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

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. To establish the safety and efficacy of psilocybin in patients with BDII in a current depressive episode. 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. 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. The primary outcome measure was change in Montgomery- sberg 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. 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. 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.