Bipolar DepressionPhase 3NCT04569448
Brexpiprazole Treatment for Bipolar I Depression
A Phase 3 study testing Brexpiprazole in people with Bipolar Depression, run by Douglas Mental Health University Institute at 3 sites in Canada.
Trial summary
Bipolar disorder (BD) is a frequent and lifelong recurrent mood disorder with treatment-resistant depressive episodes. Importantly, depressive symptoms and cognitive decline are major determinants of functionality and quality of life in this clinical population. Read more about this study
- Who is it for?
- Ages 18 to 75 yearsHealthy volunteers can take part
- Conditions the study is for
- Bipolar Depression
- What is being tested?
- Brexpiprazole
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 58 participants
- Where
- 3 sitesCanada
- Study dates
- 10 May 2021to Dec 2030
- Phase
- Phase 3
- 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
- Healthy volunteers accepted
- Adult, Older adult
Patient Inclusion Criteria:
- Age: 18-75
- Male or female
- Bipolar Disorder type I or type II
- Current treatment-resistant depressive episode (with MADRS >/= 24 and item 2 (reported sadness) >/= 3) for a minimum of 2 weeks but </= 52 weeks at screening visit and baseline visit
- Patients must have failed at least one other treatment for the current depressive episode
- If female and of childbearing potential, is using an adequate method of contraception. Adequate methods of contraception include abstinence; oral contraceptive pill or surgically implanted device; intra-uterine device; condom plus spermicidal foam or jelly; or tubal ligation
- Is treated with a mood stabilizer (lithium and/or valproate and/or lamotrigine and/or quetiapine </= 100mg/day)
- The following laboratory values are within normal limits at Screening: CBC with differential; ferritin; extended electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphate); thyroid function test(s); kidney function tests; hemoglobin A1c; lipid profile; prolactin
- Normal EKG at Screening
- Patient is able to give his(her) consent
Patient Exclusion Criteria:
- Is at high risk of suicide as defined by a score of >/= 3 to item 10 of MADRS and/or in the clinical opinion of the investigator
- Hypo(mania) episode with YMRS >/= 8
- Psychotic symptoms as defined by a score of >/= 4 to item 8 (content) of YMRS and/or in the opinion of the investigator
- Is treated with fluoxetine OR carbamazepine
- Is treated with risperidone OR olanzapine OR quetiapine > 100mg/day OR ziprazidone OR any other antipsychotic
- Is pregnant or lactating or absence of contraceptive treatment
- Drug abuse or dependence as per DSM-V (MINI)
- Unstable medical condition
- Other unstable and/or untreated psychiatric condition, organic brain disorder, unstable and/or untreated medical condition such as hypothyroidism, hyperthyroidism, diabetes, cardiac condition, hypertension
- Deficit in vitamin B12 or folate
- Rapid cycling (more than 4 mood episodes per year)
- Active or history of difficulty to swallow
- Seizures not currently controlled with medications
- Orthostatic hypotension defined as a drop in systolic blood pressure of at least 20 mmHg or of diastolic BP of at least 10 mmHg within 3 minutes of standing
- A history of clinically significant cardiovascular disorders and cardiac arrhythmias
- A low white blood cell count
- Known eye disease
- Involuntary, irregular muscle movements, especially in the face
- Known hypersensitivity to Brexpiprazole and any components of its formulation
- Known lactose intolerance or have hereditary galactose intolerance or glucose-galactose malabsorption, because Brexpiprazole and placebo tablets contain lactose (a disaccharide of glucose and galactose)
- Active inflammatory disease including lupus, colitis, Crohn's disease, psoriasis, irritable bowel syndrome (IBS)
- Mild or major neurocognitive disorder
- Previous history of sensitivity/low tolerance to medications metabolized by CYP 2D6 inhibitors, or CYP 3A4 inducers
Control Inclusion Criteria:
- Age: 18-75
- Male or female
- No current or past history of any psychiatric disorder
- Patients must have failed at least one other treatment for the current depressive episode
- If female and of childbearing potential, is using an adequate method of contraception. Adequate methods of contraception include abstinence; oral contraceptive pill or surgically implanted device; intra-uterine device; condom plus spermicidal foam or jelly; or tubal ligation
- The following laboratory values are within normal limits at Screening: CBC with differential; ferritin; extended electrolytes (sodium, potassium, chloride, calcium, magnesium, phosphate); thyroid function test(s); kidney function tests; hemoglobin A1c; lipid profile; prolactin
- Normal EKG at Screening
- Patient is able to give his(her) consent
Control Exclusion Criteria:
- Alcohol or drug abuse
- Deficit in vitamin B12 or folate
- Seizures not currently controlled with medications
- History of clinically significant cardiovascular disorders and cardiac arrhythmias
- Mild or major neurocognitive disorder
Patient/Control Exclusion Criteria for MRI:
- Pacemaker
- Heart/vascular clip
- Metal prosthesis
- Metal fragments in body
- Transdermal patch
- Aneurysm clip
- Prosthetic valve
- Claustrophobia
- Pregnant
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Canada3 sites, 1 recruiting
- Terminated
McMaster University
Hamilton, Ontario, L8S 4L8
- Withdrawn
Jewish General Hospital
Montreal, Quebec, H3T 1E2
- Recruiting
Douglas Mental Health University Institute
Montreal, Quebec, H4H 1R3
Lori Moreno, BSc, 514 444 5397, lori.moreno.comtl@ssss.gouv.qc.ca
Serge Beaulieu, MD, PhD, FRCPC, DFAPA
About this study
Official title: Low-Dose Adjunctive Brexpiprazole in the Treatment of Bipolar I Depression: An Open-Label Study
Bipolar disorder (BD) is a frequent and lifelong recurrent mood disorder with treatment-resistant depressive episodes. Importantly, depressive symptoms and cognitive decline are major determinants of functionality and quality of life in this clinical population. There is robust evidence that individuals with BD have neurocognitive deficits (especially in memory and executive functioning domains) compared to the healthy population. These deficits are present in all mood states and can greatly affect patients' functional capacity, often more so than mood symptoms themselves. Many pharmacological treatments for BD adversely affect cognition, and those that are beneficial can be difficult to use. There is thus a pressing need to identify a safe, easy-to-use medication that can target both cognitive deficits and depressive symptoms in BD. It is expected that Brexpiprazole adjunctive treatment will be efficacious in treating BD type I and type II depression by improving mood symptoms, as well as cognitive capacity and global functioning, and that such changes will be accompanied by concurrent alterations in associated brain structures.
Read the detailed description
The estimated lifetime prevalence of bipolar disorders is 0.55% for bipolar type I and 1.65% for bipolar type II. In the long term, patients with a bipolar disorder spend on average 60% of their time in depressive states, with intermittent hypomanic or manic phases. Moreover, the depressive episodes tend to become more frequent and difficult to treat as they grow in number and/or frequency. Many studies have demonstrated that even so-called stabilized bipolar patients will go through frequent subsyndromal depressive symptoms during a significant portion of any given year.
Bipolar depression is heavily loaded with general symptoms of psychomotor retardation, anergia, hypersomnolence, hyperphagia, decreased motivation, anhedonia and cognitive difficulties. All these functions are modulated by dopamine, and strategies aimed at improving dopaminergic function are frequently used to resolve residual symptoms of bipolar depression. Brexpiprazole is a new serotonin-dopamine antagonist which possesses unique capabilities with partial dopaminergic (D2) agonistic activities. Moreover, like other atypical agents, Brexpiprazole is a potent antagonist of the 5-HT2a receptor, as well as the adrenergic α1b and α2c receptors, and is a 5-HT1a post-synaptic agonist. These properties enable the molecule to provide antidepressant potentiating capabilities. While Brexpiprazole is currently recognized for its capacity to potentiate antidepressant effects in unipolar depression, there is still a need to evaluate the molecule's effect in bipolar depression.
Depressive symptoms and cognitive deficits are major determinants of functionality and quality of life in individuals with bipolar disorders. Cognitive problems tend to increase with the number of mood episodes, psychotic symptoms, and anxiety. Further, certain medications (and especially polypharmacy) can increase cognitive decline in the long term. As the average age of the patient population increases, risk for cognitive decline due to aging and prolonged medication use is of importance. From a neuroanatomical perspective, current neuroscience literature has related treatment with Aripiprazole to improved memory performance and structural changes in the hippocampus in patients at an early stage of psychosis. The chemically and pharmacologically related compound Brexpiprazole is thus a promising candidate for targeting both depressive symptoms and cognitive deficits observed in bipolar depression given its partial agonistic activity at the D2 receptor and, possibly, because of its 5-HT7 antagonistic activity.
Treatment of bipolar depression is further complicated by the knowledge that, in the long-term, use of antidepressants may be associated with manic/hypomanic switches, rapid cycling, and mixed features. These further increase the risk of cognitive decline and suicidality. In fact, the suicide rate in bipolar disorders is relatively high compared with other disorders, with certain studies reporting that up to 50% of bipolar patients will attempt suicide. Further, mortality is considerably higher among patients with bipolar disorders as compared to the general population given patients' high risk for diabetes and cardiovascular disorders (considerably increased by valproate and antipsychotic treatment). In the prevention of excess mortality, selection of first-line medications with a smaller effect on weight is essential.
Further, an interesting new phenotype for the personalized treatment of bipolar disorders is dysregulated biological rhythms (i.e., sleeping and eating patterns). This is a core etiopathological feature of bipolar disorders, and has been associated with obesity, cancer, and accelerated mortality in the general population. It has been previously shown that a majority of patients with bipolar disorders show a specific pattern of disorganized activity rhythm that is associated with treatment resistance, mood lability and obesity. It was recently reported that Aripiprazole can correct this type of disorganized rhythm. Based on an animal model, this effect is linked to dopaminergic activity. It is expected that Brexpiprazole will have a similar effect. This is supported by a recent sleep study of Brexpiprazole in treatment-resistant major depressive disorder that found an improvement of most sleep parameters in addition to decreasing daytime sleepiness and improving mood symptoms.
In addition, insulin resistance is shown to be one of the most robust predictors of a more chronic course of bipolar disorder. C-reactive protein (CRP) was shown to be two times greater in patients with insulin resistance compared to those without. Higher CRP is thus considered to be a predictor of treatment-resistance and cardiovascular risk in this clinical population. Most importantly, treatment response has been associated with decreasing CRP, decreasing insulin resistance, and decreasing depressive symptoms. As such, treatment-resistant bipolar depression can be viewed as a metabolic mood syndrome that is associated with a cognitive decline.
Taken together, there is a need to improve the repertoire of treatments for bipolar depression. One would favor strategies that procure a rapid onset of action as well as a low risk of switching to hypomania and weight gain. Finally, one would favor strategies that would procure relief for the most frequent and persistent symptoms of bipolar depression, such as psychomotor retardation, cognitive deficits, and reversed neurovegetative symptoms. Thus, the current study will evaluate the efficacy and tolerability of an adjunctive, variable dose of Brexpiprazole treatment in bipolar depression.
- Conditions
- Bipolar Depression
- Being tested
- Brexpiprazole
- Keywords
- Brexpiprazole, Treatment-resistant depression, Cognition, Functioning, Rest-Activity rhythm, Hippocampus, CRP
- Medical subject headings
- Bipolar Disorder, Depressive Disorder, Treatment-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BrexpiprazoleDrug
Adjunctive variable dose (1-3 mg/day) Brexpiprazole
| Study group | Role | What they receive |
|---|---|---|
| Patient | Experimental | Individuals diagnosed with Bipolar Disorder Type I or Type II and suffering a major depressive episode who will receive an adjunctive and variable dose of Brexpiprazole treatment Receives: Drug: Brexpiprazole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from Baseline Depressive Symptoms as Assessed by MADRS at 8 weeks
Percentage of response to treatment, as defined by a 50% improvement of depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) at 8 weeks. The overall MADRS score ranges from 0 to 60, where a higher score indicates more severe depression.
Measured: 8 weeks
Secondary outcomes (32)
Change from Baseline Global Functioning as Assessed by FAST at 8 weeks
Differential scores from baseline on Functioning Assessment Short Test (FAST) after 8 weeks of treatment. The overall FAST score ranges from 0 to 72, where a higher score indicates more severe difficulties.
Measured: 8 weeks
Change from Baseline Global Functioning as Assessed by FAST at 12 weeks
Differential scores from baseline on Functioning Assessment Short Test (FAST) after 12 weeks of treatment. The overall FAST score ranges from 0 to 72, where a higher score indicates more severe difficulties.
Measured: 12 weeks
Change from Baseline Global Functioning as Assessed by FAST at 6 months
Differential scores from baseline on Functioning Assessment Short Test (FAST) after 6 months of treatment. The overall FAST score ranges from 0 to 72, where a higher score indicates more severe difficulties.
Measured: 6 months
Change from Baseline Global Functioning as Assessed by CPFQ at 8 weeks
Differential scores from baseline on Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) after 8 weeks. The overall CPFQ score ranges from 0 to 42, where a higher score indicates poorer functioning.
Measured: 8 weeks
Change from Baseline Global Functioning as Assessed by CPFQ at 12 weeks
Differential scores from baseline on Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) after 12 weeks. The overall CPFQ score ranges from 0 to 42, where a higher score indicates poorer functioning.
Measured: 12 weeks
Change from Baseline Global Functioning as Assessed by CPFQ at 6 months
Differential scores from baseline on Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) after 6 months.The overall CPFQ score ranges from 0 to 42, where a higher score indicates poorer functioning.
Measured: 6 months
Change from Baseline Global Functioning as Assessed by SDS at 8 weeks
Differential scores from baseline on Sheehan Disability Scale (SDS) after 8 weeks. The overall SDS score ranges from 0 to 30, where a higher score indicates greater impairment.
Measured: 8 weeks
Change from Baseline Global Functioning as Assessed by SDS at 12 weeks
Differential scores from baseline on Sheehan Disability Scale (SDS) after 12 weeks. The overall SDS score ranges from 0 to 30, where a higher score indicates greater impairment.
Measured: 12 weeks
Change from Baseline Global Functioning as Assessed by SDS at 6 months
Differential scores from baseline on Sheehan Disability Scale (SDS) after 6 months. The overall SDS score ranges from 0 to 30, where a higher score indicates greater impairment.
Measured: 6 months
Number of Participants with Treatment-Related Adverse Events or Serious Adverse Events
Number of safety events as measured by adverse event (AE) and serious adverse event (SAE) reporting.
Measured: Up to 6 months
Change from Baseline Impairments as Assessed by AIMS at 8 weeks
Differential scores from baseline on Abnormal Involuntary Movement Scale (AIMS) at 8 weeks. The overall scores ranges from 0 to 12, where a higher score indicates greater impairment.
Measured: 8 weeks
Change from Baseline Impairments as Assessed by BARS at 8 weeks
Differential scores from baseline impairments on Barnes-Akathisia Rating Scale (BARS) at 8 weeks. The overall score ranges from 0 to 9, where a higher score indicates greater severity.
Measured: 8 weeks
Switch Rate into Hypomania as Assessed by the YMRS at 8 weeks
Percentage of switch into hypomania as defined by a Young Mania Rating Scale (YMRS) score ≥ 8 at 8 weeks.
Measured: 8 weeks
Switch Rate into Hypomania as Assessed by the YMRS at 12 weeks
Percentage of switch into hypomania as defined by a Young Mania Rating Scale (YMRS) score ≥ 8 at 12 weeks.
Measured: 12 weeks
Change from Baseline Impairments as Assessed by CGI-I at 8 weeks
Differential scores from baseline impairments on Clinical Global Impression-Improvement (CGI-I) at 8 weeks. Scores range from 0 to 7, where a higher score indicates worsening of the illness.
Measured: 8 weeks
Change from Baseline Impairments as Assessed by CGI-I at 12 weeks
Differential scores from baseline impairments on Clinical Global Impression-Improvement (CGI-I) at 12 weeks. Scores range from 0 to 7, where a higher score indicates worsening of the illness.
Measured: 12 weeks
Change from Baseline Level of CRP at 8 weeks
Differential baseline levels of C-reactive protein (CRP) (mg/L) at 8 weeks.
Measured: 8 weeks
Change from Baseline Level of CRP at 12 weeks
Differential baseline levels of C-reactive protein (CRP) (mg/L) at 12 weeks.
Measured: 12 weeks
Change from Baseline Rest/Activity Rhythm at 8 weeks
Differential baseline rest-activity rhythm regularity at 8 weeks as measured by standard deviation of sleep onset, midpoint of sleep, and sleep consolidation.
Measured: 8 weeks
Change from Baseline Cognition as Assessed by the SCIP at 8 weeks
Differential scores from baseline cognitive impairments assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) at 8 weeks. Total scores range from 0 to 94, where higher scores indicate higher performance.
Measured: 8 weeks
Change from Baseline Cognition as Assessed by the SCIP at 12 weeks
Differential scores from baseline cognitive impairments assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) at 12 weeks. Total scores range from 0 to 94, where higher scores indicate higher performance.
Measured: 12 weeks
Change from Baseline Cognition as Assessed by the SCIP at 6 months
Differential scores from baseline cognitive impairments assessed using the Screen for Cognitive Impairment in Psychiatry (SCIP) at 6 months. Total scores range from 0 to 94, where higher scores indicate higher performance.
Measured: 6 months
Change from Baseline Cognition as Assessed by the THINC-it toolkit at 8 weeks
Differential scores from baseline cognitive impairments assessed using the THINC-it toolkit at 8 weeks. The toolkit assesses the following measures: (1) attention, (2) working memory, (3) a variety of cognitive skills, and (4) executive function. An overview performance metric is calculated, the minimum is 0 and the maximum is 4000, with higher scores indicating better performance
Measured: 8 weeks
Change from Baseline Cognition as Assessed by the THINC-it toolkit at 12 weeks
Differential scores from baseline cognitive impairments assessed using the THINC-it toolkit at 12 weeks. The toolkit assesses the following measures: (1) attention, (2) working memory, (3) a variety of cognitive skills, and (4) executive function. An overview performance metric is calculated, the minimum is 0 and the maximum is 4000, with higher scores indicating better performance
Measured: 12 weeks
Change from Baseline Cognition as Assessed by the THINC-it toolkit at 6 months
Differential scores from baseline cognitive impairments assessed using the THINC-it toolkit at 6 months. The toolkit assesses the following measures: (1) attention, (2) working memory, (3) a variety of cognitive skills, and (4) executive function. An overview performance metric is calculated, the minimum is 0 and the maximum is 4000, with higher scores indicating better performance
Measured: 6 months
Change from Baseline Cognition as Assessed by the RAVLT at 8 weeks
Differential scores from baseline cognitive impairments assessed using the Rey Auditory Verbal Learning Test (RAVLT) at 8 weeks. Total scores range from 0-15 for the following sub-scales: immediate recall, delayed recall, and recognition. Higher scores indicate higher performance for all three sub-scales.
Measured: 8 weeks
Change from Baseline Cognition as Assessed by the RAVLT at 12 weeks
Differential scores from baseline cognitive impairments assessed using the Rey Auditory Verbal Learning Test (RAVLT) at 8 weeks. Total scores range from 0-15 for the following sub-scales: immediate recall, delayed recall, and recognition. Higher scores indicate higher performance for all three sub-scales.
Measured: 12 weeks
Change from Baseline Cognition as Assessed by the RAVLT at 6 months
Differential scores from baseline cognitive impairments assessed using the Rey Auditory Verbal Learning Test (RAVLT) at 8 weeks. Total scores range from 0-15 for the following sub-scales: immediate recall, delayed recall, and recognition. Higher scores indicate higher performance for all three sub-scales.
Measured: 6 months
Change from Baseline Cognition as Assessed by the DSST at 8 weeks
Differential scores from baseline cognitive impairments assessed using the Digit Symbol Substitution Test at 8 weeks. Total scores range from 0 to 100, with higher scores indicating higher cognitive function.
Measured: 8 weeks
Change from Baseline Cognition as Assessed by the DSST at 12 weeks
Differential scores from baseline cognitive impairments assessed using the Digit Symbol Substitution Test at 12 weeks. Total scores range from 0 to 100, with higher scores indicating higher cognitive function.
Measured: 12 weeks
Change from Baseline Cognition as Assessed by the DSST at 6 months
Differential scores from baseline cognitive impairments assessed using the Digit Symbol Substitution Test at 6 months. Total scores range from 0 to 100, with higher scores indicating higher cognitive function.
Measured: 6 months
Change from Baseline Hippocampal Volume as Assessed with MRI at 6 months
Differential hippocampal volumes between baseline and 6 months as assessed with structural magnetic resonance imaging (MRI).
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Sep 2020
- Study start10 May 2021
- Primary completionSep 2030 (estimated)
- Study completionDec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (32)Papers the sponsor has linked to this study.
- Other trials for Bipolar DepressionStudies of the same condition, open and under way.
- 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 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 58 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Douglas Mental Health University Institute
- Sponsor type
- University, hospital or other
- Collaborators
- McMaster University, Jewish General Hospital
- Responsible party
- Principal investigator, Serge Beaulieu, Douglas Mental Health University Institute
- Investigators
- Serge Beaulieu, MD, PhD, FRCPC, DFAPA, Principal investigator, Douglas Mental Health University Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04569448
- Sponsor's protocol ID
- RSS 5182913
- Status last verified
- Aug 2026
- First submitted
- 4 Aug 2020
- Last updated
- 27 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Angst J. The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord. 1998 Sep;50(2-3):143-51. doi: 10.1016/s0165-0327(98)00142-6.
PubMed 9858074Parker G. How should mood disorders be modelled? Aust N Z J Psychiatry. 2008 Oct;42(10):841-50. doi: 10.1080/00048670802345458.
PubMed 18777228Pallaskorpi S, Suominen K, Ketokivi M, Mantere O, Arvilommi P, Valtonen H, Leppamaki S, Isometsa E. Five-year outcome of bipolar I and II disorders: findings of the Jorvi Bipolar Study. Bipolar Disord. 2015 Jun;17(4):363-74. doi: 10.1111/bdi.12291. Epub 2015 Mar 2.
PubMed 25726951Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, Leon AC, Rice JA, Keller MB. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002 Jun;59(6):530-7. doi: 10.1001/archpsyc.59.6.530.
PubMed 12044195Andreou C, Bozikas VP. The predictive significance of neurocognitive factors for functional outcome in bipolar disorder. Curr Opin Psychiatry. 2013 Jan;26(1):54-9. doi: 10.1097/YCO.0b013e32835a2acf.
PubMed 23154642Miskowiak KW, Burdick KE, Martinez-Aran A, Bonnin CM, Bowie CR, Carvalho AF, Gallagher P, Lafer B, Lopez-Jaramillo C, Sumiyoshi T, McIntyre RS, Schaffer A, Porter RJ, Purdon S, Torres IJ, Yatham LN, Young AH, Kessing LV, Vieta E. Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians. Bipolar Disord. 2018 May;20(3):184-194. doi: 10.1111/bdi.12595. Epub 2018 Jan 18.
PubMed 29345040Pallaskorpi S, Suominen K, Ketokivi M, Valtonen H, Arvilommi P, Mantere O, Leppamaki S, Isometsa E. Incidence and predictors of suicide attempts in bipolar I and II disorders: A 5-year follow-up study. Bipolar Disord. 2017 Feb;19(1):13-22. doi: 10.1111/bdi.12464. Epub 2017 Feb 8.
PubMed 28176421Hoang U, Goldacre MJ, Stewart R. Avoidable mortality in people with schizophrenia or bipolar disorder in England. Acta Psychiatr Scand. 2013 Mar;127(3):195-201. doi: 10.1111/acps.12045. Epub 2012 Dec 9.
PubMed 23216065Melo MC, Garcia RF, Linhares Neto VB, Sa MB, de Mesquita LM, de Araujo CF, de Bruin VM. Sleep and circadian alterations in people at risk for bipolar disorder: A systematic review. J Psychiatr Res. 2016 Dec;83:211-219. doi: 10.1016/j.jpsychires.2016.09.005. Epub 2016 Sep 13.
PubMed 27661417Hsu WY, Lane HY, Lin CH. Medications Used for Cognitive Enhancement in Patients With Schizophrenia, Bipolar Disorder, Alzheimer's Disease, and Parkinson's Disease. Front Psychiatry. 2018 Apr 4;9:91. doi: 10.3389/fpsyt.2018.00091. eCollection 2018.
PubMed 29670547Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004 Mar;161(3):564-6. doi: 10.1176/appi.ajp.161.3.564.
PubMed 14992985Zarate CA Jr, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004 Jul 1;56(1):54-60. doi: 10.1016/j.biopsych.2004.03.013.
PubMed 15219473El-Mallakh RS, Penagaluri P, Kantamneni A, Gao Y, Roberts RJ. Long-term use of pramipexole in bipolar depression: a naturalistic retrospective chart review. Psychiatr Q. 2010 Sep;81(3):207-13. doi: 10.1007/s11126-010-9130-6.
PubMed 20425143Citrome L. Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract. 2015 Sep;69(9):978-97. doi: 10.1111/ijcp.12714. Epub 2015 Aug 6.
PubMed 26250067Thase ME, Youakim JM, Skuban A, Hobart M, Augustine C, Zhang P, McQuade RD, Carson WH, Nyilas M, Sanchez R, Eriksson H. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry. 2015 Sep;76(9):1224-31. doi: 10.4088/JCP.14m09688.
PubMed 26301701
Study at a glance
From the registry record, last updated by the sponsor on 27 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Low-Dose Adjunctive Brexpiprazole in the Treatment of Bipolar I Depression: An Open-Label Study
- ClinicalTrials.gov ID
- NCT04569448
- Acronym / sponsor ID
- RSS 5182913
- Conditions
- Bipolar Depression
- Keywords
- Brexpiprazole, Treatment-resistant depression, Cognition, Functioning, Rest-Activity rhythm, Hippocampus, CRP
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 58 participants (estimated)
- Lead sponsor
- Douglas Mental Health University InstituteUniversity, hospital or other
- Collaborators
- McMaster University, Jewish General Hospital
- Study start
- 10 May 2021 (actual)
- Primary completion
- Sep 2030 (estimated)
- Study completion
- Dec 2030 (estimated)
- First posted
- 29 Sep 2020 (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.
Bipolar disorder (BD) is a frequent and lifelong recurrent mood disorder with treatment-resistant depressive episodes. Importantly, depressive symptoms and cognitive decline are major determinants of functionality and quality of life in this clinical population. There is robust evidence that individuals with BD have neurocognitive deficits (especially in memory and executive functioning domains) compared to the healthy population. These deficits are present in all mood states and can greatly affect patients' functional capacity, often more so than mood symptoms themselves. Many pharmacological treatments for BD adversely affect cognition, and those that are beneficial can be difficult to use. There is thus a pressing need to identify a safe, easy-to-use medication that can target both cognitive deficits and depressive symptoms in BD. It is expected that Brexpiprazole adjunctive treatment will be efficacious in treating BD type I and type II depression by improving mood symptoms, as well as cognitive capacity and global functioning, and that such changes will be accompanied by concurrent alterations in associated brain structures.
Detailed description
The estimated lifetime prevalence of bipolar disorders is 0.55% for bipolar type I and 1.65% for bipolar type II. In the long term, patients with a bipolar disorder spend on average 60% of their time in depressive states, with intermittent hypomanic or manic phases. Moreover, the depressive episodes tend to become more frequent and difficult to treat as they grow in number and/or frequency. Many studies have demonstrated that even so-called stabilized bipolar patients will go through frequent subsyndromal depressive symptoms during a significant portion of any given year.
Bipolar depression is heavily loaded with general symptoms of psychomotor retardation, anergia, hypersomnolence, hyperphagia, decreased motivation, anhedonia and cognitive difficulties. All these functions are modulated by dopamine, and strategies aimed at improving dopaminergic function are frequently used to resolve residual symptoms of bipolar depression. Brexpiprazole is a new serotonin-dopamine antagonist which possesses unique capabilities with partial dopaminergic (D2) agonistic activities. Moreover, like other atypical agents, Brexpiprazole is a potent antagonist of the 5-HT2a receptor, as well as the adrenergic α1b and α2c receptors, and is a 5-HT1a post-synaptic agonist. These properties enable the molecule to provide antidepressant potentiating capabilities. While Brexpiprazole is currently recognized for its capacity to potentiate antidepressant effects in unipolar depression, there is still a need to evaluate the molecule's effect in bipolar depression.
Depressive symptoms and cognitive deficits are major determinants of functionality and quality of life in individuals with bipolar disorders. Cognitive problems tend to increase with the number of mood episodes, psychotic symptoms, and anxiety. Further, certain medications (and especially polypharmacy) can increase cognitive decline in the long term. As the average age of the patient population increases, risk for cognitive decline due to aging and prolonged medication use is of importance. From a neuroanatomical perspective, current neuroscience literature has related treatment with Aripiprazole to improved memory performance and structural changes in the hippocampus in patients at an early stage of psychosis. The chemically and pharmacologically related compound Brexpiprazole is thus a promising candidate for targeting both depressive symptoms and cognitive deficits observed in bipolar depression given its partial agonistic activity at the D2 receptor and, possibly, because of its 5-HT7 antagonistic activity.
Treatment of bipolar depression is further complicated by the knowledge that, in the long-term, use of antidepressants may be associated with manic/hypomanic switches, rapid cycling, and mixed features. These further increase the risk of cognitive decline and suicidality. In fact, the suicide rate in bipolar disorders is relatively high compared with other disorders, with certain studies reporting that up to 50% of bipolar patients will attempt suicide. Further, mortality is considerably higher among patients with bipolar disorders as compared to the general population given patients' high risk for diabetes and cardiovascular disorders (considerably increased by valproate and antipsychotic treatment). In the prevention of excess mortality, selection of first-line medications with a smaller effect on weight is essential.
Further, an interesting new phenotype for the personalized treatment of bipolar disorders is dysregulated biological rhythms (i.e., sleeping and eating patterns). This is a core etiopathological feature of bipolar disorders, and has been associated with obesity, cancer, and accelerated mortality in the general population. It has been previously shown that a majority of patients with bipolar disorders show a specific pattern of disorganized activity rhythm that is associated with treatment resistance, mood lability and obesity. It was recently reported that Aripiprazole can correct this type of disorganized rhythm. Based on an animal model, this effect is linked to dopaminergic activity. It is expected that Brexpiprazole will have a similar effect. This is supported by a recent sleep study of Brexpiprazole in treatment-resistant major depressive disorder that found an improvement of most sleep parameters in addition to decreasing daytime sleepiness and improving mood symptoms.
In addition, insulin resistance is shown to be one of the most robust predictors of a more chronic course of bipolar disorder. C-reactive protein (CRP) was shown to be two times greater in patients with insulin resistance compared to those without. Higher CRP is thus considered to be a predictor of treatment-resistance and cardiovascular risk in this clinical population. Most importantly, treatment response has been associated with decreasing CRP, decreasing insulin resistance, and decreasing depressive symptoms. As such, treatment-resistant bipolar depression can be viewed as a metabolic mood syndrome that is associated with a cognitive decline.
Taken together, there is a need to improve the repertoire of treatments for bipolar depression. One would favor strategies that procure a rapid onset of action as well as a low risk of switching to hypomania and weight gain. Finally, one would favor strategies that would procure relief for the most frequent and persistent symptoms of bipolar depression, such as psychomotor retardation, cognitive deficits, and reversed neurovegetative symptoms. Thus, the current study will evaluate the efficacy and tolerability of an adjunctive, variable dose of Brexpiprazole treatment in bipolar depression.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patient | Experimental | Drug: BrexpiprazoleIndividuals diagnosed with Bipolar Disorder Type I or Type II and suffering a major depressive episode who will receive an adjunctive and variable dose of Brexpiprazole treatment |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
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 |
|---|---|---|
| BrexpiprazoleAdjunctive variable dose (1-3 mg/day) Brexpiprazole | Drug | Patient |
Primary outcome
Change from Baseline Depressive Symptoms as Assessed by MADRS at 8 weeks
Time frame: 8 weeks
Percentage of response to treatment, as defined by a 50% improvement of depressive symptoms on the Montgomery-Åsberg Depression Rating Scale (MADRS) at 8 weeks. The overall MADRS score ranges from 0 to 60, where a higher score indicates more severe depression.
32 secondary outcomes
Change from Baseline Global Functioning as Assessed by FAST at 8 weeks
Time frame: 8 weeks
Change from Baseline Global Functioning as Assessed by FAST at 12 weeks
Time frame: 12 weeks
Change from Baseline Global Functioning as Assessed by FAST at 6 months
Time frame: 6 months
Change from Baseline Global Functioning as Assessed by CPFQ at 8 weeks
Time frame: 8 weeks
Change from Baseline Global Functioning as Assessed by CPFQ at 12 weeks
Time frame: 12 weeks
Change from Baseline Global Functioning as Assessed by CPFQ at 6 months
Time frame: 6 months
Change from Baseline Global Functioning as Assessed by SDS at 8 weeks
Time frame: 8 weeks
Change from Baseline Global Functioning as Assessed by SDS at 12 weeks
Time frame: 12 weeks
Change from Baseline Global Functioning as Assessed by SDS at 6 months
Time frame: 6 months
Number of Participants with Treatment-Related Adverse Events or Serious Adverse Events
Time frame: Up to 6 months
Change from Baseline Impairments as Assessed by AIMS at 8 weeks
Time frame: 8 weeks
Change from Baseline Impairments as Assessed by BARS at 8 weeks
Time frame: 8 weeks
Switch Rate into Hypomania as Assessed by the YMRS at 8 weeks
Time frame: 8 weeks
Switch Rate into Hypomania as Assessed by the YMRS at 12 weeks
Time frame: 12 weeks
Change from Baseline Impairments as Assessed by CGI-I at 8 weeks
Time frame: 8 weeks
Change from Baseline Impairments as Assessed by CGI-I at 12 weeks
Time frame: 12 weeks
Change from Baseline Level of CRP at 8 weeks
Time frame: 8 weeks
Change from Baseline Level of CRP at 12 weeks
Time frame: 12 weeks
Change from Baseline Rest/Activity Rhythm at 8 weeks
Time frame: 8 weeks
Change from Baseline Cognition as Assessed by the SCIP at 8 weeks
Time frame: 8 weeks
Change from Baseline Cognition as Assessed by the SCIP at 12 weeks
Time frame: 12 weeks
Change from Baseline Cognition as Assessed by the SCIP at 6 months
Time frame: 6 months
Change from Baseline Cognition as Assessed by the THINC-it toolkit at 8 weeks
Time frame: 8 weeks
Change from Baseline Cognition as Assessed by the THINC-it toolkit at 12 weeks
Time frame: 12 weeks
Change from Baseline Cognition as Assessed by the THINC-it toolkit at 6 months
Time frame: 6 months
Change from Baseline Cognition as Assessed by the RAVLT at 8 weeks
Time frame: 8 weeks
Change from Baseline Cognition as Assessed by the RAVLT at 12 weeks
Time frame: 12 weeks
Change from Baseline Cognition as Assessed by the RAVLT at 6 months
Time frame: 6 months
Change from Baseline Cognition as Assessed by the DSST at 8 weeks
Time frame: 8 weeks
Change from Baseline Cognition as Assessed by the DSST at 12 weeks
Time frame: 12 weeks
Change from Baseline Cognition as Assessed by the DSST at 6 months
Time frame: 6 months
Change from Baseline Hippocampal Volume as Assessed with MRI at 6 months
Time frame: 6 months
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 27 Aug 2026.
- Background: PubMed 9858074Angst J. The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord. 1998 Sep;50(2-3):143-51. doi: 10.1016/s0165-0327(98)00142-6.
- Background: PubMed 18777228Parker G. How should mood disorders be modelled? Aust N Z J Psychiatry. 2008 Oct;42(10):841-50. doi: 10.1080/00048670802345458.
- Background: PubMed 25726951Pallaskorpi S, Suominen K, Ketokivi M, Mantere O, Arvilommi P, Valtonen H, Leppamaki S, Isometsa E. Five-year outcome of bipolar I and II disorders: findings of the Jorvi Bipolar Study. Bipolar Disord. 2015 Jun;17(4):363-74. doi: 10.1111/bdi.12291. Epub 2015 Mar 2.
- Background: PubMed 12044195Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, Leon AC, Rice JA, Keller MB. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002 Jun;59(6):530-7. doi: 10.1001/archpsyc.59.6.530.
- Background: PubMed 23154642Andreou C, Bozikas VP. The predictive significance of neurocognitive factors for functional outcome in bipolar disorder. Curr Opin Psychiatry. 2013 Jan;26(1):54-9. doi: 10.1097/YCO.0b013e32835a2acf.
- Background: PubMed 29345040Miskowiak KW, Burdick KE, Martinez-Aran A, Bonnin CM, Bowie CR, Carvalho AF, Gallagher P, Lafer B, Lopez-Jaramillo C, Sumiyoshi T, McIntyre RS, Schaffer A, Porter RJ, Purdon S, Torres IJ, Yatham LN, Young AH, Kessing LV, Vieta E. Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians. Bipolar Disord. 2018 May;20(3):184-194. doi: 10.1111/bdi.12595. Epub 2018 Jan 18.
- Background: PubMed 28176421Pallaskorpi S, Suominen K, Ketokivi M, Valtonen H, Arvilommi P, Mantere O, Leppamaki S, Isometsa E. Incidence and predictors of suicide attempts in bipolar I and II disorders: A 5-year follow-up study. Bipolar Disord. 2017 Feb;19(1):13-22. doi: 10.1111/bdi.12464. Epub 2017 Feb 8.
- Background: PubMed 23216065Hoang U, Goldacre MJ, Stewart R. Avoidable mortality in people with schizophrenia or bipolar disorder in England. Acta Psychiatr Scand. 2013 Mar;127(3):195-201. doi: 10.1111/acps.12045. Epub 2012 Dec 9.
- Background: PubMed 27661417Melo MC, Garcia RF, Linhares Neto VB, Sa MB, de Mesquita LM, de Araujo CF, de Bruin VM. Sleep and circadian alterations in people at risk for bipolar disorder: A systematic review. J Psychiatr Res. 2016 Dec;83:211-219. doi: 10.1016/j.jpsychires.2016.09.005. Epub 2016 Sep 13.
- Background: PubMed 29670547Hsu WY, Lane HY, Lin CH. Medications Used for Cognitive Enhancement in Patients With Schizophrenia, Bipolar Disorder, Alzheimer's Disease, and Parkinson's Disease. Front Psychiatry. 2018 Apr 4;9:91. doi: 10.3389/fpsyt.2018.00091. eCollection 2018.
- Background: PubMed 14992985Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004 Mar;161(3):564-6. doi: 10.1176/appi.ajp.161.3.564.
- Background: PubMed 15219473Zarate CA Jr, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry. 2004 Jul 1;56(1):54-60. doi: 10.1016/j.biopsych.2004.03.013.
- Individual participant dataSharing planned: No
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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.
Serge Beaulieu, MD, PhD, FRCPC, DFAPA principal investigator
Douglas Mental Health University Institute
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Brexpiprazole in people with Bipolar Depression, run by Douglas Mental Health University Institute at 3 sites in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
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: looking for participants now, as of the sponsor's last update on 27 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
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?
Contact Gabrielle Phillips, BA (514 444 5397, gabrielle.phillips.comtl@ssss.gouv.qc.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change from Baseline Depressive Symptoms as Assessed by MADRS at 8 weeks (time frame: 8 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04569448, which also lists 32 linked publications.
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 27 Aug 2026.