Pharmacogenomics in Psychiatry

Educational Objectives

The goal of this program is to improve management of psychiatric conditions by incorporating pharmacogenetics into practice. After hearing and assimilating this program, the clinician will be better able to:

1. Elaborate on the gene variants of concern in psychiatry and how they impact medication choices.
2. Appreciate the factors that can influence medical decision-making when considering pharmacogenomic testing.
3. Recommend pharmacogenomic testing to appropriate patient populations.

Summary

Overview: pharmacogenomics is the study of how genomic variations affect drug responses; genetic variants include single nucleotide polymorphisms, insertions, deletions, and duplications; germline genetic variants can affect drug responses; in psychiatry, cytochrome P450 (CYP450), human leukocyte antigen (HLA)-A, and HLA-B are relevant; on pharmacogenetic tests, star alleles (stars followed by a number) show if there is a genetic variant with the gene; any number other than 1 indicates a potential variant; each allele has a different meaning; the allele numbers translate into a diplotype, from which phenotype can be determined; the phenotype provides information on how a medication is metabolized

Types of metabolizers: include poor, intermediate, extensive, and ultrarapid; poor metabolizers lack a functional copy of either gene for one CYP450 isoenzyme; intermediate metabolizers may have one functional copy and one normal copy; ultrarapid metabolizers have >2 active genes for the enzyme; poor metabolizers do not break down the medication as well as normal metabolizers, resulting in increased plasma drug levels and, potentially, adverse effects; with ultrarapid metabolizers, plasma drug levels are potentially reduced and dosing may be subtherapeutic; some medications are prodrugs and the opposite effects are seen with those

Guidelines: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are evidence-based and based on preemptive testing; they do not advise on when to test, but if testing is done, they provide recommendations on what to do; the US Food and Drug Administration (FDA) has recommendations for patient care, pharmacokinetics, safety, and therapeutic response; these are not as evidence-based as the CPIC guidelines but are based on product labeling; another good resource is PharmGKB, which is a knowledge base trademarked by the Department of Health and Human Services; they use a combination of guidelines to give recommendations and have information on detailed drug metabolism pathways and supporting literature; several factors go into the selection of psychotropic medications; pharmacogenomics-informed testing can act as an aid to better predict response and can lead to more evidence-based prescribing

Evidence: a meta-analysis found that the probability of non-normal metabolism for CYP450 2D6 (CYP2D6) is 36.4% (ie, 1 in 3 patients) and almost 62% for CYP450 2C19 (CYP2C19); among people of African descent, almost 40% are likely to have non-normal metabolism for CYP2D6, and ≤66% for CYP2C19; >50% of medications are metabolized by either of these and can be impacted in people with non-normal metabolism

Brouwer et al (2024): showed that serum escitalopram concentration was higher in poor CYP2C19 metabolizers and decreased with each metabolizer; the statistically significant number of people who switched medications was higher in poor and ultrarapid metabolizers, indicating that CYP2C19 testing could help guide escitalopram use; because the study was retrospective and in a therapeutic drug monitoring clinic, the reasons for changing medication were unknown; side effects or inefficiencies could be avoided when switching using pharmacogenetics testing; the team also looked at CYP2D6 genotyping with risperidone and aripiprazole and found that both drugs had statistically significant changes for switching medication in poor or ultrarapid metabolizers; there was increased exposure for both, but this was significant only for risperidone; even though CYP2D6 substrates exist, clinical significance is not the same across the board

HLA alleles: HLA genes are part of the class 1 immune response with major histocompatibility complex and present antigens to immune cells; if presented as nonself, an immune response is triggered, causing adverse effects, eg, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN); HLA proteins are highly polymorphic and can have several genetic variants; the frequency of these alleles varies by geographic group; HLA alleles are higher in people of East Asian descent; in psychiatry, the genes of concern are HLA-B*1502 and HLA-A*3101; a meta-analysis showed that people with the HLA-B*1502 allele were 26-fold more likely to have SJS or TEN with use of carbamazepine; additional associations exist with oxcarbazepine and phenytoin, but the evidence is not as significant; the FDA recommends pharmacogenetic testing before starting carbamazepine or oxcarbazepine in patients of East Asian descent; CPIC guidelines recommend that patients who are HLA-A*3101-positive should avoid carbamazepine or have increased monitoring; while evidence is not as strong as for HLA-B*1502, it is still more likely to result in adverse effects with carbamazepine; in patients who are HLA-B-positive, all 3 agents should be avoided, specifically when starting treatment, as cutaneous reactions occur within 3 mo of starting

Supporting evidence: in the PRIME Care trial, Oslin et al (2022) looked at remission rates via Patient Health Questionairre-9 in patients with depression who had treatment guided by pharmacogenomic testing vs usual care, and found that remission and response rates over 26 wk were higher among patients who had guided care, though the effect size was not very large; a study found that pharmacogenomics is cost-effective and can lead to fewer visits, reduced pharmacy costs related to medication switching, reduced emergency department visits, and fewer hospitalizations due to adverse drug reactions

Limitations: much of pharmacogenomics is based on assumption or expert opinion, and clinical evidence is lacking; many clinical trials are underpowered since few patients have the necessary genetic variations; studies lack external validity as they often exclude patients with certain variations or taking certain medications; clinical trials have windows ≤6 mo (long-term effects are not known)

Benefit from pharmacogenomic testing: based on data from several studies, groups likely to benefit the most from pharmacogenomic testing include patients with more severe symptomatology at baseline, those who have not had a significant response with multiple medications, those who have reported multiple side effects with medications, and those at increased risk of carrying non-normal metabolizing genetic variants

Patient counseling: many psychiatry providers think pharmacogenomics may be useful but are unsure when to use it and how to interpret it, hindering its use; talk to patients before ordering testing, eg, ask what they know about genetic testing; this allows the provider to lead the conversation and set expectations; it is not possible to guarantee that an effective medication can be identified; options should be discussed, eg, whether the facility has one or multiple laboratories that test; patients should be informed about the testing process and potential cost without insurance as testing can be expensive; patients may assume that genetic testing will tell them anything they need to know and ensure that the selected medication works; this misperception should be corrected so that patients have reasonable expectations and understand what pharmacogenomics can do; the patient population in psychiatry typically has lower health literacy; pharmacogenomic testing results are long and have complex medical jargon, so they may need help identifying relevant information; other considerations include difficulty understanding the underlying concepts of the testing, its benefits, and limitations; patients should be informed that it is just a commercial laboratory test that can be sent out; laboratories often compete with each other and may not test the same variants, translate the same genotypes to phenotypes, or provide the same recommendations

Variations in testing: in one study, genetic tests were sent to different commercial laboratories to compare the agreement of phenotype, genotype, and medication recommendation; results showed only 37% genotype agreement for CYP2D6, and 53% in terms of antipsychotic recommendation; if a laboratory does not test for a certain variant, that variant shows up on the test as normal or not detected, which is misleading; it is important to know what a laboratory is testing for and how many variants they are testing for before ordering; knowing which alleles to look for instead of doing what the laboratory recommends or has an interpretation for is likely to offer the best results; laboratory recommendations should be correlated with evidence based on knowledge; patients should know about other factors that impact result interpretation, ie, if renal function is abnormal, the test results are irrelevant as the drug is not being excreted (should be addressed); phenoconversion involves nongenetic factors that change the phenotype, eg, a normal metabolizer of CYP2D6 who is taking bupropion becomes a poor metabolizer; patients who are normal CYP2C19 metabolizers but use cannabis heavily become poor metabolizers as cannabis inhibits the pathway; other considerations are comorbid diseases and side effect profile concerns; ultrarapid metabolizers can still have side effects at normal doses (dose increases should be avoided); other medications can potentially be impacted by testing, and patients should discuss this with providers

Interpretation of test results: the ABCD framework is a good guide; “A” stands for actionability; it is important to assess if the genes are clinically relevant and if the patient is taking medications that are impacted; “B” stands for being mindful of limitations; the caveats for reports and results should be understood; “C” stands for clinical practice guidelines and how they will guide and determine decision-making; “D” stands for discussion; patients should be informed about the results in simple language; they should feel respected and properly educated; some may want a detailed explanation of the test, while others may only want to know what changes should be made; it is important to know what individual patients want to know from their results; they should be encouraged to keep a summary of their results with their medication list, so that if their current medications are impacted, they can let other providers know; the importance of safety should be stressed, and patients should be able to remember safety considerations; additional open-source resources and reading material can be given so that patients can make informed decisions

Sequence2script: the clinician can enter information about genetic testing results, medications the patient is taking, and medications being considered; the tool then suggests recommendations from peer-reviewed guidelines based on the input given

Readings

Bousman CA, Wu P, Aitchison KJ, et al. Sequence2Script: A web-based tool for translation of pharmacogenetic data into evidence-based prescribing recommendations. Front Pharmacol. 2021;12:636650. Published 2021 Mar 18. doi:10.3389/fphar.2021.636650; Brouwer JMJL, Wardenaar KJ, Nolte IM, et al. Association of CYP2D6 and CYP2C19 metabolizer status with switching and discontinuing antidepressant drugs: an exploratory study. BMC Psychiatry. 2024;24(1):394. Published 2024 May 27. doi:10.1186/s12888-024-05764-6; Brown LC, Stanton JD, Bharthi K, et al. Pharmacogenomic testing and depressive symptom remission: A systematic review and meta-analysis of prospective, controlled clinical trials. Clin Pharmacol Ther. 2022;112(6):1303-1317. doi:10.1002/cpt.2748; Gross T, Daniel J. Overview of pharmacogenomic testing in clinical practice. Ment Health Clin. 2018;8(5):235-241. Published 2018 Aug 30. doi:10.9740/mhc.2018.09.235; Jeiziner C, Wernli U, Suter K, et al. HLA-associated adverse drug reactions - scoping review. Clin Transl Sci. 2021;14(5):1648-1658. doi:10.1111/cts.13062; Koopmans AB, Braakman MH, Vinkers DJ, et al. Meta-analysis of probability estimates of worldwide variation of CYP2D6 and CYP2C19. Transl Psychiatry. 2021;11(1):141. Published 2021 Feb 24. doi:10.1038/s41398-020-01129-1; Leckband SG, Kelsoe JR, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther. 2013;94(3):324-328. doi:10.1038/clpt.2013.103; Nguyen TT, Leary EJW, Lee JT, et al. Comparing commercial pharmacogenetic testing results and recommendations for antidepressants with established CPIC guidelines. Front Pharmacol. 2024;15:1500235. Published 2024 Nov 25. doi:10.3389/fphar.2024.1500235; Oslin DW, Lynch KG, Shih MC, et al. Effect of pharmacogenomic testing for drug-gene interactions on medication selection and remission of symptoms in major depressive disorder: The PRIME Care randomized clinical trial. JAMA. 2022;328(2):151-161. doi:10.1001/jama.2022.9805; Sager JE, Tripathy S, Price LS, et al. In vitro to in vivo extrapolation of the complex drug-drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation [published correction appears in Biochem Pharmacol. 2021 Jan;183:114306. doi: 10.1016/j.bcp.2020.114306]. Biochem Pharmacol. 2017;123:85-96. doi:10.1016/j.bcp.2016.11.007.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Brainerd's lecture contains information related to the off-label or investigational use of a product, therapy, or device.

Acknowledgements

Dr. Brainerd was recorded at the Iowa Psychiatric Physicians Society 2024 Fall Symposium, held in Coralville, IA, on October 25, 2024, and presented by the Iowa Psychiatric Physicians Society. For information about upcoming CME activities from this presenter, please visit https://www.iowapsychiatry.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

PS540601

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.