EARLY RESPONSE TO PSILOCYBIN IN ADULTS WITH TREATMENT-RESISTANT DEPRESSION AS A PREDICTOR FOR ANTIDEPRESSANT EFFICACY

Background

Psilocybin-assisted psychotherapy (PAP) has emerged as a novel intervention for treatment-resistant depression (TRD). TRD is associated with a lower probability of achieving remission with conventional antidepressant treatments, decreased quality of life, and increased risk of suicidality and all-cause mortality. Early symptom improvement with conventional antidepressants is a strong predictor of antidepressant efficacy, however, the predictive utility of early improvements with psilocybin has not been evaluated.

Objective

To evaluate if 24-hour post-treatment effects of psilocybin on depression symptoms are a predictor of changes in depressive symptoms at 2-8 weeks post-dose in adults with TRD.

Methods

Participants (n=30) received one 25 mg dose of psilocybin with supportive psychotherapy (psilocybin-assisted psychotherapy [PAP]) as part of a phase 2 randomized, waitlist-controlled, open-label clinical trial (NCT0502946). The primary outcome of the trial was the change in depression severity using the Montgomery-Åsberg Depression Rating Scale (MADRS) over the Week 2 primary endpoint period and up to 8 weeks of follow-up post-dose. Linear regression analyses were used to determine if participants who had reductions in depression symptoms at Day 1 post-dose (“early responders”) were more likely to have depressive symptom reductions at weeks 2, 4, 6 and 8.

Results

The linear regressions indicate that change in MADRS Day 1 post-dose significantly predicted change in MADRS at week 2, F(2, 26)=14.789, p < 0.001, week 4, F(2, 25)=16.867, p < 0.001, week 6, F(2, 23)=6.878, p=0.005 and week 8, F(2, 23) = 8.277, p=0.002. Large effect sizes were observed when converting the adjusted R2 value to Cohen’s f2 for Day 1 change predicting change in MADRS at weeks 2 (R2=0.496), 4(R2=0.540), 6, (R2=0.320) and 8 (R2=0.368). The beta coefficient for change in MADRS score at Day 1 as a predictor of change at subsequent weeks was as follows: week 2, 0.765 (p < 0.001), week 4, 0.797 (p < 0.001), week 6, 0.639 (p=0.001) and week 8, 0.680 (p < 0.001). In total, 25 out of 30 (83.3%) participants had a lower MADRS score at Day 1 post-dose compared to Baseline with a mean reduction of 35.9% (-11.21). Five (16.7%) participants had an increase in their MADRS scores from Baseline to Day 1, and did not have marked improvement in their MADRS thereafter. Baseline MADRS score did not significantly predict change in MADRS score at weeks 2-8. Change in MADRS at Day 1 was predictive of change in MADRS from weeks 2-8 when controlling for sex and age as covariates.

Conclusion

Participants who had a rapid improvement in depressive symptoms the day after receiving psilocybin were more likely to have continued antidepressant benefit after 2-8 weeks. These findings enhance our understanding of the clinical characteristics associated with “early responders” to psilocybin. The ability to communicate to patients that early symptom improvement is associated with antidepressant benefits may enhance expectancy effects and help clinicians evaluate treatment trajectories. Further research is needed to explore the underlying pathophysiological mechanisms related to early antidepressant benefit to psilocybin. Future Directions: Building on these findings, data from an ongoing federally funded, tripleblind, randomized, placebo-controlled trial (NCT06341426) will provide a larger, wellcontrolled sample (n=90) to evaluate how early changes in depression symptoms can predict more prolonged antidepressant effects with 6-months of follow-up.