Cannabidiol for Bipolar Depression (CBD-BD)

This is a Phase 3, 6-week, double-blind, parallel group randomized controlled trial to assess the efficacy, safety and tolerability of adjunctive CBD vs placebo in patients with acute bipolar depression (BD I or BD II) who have not responded to adequate trials with at least one first-line treatment for bipolar I disorder (i.e. lithium, lamotrigine, lurasidone, or quetiapine either as monotherapy or adjunctive therapy), or at least one first or second-line treatment for bipolar II depression (i.e. quetiapine, lithium, lamotrigine, sertraline, or venlafaxine as monotherapy or adjunctive therapy, or bupropion adjunctive therapy). After the baseline visit, patients who meet the eligibility criteria will enter a 6-week double-blind treatment phase during which participants will be randomized to adjunctive CBD or identical placebo.

Participants will be assessed at the screening visit, baseline visit, weeks 2, 4, and 6, or endpoint visit. All participants will receive a follow-up telephone call 2 weeks after the 6-week study endpoint or early termination visit to assess well-being.

All participants will continue treatment with their mood stabilizer and/or atypical antipsychotic as prescribed by their treating physicians.

Inclusion criteria

• Males or females aged 19 to 70 years (inclusive).
• DSM-5 diagnosis of BD I or BD II, AND a current major depressive episode confirmed by MINI 7.0.2 .
• All patients must be taking either a mood stabilizer (i.e. lithium or valproate; lamotrigine monotherapy as a mood stabilizer is acceptable for BD II patients only and not for BD I) OR an atypical antipsychotic OR a combination of these (two mood stabilizers or a mood stabilizer plus an atypical antipsychotic), at therapeutic doses. Medications and therapeutic doses are: lithium, serum level 0.6-1.2 mEq/L; divalproex/sodium valproate, serum level 350-700 uM/L(45-125 mcg/ml); risperidone 2-6 mg/day; olanzapine 5-30 mg/day; quetiapine IR or XR 300-900 mg/day; aripiprazole 10-30 mg/day; cariprazine 1.5-6 mg/day; and ziprasidone 80-160 mg/day. Combinations of these medications as outlined above, or the combination of any of them with lamotrigine 100-400 mg daily, or the combination of a mood stabilizer plus asenapine 5-20 mg/day are also permitted.
• Have received a minimum of 6-weeks treatment at adequate doses for treatment of current depressive episode with at least one CANMAT recommended first-line treatment for bipolar I disorder (i.e. lithium, lamotrigine, lurasidone, or quetiapine either as monotherapy or adjunctive therapy), or at least one first or second-line treatment for bipolar II depression (i.e. quetiapine, lithium, lamotrigine, sertraline, or venlafaxine as monotherapy or adjunctive therapy, or bupropion adjunctive therapy).
• A MADRS score of ≥ 20 and a YMRS score of ≤ 12 (these cut off scores are standard in bipolar depression RCTs).
• Inpatient or outpatient status.
• All participants are required to agree to practice highly effective methods of contraception (i.e. hormonal contraceptives, 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.
• The capability of understanding, consenting to and complying with study requirements.
• All concomitant medication must be at a stable dose for two weeks prior to the randomization visit.

Exclusion criteria

• Current depressive episode greater than 12 months.
• A history of rapid cycling, defined as ≥ 4 mood episodes in the preceding 12 months.
• Current unstable or inadequately treated medical illness with the exception of current depression.
• Recently started taking a CANMAT-recommended treatment for the management of acute bipolar depressive episode, but has not had a trial for a minimum of 6 weeks with adequate doses.
• 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).
• Recently (i.e. within the past 8 weeks) started taking a stimulant medication. Concomitant treatment with stimulant medication is acceptable provided that the dose has been stable for a minimum of 8 weeks and is taken as prescribed by a physician.
• Current use of clozapine, tricyclic antidepressants, monoamine oxidase inhibitors, and first-generation antipsychotics.
• A history of non-response or intolerance to CBD.
• Current or past month daily use of CBD, or any product or drug that contains CBD. Occasional users will be included if they agree to refrain from using during the trial.
• A history of non-response to electroconvulsive therapy for the current depressive episode.
• A current diagnosis of other primary psychiatric disorders as assessed by a study investigator to be primary and causing greater impairment than BD.
• A lifetime history of a primary psychotic disorder (e.g. schizoaffective disorder, bipolar subtype) according to DSM-5 criteria.
• Patients who have met the DSM-5 criteria for a substance use disorder (except for nicotine or caffeine) within the past 6 months.
• Significant active suicidal ideation (as evidenced by MADRS suicide item ≥ 4).
• Pregnancy or lactation.
• Liver function tests (AST and ALT) three times the upper limit of normal.