Brexpiprazole (Rexulti)
Introduction
Brexpiprazole (Rexulti) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
<div class="infobox">
<div class="infobox-header">Brexpiprazole (Rexulti)</div>
<div class="infobox-row"><div class="infobox-label">Brand Name</div><div class="infobox-value">Rexulti</div></div>
<div class="infobox-row"><div class="infobox-label">Manufacturer</div><div class="infobox-value">Otsuka/Lundbeck</div></div>
<div class="infobox-row"><div class="infobox-label">FDA Approval</div><div class="infobox-value">Schizophrenia (2015), Depression (2016), Agitation in AD (2023)</div></div>
<div class="infobox-row"><div class="infobox-label">Indication</div><div class="infobox-value">Agitation in Alzheimer's Disease</div></div>
<div class="infobox-row"><div class="infobox-label">Mechanism</div><div class="infobox-value">5-HT1A partial agonist, 5-HT2A antagonist, D2 partial agonist</div></div>
<div class="infobox-row"><div class="infobox-label">Route</div><div class="infobox-value">Oral</div></div>
<div class="infobox-row"><div class="infobox-label">ClinicalTrials.gov</div><div class="infobox-value"><a href="https://clinicaltrials.gov/search?cond=Alzheimer+Disease&intr=brexpiprazole">View Trials</a></div></div>
</div>
Overview
...Brexpiprazole (Rexulti)
Introduction
Brexpiprazole (Rexulti) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
<div class="infobox">
<div class="infobox-header">Brexpiprazole (Rexulti)</div>
<div class="infobox-row"><div class="infobox-label">Brand Name</div><div class="infobox-value">Rexulti</div></div>
<div class="infobox-row"><div class="infobox-label">Manufacturer</div><div class="infobox-value">Otsuka/Lundbeck</div></div>
<div class="infobox-row"><div class="infobox-label">FDA Approval</div><div class="infobox-value">Schizophrenia (2015), Depression (2016), Agitation in AD (2023)</div></div>
<div class="infobox-row"><div class="infobox-label">Indication</div><div class="infobox-value">Agitation in Alzheimer's Disease</div></div>
<div class="infobox-row"><div class="infobox-label">Mechanism</div><div class="infobox-value">5-HT1A partial agonist, 5-HT2A antagonist, D2 partial agonist</div></div>
<div class="infobox-row"><div class="infobox-label">Route</div><div class="infobox-value">Oral</div></div>
<div class="infobox-row"><div class="infobox-label">ClinicalTrials.gov</div><div class="infobox-value"><a href="https://clinicaltrials.gov/search?cond=Alzheimer+Disease&intr=brexpiprazole">View Trials</a></div></div>
</div>
Overview
Brexpiprazole (trade name: Rexulti) is an atypical antipsychotic developed by Otsuka Pharmaceutical and Lundbeck[@citrome2016]. It received FDA approval in 2023 for the treatment of agitation associated with Alzheimer's disease[@fda2023], making it the first antipsychotic approved specifically for this indication in nearly two decades.
Brexpiprazole belongs to a class of drugs called serotonin-dopamine activity modulators (SDAMs). It has a unique pharmacological profile with high affinity for multiple receptor subtypes, which may provide efficacy with a more favorable side effect profile compared to older antipsychotics.
Mechanism of Action
Brexpiprazole's therapeutic effects in Alzheimer's disease agitation result from its activity at multiple neurotransmitter receptors:
Receptor Pharmacology
| Receptor | Activity | Functional Effect |
|----------|----------|------------------|
| 5-HT1A | Partial agonist | Anxiolytic, antidepressant effects |
| 5-HT2A | Antagonist | Reduced psychosis, improved sleep |
| 5-HT2C | Antagonist | Weight neutrality |
| D2 | Partial agonist | Antipsychotic, antiagitation |
| D3 | Partial agonist | Cognitive effects |
| H1 | Antagonist | Sedation (mild) |
| α1 | Antagonist | Orthostatic hypotension (potential) |
Advantages Over Older Antipsychotics
Lower D2 striatal occupancy — Reduced risk of extrapyramidal symptoms (EPS)
5-HT2A antagonism — May reduce psychosis without causing significant sedation
5-HT1A partial agonism — May provide anxiolytic and cognitive benefits
Reduced prolactin elevation — Less endocrine disruptionClinical Development for AD Agitation
Phase III Trials (BREVIVE)
Two pivotal Phase III trials (BREVIVE-1 and BREVIVE-2) evaluated brexpiprazole for agitation in Alzheimer's disease[@clinicaltrialsgov2023]:
| Study | Dose | Primary Endpoint | Result |
|-------|------|-----------------|--------|
| BREVIVE-1 | 2 mg/day | CMAI change at week 12 | -20.6 vs -12.5 (placebo), p=0.0026 |
| BREVIVE-2 | 2 mg/day | CMAI change at week 12 | -18.6 vs -15.4 (placebo), p=0.0769 |
The BREVIVE-1 trial demonstrated statistically significant improvement in agitation symptoms as measured by the Cohen-Mansfield Agitation Inventory (CMAI).
Efficacy Measures
- CMAI (Cohen-Mansfield Agitation Inventory): Reduced agitation frequency and severity
- NPI-Agitation/Aggression: Improved caregiver-reported agitation
- CGI-C: Clinician's impression of global improvement
- ADCS-ADL: No significant worsening of functional abilities
Indications and Usage
Brexpiprazole is FDA-approved for:
Agitation in Alzheimer's disease (2023) — Approved indication
Schizophrenia (2015)
Major depressive disorder (adjunctive treatment) (2016)Recommended dosing for AD agitation:
- Starting dose: 0.5 mg once daily
- Target dose: 2 mg once daily
- Maximum dose: 3 mg once daily
Adverse Effects
Common Adverse Reactions
| Adverse Event | Frequency (Brexpiprazole) | Frequency (Placebo) |
|--------------|--------------------------|---------------------|
| Headache | 6.7% | 5.8% |
| Dizziness | 5.2% | 2.5% |
| Somnolence | 5.2% | 2.1% |
| Constipation | 4.6% | 2.1% |
| Weight gain | 3.8% | 1.7% |
Boxed Warning
Brexpiprazole carries a boxed warning for:
- Increased mortality in elderly patients with dementia-related psychosis
- Black box warning for suicidal thoughts and behaviors in children, adolescents, and young adults
Special Considerations
- Cerebrovascular events: Increased risk of stroke in elderly with dementia
- Metabolic effects: Monitor weight, glucose, lipids
- Extrapyramidal symptoms: Lower risk than older antipsychotics but monitor
- Sedation: May impair alertness
Use in Alzheimer's Disease
Patient Selection
Brexpiprazole should be considered for patients with:
- Clinically significant agitation affecting quality of life
- Aggression or physical agitation posing safety risks
- Failure of non-pharmacological interventions
- Moderate to severe agitation (CMAI score > 30)
Monitoring Requirements
| Parameter | Baseline | 4 weeks | 8 weeks | 12 weeks | Ongoing |
|-----------|---------|---------|---------|----------|---------|
| Weight | ✓ | ✓ | ✓ | ✓ | Quarterly |
| Blood pressure | ✓ | ✓ | - | ✓ | Quarterly |
| Fasting glucose | ✓ | - | - | ✓ | Quarterly |
| Lipid panel | ✓ | - | - | ✓ | Quarterly |
| EPS assessment | ✓ | ✓ | ✓ | ✓ | As needed |
Comparison with Other Antipsychotics
| Drug | Receptor Profile | EPS Risk | Sedation | Weight Gain | FDA AD Indication |
|------|------------------|----------|----------|-------------|-------------------|
| Brexpiprazole | 5-HT1A/2A/D2 | Low | Low | Low | Yes (2023) |
| Risperidone | D2/5-HT2 | Moderate | Moderate | Moderate | No |
| Quetiapine | D2/5-HT2/H1 | Low | High | Moderate | No |
| Olanzapine | D2/5-HT2/H1 | Moderate | High | High | No |
| Aripiprazole | D2 partial | Low | Low | Low | No |
Regulatory Status
- FDA (US): Approved for agitation in AD (2023)
- EMA (Europe): Under review
- PMDA (Japan): Approved for schizophrenia and related conditions
- Health Canada: Under review
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Agitation in Alzheimer's Disease](/diseases/agitation-alzheimers)
- [Antipsychotics in Neurodegeneration](/therapeutics/antipsychotics-neurodegeneration)
- [Non-Pharmacological Interventions for Behavioral Symptoms](/therapeutics/non-pharmacological-interventions)
- [Pimavanserin](/therapeutics/pimavanserin) — Parkinson's disease psychosis
- [Neuropsychiatric Symptoms in Dementia](/mechanisms/neuropsychiatric-symptoms)
External Links
- [Rexulti Official Website](https://www.rexulti.com/)
- [FDA Approval Announcement (2023)](https://www.fda.gov/drugs/news-events-human-drug-alerts/fda-approves-brexpiprazole-treatment-agitation-alzheimers-disease)
- [ClinicalTrials.gov - Brexpiprazole](https://clinicaltrials.gov/search?cond=Alzheimer+Disease&intr=brexpiprazole)
- [Prescribing Information](https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213971s000lbl.pdf)
Background
The study of Brexpiprazole (Rexulti) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Allen Brain Atlas Resources
- [Allen Brain Atlas - Gene Expression](https://human.brain-map.org/) - Search for gene expression data across brain regions
- [Allen Brain Atlas - Cell Types](https://celltypes.brain-map.org/) - Explore neuronal cell type taxonomy
- [Allen Brain Atlas - Aging, Dementia & TBI](https://aging.brain-map.org/) - Data on aging and traumatic brain injury
References
Citrome L, Brexpirazole for schizophrenia: a review of the efficacy and safety profile of this new "dopamine partial agonist-like" antipsychotic (2016)
FDA, FDA Approves First Drug to Treat Agitation Symptoms Associated with Dementia Due to Alzheimer's Disease (2023)
ClinicalTrials.gov, Brexpiprazole for the Treatment of Patients With Agitation Associated With Dementia of the Alzheimer's Type (NCT03620981) (2023)
[Maeda K, Sugino H, Akazawa H, et al, Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator (2014)](https://doi.org/10.1124/jpet.114.213793)
[Thase ME, Youakim JM, Skuban A, et al, 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 (2015)](https://pubmed.ncbi.nlm.nih.gov/26301701/)