Brexpiprazole

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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.{{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00222 | title=Regulatory Decision Summary for Rexulti }}{{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00506 | title=Regulatory Decision Summary for Rexulti }} 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.{{cite web |title=Rexulti (Brexpiprazole): novo registro | work =Č Informações Técnicas - Anvisa |url=http://antigo.anvisa.gov.br/informacoes-tecnicas13?p_p_id=101_INSTANCE_WvKKx2fhdjM2&p_p_col_id=column-2&p_p_col_pos=1&p_p_col_count=2&_101_INSTANCE_WvKKx2fhdjM2_groupId=219201&_101_INSTANCE_WvKKx2fhdjM2_urlTitle=rexulti-brexpiprazole-novo-registro&_101_INSTANCE_WvKKx2fhdjM2_struts_action=/asset_publisher/view_content&_101_INSTANCE_WvKKx2fhdjM2_assetEntryId=5876142&_101_INSTANCE_WvKKx2fhdjM2_type=content |access-date=25 September 2022 }}{{cite web |title=Rexulti (Brexpiprazole): novo registro |url=https://www.gov.br/anvisa/pt-br/assuntos/medicamentos/novos-medicamentos-e-indicacoes/rexulti-brexpiprazole-novo-registro |access-date=25 September 2022 |website=Agência Nacional de Vigilância Sanitária - Anvisa |language=pt-br}}

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%).{{cite web|title=Otsuka Pharmaceutical reports OPC-34712 Phase 2 trial results in major depressive disorder|url=http://www.news-medical.net/news/20110516/Otsuka-Pharmaceutical-reports-OPC-34712-Phase-2-trial-results-in-major-depressive-disorder.aspx?page=2|publisher=News-Medical.Net|access-date=10 February 2012|date=16 May 2011}} Brexpiprazole can cause impulse control disorders.{{cite journal | vauthors = Fusaroli M, Raschi E, Giunchi V, Menchetti M, Rimondini Giorgini R, De Ponti F, Poluzzi E | title = Impulse Control Disorders by Dopamine Partial Agonists: A Pharmacovigilance-Pharmacodynamic Assessment Through the FDA Adverse Event Reporting System | journal = The International Journal of Neuropsychopharmacology | volume = 25 | issue = 9 | pages = 727–736 | date = September 2022 | pmid = 35639870 | pmc = 9515127 | doi = 10.1093/ijnp/pyac031 }}

{{Confusing section|small=left|date=May 2025|reason=it has poor grammar and too many parentheticals}}

{{See also|Atypical antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}}

Brexpiprazole acts as a partial agonist of the serotonin 5-HT_1A receptor and the dopamine D₂ and D₃ receptors.{{cite journal | vauthors = Maeda K, Sugino H, Akazawa H, Amada N, Shimada J, Futamura T, Yamashita H, Ito N, McQuade RD, Mørk A, Pehrson AL, Hentzer M, Nielsen V, Bundgaard C, Arnt J, Stensbøl TB, Kikuchi T | title = Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 350 | issue = 3 | pages = 589–604 | date = September 2014 | pmid = 24947465 | doi = 10.1124/jpet.114.213793 | s2cid = 10768032 }} Partial agonists have both blocking properties and stimulating properties at the receptor they bind to. The ratio of blocking activity to stimulating activity determines a portion of its clinical effects. Brexpiprazole has more blocking and less stimulating activity at the dopamine receptors than its predecessor, aripiprazole, which may decrease its risk for agitation and restlessness. Specifically, where aripiprazole has an intrinsic activity or agonist effect at the D₂ receptor of 60%+, brexpiprazole has an intrinsic activity at the same receptor of about 45%. For aripiprazole, this means more dopamine receptor activation at lower doses, with blockade being reached at higher doses, while brexpiprazole has the inverse effect because a partial agonist is considered to terminate its motoric side effects due to their agonistic behaviour which gets suppressed earlier with lower dosages when they have less intrinsic value. This is also the reason (nevertheless with the seemingly against-decided competition in the antipsychotic of choice, and this also with the fact, that brexpiprazole fell into the age of development having much more information privileges of considering and adjust of its maximum recommended dose, right under before it went off-label) why through its significant lower value than all other neuroleptics from the 3rd generation (e.g. cariprazine(D3,70% for example), it could be considered as working with some similar efficacy than a full antagonist (like perphenazine) at the D2 receptor, so a receptor occupation of only 68+% at the maximum recommended dose is seen enough (compared with the necessary occupation of 90% at the D2 receptor when administered aripiprazole or cariprazine). What is being surprisingly is to did the effort of evaluating this molecules all nanoMolar affinitys in with at development, because yet, (like transporteraffinity, one can also see in ziprasidone for example) some antipsychotics are capable of blocking transporters. But it turned out that (also together with ziprasidones also weak nanoMolar ability of 112) brexpiprazole has just the weak DAT-transporter nanoMolar affinity of the multiple of 0.8 compared with its affinity at dopamin D2 receptors (meaning that there has to be the 8-fold of the maximum recommended dose to be as sufficient as at this transporters then brexpiprazole does on postsynaptic D2-dopaminreceptors).{{cite web | url=https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=ziprasidone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | title=PDSP Database - UNC }}{{cite journal | pmc=7075883 | date=2019 | title=A positron emission tomography occupancy study of brexpiprazole at dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors, and serotonin reuptake transporters in subjects with schizophrenia | journal=Neuropsychopharmacology | volume=45 | issue=5 | pages=786–792 | doi=10.1038/s41386-019-0590-6 | pmid=31847007 | vauthors = Girgis RR, Forbes A, Abi-Dargham A, Slifstein M }}{{cite journal | url=https://link.springer.com/article/10.1007/s002130050069 | doi=10.1007/s002130050069 | title=High 5HT 2A receptor occupancy in M100907-treated schizophrenic patients | date=2000 | journal=Psychopharmacology | volume=148 | issue=4 | pages=400–403 | pmid=10928313 | vauthors = Talvik-Lotfi M, Nyberg S, Nordström A, Ito H, Halldin C, Brunner F, Farde L | url-access=subscription }}{{cite journal | vauthors = Girgis RR, Forbes A, Abi-Dargham A, Slifstein M | title = A positron emission tomography occupancy study of brexpiprazole at dopamine D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors, and serotonin reuptake transporters in subjects with schizophrenia | journal = Neuropsychopharmacology | volume = 45 | issue = 5 | pages = 786–792 | date = April 2020 | pmid = 31847007 | pmc = 7075883 | doi = 10.1038/s41386-019-0590-6 }}{{cite journal | vauthors = Gründer G | title = Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression | journal = Current Opinion in Investigational Drugs | volume = 11 | issue = 7 | pages = 823–832 | date = July 2010 | pmid = 20571978 }}{{cite journal | vauthors = Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF | title = Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride | journal = Neuropsychopharmacology | volume = 27 | issue = 2 | pages = 248–259 | date = August 2002 | pmid = 12093598 | doi = 10.1016/S0893-133X(02)00304-4 }}{{cite web | url=http://www.pdg.cnb.uam.es/cursos/Barcelona2002/pages/Farmac/Comput_Lab/Guia_Glaxo/chap2c.html#relative | title=Glaxo Wellcome pharmacology guide | access-date=14 February 2023 | archive-date=26 July 2019 | archive-url=https://web.archive.org/web/20190726074523/http://www.pdg.cnb.uam.es/cursos/Barcelona2002/pages/Farmac/Comput_Lab/Guia_Glaxo/chap2c.html#relative }}{{cite journal | vauthors = Clarke WP, Bond RA | title = The elusive nature of intrinsic efficacy | journal = Trends in Pharmacological Sciences | volume = 19 | issue = 7 | pages = 270–276 | date = July 1998 | pmid = 9703760 | doi = 10.1016/s0165-6147(97)01138-3 }}{{cite journal | vauthors = Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF | title = Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride | journal = Neuropsychopharmacology | volume = 27 | issue = 2 | pages = 248–259 | date = August 2002 | pmid = 12093598 | doi = 10.1016/S0893-133X(02)00304-4 | s2cid = 26101524 | doi-access = free }}{{cite book |doi=10.1007/978-3-540-38918-7_6001 |chapter=Intrinsic Efficacy |title=Encyclopedia of Molecular Pharmacology |year=2008 |page=652 |isbn=978-3-540-38916-3 | vauthors = Offermanns S, Rosenthal W }} Brexpiprazole has a high affinity for the 5-HT_1A receptor, acting as a potent antagonist at 5-HT_2A receptors, and a potent partial agonist at dopamine D₂ receptors with lower intrinsic activity compared to aripiprazole.{{cite journal | vauthors = Kikuchi T, Maeda K, Suzuki M, Hirose T, Futamura T, McQuade RD | title = Discovery research and development history of the dopamine D₂ receptor partial agonists, aripiprazole and brexpiprazole | journal = Neuropsychopharmacology Reports | volume = 41 | issue = 2 | pages = 134–143 | date = June 2021 | pmid = 33960741 | pmc = 8340839 | doi = 10.1002/npr2.12180 }} In vivo characterization of brexpiprazole shows that it may act as a near-full agonist of the 5-HT_1A 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-HT_1A receptor agonism. It is also an antagonist of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT₇ receptors, which may contribute to antidepressant effect. It also binds to and blocks the α_1A-, α_1B-, α_1D-, and α_2C-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.{{cite journal | vauthors = Stahl SM | title = Mechanism of action of brexpiprazole: comparison with aripiprazole | journal = CNS Spectrums | volume = 21 | issue = 1 | pages = 1–6 | date = February 2016 | pmid = 26899451 | doi = 10.1017/S1092852915000954 | doi-access = free }}

Brexpiprazole was in clinical trials for adjunctive treatment of major depressive disorder, adult attention deficit hyperactivity disorder, bipolar disorder,{{cite web | title = Otsuka, Lundbeck initiate phase 3 trials of Rexulti for bipolar I disorder |url=https://www.healio.com/psychiatry/bipolar-disorder/news/online/%7B7281829f-0895-4785-88bc-9c76235e095c%7D/otsuka-lundbeck-initiate-phase-3-trials-of-rexulti-for-bipolar-i-disorder |website=www.healio.com|access-date=16 October 2017}} schizophrenia,{{cite web|title=OPC-34712 search results|url=http://clinicaltrials.gov/ct2/results?term=OPC-34712|access-date=10 February 2012}} and agitation associated with dementia due to Alzheimer's disease.

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.{{ClinicalTrialsGov|NCT00797966|Study of the Safety and Efficacy of OPC-34712 as Adjunctive Therapy in the Treatment of Patients With Major Depressive Disorder}}

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)".{{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)}} 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.

• Attention Deficit/Hyperactivity Disorder (STEP-A){{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)}}

• Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder{{ClinicalTrialsGov|NCT01423916|Trial to Evaluate the Effects of OPC-34712 on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder}}

• A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia{{ClinicalTrialsGov|NCT01451164|A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia}}

• Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON){{ClinicalTrialsGov|NCT01393613|Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)}}{{ClinicalTrialsGov|NCT01397786|Safety and Tolerability Study of Oral OPC-34712 as Maintenance Treatment in Adults With Schizophrenia (ZENITH)}}
• Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR){{ClinicalTrialsGov|NCT01396421|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{{ClinicalTrialsGov|NCT01456897|A Long-term Trial of OPC-34712 in Patients With Schizophrenia}}

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.

In January 2018, it was approved for the treatment of schizophrenia in Japan.{{cite news|url=https://www.otsuka.co.jp/en/company/newsreleases/2018/20180119_1.html|title=Otsuka Receives Approval in Japan for the Manufacture and Sale of New Antipsychotic Drug Rexulti Tablets for Schizophrenia｜News Releases |work=Otsuka Pharmaceutical Co., Ltd.|access-date=4 October 2018}}

In November 2011, Otsuka Pharmaceutical and Lundbeck announced a global alliance.{{cite web|title=Lundbeck and Otsuka Pharmaceutical sign historic agreement to deliver innovative medicines targeting psychiatric disorders worldwide|url=http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=622993|publisher=Lundbeck|access-date=10 February 2012|archive-url=https://web.archive.org/web/20120401191731/http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=622993|archive-date=1 April 2012}}

• {{US Patent|8071600}}
• WIPO PCT/JP2006/317704
• Canadian patent: 2620688{{cite web|title=Canadian Patents Database 2620688|url=http://brevets-patents.ic.gc.ca/opic-cipo/cpd/eng/patent/2620688/summary.html|access-date=16 February 2012}}

Brexpiprazole was under development for the treatment of attention deficit hyperactivity disorder (ADHD) as an adjunct to stimulants, but was discontinued for this indication.{{cite web|url=https://adisinsight.springer.com/drugs/800029282|title=Brexpiprazole - Lundbeck/Otsuka | work = AdisInsight | publisher = Springer Nature Switzerland AG }}{{cite journal | vauthors = Howland RH | title = Brexpiprazole: another multipurpose antipsychotic drug? | journal = Journal of Psychosocial Nursing and Mental Health Services | volume = 53 | issue = 4 | pages = 23–25 | date = April 2015 | pmid = 25856810 | doi = 10.3928/02793695-20150323-01 }}{{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}} 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.{{cite journal | vauthors = Grant JE, Valle S, Chesivoir E, Ehsan D, Chamberlain SR | title = A double-blind placebo-controlled study of brexpiprazole for the treatment of borderline personality disorder | journal = The British Journal of Psychiatry | volume = 220 | issue = 2 | pages = 58–63 | date = November 2021 | pmid = 35049469 | pmc = 7612273 | doi = 10.1192/bjp.2021.159 }}

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