Pharmacogenetic Testing

Pharmacogenetic Testing

Pharmacogenetic Testing

Primer

Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. There is increasing interest in trying to use pharmacogenetics to understand which patients will respond best to which psychotropic medications.

Current Tests

Most commercial pharmacogenetic companies test for variations of the cytochrome P450 enzymes, and one tests for the HLA allele polymorphisms. These tests can only tell a clinician if someone may need a lower than usual dose of a medication to minimize side effects, or a higher dose if they metabolize a drug too rapidly.
It does not tell you which drug will work best for a patient. In unique cases, it may be useful to identify ultrafast CYP metabolizers, if there is a suspicious of metabolism differences.
Both the American Psychiatric Association (APA) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) do not recommend the routine use of pharmacogenetic tests.^[1]^[2]
- Pharmacogenetic testing or plasma level monitoring may be useful in select clinical situations such as when there are severe or unusual adverse effects with low doses of medications, or when there is poor response to therapeutic doses. In these situations, the tests may help identify the small proportion (although this can vary in certain populations) of individuals with atypical metabolizer status and/or unexpected plasma levels.^[3]

Hold Up!

Pharmacogenetic testing remains in the early stages and in its infancy, be aware that many commercial entities overpromise the impact of pharmacogenetic testing, and public expectations of pharmacogenetics exceeds the actual clinical evidence. For example, it remains unclear if the genetic test itself can accurately detect the genetic variant in a real-world setting. It also remains unclear if genetic testing will change clinical management and actually improve clinical outcomes. At the end of the day, there are multiple factors that affect medication effectiveness and response, including: age, ethnicity, drug-drug interactions, and substance use. Forgetting about these factors can make pharmacogenetic testing a red herring in clinical practice.

CYP 2C19 "Poor Metabolizers"

The FDA has recommended that patients who carry the CYP2C19 “poor metabolizer” phenotype not be prescribed more than 20mg citalopram without an ECG.^[4]

HLA-B*1502

The human leukocyte antigen (HLA) complex is a gene complex that encodes the major histocompatibility complex (MHC) proteins in humans. This plays a critical role in the immune system and response. There is a strong link between the human leukocyte antigen HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) in Han-Chinese, Thai, and Malaysian populations.^[5]^[6] HLA-B*1502 screening in patients is required prior to starting carbamazepine therapy.^[7] SJS/TEN is also thought to be triggered by from lamotrigine by a similar mechanism with this allele.

HLA-A*3101

The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, is also significantly associated with the hypersensitivity, similar to HLA-B*1502.

Future

See also: O’Connell, C. P., Goldstein-Piekarski, A. N., Nemeroff, C. B., Schatzberg, A. F., Debattista, C., Carrillo-Roa, T., ... & Williams, L. M. (2017). Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein. American Journal of Psychiatry, appi-ajp.

Resources

Articles

Research

Rahman, T., Ash, D. M., Lauriello, J., & Rawlani, R. (2017). Misleading Guidance From Pharmacogenomic Testing. American Journal of Psychiatry, 174(10), 922-924.

effects-and-monitoring

¹⁾ Lam, R. W., Kennedy, S. H., Adams, C., Bahji, A., Beaulieu, S., Bhat, V., ... & Milev, R. V. (2024). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023: Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes. The Canadian Journal of Psychiatry, 07067437241245384.

²⁾ Baum, M. L., Widge, A. S., Carpenter, L. L., McDonald, W. M., Cohen, B. M., Nemeroff, C. B., & American Psychiatric Association (APA) Workgroup on Biomarkers and Novel Treatments. (2024). Pharmacogenomic clinical support tools for the treatment of depression. American Journal of Psychiatry, 181(7), 591-607.

³⁾ Lam, R. W., Kennedy, S. H., Adams, C., Bahji, A., Beaulieu, S., Bhat, V., ... & Milev, R. V. (2024). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults: Réseau canadien pour les traitements de l'humeur et de l'anxiété (CANMAT) 2023: Mise à jour des lignes directrices cliniques pour la prise en charge du trouble dépressif majeur chez les adultes. The Canadian Journal of Psychiatry, 07067437241245384.

⁴⁾ FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses

⁵⁾ Chung, W. H., Hung, S. I., Hong, H. S., Hsih, M. S., Yang, L. C., Ho, H. C., ... & Chen, Y. T. (2004). Medical genetics: a marker for Stevens–Johnson syndrome. Nature, 428(6982), 486.

⁶⁾ Tangamornsuksan, W., Chaiyakunapruk, N., Somkrua, R., Lohitnavy, M., & Tassaneeyakul, W. (2013). Relationship between the HLA-B* 1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA dermatology, 149(9), 1025-1032.

⁷⁾ Ferrell, P. B., & McLeod, H. L. (2008). Carbamazepine, HLA-B* 1502 and risk of Stevens–Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations.

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