Sequential Multiple Assignment Randomized Trial for Bipolar Depression

Conditions

• Bipolar I Disorder
• Depression

Eligibility Criteria

Sex

ALL

Age

18 Years - 75 Years

Healthy Volunteers

Not accepted

Interventions

• Cariprazine — DRUG
  1. Cariprazine monotherapy outperformed placebo in improving depressive symptoms in most large randomized control trials (RCT). Pooled data showed higher remission rates (30.2%) with cariprazine (1.5 mg and 3 mg/day) compared to placebo (20.9%). Its efficacy extends to bipolar I depression, including mixed features and anxiety. 2. Common adverse effects include nausea (8%) and akathisia (7%). Somnolence and sedation were slightly more common with cariprazine than placebo. 3. Results from a large RCT evaluating cariprazine for bipolar disorder maintenance treatment (NCT03573297) are awaited. An open-label trial reported reduced manic symptoms over 16 weeks. 4. Cariprazine is a D3-preferring partial agonist for D3 and D2 receptors. It antagonizes 5-HT2A and 5-HT2B receptors and partially agonizes 5-HT1A receptors. Affinity for 5-HT1C and histamine 1 receptors is low to moderate.
• Aripiprazole/Escitalopram combination — DRUG
  1. 40-70% of bipolar patients use antidepressants, often with antipsychotics or mood stabilizers. Aripiprazole lacks efficacy in bipolar depression but is used for mania. Escitalopram, studied alongside mood stabilizers, showed some efficacy. 2. Aripiprazole in bipolar depression trials led to higher rates of akathisia, insomnia, nausea, fatigue, and impulse control disorders. Escitalopram's is generally safe but adverse effects include nausea, diarrhea, insomnia, dry mouth, ejaculatory dysfunction and dizziness. 3. Aripiprazole monotherapy in bipolar I patients reduced relapse rates and delayed relapse time, but not for depressive episodes. 4. Aripiprazole acts as a partial agonist at D2, D3, 5-HT1A, and 5-HT2C receptors, with antagonistic effects on α1 and possibly H1 receptors. Escitalopram is highly selective for the serotonin transporter, with no significant activity at other receptors.
• Quetiapine — DRUG
  1. Both immediate and extended-release quetiapine monotherapies showed superiority over placebo in acute BD depression across three 8-week randomized trials, confirmed by meta-analysis. Quetiapine exhibited significantly higher remission rates (52.8%) compared to placebo (34.7%) and improved various aspects of life, including quality of life, clinical global impression, sleep, functioning, and anxiety. 2. Common adverse events of quetiapine include sedation, hypotension, increased appetite, weight gain, dyslipidemia, and elevated glucose levels, particularly in a population already at risk. 3. Four studies examined quetiapine's maintenance effects in patients with manic, mixed, or depressive episodes. Overall, quetiapine prolonged the time to recurrence for both depressive and manic episodes.
• Lurasidone — DRUG
  1. Lurasidone, either alone or with lithium/valproate, proved more effective than placebo for acute BD depression in two 6-week randomized trials. Remission rates were significantly higher with lurasidone monotherapy (40.9%) and in combination (50.3%) compared to placebo (24.7% and 35.4% respectively). Lurasidone also improved anxiety, quality of life, and disability. 2. Common mild adverse events included nausea, headache, akathisia, somnolence, sedation, dry mouth, and vomiting. Weight gain, dyslipidemia, and increased glucose levels were not observed. 3. In a 6-month double-blind discontinuation study post-acute treatment response, lurasidone combined with lithium/valproate prolonged time to depressive episode recurrence compared to placebo (hazard ratio: 0.68). Although not statistically significant due to low placebo recurrence and shorter follow-up, it hints at maintenance efficacy.

Study Details

This is a sequential multiple assignment randomized trial for adults (ages \> 18) with a bipolar disorder type 1 and type 2 diagnosis currently experiencing a depressive episode. It is a randomized pragmatic trial that will compare four commonly prescribed treatments for bipolar depression, which includes three FDA-approved medications (Cariprazine, Quetiapine and Lurasidone) and one antipsychotic/antidepressant combination (Aripiprazole/Escitalopram).

Key Dates

Start date

Oct 1, 2024

Status verified

Dec 2025

Primary completion

Feb 28, 2030

Completion

Feb 28, 2030

Study Design

Enrollment

2,726 participants (estimated)

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Arms

• Experimental: Cariprazine
• Experimental: Aripiprazole /Escitalopram combination
• Experimental: Quetiapine
• Experimental: Lurasidone

Primary Outcome Measure

The Remission from Depression Questionnaire [ Time Frame: Investigators will administer this measure every 2 weeks for the first 12 weeks (weeks:0,2,4,6,8,10,12), and then at each study visit during the follow up phase until they are discharged from the study (weeks:20,28,36,44,52 ). ]

Locations (17)

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