Sequential Multiple Assignment Randomized Trial for Bipolar Depression

NCT06433635 | Active Not Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: 2024P000831
• Study Type: interventional
• Target: 2,726
• Locations: 2 countries
• Sites: 18

Brief Summary

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).

Conditions

Bipolar I Disorder; Depression

Keywords

Bipolar; Depression; Adults; Medication

Outcome Measures

Primary Outcomes (1)

• The Remission from Depression Questionnaire

  RDQ is a 41 items self report questionnaire used to assess the seven domains found in extensive previous research to be important to patients: depressive symptoms, anxiety, coping ability, positive mental health, functioning, life satisfaction and a general sense of well-being. Using a score of 27 as the cutoff, the RDQ scale has a sensitivity of 83.7% and specificity of 77.9% in predicting self-reported remission status. The RDQ has excellent internal consistency reliability (Cronbach's alpha of 0.97 for the total scale and above 0.80 for each of the 7 subscales with test-retest reliability of the total scale = 0.85 and \> 0.60 for each subscale). The primary outcome will be remission as defined by a RDQ score \< 27. This test will be administered in all assessment visits. The RDQ scale ranges from 0-27 per domain, with higher scores indicating greater remission rates.

  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 ).

Secondary Outcomes (4)

• Safety: Concise Health Risk Tracking Scale

  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 ).

• Frequency and Intensity of Side Effects Ratings - Intensity

  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 ).

• Frequency and Intensity of Side Effects Ratings - Frequency

  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 ).

• Frequency and Intensity of Side Effects Ratings - Burden

  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 ).

Other Outcomes (8)

• Altman Self-Rating Mania Scale

  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 ).

• Generalized Anxiety Disorder Assessment

  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 ).

• Medication Reconciliation Tracking Form

  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 ).

Study Arms (4)

Cariprazine

EXPERIMENTAL

Drug: Cariprazine

Aripiprazole /Escitalopram combination

EXPERIMENTAL

Drug: Aripiprazole/Escitalopram combination

Quetiapine

EXPERIMENTAL

Drug: Quetiapine

Lurasidone

EXPERIMENTAL

Drug: Lurasidone

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.

Also known as: Vraylar

Cariprazine

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.

Also known as: Abilify/ Lexapro

Aripiprazole /Escitalopram combination

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.

Also known as: Seroquel

Quetiapine

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.

Also known as: Latuda

Lurasidone

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged between 18 years to 75 years
• Meets criteria for DSM-V Bipolar I or II disorder with a history of manic or hypomanic episodes and current major depressive episode lasting at least 2 weeks
• Can be managed as an outpatient and participate in the study
• Willing to be randomized; able to perform study assessments
• Women of childbearing potential must agree to use adequate contraception (e.g. oral contraceptives, intrauterine device, barrier methods, or total abstinence; Depo Provera is acceptable if it is started 3 months prior to enrollment), and inform staff of their plans to conceive.

You may not qualify if:

• Meets current criteria for a manic episode, rapid cycling within the past year (history of 4 or more mood episodes per year)
• History of schizophrenia or other nonaffective psychosis
• Current substance use disorder that will interfere with participation in the study
• Currently taking the study medications or a history of serious adverse events to any of the study medications, to the extent that as determined by site PI, another trial would not be clinically indicated
• A history of non-response for depressive episodes, to any of the study medications, when given at adequate doses for at least 6 weeks
• Current acute suicidal risk that requires inpatient treatment
• Pregnancy or breastfeeding

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Patient-Centered Outcomes Research Institute: collaborator

Study Sites (18)

University of Alabama Birmingham

Birmingham, Alabama, 35294, United States

Location

Steve Strakowski

Bloomington, Indiana, 47405, United States

Location

John Hopkins

Baltimore, Maryland, 21218, United States

Location

McLean Hospital

Belmont, Massachusetts, 02478, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Nagy Youssef

Grand Rapids, Michigan, 49548, United States

Location

University of New Mexico Health Sciences Center Albuquerque

Albuquerque, New Mexico, 87131-0001, United States

Location

New York University Grossman School of Medicine NYU

New York, New York, 10016, United States

Location

Montefiore Medical Center and Albert Einstein College of Medicine

New York, New York, 10461, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44106-1712, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15260, United States

Location

University of Texas at Austin

Austin, Texas, 78712, United States

Location

UT Southwestern Medical Center

Dallas, Texas, 75390-7208, United States

Location

UT Health Houston Texas

Houston, Texas, 77030, United States

Location

University of British Columbia

Vancouver, British Columbia, V6T 1Z4, Canada

Location

MeSH Terms

Conditions

Depression

Interventions

cariprazine; Aripiprazole; Escitalopram; Quetiapine Fumarate; Lurasidone Hydrochloride

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Dibenzothiazepines; Thiazepines; Thiepins; Sulfur Compounds; Heterocyclic Compounds, 3-Ring; Thiazoles; Azoles; Isoindoles

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Dauten Family Center for Bipolar Treatment Innovation

Study Record Dates

• First Submitted: April 22, 2024
• First Posted: May 30, 2024
• Study Start: October 1, 2024
• Primary Completion (Estimated): February 28, 2030
• Study Completion (Estimated): February 28, 2030
• Last Updated: December 16, 2025

Record last verified: 2025-12

Locations

US (17); CA (1)