Risperidone

The Risperdal label says the way risperidone works in schizophrenia is unclear, but its effect could come from blocking dopamine D2 and serotonin 5-HT2 receptors in the brain [2]. In the US, the tablets, orally disintegrating tablets and oral solution are approved for schizophrenia in adults and adolescents, for acute manic or mixed episodes of bipolar I disorder (alone or with lithium or valproate), and for irritability associated with autistic disorder [2].

The liver clears risperidone mainly by CYP2D6, which adds a hydroxyl group to make 9-hydroxyrisperidone; a minor route is N-dealkylation. The label says 9-hydroxyrisperidone has similar pharmacological activity to risperidone, so the clinical effect comes from the two combined, a total often called the active moiety [2]. This is the main reason CYP2D6 matters less for risperidone than the change in risperidone levels alone would suggest: a slow converter has more risperidone and less metabolite, but the total that acts on the brain shifts much less.

Risperidone's common side effects include movement effects called extrapyramidal symptoms (stiffness, tremor, restlessness), sedation, weight gain and raised prolactin. The label notes that prolactin rises and stays raised during long-term use, and that the risk of tardive dyskinesia, a movement disorder that can be permanent, increases with the length of treatment and the total dose taken [2].

CYP2D6 is a liver enzyme with many inherited variants. Each copy of the gene is given an activity value, and the two values are added to give an activity score. A score of 0 means a poor metabolizer (for example two no-function alleles such as *3, *4 or the *5 gene deletion), a score above 0 and below 1.25 an intermediate metabolizer, 1.25 to 2.25 a normal metabolizer, and above 2.25 an ultrarapid metabolizer, which requires extra copies of the gene [5]. CPIC and the DPWG agreed on these cut-offs in 2020.

CPIC estimates that about 6.5% of people of European ancestry are poor metabolizers, compared with about 2% to 3% of most other groups and under 1% of people of East Asian or Oceanian ancestry [6].

What happens to drug levels

CYP2D6 has a large effect on risperidone itself. In the label's figures, the apparent half-life of risperidone is about 3 hours in people with normal CYP2D6 activity and about 20 hours in poor metabolizers. The label also states that the combined pharmacokinetics of risperidone and 9-hydroxyrisperidone were similar in the two groups, with an overall half-life of about 20 hours [2].

Larger studies in patients found a modest difference in the combined total. In a Norwegian drug-monitoring study of more than 1,200 people taking risperidone, the dose-adjusted active moiety was about 1.6 times higher in poor metabolizers and about 1.4 times higher in intermediate metabolizers than in normal metabolizers. Prescribers had already lowered poor metabolizers' daily doses by about 19% on average [7].

What the studies found

The DPWG reviewed the published studies for its guideline. Most pharmacokinetic studies found that CYP2D6 phenotype affects exposure to risperidone and 9-hydroxyrisperidone. A large study with 90 poor, 91 intermediate and 35 ultrarapid metabolizers found more therapy failure in poor and ultrarapid metabolizers than in normal metabolizers, but not in intermediate metabolizers. Smaller studies gave conflicting results on response and side effects [1]. In that large study, failure was measured as switching to another antipsychotic within a year [7].

The DPWG puts the effect this way: the share of patients with therapy failure rises from 16% to 26% in poor metabolizers and from 16% to 37% in ultrarapid metabolizers. In poor metabolizers the combined level is higher and a larger share of it is risperidone, which the DPWG says crosses the blood-brain barrier more readily than the metabolite. In ultrarapid metabolizers the balance shifts toward 9-hydroxyrisperidone [4].

The DPWG, a group set up by the Royal Dutch Pharmacists Association, published its guideline on CYP2D6, CYP3A4, CYP1A2 and antipsychotics in 2024; its current risperidone recommendations date from a 2020 update [4]. For risperidone it advises a change for CYP2D6 poor and ultrarapid metabolizers and no change for other results. In its recommendations, "normal dose" means the dose the same person would be given without the gene variant [1]. A Gene2Rx report shows the DPWG recommendation for your CYP2D6 result.

The DPWG rates testing before treatment as "potentially beneficial" for risperidone, because no severe clinical effects were seen in people with gene variants. It does not recommend testing everyone who starts an antipsychotic, but advises following the guideline when a genotype is already known, and suggests testing case by case, for example when someone takes several drugs cleared by CYP2D6 or CYP3A4 [1].

Other guidance

The FDA's Table of Pharmacogenetic Associations lists risperidone and CYP2D6 poor metabolizers in its third section, for associations shown to affect pharmacokinetics only, with the description "Alters systemic parent drug and metabolite concentrations." The FDA notes that for this section the effect on safety or response has not been established [3]. The Risperdal label gives no dose based on genotype; its dose changes are for interacting drugs [2]. CPIC has not published a risperidone guideline. Its gene-drug list gives CYP2D6 and risperidone a provisional level of B [8].

Bring the report to your prescriber with a full list of what you take, including over-the-counter products and supplements. A poor metabolizer result is most useful when risperidone is started or its dose is being set. Someone who has been on a steady dose for months may already be on a dose that reflects how they responded.

Medicines that change the picture

Other drugs can make CYP2D6 behave as if your genes were different, an effect called phenoconversion. The Risperdal label names fluoxetine and paroxetine as CYP2D6 inhibitors that raise risperidone levels. In its studies, fluoxetine 20 mg/day raised the combined active moiety about 1.4-fold, and paroxetine raised it 1.3-fold at 10 mg/day, 1.6-fold at 20 mg/day and 1.8-fold at 40 mg/day. With either drug the label advises reducing the risperidone dose and not exceeding 8 mg/day in adults, and says the dose may need to rise again when the inhibitor is stopped [2]. The label also says quinidine gives essentially everyone a risperidone profile typical of poor metabolizers [2]. The FDA classes bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [9].

Enzyme inducers work the other way. In the label's study, carbamazepine roughly halved the combined active moiety (to 0.51 of its usual exposure). The label advises increasing risperidone up to double the usual dose with carbamazepine, expects a similar effect from phenytoin, rifampin and phenobarbital, and says the dose may need to come down when the inducer is stopped [2].

Risperidone itself is only a weak CYP2D6 inhibitor, and the label does not expect it to substantially slow the clearance of other CYP2D6 drugs [2].

Other factors

The label advises a lower starting dose (0.5 mg twice daily) for people with severe kidney impairment or liver impairment [2]. Age, other medicines and other illnesses all affect how risperidone is tolerated, whatever the genotype.

Do not start, stop or change risperidone 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 tell you whether risperidone will work for you or which side effects you will have. Movement effects, weight gain and raised prolactin depend on dose, age, other medicines and other conditions as well as on drug levels. 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 risperidone?

Yes. The DPWG does not advise avoiding it in poor metabolizers; it advises a lower dose, 67% of the normal dose, and 50% if central nervous system side effects still occur (see What the guidelines recommend).

I am an intermediate metabolizer. Does my dose need to change?

Not under the DPWG guideline. Combined levels may be somewhat higher, but there is little evidence of more side effects, and the DPWG judges the effect on dose to be smaller than the normal variation between people [4].

Why doesn't CYP2D6 matter more, if it does most of the work?

Because the product of CYP2D6, 9-hydroxyrisperidone, has activity similar to risperidone's. Slow conversion shifts the balance between the two more than it changes the total, which is what drives the effect [2].

How is risperidone related to paliperidone (Invega)?

Paliperidone is 9-hydroxyrisperidone, the active metabolite that CYP2D6 makes from risperidone. Taken as a drug in its own right, it relies little on liver enzymes: the Invega label says about 59% of a dose leaves the body unchanged in the urine, that CYP2D6 and CYP3A4 play a limited role, and that population studies found no difference in paliperidone exposure between normal and poor CYP2D6 metabolizers [10]. This is why the DPWG uses paliperidone's maximum doses (the same 12 mg/day and 6 mg/day limits as the Invega label) as the reference when titrating risperidone in ultrarapid metabolizers [1]. Because the kidneys do most of the clearing, the Invega label lowers the dose for kidney impairment [10].

Does the result apply to the long-acting injections?

Risperidone is available as Risperdal Consta and Rykindo (intramuscular injections every 2 weeks), Perseris (a subcutaneous injection once a month) and Uzedy (a subcutaneous injection once a month or once every 2 months) [11] [12] [13] [14]. All contain the same drug, so CYP2D6 converts it in the same way. The DPWG's recommendations are stated for risperidone without separating tablets from injections; the intramuscular limit it gives (75 mg per 2 weeks) is for the active metabolite, and the Risperdal Consta label sets its own maximum of 50 mg every 2 weeks [11]. The injection labels give their own steps for starting or stopping fluoxetine, paroxetine or strong inducers. How to apply a genetic result to a particular product is a decision for your prescriber.

1. 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). Risperidone evidence summary, dose recommendations and testing advice.
2. Risperdal (risperidone) tablets, orally disintegrating tablets and oral solution: prescribing information (Janssen). DailyMed. Indications, mechanism, metabolism, CYP2D6 pharmacokinetics, drug interactions and dosing.
3. US Food and Drug Administration. Table of Pharmacogenetic Associations. Section 3: CYP2D6 poor metabolizers and risperidone.
4. ClinPGx. Annotation of DPWG guideline for risperidone and CYP2D6. Full recommendation text, therapy-failure figures and history of the guideline.
5. 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). CYP2D6 activity scores and phenotype cut-offs.
6. CPIC. CYP2D6 frequency table (spreadsheet). Estimated phenotype frequencies by biogeographic group.
7. Jukic MM et al. Effect of CYP2D6 genotype on exposure and efficacy of risperidone and aripiprazole: a retrospective, cohort study. Lancet Psychiatry (2019). Active moiety exposure, doses and switching in a Norwegian drug-monitoring cohort.
8. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level B for CYP2D6 and risperidone.
9. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 inhibitors.
10. Invega (paliperidone) extended-release tablets: prescribing information (Janssen). DailyMed. Elimination, CYP2D6 and dosing limits.
11. Risperdal Consta (risperidone) long-acting injection: prescribing information (Janssen). DailyMed. Dosing schedule and drug interactions.
12. Rykindo (risperidone) extended-release injectable suspension: prescribing information. DailyMed. Dosing schedule and drug interactions.
13. Perseris (risperidone) extended-release injectable suspension: prescribing information. DailyMed. Dosing schedule and drug interactions.
14. Uzedy (risperidone) extended-release injectable suspension: prescribing information. DailyMed. Dosing schedule and drug interactions.