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

Roberta Murphy, Hannes Kettner, Rick Zeifman, Bruna Giribaldi, Laura Kartner, Jonny Martell, Tim Read, Ashleigh Murphy-Beiner, Michelle Baker-Jones, David Nutt, David Erritzoe, Rosalind Watts, Robin Carhart-Harris, Roberta Murphy, Hannes Kettner, Rick Zeifman, Bruna Giribaldi, Laura Kartner, Jonny Martell, Tim Read, Ashleigh Murphy-Beiner, Michelle Baker-Jones, David Nutt, David Erritzoe, Rosalind Watts, Robin Carhart-Harris

Abstract

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 (β = -0.22, R 2 = 0.42 for EBIMax; β = -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 (β = 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 (β = -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 https://ichgcp.net/clinical-trials-registry/NCT03429075" title="See in ClinicalTrials.gov">NCT03429075).

Keywords: acute psychedelic experience; depression; emotional breakthrough; mystical experience; psilocybin; psychedelic assisted therapy; therapeutic alliance; therapeutic relationship.

Conflict of interest statement

Carhart-Harris sits on the scientific advisory boards of: Entheon Biomedical, Mydecine, Synthesis Institute, Tryp Therapeutics, Usona Institute, Osmind, Beckley Pscyhtech, Journey Collab and Maya Health. Giribaldi, receiving consulting fees from SmallPharma; Watts, receiving advisory board fees from Usona Institute and being employed by Synthesis Institute; Baker-Jones, receiving fees from Synthesis Institute and employed by Small Pharma; Erritzoe, receiving consulting fees from Field Trip and Mydecine; and Nutt, receiving consulting fees from Awakn, H. Lundbeck, and Psyched Wellness, advisory board fees from COMPASS Pathways, and lecture fees from Takeda Medical Research Foundation and owning stock in Alcarelle. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Murphy, Kettner, Zeifman, Giribaldi, Kartner, Martell, Read, Murphy-Beiner, Baker-Jones, Nutt, Erritzoe, Watts and Carhart-Harris.

Figures

FIGURE 1
FIGURE 1
Flow-chart outlining study procedures for the psilocybin and escitalopram arms of the trial featured in this article, outlined in “Design and Procedures”. All participants included in this analysis followed the outlined procedures, unless otherwise stated in the “Descriptives” section of the results. After the 6-weeks key endpoint, participants completed remote monthly follow-up assessments until 6 months post-study. The dotted line separates pre-enrolment screening procedures (above line) from post-enrolment study procedures (below line). Info Sheet: Participant Information Sheet, HAM-D: 17-item Hamilton Depression Scale (clinician-rated), GP: General Practitioner, STAR-P: Scale To Assess the Therapeutic Relationship (participant-rated version), QIDS-SR-16: 16-item Self-Reported Quick Inventory of Depressive Symptomatology (primary outcome), EBI: Emotional Breakthrough Inventory, MEQ: Mystical Experience Questionnaire.
FIGURE 2
FIGURE 2
Directed Acyclic Graph (DAG) displaying the path structure of a fully saturated sequential mediation model testing the serial mediation effect of therapeutic alliance on depression outcomes via the active psychedelic experience. The model is completely unrestricted, meaning that all possible paths between all variables are specified.
FIGURE 3
FIGURE 3
Path models testing the primary hypothesis that therapeutic alliance would lead to better depression scores 6 weeks following psychedelic-assisted psychotherapy. Serial mediation of therapeutic alliance via pre-session rapport and A) Emotional Breakthrough and B) Mystical-type experiences were supported by the models. Depression severity at the 6-weeks Endpoint was adjusted for baseline depression scores (p > 0.1, not displayed in the figure), which by itself accounts for R2 = 0.12, i.e., 12% of variance in the final outcome. Numbers represent standardised regression coefficients for significant (solid) and non-significant (dashed) paths. **indicates p < 0.01, *** p < 0.001.
FIGURE 4
FIGURE 4
Near-saturated sequential mediation models exploring the relationship between therapeutic alliance during the first psilocybin session and depression scores 6 weeks following a two-dose course of psychedelic-assisted psychotherapy. Sequential mediation of therapeutic alliance via pre-session rapport and A) Emotional Breakthrough and B) Mystical-type Experiences were supported by the models in the case of depression severity, but not for intermediate therapeutic alliance measured ahead of the second psilocybin session, which was only significantly predicted by Emotional Breakthrough scores. Depression severity at 6 weeks was controlled for baseline depression scores, which by itself accounted for R2 = 0.12, i.e., 12% of variance in the final outcome. MEQ, but not EBI scores were furthermore affected by baseline depression severity, although only at trend level. Numbers represent standardised regression coefficients for significant (solid, p > 0.1) but not non-significant (dashed) paths. Subscript numbers refer to the different psilocybin sessions, one and two; e.g., Therapeutic Alliance1 refers to STAR-P scores ahead of psilocybin session one and Therapeutic Alliance2 refers to STAR-P scores ahead of psilocybin session 2. ☨ indicates p < 0.1, *p < 0.05, **p < 0.01, ***p < 0.001.
FIGURE 5
FIGURE 5
Fully saturated sequential mediation models exploring the relationship between therapeutic alliance during the second psilocybin session and depression scores 6 weeks following a two-dose course of psychedelic-assisted psychotherapy. Sequential mediation of therapeutic alliance via pre-session rapport and B) Mystical-type Experiences, but not A) Emotional Breakthrough was supported by the models for this second session. Importantly, depression severity at 6 weeks was controlled for midline (3 weeks post-first dose) depression scores, which by itself accounted for R2 = 0.55, i.e., 55% of variance in the final outcome. Greater midline depression severity significantly predicted worse therapeutic alliance and pre-session rapport scores. Decimal values represent standardised regression coefficients (β values) for significant (solid, p > 0.1) but not non-significant (dashed) paths. The subscript number two refers to the second psilocybin session. ☨ indicates p < 0.1, *p < 0.05, **p < 0.01, ***p < 0.001

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