From the Editor
This month’s issue features The Complicated Patient Special Report with an article by Drs Fabbri and Serretti, “Overcoming Treatment Resistance: Can Pharmacogenetics Help?” It comes on the heels of “Using Pharmacogenetics in Making Treatment Decisions for Schizophrenia” a Special Report by Drs Yoshida and Muller in the March issue.1 Both articles reinforce the current expert consensus that clinically actionable genetic testing in psychiatry is quite limited. Specifically, all current evidence-based guidelines support only four genes that have risen to the level of “clinically actionable” in our entire field of psychopharmacology: cytochrome P450 2D6 (CYP2D6), cytochrome P450 2C19 (CYP2C19), human leukocyte antigen, B type, allele 15:02 (HLA-B*15:02), and human leukocyte antigen, A type, allele 31:01 (HLA-A*31:01).
Current expert consensus on psychiatric pharmacogenomic panels
Expert consensus publications and editorials from thought leaders in psychiatry in the past 3 years have consistently concluded that psychiatric pharmacogenomic panels (AKA combinatorial pharmacogenetic tests) are not currently evidence based, and clinical decisions should not be based on their reports.2-9 In fact, on October 31, 2018, the FDA published a safety communication warning against the use of many pharmacogenomic tests with the statement:
For example, the FDA is aware of genetic tests that claim results can be used to help physicians identify which antidepressant medication would have increased effectiveness or side effects compared to other antidepressant medications. However, the relationship between DNA variations and the effectiveness of antidepressant medication has never been established. The FDA is aware that health care providers may have made inappropriate changes to a patient's medication based on the results from genetic tests that claim to provide information on the personalized dosage or treatment regimens for some antidepressants. Patients and health care providers should not make changes to a patient's medication regimen based on the results from genetic tests that claim to predict a patient's response to specific medications, but are not supported by scientific or clinical evidence to support this use, because doing so may put the patient at risk for potentially serious health consequences.10
As a psychopharmacologist with a strong background in molecular genetics I am very excited about the future of evidence based and clinically actionable pharmacogenomic testing that has the potential to improve clinical outcomes in psychiatry. However, in my opinion, based on reviewing a large body of recently published literature, we are not yet at the point where pharmacogenomic panels of testing numerous genes is either evidence based or actionable for clinical practice.
Psychiatric pharmacogenomics began with CYP2D6
My interest in the clinical actionability of pharmacogenomics goes back to the early 1990s, at which time the human cytochrome P450 (CYP) enzyme system was just being delineated. At that time, there was one gene that could be phenotyped by psychiatrists—CYP2D6. This was an important gene in psychiatry even then, as many of the tricyclic antidepressants (TCA) and antipsychotics are metabolized by this enzyme pathway. Two important TCAs metabolized by CYP2D6 are desipramine and nortriptyline. This was long before the entire human genome had been sequenced (2003), and long before our first FDA-approved pharmacogenomic test became available in 2004, Roche’s AmpliChip CYP450 Test.
In the early years of pharmaco- genomic testing, the CYP2D6 gene could be phenotyped into 2 different levels of enzyme activity—poor metabolizer or extensive metabolizer—by administering a known oral dose of dextromethorphan to a patient, and then obtaining serial serum levels from which the ratio of dextromethorphan to dextrorphan (its metabolite post CYP2D6) could be calculated. Based on this ratio, the patient’s CYP2D6 activity could be determined.11 It is significant to note that this allowed the clinician to then dose the desipramine or nortriptyline slowly or aggressively depending on the phenotype. The clinical relevance was established by serum desipramine or nortriptyline levels that were usually consistent with the determined phenotype.
1. Yoshida K, Muller DJ. Using pharmacogenetics in making treatment decisions for schizophrenia. Psychiatric Times. 36(3):19-21.
2. Zeier Z, Carpenter LL, Kalin NH, et al. Clinical implementation of pharmacogenetic decision support tools for antidepressant drug prescribing. Am J Psychiatry. 2018;175:873-886.
3. Nurnberger JI Jr, Austin J, Berrettini WH, et al. What should a psychiatrist know about genetics? Review and recommendations from the Residency Education Committee of the International Society of Psychiatric Genetics. J Clin Psychiatry. 2019;80:17nr12046.
4. Zubenko GS, Sommer BR, Cohen BM. On the marketing and use of pharmacogenetic tests for psychiatric treatment. JAMA Psychiatry. 2018;75:769-770.
5. Rosenblat JD, Lee Y, McIntyre RS. Does pharmacogenomic testing improve clinical outcomes for major depressive disorder? A systematic review of clinical trials and cost-effectiveness studies. J Clin Psychiatry. 2017;78:720-729.
6. Singh AB, Bousman CA. Antidepressant pharmacogenetics. Am J Psychiatry. 2017;174:417-418.
7. Preskorn SH. Genetic and related laboratory tests in psychiatry: What mental health practitioners need to know. Curr Psychiatry. 2016;15:19-22.
8. Rosenblat JD, Lee Y, Mansur RB, et al. Letter to the editor: Inadequate evidence to support improved patient outcomes with combinatorial pharmacogenomics. J Psych Res. 2018;107:136-137.
9. Goldberg JF. Do you order pharmacogenetic testing? Why? J Clin Psychiatry. 2017;78:1155-1156.
10. US Food and Drug Administration. The FDA Warns Against the Use of Many Genetic Tests With Unapproved Claims to Predict Patient Response to Specific Medications. https://www.fda.gov/medical-devices/safety-communications/fda-warns-against-use-many-genetic-tests-unapproved-claims-predict-patient-response-specific. Accessed May 13, 2019.
11. Mortimer O, Lindstrom B, Laurell H, et al. Dextromethorphan: polymorphic serum pattern of the O-demethylated and didemethylated metabolites in man. Br J Clin Pharma. 1989;27:223-227.
12. PharmGKB. https://www.pharmgkb.org. Accessed May 13, 2019.
13. Clinical Pharmacogenetics Implementation Consortium. https://cpicpgx.org. Accessed May 13, 2019.
14. Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98:127-34.
15. International Society of Psychiatric Genetics. Genetic Testing Statement. https://ispg.net/genetic-testing-statement. Accessed May 13, 2019.