Brexpiprazole, sold under the brand name Rexulti among others, is an

atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurol ...

medication used for the treatment of

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

, and agitation associated with dementia due to

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. The most common side effects include

akathisia Akathisia (IPA: /æ.kə.ˈθɪ.si.ə/) is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and/or an inability to sit still. Usually, the legs are most prominently affected. Those a ...

(a constant urge to move) and weight gain. The most common side effects among people with agitation associated with dementia due to Alzheimer's disease include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances (both somnolence and insomnia). Brexpiprazole was developed by Otsuka and

Lundbeck H. Lundbeck A/S, commonly referred to as Lundbeck, is a Denmark, Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products ar ...

, and is considered to be a successor to

aripiprazole Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...

(Abilify). It was approved for medical use in the United States in July 2015. A generic version was approved in August 2022. Brexpiprazole is the first treatment approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) for agitation associated with dementia due to Alzheimer's disease.

Medical uses

In the United States and Canada, brexpiprazole is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

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 An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore throat ...

(6.9% vs. 4.8%),

(6.6% vs. 3.2%),

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

(6.3% vs. 0.8%), and

nasopharyngitis The common cold, or the cold, is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear in as little as two days after ...

(5.0% vs. 1.6%). Brexpiprazole can cause impulse control disorders.

Pharmacology

Pharmacodynamics

Brexpiprazole acts as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_1A receptor and the

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

D₂ and D₃ receptors. 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,

, 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). 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

. ''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 An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.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 Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

s, and hence has no

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

effects. Although brexpiprazole has less affinity for H₁ compared to

, weight gain can occur.

History

Clinical trials

Brexpiprazole was in clinical trials for adjunctive treatment of

adult attention deficit hyperactivity disorder Adult Attention Deficit Hyperactivity Disorder (adult ADHD) refers to ADHD that persists into adulthood. It is a neurodevelopmental disorder, meaning impairing symptoms must have been present in childhood, except for when ADHD occurs after traum ...

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

, 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 Escitalopram ( ), sold under the brand names Lexapro and Cipralex, among others, is an antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class. It is mainly used to treat major depressive disorder, generalized ...

fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

sertraline Sertraline, sold under the brand name Zoloft among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, generalized anxiety disorder, socia ...

, and

venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...

=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

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

in Japan.

Economics

In November 2011,

Otsuka Pharmaceutical (), abbreviated OPC, is a pharmaceutical company headquartered in Tokyo, Osaka and Naruto, Tokushima, Naruto, Japan. The company was established August 10, 1964. History OPC's parent company Otsuka Holdings Co. Ltd. joined the Tokyo Stock Excha ...

and

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 Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD) as an adjunct to

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

s, but was discontinued for this indication. It reached phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for this use prior to discontinuation. Brexpiprazole has shown promise in clinical trials for the treatment of

borderline personality disorder Borderline personality disorder (BPD) is a personality disorder characterized by a pervasive, long-term pattern of significant interpersonal relationship instability, an acute fear of Abandonment (emotional), abandonment, and intense emotiona ...

References

External links

* {{Authority control 5-HT1A agonists 5-HT2A antagonists 5-HT2B antagonists 5-HT7 antagonists Alpha-1 blockers Alpha-2 blockers Atypical antipsychotics Benzothiophenes D2 receptor agonists D3 receptor agonists Experimental anxiolytics Otsuka Pharmaceutical Serotonin-dopamine activity modulators Treatment of Alzheimer's disease Piperazines 2-Quinolones