Bipolar I DisorderPhase 4SMART-BDNCT06433635
Sequential Multiple Assignment Randomized Trial for Bipolar Depression
A Phase 4 study testing Cariprazine, Aripiprazole/Escitalopram combination and Quetiapine in people with Bipolar I Disorder and Depression, run by Massachusetts General Hospital at 18 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Bipolar I Disorder, Depression
- What is being tested?
- Cariprazine, Aripiprazole/Escitalopram combination and Quetiapine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2,726 participants
- Where
- 18 sitesin 2 countries
- Study dates
- 1 Oct 2024to 28 Feb 2030
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
18 sites in 2 countries.
18 sites in 2 countries
United States17 sites
University of New Mexico Health Sciences Center Albuquerque
Albuquerque, New Mexico, 87131-0001
University of Michigan
Ann Arbor, Michigan, 48109
University of Texas at Austin
Austin, Texas, 78712
John Hopkins
Baltimore, Maryland, 21218
McLean Hospital
Belmont, Massachusetts, 02478
University of Alabama Birmingham
Birmingham, Alabama, 35294
Steve Strakowski
Bloomington, Indiana, 47405
Massachusetts General Hospital
Boston, Massachusetts, 02114
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599
Case Western Reserve University
Cleveland, Ohio, 44106-1712
UT Southwestern Medical Center
Dallas, Texas, 75390-7208
Nagy Youssef
Grand Rapids, Michigan, 49548
UT Health Houston Texas
Houston, Texas, 77030
New York University Grossman School of Medicine NYU
New York, New York, 10016
Montefiore Medical Center and Albert Einstein College of Medicine
New York, New York, 10461
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
University of Pittsburgh
Pittsburgh, Pennsylvania, 15260
Canada1 site
University of British Columbia
Vancouver, British Columbia, V6T 1Z4
About this study
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).
Read the detailed description
This is a comparative effectiveness study to address the critical questions of how best to treat people with bipolar disorder who have a major depressive episode: how to get them well, provide second-line treatment when they don't initially get well, and keep them well after they get well. This is a multisite Sequential Multiple Assignment Randomized Trial (SMART) comparative effectiveness design. Investigators will recruit 2726 participants who have BD I or II with a current major depressive episode lasting at least 2 weeks. In Stage 1, investigators will compare four treatment arms, including three FDA approved monotherapies and the most widely used, but understudied, treatment for BD major depressive episode (i.e., a non-FDA approved combination of an antipsychotic and antidepressant). In Stage 2, participants who do not remit will be re-randomized to treatments not used in Stage 1. Investigators will follow all participants for a total of 52 weeks. This study will be conducted in two phases, a feasibility phase and a full study phase. In the feasibility phase, investigators will recruit at 8 of the 19 study sites based on readiness and interest, to ensure the efficacy of the study design before launching the full study phase.
Feasibility Aim 1: To ensure that 8 of the 19 selected sites can recruit, randomize, and retain participants. During the feasibility phase, the selected sites will recruit 133 participants, administer baseline assessments, randomize the participants (at baseline and again at 6-weeks for non-remitters), and conduct follow-up assessments at the end of Stage 1 (6-weeks) and the end of Stage 2 (12-weeks) and end of study (52 weeks or end of feasibility phase, whichever is sooner) and all other scheduled visits.
Feasibility Aim 2: To refine and finalize all study standard operating procedures for the full-scale study. After Aim 1 is complete, any changes in standard operating procedures will be made as needed to be implemented in the full study phase.
Full Scale Study Full-Scale Study Aim 1: To compare the effectiveness, tolerability, and safety of the four treatments for BD major depressive episodes.
Hypothesis 1a: There will be significant differences across the Stage 1 treatments in the proportion of remitters at week 6 (primary endpoint, effectiveness) and in the average adverse event burden and suicidal ideation/behavior at week 6 (secondary endpoints, tolerability and safety).
Hypothesis 1b: Among non-remitters of a given Stage 1 treatment (i.e., participants who do not remit by week 6), there will be significant differences across the three remaining Stage 2 treatments in the proportion of remitters at week 12 (primary endpoint, effectiveness) and the average side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
Full-Scale Study Aim 2: To characterize the effectiveness, tolerability, and safety of the 12 adaptive interventions for BD major depressive episodes embedded within the SMART design.
Hypothesis 2: On average, there will be significant differences across the 12 embedded adaptive interventions in the proportion of remitters at week 12 (primary endpoint, effectiveness) and in the average side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
Full-Scale Study Aim 3: To determine individual-level characteristics that predict heterogeneity of treatment effect (HTE) across the 12 adaptive interventions for BD major depressive episodes embedded within the SMART design.
Hypothesis 3a: Individual-level characteristics and symptoms assessed at baseline as well as symptom changes and side effect profiles at week 6 will predict HTE at weeks 12 and 52. Hypothesis 3b: Investigators hypothesize that an optimal personalized adaptive intervention will perform significantly better than the best aggregate embedded adaptive intervention identified in Aim 2 in terms of the proportion of remitters at week 12 (primary endpoint, effectiveness) and the side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
- Conditions
- Bipolar I Disorder, Depression
- Being tested
- Cariprazine, Aripiprazole/Escitalopram combination, Quetiapine, Lurasidone
- Keywords
- Bipolar, Depression, Adults, Medication
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CariprazineDrug
Also called Vraylar
- 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.
- Common adverse effects include nausea (8%) and akathisia (7%). Somnolence and sedation were slightly more common with cariprazine than placebo.
- 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.
- 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 combinationDrug
Also called Abilify/ Lexapro
- 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.
- 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.
- Aripiprazole monotherapy in bipolar I patients reduced relapse rates and delayed relapse time, but not for depressive episodes.
- 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.
QuetiapineDrug
Also called Seroquel
- 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.
- Common adverse events of quetiapine include sedation, hypotension, increased appetite, weight gain, dyslipidemia, and elevated glucose levels, particularly in a population already at risk.
- 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.
LurasidoneDrug
Also called Latuda
- 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.
- Common mild adverse events included nausea, headache, akathisia, somnolence, sedation, dry mouth, and vomiting. Weight gain, dyslipidemia, and increased glucose levels were not observed.
- 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 group | Role | What they receive |
|---|---|---|
| Cariprazine | Experimental | Not described Receives: Drug: Cariprazine |
| Aripiprazole /Escitalopram combination | Experimental | Not described Receives: Drug: Aripiprazole/Escitalopram combination |
| Quetiapine | Experimental | Not described Receives: Drug: Quetiapine |
| Lurasidone | Experimental | Not described Receives: Drug: Lurasidone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
CHRT is a 14 item self-report measure of suicidal ideation and behavior in individuals with mood disorders. The CHRT has excellent psychometric properties, with an internal consistency reliability (Cronbach's alpha) of 0.78 and a consistent factor structure with 3 independent factors (current suicidal thoughts and plans, perceived lack of social support, and hopelessness).
The range is from 14-70, higher scores reflect an increase in suicidality behaviors.
Measured: 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
This subscale of the FIBSER scale is a reliable self-report measure of the intensity of side effects from medications in a population receiving treatment for depression. This scale measures the participants side effects intensity from the previous week and has them rate each on a scale from 0-6. The results will help the clinician determine the appropriate level of response.
The range is from 0-6, higher scores reflect an greater intensity in medication side effects.
Measured: 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
This subscale of the FIBSER scale is a reliable and valid self-report measure on the frequency of medication side effects in a population receiving treatment for depression. This scale measures the participants side effects frequency from the previous week and has them rate each on a scale from 0-6. The results will help the clinician determine the appropriate level of response.
The range is from 0-6, higher scores reflect an greater frequency in medication side effects.
Measured: 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
This subscale of the FIBSER scale is a reliable self-report measure of the side effects burden of medications in a population receiving treatment for depression. This scale measures the participants side effects burden from the previous week and has them rate each on a scale from 0-6. The results will help the clinician determine the appropriate level of response.
The range is from 0-6, higher scores reflect an greater burden in medication side effects.
Measured: 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 ).
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 May 2024
- Study start1 Oct 2024
- Primary completion28 Feb 2030 (estimated)
- Study completion28 Feb 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Bipolar I DisorderStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 2,726 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Responsible party
- Principal investigator, Andrew A. Nierenberg, MD, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06433635
- Sponsor's protocol ID
- 2024P000831
- Acronym
- SMART-BD
- Status last verified
- Dec 2025
- First submitted
- 22 Apr 2024
- Last updated
- 16 Dec 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Sequential Multiple Assignment Randomized Trial for Bipolar Depression
- ClinicalTrials.gov ID
- NCT06433635
- Acronym / sponsor ID
- SMART-BD / 2024P000831
- Conditions
- Bipolar I Disorder, Depression
- Keywords
- Bipolar, Depression, Adults, Medication
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 2,726 participants (estimated)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Study start
- 1 Oct 2024 (actual)
- Primary completion
- 28 Feb 2030 (estimated)
- Study completion
- 28 Feb 2030 (estimated)
- First posted
- 30 May 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
This is a comparative effectiveness study to address the critical questions of how best to treat people with bipolar disorder who have a major depressive episode: how to get them well, provide second-line treatment when they don't initially get well, and keep them well after they get well. This is a multisite Sequential Multiple Assignment Randomized Trial (SMART) comparative effectiveness design. Investigators will recruit 2726 participants who have BD I or II with a current major depressive episode lasting at least 2 weeks. In Stage 1, investigators will compare four treatment arms, including three FDA approved monotherapies and the most widely used, but understudied, treatment for BD major depressive episode (i.e., a non-FDA approved combination of an antipsychotic and antidepressant). In Stage 2, participants who do not remit will be re-randomized to treatments not used in Stage 1. Investigators will follow all participants for a total of 52 weeks. This study will be conducted in two phases, a feasibility phase and a full study phase. In the feasibility phase, investigators will recruit at 8 of the 19 study sites based on readiness and interest, to ensure the efficacy of the study design before launching the full study phase.
Feasibility Aim 1: To ensure that 8 of the 19 selected sites can recruit, randomize, and retain participants. During the feasibility phase, the selected sites will recruit 133 participants, administer baseline assessments, randomize the participants (at baseline and again at 6-weeks for non-remitters), and conduct follow-up assessments at the end of Stage 1 (6-weeks) and the end of Stage 2 (12-weeks) and end of study (52 weeks or end of feasibility phase, whichever is sooner) and all other scheduled visits.
Feasibility Aim 2: To refine and finalize all study standard operating procedures for the full-scale study. After Aim 1 is complete, any changes in standard operating procedures will be made as needed to be implemented in the full study phase.
Full Scale Study Full-Scale Study Aim 1: To compare the effectiveness, tolerability, and safety of the four treatments for BD major depressive episodes.
Hypothesis 1a: There will be significant differences across the Stage 1 treatments in the proportion of remitters at week 6 (primary endpoint, effectiveness) and in the average adverse event burden and suicidal ideation/behavior at week 6 (secondary endpoints, tolerability and safety).
Hypothesis 1b: Among non-remitters of a given Stage 1 treatment (i.e., participants who do not remit by week 6), there will be significant differences across the three remaining Stage 2 treatments in the proportion of remitters at week 12 (primary endpoint, effectiveness) and the average side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
Full-Scale Study Aim 2: To characterize the effectiveness, tolerability, and safety of the 12 adaptive interventions for BD major depressive episodes embedded within the SMART design.
Hypothesis 2: On average, there will be significant differences across the 12 embedded adaptive interventions in the proportion of remitters at week 12 (primary endpoint, effectiveness) and in the average side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
Full-Scale Study Aim 3: To determine individual-level characteristics that predict heterogeneity of treatment effect (HTE) across the 12 adaptive interventions for BD major depressive episodes embedded within the SMART design.
Hypothesis 3a: Individual-level characteristics and symptoms assessed at baseline as well as symptom changes and side effect profiles at week 6 will predict HTE at weeks 12 and 52. Hypothesis 3b: Investigators hypothesize that an optimal personalized adaptive intervention will perform significantly better than the best aggregate embedded adaptive intervention identified in Aim 2 in terms of the proportion of remitters at week 12 (primary endpoint, effectiveness) and the side effect burden and suicidal ideation/behavior at week 12 (secondary endpoints, tolerability and safety).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Cariprazine | Experimental | Drug: Cariprazine |
| Aripiprazole /Escitalopram combination | Experimental | Drug: Aripiprazole/Escitalopram combination |
| Quetiapine | Experimental | Drug: Quetiapine |
| Lurasidone | Experimental | Drug: Lurasidone |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CariprazineAlso: Vraylar1. 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. | Drug | Cariprazine |
| Aripiprazole/Escitalopram combinationAlso: Abilify/ Lexapro1. 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. | Drug | Aripiprazole /Escitalopram combination |
| QuetiapineAlso: Seroquel1. 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. | Drug | Quetiapine |
| LurasidoneAlso: Latuda1. 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. | Drug | Lurasidone |
Primary outcome
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 ).
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.
4 secondary outcomes
Safety: Concise Health Risk Tracking Scale
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 ).
Frequency and Intensity of Side Effects Ratings - Intensity
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 ).
Frequency and Intensity of Side Effects Ratings - Frequency
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 ).
Frequency and Intensity of Side Effects Ratings - Burden
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 ).
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Dec 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
18 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Cariprazine, Aripiprazole/Escitalopram combination and Quetiapine in people with Bipolar I Disorder and Depression, run by Massachusetts General Hospital at 18 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 16 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the 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 ).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Dec 2025.