Trial of Psilocybin versus Escitalopram for Depression.

BACKGROUND: Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. METHODS: In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6. RESULTS: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were -8.0±1.0 points in the psilocybin group and -6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], -5.0 to 0.9) (P = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, -3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups. CONCLUSIONS: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London's Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.).

Personality change in a trial of psilocybin therapy v. escitalopram treatment for depression.

BACKGROUND: Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PT's therapeutic action. METHODS: In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up. RESULTS: PT was associated with decreases in neuroticism (B = -0.63), introversion (B = -0.38), disagreeableness (B = -0.47), impulsivity (B = -0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = -0.47) and disagreeableness (B = -0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (B = -0.38), disagreeableness (B = -0.26), impulsivity (B = -0.35), and increases in openness (B = 0.28) at week 6, with neuroticism (B = -0.46) remaining decreased at month 6. No significant between-condition differences were observed. CONCLUSIONS: Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.

ARC: a framework for access, reciprocity and conduct in psychedelic therapies.

The field of psychedelic assisted therapy (PAT) is growing at an unprecedented pace. The immense pressures this places on those working in this burgeoning field have already begun to raise important questions about risk and responsibility. It is imperative that the development of an ethical and equitable infrastructure for psychedelic care is prioritized to support this rapid expansion of PAT in research and clinical settings. Here we present Access, Reciprocity and Conduct (ARC); a framework for a culturally informed ethical infrastructure for ARC in psychedelic therapies. These three parallel yet interdependent pillars of ARC provide the bedrock for a sustainable psychedelic infrastructure which prioritized equal access to PAT for those in need of mental health treatment (Access), promotes the safety of those delivering and receiving PAT in clinical contexts (Conduct), and respects the traditional and spiritual uses of psychedelic medicines which often precede their clinical use (Reciprocity). In the development of ARC, we are taking a novel dual-phase co-design approach. The first phase involves co-development of an ethics statement for each arm with stakeholders from research, industry, therapy, community, and indigenous settings. A second phase will further disseminate the statements for collaborative review to a wider audience from these different stakeholder communities within the psychedelic therapy field to invite feedback and further refinement. By presenting ARC at this early stage, we hope to draw upon the collective wisdom of the wider psychedelic community and inspire the open dialogue and collaboration upon which the process of co-design depends. We aim to offer a framework through which psychedelic researchers, therapists and other stakeholders, may begin tackling the complex ethical questions arising within their own organizations and individual practice of PAT.

Therapeutic Alliance and Rapport Modulate Responses to Psilocybin Assisted Therapy for Depression.

Background: Across psychotherapeutic frameworks, the strength of the therapeutic alliance has been found to correlate with treatment outcomes; however, its role has never been formally assessed in a trial of psychedelic-assisted therapy. We aimed to investigate the relationships between therapeutic alliance and rapport, the quality of the acute psychedelic experience and treatment outcomes. Methods: This 2-arm double-blind randomized controlled trial compared escitalopram with psychedelic-assisted therapy for moderate-severe depressive disorder (N = 59). This analysis focused on the psilocybin condition (n = 30), who received two oral doses of 25 mg psilocybin, 3-weeks apart, with psychological preparation, in-session support, and integration therapy. A new psychedelic therapy model, called "Accept-Connect-Embody" (ACE), was developed in this trial. The primary outcome was depression severity 6 weeks post treatment (Quick Inventory of Depressive Symptomatology, QIDS-SR-16). Path analyses tested the hypothesis that therapeutic alliance (Scale To Assess the Therapeutic Relationship Patient Version, STAR-P) would predict depression outcomes via its influence on the acute psychedelic experience, specifically emotional-breakthrough (EBI) and mystical-type experiences (MEQ). The same analysis was performed on the escitalopram arm to test specificity. Results: The strength of therapeutic alliance predicted pre-session rapport, greater emotional-breakthrough and mystical-type experience (maximum EBI and MEQ scores across the two psilocybin sessions) and final QIDS scores (ß = -0.22, R 2 = 0.42 for EBIMax; ß = -0.19, R 2 = 0.32 for MEQMax). Exploratory path models revealed that final depression outcomes were more strongly affected by emotional breakthrough during the first, and mystical experience during the second session. Emotional breakthrough, but not mystical experience, during the first session had a positive effect on therapeutic alliance ahead of the second session (ß = 0.79, p < 0.0001). Therapeutic alliance ahead of the second session had a direct impact on final depression scores, not mediated by the acute experience, with a weaker alliance ahead of the second psilocybin session predicting higher absolute depression scores at endpoint (ß = -0.49, p < 0.001) Discussion: Future research could consider therapist training and characteristics; specific participant factors, e.g., attachment style or interpersonal trauma, which may underlie the quality of the therapeutic relationship, the psychedelic experience and clinical outcomes; and consider how therapeutic approaches might adapt in cases of weaker therapeutic alliance. Clinical Trial Registration: This trial is registered at http://clinicaltrials.gov, identifier (NCT03429075).

Problem-based, peer-to-peer global mental health e-learning between the UK and Somaliland: a pilot study.

BACKGROUND: WHO's mental health gap action programme intervention guide (mhGAP-IG) is an evidence-based tool aimed at front-line health workers in low-income and middle-income countries (LMICs). Its potential to improve global mental health education, especially through digital technologies, has been little studied. Problem-based learning (PBL) is usually conducted face-to-face, but its remote application could facilitate cross-cultural education. OBJECTIVE: To evaluate PBL, applied to peer-to-peer global mental health e-learning (Aqoon), using mhGAP-IG. METHODS: Twelve pairs of UK and Somaliland medical students completed the full programme. Participants self-directedly met online, via the low-bandwidth Medicine Africa website, for PBL-style tutorials focused on modules of the mhGAP-IG, V.2.0. Preparticipation and postparticipation surveys used mixed methods to evaluate Aqoon, including the Attitudes Toward Psychiatry (ATP-30) instrument. FINDINGS: Median ATP-30 scores for Somaliland (82.0 vs 95.0, p=0.003) and UK students (82.0 vs 95.0, p=0.011) improved significantly following Aqoon. Qualitative feedback showed that participants valued peer connectivity and learning about cultural and psychosocial differences in their partner's country. Somaliland students were motivated by clinical learning and UK students by global health education. Feedback on the PBL structure was positive. CONCLUSIONS: Digital PBL represents an innovative method to extend the benefits of mhGAP-IG beyond front-line clinical staff, to healthcare students in LMICs. CLINICAL IMPLICATIONS: Educational resource limitations in LMICs may be overcome using digital platforms and PBL. Replication with non-medical healthcare students is the next step for this model to explore Aqoon's relevance to pressing global mental health workforce challenges.