Brexpiprazole

Brexpiprazole is a partial agonist at serotonin 5-HT1A and dopamine D2 receptors and an antagonist at serotonin 5-HT2A receptors. The label says its mechanism is unknown but that this combination may explain its effects [1].

CYP3A4 and CYP2D6 carry out most of its metabolism. Its main metabolite, DM-3411, makes up 23% to 48% of brexpiprazole exposure but is not thought to contribute to the effect, so the parent drug does the work. The half-life is about 91 hours, and steady levels take 10 to 12 days to reach [1].

Doses are small. For depression the label starts at 0.5 or 1 mg a day, aims for 2 mg and allows up to 3 mg. For schizophrenia in adults it starts at 1 mg, moves to 2 mg on day 5 and allows up to 4 mg. For agitation in Alzheimer's dementia it starts at 0.5 mg and aims for 2 mg [1].

CYP2D6 is a liver enzyme with many inherited variants. People with two non-working copies are poor metabolizers; people with reduced function are intermediate metabolizers. CPIC estimates that about 6.5% of people of European ancestry are poor metabolizers, compared with about 2% to 3% in most other groups and under 1% of people of East Asian or Oceanian ancestry [3].

The label says poor metabolizers "have higher brexpiprazole concentrations than normal metabolizers" and recommends adjusting the dose. It also models what happens when genes and drugs combine: a poor metabolizer who takes a strong CYP3A4 inhibitor is expected to have about 4.8 times the usual exposure, and a normal metabolizer who takes strong inhibitors of both enzymes about 5.1 times [1].

The DPWG's assessment, in its recommendation text, is that the risk of side effects in poor metabolizers is "theoretically increased" because the drug is broken down more slowly. For intermediate metabolizers it found signs of higher exposure but none of more side effects, and for ultrarapid metabolizers lower exposure but no sign of a weaker effect [2].

The halved dose may be more than enough. A 2022 modeling study simulated brexpiprazole in poor and normal metabolizers and concluded that the label's titration for poor metabolizers "likely overcompensates" for their slower clearance, so they take longer to reach effective levels. The authors called for new steady-state studies in poor metabolizers [4]. This was a simulation, not a trial, and the label has not changed.

The FDA label for Rexulti adjusts the dose for CYP2D6 status and interacting drugs (section 2.7). When the interacting drug is stopped, the dose goes back to its original level [1].

The depression exception applies only to CYP2D6 inhibitors. In the depression trials the dose was not adjusted for strong CYP2D6 inhibitors such as paroxetine or fluoxetine, so the label treats the usual depression doses as already allowing for them. The label does not extend that exception to poor metabolizers [1].

The FDA's Table of Pharmacogenetic Associations lists brexpiprazole and CYP2D6 in its first section, where the data support therapeutic management recommendations [5]. A Gene2Rx report shows that FDA statement and the DPWG recommendation for your CYP2D6 result. Both halve the dose for poor metabolizers and change nothing for other results.

Other guidance

The DPWG's 2024 antipsychotic guideline advises half the normal dose for CYP2D6 poor metabolizers and no change for other results. It considers testing before treatment potentially beneficial but not needed for everyone, and advises following the guideline when a genotype is already known [6]. CPIC has not published a brexpiprazole guideline; its gene-drug list gives the pair a provisional level of B/C [7].

Bring the report to your prescriber or pharmacist with a full list of your medicines, including over-the-counter products and supplements. A poor metabolizer result is most useful when brexpiprazole is started, and again whenever an interacting drug is added or stopped.

Other medicines can make CYP2D6 behave as if your genes were different, an effect called phenoconversion. The FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors, and clarithromycin, itraconazole and ketoconazole as strong CYP3A4 inhibitors [8]. For brexpiprazole, the CYP3A4 side matters as much as the genes, and the largest increases in the label come from combinations.

The label also lowers the maximum dose for moderate to severe liver impairment and for reduced kidney function (creatinine clearance below 60 mL/minute) [1]. Do not start, stop or change brexpiprazole or any other medicine because of a genetic result without talking to your prescriber.

Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use. They read fixed positions, and Gene2Rx uses imputation to infer some variants that were not measured directly. A normal result means none of the assessed variants was found among the positions your data covers; it cannot rule out a variant at a position the data does not cover. If a prescriber plans to halve the dose on the strength of a result, a clinical CYP2D6 test is reasonable. If a clinical test (GeneSight, Genomind or another lab) has already reported your CYP2D6 genotype, those results can be entered for a Panel Report.

A genotype does not predict whether brexpiprazole will help you or which side effects you will have.

I take brexpiprazole with an antidepressant. Does the CYP2D6 exception cover me?

The depression exception covers CYP2D6 inhibitors such as paroxetine and fluoxetine, not poor metabolizer genotypes. For known poor metabolizers the label's half dose applies to every use [1].

I am an intermediate metabolizer. Should my dose change?

Neither the FDA label nor the DPWG recommends a change for intermediate metabolizers (see What the guidelines recommend).

1. Rexulti (brexpiprazole) tablets: prescribing information (Otsuka). DailyMed. Indications, dosing, CYP2D6 and interaction adjustments, pharmacokinetics.
2. ClinPGx. Annotation of DPWG Clinical Guideline for brexpiprazole and CYP2D6. The Dutch recommendation text for each CYP2D6 result.
3. CPIC. CYP2D6 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographic group.
4. Elmokadem A et al. Brexpiprazole pharmacokinetics in CYP2D6 poor metabolizers: using physiologically based pharmacokinetic modeling to optimize time to effective concentrations. J Clin Pharmacol (2022). Simulated exposure in poor and normal metabolizers.
5. US Food and Drug Administration. Table of Pharmacogenetic Associations. The FDA statement for brexpiprazole and CYP2D6 poor metabolizers.
6. Beunk L et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. Eur J Hum Genet (2024). DPWG recommendations and testing advice.
7. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level B/C for CYP2D6 and brexpiprazole.
8. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 and CYP3A4 inhibitors.