Acceptability and safety of two sequential doses of psilocybin in bipolar II depression: protocol for an open-label single-arm feasibility study.

introductionBipolar II disorder (BD-II) is characterised by hypomanic and depressive episodes with the latter tending to dominate the clinical course of the disorder, and they are often associated with suicidality. Despite available guideline-based recommendations for first-line pharmacological treatments, patient outcomes remain suboptimal, especially for those with chronic depression and suicidal ideation. The dearth of viable treatment options for this population is evident, which is where psychedelics propose an additional alternative path. Psilocybin has recently shown promise in treating major depressive disorder and treatment-resistant depression; however, individuals with bipolar disorder or suicidality are typically excluded from such trials due to safety concerns (ie, risk of emerging suicidal behaviour, psychosis and/or mania). Here, we present the protocol of a study which aims to explore the acceptability, safety and treatment preferences of psilocybin-assisted therapy in patients with BD-II struggling with suicidal ideation. METHODS AND ANALYSIS: This outpatient, single-site, phase II, single-arm, open-label clinical trial feasibility study will include 10 participants diagnosed with BD-II depression and moderately passive suicidal ideation. Participants may receive up to two oral doses of 25 mg psilocybin, approximately 4 weeks apart, alongside a structured therapeutic protocol (based on mindfulness cognitive-behavioural therapy) that includes preparatory therapy sessions, psychological support during administration and post-treatment integration therapy sessions. The purpose is to examine the acceptability and safety of using psilocybin as a therapeutic for mild to moderate suicidality in patients currently diagnosed with BD-II and to obtain preliminary data on its effects. This will be measured using the following: Primary outcomes include change in suicidality, that is, the Interpersonal Needs Questionnaire and the Columbia Suicide Severity Rating Scale from baseline to main endpoint (3 weeks post initial administration) and feasibility and acceptability (as assessed by number of participants who complete the trial, number of therapy sessions attended and number of assessments completed). Secondary outcomes include changes in the following associated measures: Montgomery-Asberg Depression Rating Scale, Quick Inventory of Depressive Symptomatology, Young Mania Rating Scale, Brief Psychiatric Rating Scale Positive Symptom Subscale, Altman Self-Rating Mania Scale. Findings will also be used to estimate effect sizes and inform the design of a future randomised controlled trial. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the UTHealth Committee for the Protection of Human Subjects (CPHS RB# HSC-MS-23-0905). The results of the study will be disseminated to the public (ie, clinicians, researchers, patients and policymakers) through peer-reviewed journals, conferences and scientific meetings and clinical registries. TRIAL REGISTRATION NUMBER: NCT06706232.