showed a possible sex-related pattern, though less strongly than anxiety. On the SHAPS, women in the escitalopram group tended to have lower post-treatment anhedonia than men, with a posterior mean contrast of -2.36 and an upper credible limit touching zero. Under psilocybin, the sex difference was smaller and more uncertain. The interaction estimate suggested some difference between treatment arms in the size of the female-male contrast, but the evidence remained imprecise and did not establish a robust interaction. Thought suppression on the WBSI showed no meaningful sex-specific pattern. Female-male contrasts were small, credible intervals were wide, and Bayes factors were close to 1, indicating that the data were compatible with both small effects and practical equivalence. Well-being on the WEMWBS was numerically slightly higher in women across both treatment groups, but again the estimates were imprecise and the evidence was modest rather than definitive. The sensitivity analyses using wider priors produced very similar posterior estimates and did not change the qualitative interpretation. Depression, well-being, and thought suppression remained inconclusive, while the psilocybin-related female advantage in anxiety and the possible escitalopram-related female advantage in anhedonia persisted. For sexual dysfunction at six weeks, the descriptive distribution suggested lower severity in women than in men in both treatment arms, and lower severity overall in the psilocybin group than in the escitalopram group. In the escitalopram arm, 89% of women were classified as having no sexual dysfunction compared with 25% of men; in the psilocybin arm, 91% of women and 68% of men were classified as having no sexual dysfunction. Ordinal regression showed lower odds of more severe sexual dysfunction with psilocybin than with escitalopram and lower odds in women than in men, but the treatment-by-sex interaction was not significant. Within-arm testing found a significant sex difference in the escitalopram group, with men reporting greater sexual dysfunction than women, whereas no significant sex difference was detected in the psilocybin group.

The authors interpret the findings as evidence that sex-related variation in response to psilocybin and escitalopram may be domain-specific rather than broad and uniform across depressive symptoms. They emphasise two main patterns: women in the psilocybin arm had greater reductions in anxiety, and women in the escitalopram arm had greater reductions in anhedonia. By contrast, sex differences in overall depression severity, thought suppression, and well-being were small or uncertain. They also note that sexual dysfunction severity was lower in women than in men and lower overall in the psilocybin group, although this did not amount to a clear sex-by-treatment interaction. In discussing possible mechanisms, the authors suggest that ovarian hormones may help explain the anxiety finding with psilocybin, because estradiol and progesterone influence fear and stress circuitry, synaptic plasticity, and anxiety regulation. They also connect the escitalopram-related anhedonia finding to previous work suggesting that women may respond more favourably to SSRIs, potentially because of sex differences in serotonergic metabolism, transporter binding, and neurosteroid pathways such as allopregnanolone. These explanations are presented as speculative because the dataset contained no direct hormonal measures. The authors place their findings in the context of earlier research showing sex differences in depression prevalence, symptom profiles, and antidepressant response. They argue that the present results are consistent with the idea that psilocybin and escitalopram may differ in how they interact with sex-related biology, but that this is more apparent in specific symptom domains than in global depression scores. They also note that the QIDS-SR-16, which was the primary outcome in the original trial, showed little evidence of sex-related effects, and they suggest this may reflect the conservativeness of that measure in this small dataset. Several limitations are highlighted. The study was a secondary, retrospective analysis of a trial that was not designed or powered to test sex-by-treatment interactions, and the sample was small with relatively few women. The authors also lacked information on hormonal contraceptive use, menstrual cycle phase, premenstrual symptom worsening, and menopausal status, all of which could have influenced outcomes. They further note that the analysis relied only on questionnaire data and did not include biological or neurophysiological markers, so mechanistic explanations remain untested. As a result, they describe the findings as hypothesis-generating rather than confirmatory. For future work, the authors recommend larger, sex-balanced trials that incorporate hormone-related information and recruit women across different reproductive stages. They suggest that cycle-aware or hormone-informed designs could improve interpretation of psychedelic and SSRI treatment effects, reduce unexplained variability, and help distinguish biological sex effects from hormone-context effects. They also argue that mechanistic studies combining clinical outcomes with hormonal, neuroimaging, or other biological measures will be needed to clarify how serotonergic and stress-related pathways shape differential treatment response.