Psilocybin-Assisted Psychotherapy for Treatment-Resistant Depression in Bipolar II Disorder

Introduction

Over the past two decades, psilocybin and other classic serotonergic psychedelics have re-emerged as potential treatments for psychiatric disorders, particularly depression. Previous psilocybin-assisted psychotherapy (PAP) trials have suggested rapid and robust antidepressant effects in major depressive disorder (MDD), treatment-resistant depression (TRD) and in patients with life-threatening illness, but most trials used small, highly selected samples and intensive psychotherapy protocols. These exclusions—commonly omitting individuals with substantial comorbidity, bipolarity, suicidality or very high degrees of treatment resistance—limit the generalisability of existing evidence to real-world clinical populations. Important open questions also remain about durability of effect, the role of repeat dosing for relapse, and the minimal necessary ‘‘dose’’ of adjunctive psychotherapy for safe and scalable delivery. Rosenblat and colleagues designed a randomised, waitlist-controlled clinical trial to address these gaps by testing a brief four-session PAP model in a more complex TRD population. The trial deliberately broadened eligibility to include both MDD and bipolar II disorder (BDII), participants with comorbid psychiatric conditions and baseline suicidality, and imposed no upper limit on prior failed treatment trials. A secondary aim was to evaluate the feasibility, safety and preliminary efficacy of offering repeat psilocybin doses to participants who showed clinical relapse after an initial response. The investigators framed this study as a feasibility trial intended to reflect how PAP might be implemented in real-world clinical practice.