Project Summary

What is the research about?

This is a comparative effectiveness study to address the critical questions of how best to treat people with bipolar disorder who have major depressive episodes. Bipolar disorder is a psychiatric disorder that occurs in about 1-2% of the population and is characterized by episodes of depression that include low mood and energy, and episodes of mania, that are associated with elevated mood, high energy, and lack of sleep. Over 90% of patients experience multiple mood episodes over their lifetime with depressive episodes being much more frequent and burdensome than manic episodes. Depressive episodes are associated with poor functioning over time and are associated with a substantially increased risk of suicidal thoughts, suicidal behavior, and death by suicide. Even though it is a top ten cause of global disability, much less is known about the treatment of bipolar than nonbipolar depressive episodes because of chronic under-investment in bipolar research compared to other psychiatric disorders. Importantly, no studies have compared the four FDA approved treatment options for depression in bipolar disorder. Thus, clinicians have no evidence base to decide which agent to choose first or what to use next if the first agent does not help. This research aims to compare the short- and long-term effectiveness, side effect burden, and safety of three FDA approved medications for the treatment of bipolar depression (cariprazine, lurasidone and quetiapine) with a commonly used antipsychotic and antidepressant combination, namely aripiprazole and escitalopram. The study team also aims to identify specific clinical features in patients that can help with choice of medication.

Who can this research help?

The results of this study will help patients with bipolar depression who are seeking treatment and clinicians treating such patients with deciding which medication to try first, and what to choose next if the first option does not work or has unbearable side effects. It will help them compare both effectiveness of the medication options and side effects and safety of three FDA approved medications for bipolar depression and a commonly used, but unstudied antipsychotic/antidepressant combination (i.e., aripiprazole and escitalopram). The study will reach out and engage representative stakeholders (patients with bipolar depression, clinicians, insurance providers) and incorporate their input in all areas of study design, implementation, and dissemination of results.

What is the research team doing?

The study will be conducted at 19 academic medical centers (across the US with two sites in Canada) who will each partner with a local health center in the community. The research team proposes to recruit 2800 participants from these sites who have bipolar disorder and are seeking treatment for a major depressive episode. Willing participants will be randomized to one of four arms in the study. The treatment will consist of an initial acute treatment period of up to 12 weeks. Participants who do not respond to treatment after the initial 6 weeks will be re-randomized into one of the remaining therapy arms for the next 6 weeks. Both those who respond and those who do not respond to treatment at the 12-week time point will be followed for a total of 52 weeks from the time that they start the study.

Research methods at a glance

Design: Multicenter Sequential Multiple Assignment Randomized Trial (SMART) comparative effectiveness design.

Population: Adults 18-75 years and older with Bipolar type I, who are currently depressed and seeking treatment.

Interventions/Comparators: Randomization to one of 4 treatment arms: 1) Cariprazine, 2) Lurasidone, 3) Quetiapine, 4) A combination of Aripiprazole and Escitalopram.

Outcomes: Primary: Remission of depression at weeks 6 and 12; Secondary: Side effects and safety of treatment at weeks 6 and 12; Exploratory: Remission from depression, side effects, safety, quality of life, and cognitive and social functioning at 52 weeks.

Project Information

Andrew Nierenberg, MD
Andrea Foulkes, PhD
Massachusetts General Hospital
$24,777,559 *

Key Dates

78 months *
2022

*All proposed projects, including requested budgets and project periods, are approved subject to a programmatic and budget review by PCORI staff and the negotiation of a formal award contract.

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Last updated: August 5, 2022