Cannabidiol for Bipolar Depression (CBD-BD)

Study Overview
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Brief Summary
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Bipolar disorder (BD) is a lifelong condition characterized by recurrent episodes of depression and (hypo) mania. Periods of chronic and recurring depressive episodes are more common and can be severely disabling. Effective treatments exist; however, a significant portion of bipolar depressed patients do not respond to or have difficulty tolerating many of these interventions and thus look beyond established treatments to achieve symptom relief. Cannabidiol (CBD), a chemical from the Cannabis sativa plant has shown to have some beneficial effects on mood symptoms in a few small studies which assessed its effects in other mental and physical health conditions, but no large studies have been conducted to assess the safety and efficacy in bipolar depression. Additionally, several clinical studies have shown CBD to be safe and tolerable. The primary objective of this study is to assess the effectiveness, safety and tolerability of Cannabidiol in patients with bipolar depression (BD I or BD II) who have not responded to adequate trials with at least one first-line treatment for bipolar depression in comparison to those who will be treated with placebo. Placebo is an inactive substance that looks identical to the study medication but contains no therapeutic ingredient. This study is a randomized (like the flip of a coin), double-blind (you and the study team will not know which treatment arm you receive) study in which participants will receive either CBD or placebo added to their current treatment. Participants will have 5 clinical appointments and a phone appointment over a period of 10 weeks.

Detailed Description
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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.

Official Title
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Cannabidiol Adjunctive Therapy for Acute Bipolar Depression: A Randomized Double-Blind, Placebo Controlled Trial

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Cannabidiol
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged 19 to 70 years (inclusive). Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnosis of Bipolar Disorder Type I or Type II, AND a current major depressive episode. 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. 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. Inpatient or outpatient status. Females of childbearing potential are required to take contraceptive pills OR agree to practice effective 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 6 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cannabidiol<br>Cannabidiol 200 - 600 mg / day added to current treatment for 6 weeks. | Drug: Cannabidiol<br>* Cannabinoid<br>* Other names: CBD;|
| Placebo Comparator: Placebo<br>Placebo added to current treatment for 6 weeks. | Other: Placebo<br>* Inactive substance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in depressive symptoms in bipolar patients treated with Cannabidiol vs Placebo adjunctive therapy | The Montgomery Asberg Depression Rating Scale (MADRS) will be used to measure change in depressive symptoms from baseline to endpoint. Scores range from 0 to 60, and lower scores reflect better clinical outcomes. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rates | Response rates are defined as patients showing ≥50% reduction in MADRS scores. | 6 weeks | 
| Remission rates | Remission rates are defined as MADRS ≤ 10 and YMRS ≤ 8 at endpoint. | 6 weeks | 
| Treatment-emergent manic/hypomanic events | The Young Mania Rating Scale (YMRS) will be used to determine the presence of any treatment-emergent manic or hypomanic events from baseline to endpoint. Scores range from 0 to 60, and lower scores reflect better clinical outcomes. | 6 weeks | 
| Objective depressive symptoms | The 21-item Hamilton Depression Rating Scale (HAM-D 21) will be used to measure change in objective depressive symptoms from baseline to endpoint. Scores range from 0 to 62, and lower scores reflect better clinical outcomes. | 6 weeks | 
| Subjective depressive symptoms | The Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) and the Dimensional Anhedonia Rating Scale (DARS) will be used to measure change in subjective depressive symptoms from baseline to endpoint. Lower scores on the QIDS-SR reflect better clinical outcomes; higher scores on the DARS reflect better clinical outcomes. | 6 weeks | 
| Objective anxiety symptoms | The Hamilton Anxiety Rating Scale (HAM-A) will be used to measure change in objective anxiety symptoms from baseline to endpoint. Scores range from 0 to 56 and lower scores reflect better clinical outcomes. | 6 weeks | 
| Subjective anxiety symptoms assessed by STAI | The State-Trait Anxiety Inventory (STAI) will be used to measure change in subjective anxiety symptoms. Lower scores on the STAI reflect better clinical outcomes. | 6 weeks | 
| Subjective anxiety symptoms assessed by GAD-7 | The Generalized Anxiety Disorder 7-item (GAD-7) will be used to measure change in subjective anxiety symptoms. Lower scores on the GAD-7 reflect better clinical outcomes. | 6 weeks | 
| Overall psychiatric status | The Clinical Global Impression - severity & change scales will be used to measure change in global severity and global improvement in symptoms from baseline to endpoint. Scores range from 3 to 42, and higher scores reflect worsening in overall psychiatric status. | 6 weeks | 
| Psychotic symptoms | The Positive and Negative Syndrome Scale (PANSS) will be used to measure change in psychotic symptoms from baseline to endpoint. Scores range from 7 to 49, and lower scores reflect better clinical outcomes. | 6 weeks | 
| Subjective cognitive functioning | The Cognitive Complaints in Bipolar Disorder Risk Assessment (COBRA) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function scale will be used to measure change in subjective cognitive functioning from baseline to endpoint. COBRA scores range from 0 to 48, and lower scores reflect better outcomes; PROMIS cognitive function scale scores range from 8 to 40, and higher scores reflect better outcomes. | 6 weeks | 
| Objective cognitive functioning | The Screen for Cognitive Impairment in Psychiatry (SCIP) will be used to measure change in objective cognitive functioning from baseline to endpoint. Higher scores reflect better outcomes. | Week 6 | 
| Sleep quality | The Pittsburgh Sleep Quality Index (PSQI) will be used to measure changes in sleep quality and disturbance from baseline to endpoint. Lower scores reflect better sleep quality. | 6 weeks | 
| Suicidal thoughts and behaviours | The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to measure change in suicidal thoughts and behaviours from baseline to endpoint. Scores range from 0 to 37, and lower scores reflect better clinical outcomes. | 6 weeks | 
| Quality of Life assessed by QoL.BD | The Brief Quality of Life in Bipolar Disorder (QoL.BD) will be used to measure change in quality of life from baseline to endpoint. Higher scores reflect higher quality of life. | 6 weeks | 
| Daily functioning | The Functioning Assessment Short Test (FAST) will be used to measure change in daily functioning from baseline to endpoint. Lower scores reflect better daily functioning. | 6 weeks | 
| Health services utilization | A healthcare utilization diary will be used to measure improvement in health services utilization from baseline to endpoint. | 6 weeks | 
| Adverse events | Adverse events will be measured objectively using an open-ended form and subjectively using the Frequency, Intensity, and Burden of Side Effects Rating (FIBSER). FIBSER scores range from 0 to 18, and lower scores reflect better outcomes. | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cannabidiol, Bipolar Disorder, Bipolar Depression