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

This study is a 12-week (in addition to up to 30 days of screening) randomized, double-blind, placebo-controlled, parallel-group trial. The primary objective of this study is to assess the effectiveness, safety, and tolerability of single-dose psilocybin (25 mg)-assisted therapy in comparison to active placebo (1 mg micro-dose) psilocybin-assisted therapy in patients with bipolar II depression who have not responded to adequate trials with at least two first or second-line treatments for bipolar II depression (i.e. quetiapine, lithium, lamotrigine, sertraline, or venlafaxine as monotherapy or adjunctive therapy, or bupropion adjunctive therapy). The active placebo is a substance that looks identical to the study medication but contains less therapeutic ingredients, and thus is less capable of producing the transformative and meaningful aspects of psychedelic experience compared to the 25 mg dose. Participants will have a total of 11 study visits over a period of up to 16 weeks, which includes 5 therapy sessions from trained study therapists.

Bipolar disorders (BD) are lifelong conditions characterized by recurrent episodes of depression and (hypo)mania. Statistics Canada data indicate over a million Canadians are affected by this illness. Bipolar II disorder is characterised by recurrent episodes of hypomania and depression and individuals with BD-II are symptomatic about 50% of the time despite treatment. The majority of this time is spent being depressed thus there is an urgent need to develop new treatments that are safe and effective. Psilocybin, a naturally occurring psychedelic compound found in mushrooms, has been noted to result in an increase in psychological well-being in healthy volunteers as well as have antidepressant effects when administered in conjunction with psychological support. Two recent open-label pilot trials of Psilocybin-Assisted Therapy (PAT) in treatment-resistant depression, including BD-II participants, demonstrated high response rates and excellent tolerability, thereby providing strong justification for the current study.

Eligibility Criteria:
Inclusion Criteria:

1. You are male or female aged 18 to 65 years inclusive.
2. You have a diagnosis of bipolar disorder type II, and are currently in a major depressive episode.
3. You are not using, or are willing to discontinue, certain medications for at least 2 weeks before the dosing visit and throughout the entire duration of the study (see 'Prohibited Medications and Wash-out' under Section 10 for details). Lamotrigine, valproate, lithium, and lorazepam (up to 2 mg/day) will be permitted.
4. Your current depressive episode has been treated with 2 recommended medications for bipolar II depression for a minimum of 6 weeks.
5. You are willing, for the entire duration of the study, to practice highly effective methods of contraception (e.g., contraceptive pills, intrauterine device or system, vasectomy and tubal ligation, or double-barrier methods of contraception) OR agree to completely abstain from heterosexual intercourse. Females who do not have childbearing potential are required to be postmenopausal for at least 1 year before the screening visit (confirmed by an FSH test) OR surgically sterile.
6. You have sufficient English language skills to understand, consent to, and comply with study requirements, study visits, and to return to the clinic for follow-up evaluations.
7. Your current medications have been at a stable dose for two weeks prior to the dosing visit.

Exclusion Criteria:

1. You have a history of rapid cycling, defined as 4 or more mood episodes in the preceding 12 months.
2. You have a current diagnosis of other primary psychiatric diagnoses as assessed by a study doctor to be primary and causing greater impairment than your bipolar depression.
3. You have a lifetime history of a primary psychotic disorder (e.g., schizoaffective disorder).
4. You have a history of psychotic symptoms.
5. You have a substance use disorder (except for nicotine or caffeine) within the past 6 months.
6. You have a history of seizures.
7. You have a current unstable or inadequately treated medical illness, especially cardiovascular illness, except for the current depression.
8. You recently (i.e., within the past 6 weeks) started taking treatment for your acute bipolar depressive episode.
9. You recently (i.e., within the past 8 weeks) began structured psychotherapy (i.e., cognitive-behavioral therapy, interpersonal psychotherapy, family-focused therapy, or interpersonal and social rhythm therapy).
10. You have a history of nonresponse or intolerance to psilocybin.
11. You have, in the past 6 months, used any psychedelic drugs, including ketamine, LSD, or psilocybin-containing mushrooms.
12. You have a history of non-response to electroconvulsive therapy.
13. You are at a significant risk of harm to yourself or others.
14. You are pregnant or lactating.