Pharmacogenomic Testing as a Preventive Approach to Tardive Dyskinesia Risk Reduction and Management

• Tardive dyskinesia (TD) is a chronic, potentially irreversible movement disorder caused by prolonged use of dopamine receptor-blocking agents, primarily antipsychotic medications. Symptoms include involuntary orofacial, truncal, and limb movements, impairing eating, breathing, mobility, employment and quality of life.
• TD affects ~25% of patients on antipsychotics, with increased risk in elderly adults and prolonged exposure (1).
• The increasing use of antipsychotics for conditions beyond schizophrenia—including depression, bipolar disorder, personality disorders, and irritability in autism spectrum disorder—has widened the at-risk population (2-4). At-risk population also include children or adolescents exposed to antipsychotics, with an estimated TD prevalence of 5–20% (5).
• Approximately 600,000 people in the U.S. live with TD, with 65% remain undiagnosed (6).

• Highest risk of TD is observed with first-generation antipsychotics (FGAs); some second-generation antipsychotics (SGAs) also pose risk. A 2025 study found that antipsychotic doses exceeding 75 mg/day are associated with an increased risk of developing TD (7).
• Recent research highlights genetic variability in drug metabolism as a key contributor to TD risk. Many commonly prescribed antipsychotics and adjunctive agents are substrates of CYP2D6 and CYP2C19 enzymes. The risk of TD amplified in extreme CYP2D6 metabolizer phenotypes, poor metabolizers and ultrarapid metabolizers, having altered antipsychotic metabolism and abnormal levels of parent or toxic metabolites. (8-10).
• Anticholinergic medications can worsen TD symptoms and cognitive decline, particularly in elderly patients. They Increase the risk of falls, confusion, and functional impairment, compounding the burden of TD (11).
• TD can be triggered by concurrent use of drugs like metoclopramide (antiemetic), certain antidepressants (SSRIs, SNRIs, TCAs), lithium, oxybutynin, cyclobenzaprine and some antihistamines. Many of these agents are also affected by genetic variants in CYP2D6 or CYP2C19 enzymes (12-14).

• Pharmacogenomic (PGx) testing helps tailor antipsychotic dosing, especially for those with CYP2D6 variants.
• Evidence-based recommendations for CYP2D6-guided antipsychotic dose and drug selection strategies exist (14, 15).
• Testing can inform safer drug selection and dosing, especially in high-risk populations (e.g., elderly, poor metabolizers). Minimizing antipsychotic exposure in at-risk populations has the potential to reduce TD incidence.
• Medications beyond antipsychotics: several agents that contribute to the risk of TD that are often prescribed to elderly patients have PGx implications. Testing supports proactive prevention of TD by minimizing exposure to high plasma drug levels from these medications.

Pharmacogenetic testing can aid in risk stratification and drug selection. FDA-supported PGx recommendations and recent expert guidelines (12-15) now provide genotype-guided dose adjustments for several agents:

• FGAs like haloperidol and pimozide: Reduced dose or avoidance in CYP2D6 poor metabolizers due to QT prolongation risk.
• SGAs like risperidone, aripiprazole, and brexpiprazole: Lower doses recommended in poor metabolizers to avoid excessive exposure.
• Newer agents like lumateperone and xanomeline-trospium have lower TD risk due to non-dopaminergic mechanisms. Xanomeline-trospium dose adjustment is still necessary in CYP2D6 poor metabolizers.
• Antidepressants (SSRIs, SNRIs, Tricyclics) that can amplify risk of TD: CYP2D6 Poor metabolizers and/or CYP2C19 poor metabolizers are at greater risk for elevated drug levels supporting the need for lower initial doses or alternative agents.

In established TD, first-line treatment includes VMAT2 inhibitors: valbenazine, deutetrabenazine, and tetrabenazine. These agents also carry PGx-based dosing considerations tied to CYP2D6 metabolism, especially to mitigate risks of QT prolongation and CNS side effects (14).

Clinicians are advised to consider PGx testing in several scenarios:

• Initiating antipsychotic therapy in high-risk populations (e.g., elderly, pediatric, mood disorder patients).
• Managing patients on complex polypharmacy involving CYP2D6 or CYP2C19 impacted medications and those with anticholinergic properties.
• Evaluating treatment failure or unexpected side effects.
• Selecting and dosing VMAT2 inhibitors in patients with established TD.

• PGx testing offers a powerful tool in the effort to reduce the incidence and improve the treatment of tardive dyskinesia.
• By identifying genetic variations that impact drug metabolism—particularly CYP2D6 and CYP2C19—clinicians can personalize antipsychotic and related medication regimens (e.g antidepressants,) to lower TD risk before symptoms emerge.
• Tailored dosing strategies, such as initiating therapy at the lower end of the therapeutic range in poor metabolizers, help minimize prolonged exposure to high plasma drug levels that contribute to TD development.
• Furthermore, in patients already diagnosed with TD, PGx testing enhances treatment safety by guiding dose adjustments of VMAT2 inhibitors and other therapies based on CYP2D6 metabolic capacity. This reduces the risk of dose-dependent side effects such as QT prolongation, especially in vulnerable populations like the elderly.
• The incorporation of PGx testing into clinical decision-making promotes safer prescribing, earlier intervention, and more effective symptom control, ultimately improving outcomes and quality of life for patients at risk of or living with TD.

References

1. Carbon, M., Hsieh, C. H., Kane, J. M., & Correll, C. U. (2017). Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis. The Journal of clinical psychiatry, 78(3), e264–e278
2. Cummings, M. A., Proctor, G. J., & Stahl, S. M. (2018). Deuterium Tetrabenazine for Tardive Dyskinesia. Clinical schizophrenia & related psychoses, 11(4), 214–220
3. Niemann, N., & Jankovic, J. (2018). Treatment of Tardive Dyskinesia: A General Overview with Focus on the Vesicular Monoamine Transporter 2 Inhibitors. Drugs, 78(5), 525–541.
4. Scorr, L. M., & Factor, S. A. (2018). VMAT2 inhibitors for the treatment of tardive dyskinesia. Journal of the neurological sciences, 389, 43–47.
5. Besag, F. M. C., Vasey, M. J., Salim, I., & Hollis, C. (2024). Tardive Dyskinesia with Antipsychotic Medication in Children and Adolescents: A Systematic Literature Review. Drug safety, 47(11), 1095–1126
6. Tardive Dyskinesia: A Comprehensive Look at the Condition and Its Management. (2024) –https://www.physiciansweekly.com/tardive-dyskinesia-a-comprehensive-look-at-the-condition-and-its-management/. Accessed May 2025.
7. Gouda, M., Abe, M., Watanabe, Y., & Kato, T. A. (2024). Analysis of Antipsychotic Dosage in Patients With Tardive Dyskinesia: A Case-Control Study Using the Claims Database of the Corporate Health Insurance Association. Journal of clinical psychopharmacology, 44(4), 378–385.
8. Lu, J. Y., Tiwari, A. K., Freeman, N., Zai, G. C., Luca, V., Müller, D. J., Tampakeras, M., Herbert, D., Emmerson, H., Cheema, S. Y., King, N., Voineskos, A. N., Potkin, S. G., Lieberman, J. A., Meltzer, H. Y., Remington, G., Kennedy, J. L., & Zai, C. C. (2020). Liver enzyme CYP2D6gene and tardive dyskinesia. Pharmacogenomics, 21(15), 1065–1072.
9. Patsopoulos, N. A., Ntzani, E. E., Zintzaras, E., & Ioannidis, J. P. (2005). CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis. Pharmacogenetics and genomics, 15(3), 151–158.
10. Koola, M. M., Tsapakis, E. M., Wright, P., Smith, S., Kerwin Rip, R. W., Nugent, K. L., & Aitchison, K. J. (2014). Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?. Journal of psychopharmacology (Oxford, England), 28(7), 665–670.
11. Ward, K. M., & Citrome, L. (2018). Antipsychotic-Related Movement Disorders: Drug-Induced Parkinsonism vs. Tardive Dyskinesia-Key Differences in Pathophysiology and Clinical Management. Neurology and therapy, 7(2), 233–248.
12. Hicks, J. K., Sangkuhl, K., Swen, J. J., Ellingrod, V. L., Müller, D. J., Shimoda, K., Bishop, J. R., Kharasch, E. D., Skaar, T. C., Gaedigk, A., Dunnenberger, H. M., Klein, T. E., Caudle, K. E., & Stingl, J. C. (2017). Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clinical pharmacology and therapeutics, 102(1), 37–44.
13. Bousman, C. A., Stevenson, J. M., Ramsey, L. B., Sangkuhl, K., Hicks, J. K., Strawn, J. R., Singh, A. B., Ruaño, G., Mueller, D. J., Tsermpini, E. E., Brown, J. T., Bell, G. C., Leeder, J. S., Gaedigk, A., Scott, S. A., Klein, T. E., Caudle, K. E., & Bishop, J. R. (2023). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants. Clinical pharmacology and therapeutics, 114(1), 51–68.
14. Food and Drug Administration, Table of Pharmacogenetic Associations. https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations. Accessed May 2025
15. Beunk, L., Nijenhuis, M., Soree, B., de Boer-Veger, N. J., Buunk, A. M., Guchelaar, H. J., Houwink, E. J. F., Risselada, A., Rongen, G. A. P. J. M., van Schaik, R. H. N., Swen, J. J., Touw, D., van Westrhenen, R., Deneer, V. H. M., & van der Weide, J. (2024). Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6, CYP3A4 and CYP1A2 and antipsychotics. European journal of human genetics : EJHG, 32(3), 278–285.