Aripiprazole

Aripiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors. The label says its mechanism in schizophrenia and bipolar mania is unclear, but that this combination could account for its effects [1].

Most of the effect comes from aripiprazole itself. Its main metabolite, dehydro-aripiprazole, binds D2 receptors about as strongly and reaches about 40% of the parent drug's exposure. CYP2D6 and CYP3A4 both carry out the dehydrogenation and hydroxylation steps, and CYP3A4 alone carries out N-dealkylation. The mean half-life is about 75 hours (94 hours for dehydro-aripiprazole), so steady levels take about 2 weeks to reach, and the label advises waiting that long before raising the dose. In CYP2D6 poor metabolizers the half-life is about 146 hours [1].

For adults with schizophrenia the label's starting and target dose is 10 or 15 mg a day, and higher doses were no more effective in trials. Add-on treatment for depression starts at 2 to 5 mg a day [1]. The monthly injection, Abilify Maintena, is usually 400 mg [2], and Abilify Asimtufii is 960 mg every 2 months [3].

CYP2D6 is a liver enzyme that clears many psychiatric medicines. Each copy of the gene is given an activity value (1 for normal function, 0.5 or 0.25 for decreased function, 0 for no function), and the two copies are added to give an activity score. A score of 0 means poor metabolizer, above 0 and below 1.25 intermediate, 1.25 to 2.25 normal, and above 2.25 ultrarapid [4]. Every increased-function CYP2D6 allele is a duplicated gene, so ultrarapid metabolism requires extra copies [5].

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. Intermediate metabolizers are far more common, at roughly 23% to 39% of most groups [6].

What changes in each group

Poor metabolizers clear aripiprazole more slowly. A 2021 meta-analysis pooled 5 studies with 90 poor metabolizers and found that their dose-adjusted levels of aripiprazole plus dehydro-aripiprazole were 1.51 times those of normal metabolizers. Intermediate metabolizers were close behind, at 1.47 times across 9 studies, though those studies varied more [7].

The largest single study used a drug-monitoring database in Oslo, Norway, that included 1,334 people taking aripiprazole, 890 of whom had drug levels suitable for analysis. Poor metabolizers had about 1.6 times the dose-adjusted level of normal metabolizers, and clinicians had prescribed them doses 15% lower on average [8]. A later study from the same Oslo center found increases of the same size with long-acting injections: 1.7-fold in poor and 1.5-fold in intermediate metabolizers. Age did not significantly affect exposure [9].

Higher levels have not translated clearly into different outcomes. In the Oslo study, switching from aripiprazole to another antipsychotic within a year was not significantly related to CYP2D6 status [8]. The DPWG's recommendation text says the risk of side effects is increased in poor metabolizers. For intermediate and ultrarapid metabolizers it judges the change in levels to be limited: there is insufficient evidence of more side effects in intermediate metabolizers and no evidence of a weaker effect in ultrarapid metabolizers [10].

The FDA label for Abilify tablets recommends these adjustments (section 2.6). When the interacting drug is stopped, the dose goes back to its original level [1].

The label makes one exception: as an add-on treatment for depression, aripiprazole is given without these adjustments, using the depression dosing in section 2.3 [1]. The injections have their own rules. For known poor metabolizers, Abilify Maintena drops from 400 mg to 300 mg a month; a poor metabolizer who also takes a CYP3A4 inhibitor gets 200 mg or should avoid the injection, depending on how treatment was started [2]. Abilify Asimtufii drops from 960 mg to 720 mg every 2 months, and the label says to avoid it in poor metabolizers taking CYP3A4 inhibitors [3].

The FDA's Table of Pharmacogenetic Associations lists aripiprazole and CYP2D6 in its first section, where the data support therapeutic management recommendations [11]. A Gene2Rx report shows that FDA statement and the DPWG recommendation for your CYP2D6 result. The two agree that only poor metabolizers need a lower dose.

Other guidance

The DPWG published its antipsychotic guideline in 2024. For CYP2D6 poor metabolizers it advises no more than 10 mg a day by mouth or 300 mg a month by injection (68% to 75% of the normal maximum dose), 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 [12]. A later revision of the Dutch recommendation text adds a limit of 720 mg every 2 months for the two-monthly injection [10]. CPIC has not published an aripiprazole guideline. Its gene-drug list gives the pair a provisional level B [13].

Bring the report to your prescriber or pharmacist with a full list of what you take, including over-the-counter products and supplements. A poor metabolizer result is most useful when aripiprazole is started or its dose changes, and when an interacting medicine is added or stopped. After months on a steady dose, the dose may already reflect how you responded.

Medicines that change the picture

Other drugs 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 [14], and the aripiprazole label treats someone on a strong inhibitor much like a poor metabolizer. CYP3A4 matters too. From simulations, the label expects about a 3-fold increase in aripiprazole levels in poor metabolizers who take a strong CYP3A4 inhibitor, and about a 4.5-fold increase in normal metabolizers who take strong inhibitors of both enzymes. Strong CYP3A4 inducers such as carbamazepine lower levels [1].

Other factors

The label recommends no dose change for age, sex, race, smoking, or liver or kidney impairment [1], so its dose adjustments center on CYP2D6 status and interacting drugs. Do not start, stop or change aripiprazole 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 can miss rare variants. Gene2Rx uses imputation to infer some variants that were not measured directly, but a variant at a position your data does not cover cannot be seen. A normal result means none of the assessed variants was found among the positions your data covers.

A genotype does not predict whether aripiprazole will help you or which side effects you will have. If a clinical test (GeneSight, Genomind or another lab) has already reported your CYP2D6 genotype, those results can be entered for a Panel Report.

I am a CYP2D6 poor metabolizer. Can I still take aripiprazole?

Yes. Neither the FDA label nor the DPWG advises avoiding it; both lower the dose (see What the guidelines recommend).

Does the result matter if aripiprazole is added to an antidepressant?

For add-on treatment of depression, the label uses its depression dosing without the genotype and interaction adjustments [1]. The DPWG's 10 mg maximum for poor metabolizers makes no exception for depression [12]. Your prescriber can weigh both.

1. Abilify (aripiprazole) tablets: prescribing information (Otsuka). DailyMed. Indications, dosing, CYP2D6 and interaction adjustments, pharmacokinetics.
2. Abilify Maintena (aripiprazole) extended-release injectable suspension: prescribing information (Otsuka). DailyMed. Monthly injection doses for poor metabolizers and with interacting drugs.
3. Abilify Asimtufii (aripiprazole) extended-release injectable suspension: prescribing information (Otsuka). DailyMed. Two-monthly injection doses for poor metabolizers.
4. Caudle KE et al. Standardizing CYP2D6 genotype to phenotype translation: consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci (2020). The CYP2D6 activity score ranges.
5. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including duplications.
6. CPIC. CYP2D6 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographic group, with methods and caveats.
7. Milosavljevic F et al. Association of CYP2C19 and CYP2D6 poor and intermediate metabolizer status with antidepressant and antipsychotic exposure: a systematic review and meta-analysis. JAMA Psychiatry (2021). Pooled aripiprazole exposure by CYP2D6 group.
8. Jukic MM et al. Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study. Lancet Psychiatry (2019). Exposure, doses and switching in a Norwegian drug-monitoring cohort.
9. Tveito M et al. Impact of age and CYP2D6 genetics on exposure of aripiprazole and dehydroaripiprazole in patients using long-acting injectable versus oral formulation. Eur J Clin Pharmacol (2020). CYP2D6 and exposure with tablets and injections.
10. ClinPGx. Annotation of DPWG Clinical Guideline for aripiprazole and CYP2D6. The Dutch recommendation text for each CYP2D6 result, including the 2024 revision.
11. US Food and Drug Administration. Table of Pharmacogenetic Associations. The FDA statement for aripiprazole and CYP2D6 poor metabolizers.
12. 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 evidence summary.
13. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level B for CYP2D6 and aripiprazole.
14. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong and moderate CYP2D6 and CYP3A4 inhibitors and inducers.