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Clinical Trial
. 2024 Jun 1;81(6):555-562.
doi: 10.1001/jamapsychiatry.2023.4685.

Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Open-Label Trial

Scott T Aaronson  1   2 , Andrew van der Vaart  2 , Tammy Miller  1 , Jeffrey LaPratt  1 , Kimberly Swartz  1 , Audrey Shoultz  1 , Margo Lauterbach  1   2 , Harold A Sackeim  3   4 , Trisha Suppes  5   6
Affiliations
Clinical Trial

Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes: A Nonrandomized Open-Label Trial

Scott T Aaronson et al. JAMA Psychiatry. .

Erratum in

  • Error in Title and Text.
    [No authors listed] [No authors listed] JAMA Psychiatry. 2024 Jun 1;81(6):634. doi: 10.1001/jamapsychiatry.2024.0481. JAMA Psychiatry. 2024. PMID: 38598187 Free PMC article. No abstract available.

Abstract

Importance: Bipolar II disorder (BDII) is a debilitating condition frequently associated with difficult-to-treat depressive episodes. Psilocybin has evidence for rapid-acting antidepressant effects but has not been investigated in bipolar depression.

Objective: To establish the safety and efficacy of psilocybin in patients with BDII in a current depressive episode.

Design, setting, and participants: This was a 12-week, open-label nonrandomized open-label trial conducted at Sheppard Pratt Hospital. Participants aged 18 to 65 years with BDII, a current depressive episode longer than 3 months, and documented insufficient benefit with at least 2 pharmacologic treatments during the current episode were invited to participate. Of 70 approached, 19 met inclusion criteria and were enrolled. The trial was conducted between April 14, 2021, and January 5, 2023.

Interventions: A single dose of synthetic psilocybin, 25 mg, was administered. Psychotropic medications were discontinued at least 2 weeks prior to dosing. Therapists met with patients for 3 sessions during pretreatment, during the 8-hour dosing day, and for 3 integration sessions posttreatment.

Main outcomes and measures: The primary outcome measure was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Secondary measures included MADRS scores 12 weeks posttreatment, the self-rated Quick Inventory of Depression Symptoms-Self Rating (QIDS-SR), and the self-rated Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), each completed at baseline and all subsequent visits. Safety measures included the Columbia Suicide Severity Rating Scale (CSSRS) and the Young Mania Rating Scale (YMRS) completed at each visit.

Results: Of the 15 participants in this study (6 male and 9 female; mean [SD] age, 37.8 [11.6] years), all had lower scores at week 3, with a mean (SD) change of -24.00 (9.23) points on the MADRS, (Cohen d = 4.08; 95% CI, -29.11 to -18.89; P < .001). Repeat measures analysis of variance showed lower MADRS scores at all tested posttreatment time points, including the end point (Cohen d = 3.39; 95% CI, -33.19 to -16.95; adjusted P < .001). At week 3, 12 participants met the response criterion (50% decrease in MADRS), and 11 met remission criterion (MADRS score ≤10). At the study end point, 12 patients met both response and remission criteria. QIDS-SR scores and Q-LES-Q-SF scores demonstrated similar improvements. YMRS and CSSRS scores did not change significantly at posttreatment compared to baseline.

Conclusions and relevance: The findings in this open-label nonrandomized open-label trial suggest efficacy and safety of psilocybin with psychotherapy in BDII depression and supports further study of psychedelics in this population.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Aaronson reported grants and nonfinancial support (supply of drug) from COMPASS Pathways during the conduct of the study and personal fees from LivaNova, Neuronetics, Genomind, and Sage Therapeutics outside the submitted work. Dr Miller reported personal fees from COMPASS Pathways during the conduct of the study. Dr LaPratt reported grants from COMPASS Pathways during the conduct of the study. Dr Lauterbach reported other from Sheppard Pratt/COMPASS Pathways (supported study) during the conduct of the study and other from Brain Educators (one-third owner) outside the submitted work. Dr Sackeim reported personal fees from Cerebral Therapeutics, LivaNova, Neurolief, Neuronetics, Parow Enthiobiosciences, and SigmaStim outside the submitted work. Dr Suppes reported other from Psilotec (stock options) outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Individual Montgomery-Åsberg Depression Rating Scale (MADRS) Scores Over the Study Period
The dotted line indicates the threshold for remission from bipolar depression. Each color represents an individual patient.
Figure 2.
Figure 2.. Mood Symptom Assessments Following Psilocybin Treatment
MADRS indicates Montgomery-Åsberg Depression Rating Scale; QIDS-SR, Quick Inventory of Depression Symptoms-Self Rating.
Figure 3.
Figure 3.. Assessment of Suicidal Ideation Severity and Quality of Life
CSSRS indicates Columbia Suicide Severity Rating Scale; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form.
Figure 4.
Figure 4.. Association Between Psychedelic Experience and Sustained Antidepressant Effect
5D-ASC indicates Five Dimension Altered State of Consciousness Questionnaire; MADRS, Montgomery-Åsberg Depression Rating Scale.
See this image and copyright information in PMC

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