Should you order genetic testing to identify how patients metabolize antipsychotics?
Use in clinical practice
Proposed expert guidelines recommend halving the normal target dose of risperidone and avoiding haloperidol and phenothiazine antipsychotics in CYP2D6 PMs.12 These guidelines are based on expert review of the pharmacokinetic effects of CYP2D6 PM status as well as case reports and studies associating CYP2D6 with poor outcomes, usually side effects. Although these studies suggest that determining metabolizer status may be clinically important, many other studies—some very large—have not found evidence for associations between drug metabolizing enzyme variants and clinical outcomes from antipsychotics.13
There are 2 clinical scenarios in which one may consider obtaining CYP2D6 genotype information:
- before initiating treatment (Table 2)
- after trying ≥1 agent primarily dependent on CYP2D6 with evidence of dose-related side effect (Table 3).
Identifying PMs could influence drug selection and dosing if this information is available before antipsychotic exposure. Studies have found evidence that CYP2D6 PMs may be at greater risk of experiencing adverse reactions to risperidone compared with other metabolizer groups.14 Also, prescribing information for aripiprazole and iloperidone recommends halving the dose of these drugs in the presence of CYP2D6 inhibitors, a condition that pharmacokinetically mimics PM status.
Knowing genotype information after ≥1 drugs have been tried may not be as useful. Clinicians often base drug switches or dose titrations on a patient’s experience with present or past doses of the antipsychotic. Examples include slowing titrations or reducing a target dose when a patient, such as Mr. P, experiences side effects, or selecting non-2D6 substrate agents after detecting a pattern of drug sensitivity.
Table 2
CYP2D6 testing before initiating antipsychotics: Benefits vs drawbacks
| Benefits | Drawbacks |
|---|---|
| Clinicians could avoid 2D6 substrate drugs with high likelihood for ADEs or increased risk of 2D6-based interactions in PMs | No empiric evidence shows that routine genotyping produces better clinical outcomes (eg, fewer side effects and better treatment adherence) |
| May lower initial dose, slow titration, and lower initial target dose to minimize risk of side effects in PMs | Many clinicians titrate slowly or adjust titration schedule and target doses based on initial tolerability as part of routine practice |
| The test would need to be done only once and the information may be useful for other therapy decisions | Patients who need immediate drug therapy may not be able to wait for test results |
| Testing may not be covered by a patient’s health insurance | |
| ADEs: adverse drug events; PMs: poor metabolizers | |
Table 3
Genotype testing after a patient experiences side effects
| Benefits |
| Identifying a biologic reason for side effect sensitivity may aid choice and dosing of subsequent antipsychotics and other medications |
| Drawbacks |
| In clinical practice, antipsychotic switching because of tolerability (and response) often is guided by outcomes experienced from previously used agents. In general, patients with a history of experiencing side effects at lower doses of antipsychotics are likely to be initiated at lower doses and titrated more cautiously during subsequent therapy choices regardless of whether side effects were caused by metabolizer status or other factor(s) |
Better patient outcomes?
It is not known if obtaining genotype information will provide better outcomes than a “trial and error” approach. Currently, obtaining genotype information before antipsychotic treatment is not standard clinical practice. Because this testing is expensive and requires prior approval from third party payers or out-of-pocket financial resources, testing is not recommended for all patients at this time.
However, a growing body of evidence suggests that knowing metabolizer status could be useful in drug selection or dosing for antipsychotics. This scientific knowledge continues to accumulate, and CYP2D6 genotyping may some day be integrated into routine clinical care. Currently, for patients and physicians with the resources to obtain and the ability to appropriately interpret the test results, this information may prove useful on an individual basis. However, additional studies are needed to support better outcomes from dosing and drug selection based on CYP2D6 genotype information.
Related Resources
- Evaluation of Genomic Applications in Practice and Prevention (EGAPP). www.egappreviews.org.
- Pharmacogenomics Knowledge Base. www.pharmgkb.org.
- Indiana University School of Medicine. P450 drug interaction table. https://medicine.iupui.edu/clinpharm/ddis/table.asp.
Drug Brand Names
- Aripiprazole • Abilify
- Asenapine • Saphris
- Chlorpromazine • Thorazine
- Clozapine • Clozaril
- Fluphenazine • Prolixin
- Haloperidol • Haldol
- Iloperidone • Fanapt
- Olanzapine • Zyprexa
- Paliperidone • Invega
- Perphenazine • Trilafon
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Thioridazine • Mellaril
- Ziprasidone • Geodon
Disclosures
Dr. Bishop receives grant/research support from the National Institute of Mental Health, NARSAD, and Ortho-McNeil-Janssen and has received honoraria from Eli Lilly and Company.
Ms. Chae reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.
