# Brexpiprazole

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.
The most common side effects include akathisia (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, and is considered to be a successor to aripiprazole (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 (FDA) for agitation associated with dementia due to Alzheimer's disease.

## 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

Brexpiprazole :
| Site | Human K$_i$ (nM) | IA (%) | Action | Ref |
| SERTTooltip Serotonin transporter | 65% at 10 μM | | Blocker | |
| NETTooltip Norepinephrine transporter | 0% at 10 μM | | Blocker | |
| DATTooltip Dopamine transporter | 90% at 10 μM | | Blocker | |
| 5-HT$_{1A}$ | 0.12 | ~60% | Partial agonist | |
| 5-HT$_{1B}$ | 32 | | ND | |
| 5-HT$_{2A}$ | 0.47 | | Antagonist | |
| 5-HT$_{2B}$ | 1.9 | | Antagonist | |
| 5-HT$_{2C}$ | 34 | | Antagonist | |
| 5-HT$_{5A}$ | 140 | | ND | |
| 5-HT$_6$ | 58 | | Antagonist | |
| 5-HT$_7$ | 3.7 | | Antagonist | |
| D$_1$ | 160 | | ND | |
| D$_{2L}$ | 0.30 | ~45% | Partial agonist | |
| D$_3$ | 1.1 | ~15% | Partial agonist | |
| D$_4$ | 6.3 | | ND | |
| D$_5$ | ND | | ND | ND |
| α$_{1A}$ | 3.8 | | Antagonist | |
| α$_{1B}$ | 0.17 | | Antagonist | |
| α$_{1D}$ | 2.6 | | Antagonist | |
| α$_{2A}$ | 15 | | Antagonist | |
| α$_{2B}$ | 17 | | Antagonist | |
| α$_{2C}$ | 0.59 | | Antagonist | |
| β$_1$ | 59 | | Antagonist | |
| β$_2$ | 67 | | Antagonist | |
| β$_3$ | >10,000 | | ND | |
| H$_1$ | 19 | | Antagonist | |
| H$_2$ | >10,000 | | ND | |
| H$_3$ | >10,000 | | ND | |
| mAChTooltip Muscarinic acetylcholine receptor | 52% at 10 μM | | ND | |
| M$_1$ | 67% at 10 μM | | ND | |
| M$_2$ | >10,000 | | ND | |
| σ | 96% at 10 μM | | ND | |
| Values are K$_i$ (nM). The smaller the value, the more strongly the drug binds to the site. Most or all data are for human cloned proteins. IA = Intrinsic Activity |||||
Brexpiprazole acts as a partial agonist of the serotonin 5-HT$_{1A}$ receptor and the dopamine D$_2$ and D$_3$ 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, aripiprazole, which may decrease its risk for agitation and restlessness. Specifically, where aripiprazole has an intrinsic activity or agonist effect at the D$_2$ 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 D$_2$ 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-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-HT$_7$ 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 H$_1$ compared to aripiprazole, weight gain can occur.

## 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

* U.S. patent 8,071,600
* 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.