Brexpiprazole

Medical uses

In the United States and Canada, brexpiprazole is indicated as an adjunctive therapy to antidepressants for the treatment of major depressive disorder and for the treatment of schizophrenia. In May 2023, the indication for brexpiprazole was expanded in the US to include the treatment of agitation associated with dementia due to Alzheimer's disease.

In Australia and the European Union, brexpiprazole is indicated for the treatment of schizophrenia.

In 2020, it was approved in Brazil only as an adjunctive to the treatment of major depressive disorder.

Side effects

The most common adverse events associated with brexpiprazole (all doses of brexpiprazole cumulatively greater than or equal to 5% vs. placebo) were upper respiratory tract infection (6.9% vs. 4.8%), akathisia (6.6% vs. 3.2%), weight gain (6.3% vs. 0.8%), and nasopharyngitis (5.0% vs. 1.6%). Brexpiprazole can cause impulse control disorders.

Pharmacology

Pharmacodynamics

It exerts its pharmacodynamic actions mainly by modulating signaling of multiple serotonin, dopamine and noradrenaline receptors.

Brexpiprazole acts as a partial agonist of the serotonin 5-HT1A receptor and the dopamine D2 and D3 receptors. Brexpiprazole is a less stimulating partial agonist of the dopamine receptors than its predecessor, aripiprazole, potentially decreasing its risk for agitation and restlessness. Brexpiprazole has a high affinity for the 5-HT1A receptor, acting as a potent antagonist at 5-HT2A receptors, and a potent partial agonist at dopamine D2 receptors with lower intrinsic activity compared to aripiprazole. In vivo characterization of brexpiprazole shows that it may act as a near-full agonist of the 5-HT1A receptor. This may further underlie a lower potential than aripiprazole to cause treatment-emergent, movement-related disorders such as akathisia due to the downstream dopamine release that is triggered by 5-HT1A receptor agonism. It is also an antagonist of the serotonin 5-HT2A, 5-HT2B, and 5-HT7 receptors, which may contribute to antidepressant effect. It also binds to and blocks the α1A-, α1B-, α1D-, and α2C-adrenergic receptors. The drug has negligible affinity for the muscarinic acetylcholine receptors, and hence has no anticholinergic effects. Although brexpiprazole has less affinity for H1 compared to aripiprazole, weight gain can occur.

It has also been identified as a potent vesicular monoamine transporter 2 (VMAT2) inhibitor ( = 22nM).

History

Clinical trials

Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.

Major depressive disorder

Phase II

The phase II multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three approved antidepressant treatments (ADTs) in the current episode. The study was designed to assess the efficacy and safety of brexpiprazole as an adjunctive treatment to standard antidepressant treatment. The antidepressants included in the study were desvenlafaxine, escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine.

Phase III

A phase III study was in the recruiting stage: "Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)". Its goal is "to compare the effect of brexpiprazole to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with major depressive disorder who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT". Estimated enrollment was 1250 volunteers.

Adult attention deficit hyperactivity disorder

• Attention Deficit/Hyperactivity Disorder (STEP-A)

Schizophrenia

Phase I

• Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder

Phase II

• A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia

Phase III

• Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)
• Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)
• A Long-term Trial of OPC-34712 in Patients With Schizophrenia

Agitation associated with dementia due to Alzheimer's disease

The effectiveness of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies. In these studies, participants were required to have a probable diagnosis of Alzheimer's dementia; have a score between 5 and 22 on the Mini-Mental State Examination, a test that detects whether a person is experiencing cognitive impairment; and exhibit the type, frequency, and severity of agitation behaviors that require medication. Trial participants ranged between 51 and 90 years of age.

Society and culture

Legal status

In January 2018, it was approved for the treatment of schizophrenia in Japan.

Economics

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance.

Patents

• WIPO PCT/JP2006/317704
• Canadian patent: 2620688

Research

Brexpiprazole was under development for the treatment of attention deficit hyperactivity disorder (ADHD) as an adjunct to stimulants, but was discontinued for this indication. It reached phase II clinical trials for this use prior to discontinuation.

Brexpiprazole has shown promise in clinical trials for the treatment of borderline personality disorder.

References

References

1. (10 February 2020). "Brexpiprazole (Rexulti) Use During Pregnancy".
2. "Rexulti brexpiprazole 4 mg film coated tablets blisters (273224)".
3. [https://www.tga.gov.au/resources/auspar/auspar-brexpiprazole AusPAR: Brexpiprazole]
4. (21 June 2022). "Prescription medicines: registration of new chemical entities in Australia, 2017".
5. (21 June 2022). "Prescription medicines and biologicals: TGA annual summary 2017".
6. Anvisa. (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial". [[Diário Oficial da União]].
7. "Rexulti Product information".
8. [https://pdf.hres.ca/dpd_pm/00058124.PDF Rexulti monograph]
9. (9 May 2018). "Mental health".
10. (21 February 2023). "Rexulti- brexpiprazole tablet Rexulti- brexpiprazole kit".
11. (17 September 2018). "Rxulti EPAR".
12. (December 2023). "Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia: A Randomized Clinical Trial". JAMA Neurology.
13. (11 May 2023). "FDA Approves First Drug to Treat Agitation Symptoms Associated with Dementia due to Alzheimer's Disease".
14. (3 January 2011). "Otsuka HD places top priority on development of OPC-34712.". Chemical Business Newsbase.
15. (10 July 2015). "Rexulti (brexpiprazole) Tablets".
16. (13 July 2015). ["FDA approves new drug to treat schizophrenia and as an add on to an antidepressant to treat ]"](https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm454647.htm). U.S. [[Food and Drug Administration]] (FDA).
17. (3 March 2023). "2022 First Generic Drug Approvals". U.S. [[Food and Drug Administration]] (FDA).
18. "Regulatory Decision Summary for Rexulti".
19. "Regulatory Decision Summary for Rexulti".
20. "Rexulti (Brexpiprazole): novo registro". Č Informações Técnicas - Anvisa.
21. "Rexulti (Brexpiprazole): novo registro".
22. (16 May 2011). "Otsuka Pharmaceutical reports OPC-34712 Phase 2 trial results in major depressive disorder". News-Medical.Net.
23. (September 2022). "Impulse Control Disorders by Dopamine Partial Agonists: A Pharmacovigilance-Pharmacodynamic Assessment Through the FDA Adverse Event Reporting System". The International Journal of Neuropsychopharmacology.
24. "PDSP K_i Database". University of North Carolina at Chapel Hill and the United States National Institute of Mental Health.
25. (February 2016). "Brexpiprazole: so far so good". Therapeutic Advances in Psychopharmacology.
26. (25 January 2022). "Dopamine Receptor Partial Agonists: Do They Differ in Their Clinical Efficacy?". Frontiers in Psychiatry.
27. (September 2014). "Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator". The Journal of Pharmacology and Experimental Therapeutics.
28. (June 2021). "Discovery research and development history of the dopamine D₂ receptor partial agonists, aripiprazole and brexpiprazole". Neuropsychopharmacology Reports.
29. (23 October 2020). "Aripiprazole - Mechanism of Action, Psychopharmacology and Clinical Application".
30. (February 2016). "Mechanism of action of brexpiprazole: comparison with aripiprazole". CNS Spectrums.
31. (22 December 2025). "Evaluation of the Relationship between Vesicular Monoamine Transporter 2 (VMAT2) Inhibition and Neurologic Adverse Events in Approved Drugs". ACS Pharmacology & Translational Science.
32. "Otsuka, Lundbeck initiate phase 3 trials of Rexulti for bipolar I disorder".
33. "OPC-34712 search results".
34. {{ClinicalTrialsGov. NCT00797966. Study of the Safety and Efficacy of OPC-34712 as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder
35. {{ClinicalTrialsGov. NCT01360632. Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)
36. {{ClinicalTrialsGov. NCT01074294. Study of the Safety and Efficacy of OPC-34712 as a Complementary Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder (STEP-A)
37. {{ClinicalTrialsGov. NCT01423916. Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder
38. {{ClinicalTrialsGov. NCT01451164. A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia
39. {{ClinicalTrialsGov. NCT01393613. Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)
40. {{ClinicalTrialsGov. NCT01397786. Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)
41. {{ClinicalTrialsGov. NCT01396421. Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)
42. {{ClinicalTrialsGov. NCT01456897. A Long-term Trial of OPC-34712 in Patients With Schizophrenia
43. "Otsuka Receives Approval in Japan for the Manufacture and Sale of New Antipsychotic Drug Rexulti Tablets for Schizophrenia｜News Releases". Otsuka Pharmaceutical Co., Ltd..
44. "Lundbeck and Otsuka Pharmaceutical sign historic agreement to deliver innovative medicines targeting psychiatric disorders worldwide". Lundbeck.
45. "Canadian Patents Database 2620688".
46. "Brexpiprazole - Lundbeck/Otsuka". Springer Nature Switzerland AG.
47. (April 2015). "Brexpiprazole: another multipurpose antipsychotic drug?". Journal of Psychosocial Nursing and Mental Health Services.
48. {{ClinicalTrialsGov. NCT01074294. A Phase 2, Multicenter, Randomized, Double-blind, Placebo Controlled Study of the Safety and Efficacy of OPC-34712 as Adjunctive Therapy in the Treatment of Adult Attention Deficit/Hyperactivity Disorder
49. (November 2021). "A double-blind placebo-controlled study of brexpiprazole for the treatment of borderline personality disorder". The British Journal of Psychiatry.