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Bri Englett, PharmD, BCPP

This session can be purchased in CPNP University.

As the world of pharmacogenomic testing continues to grow, there are questions surrounding the utility of testing in clinical practice. Drs. Jeffery Bishop, PharmD, MS, BCPP and Vicki Ellingrod, PharmD, FCCP shared their expertise at CPNP 2016 in back to back sessions focused on pharmacogenomic testing. This article will focus on Dr. Bishop’s session entitled, Psychiatry and Neurology Pharmacogenomics: Implications for Patient Care and Resources for Implementation, which was designed to aid in the understanding and use of this expanding technology.

Overview of Pharmacogenomics

Dr. Bishop provided an overview of pharmacogenomics as the study of how genetic variations and resulting enzymatic activity affect drug response.1-2 There are several areas in which genetics may impact how people respond to medications, whether as a side effect, hypersensitivity reaction or other aspects of treatment response. Potentially meaningful pathways include drug targets (e.g., serotonin and dopamine receptors and transporters), drug metabolizing enzymes, immunological markers (e.g., Human Leukocyte Antigen (HLA)), and second messengers and signaling cascades. Pharmacogenomic results may be reported as alleles using the star nomenclature (e.g., CYP2D6*1/*4, CYP2C19*17/*17).

There is tremendous variability in how individuals respond to medications. By integrating pharmacogenomics results into treatment considerations, one can identify a genetic profile that may be predictive of toxicity. A provider could then decide to alter the medication selection or dosing strategy. Alternatively, a provider could identify a genetic profile predictive of a less-robust response and choose an agent that may be more likely to result in effective treatment.

Immune Response

Dr. Bishop discussed the topic of immune response or hypersensitivity reactions in relation to pharmacogenomics. HLA complexes bind to drugs or drug metabolites and present them to T-cells.3 There are variants in HLA genes that can alter the way the drugs are presented to the T-cells and can ultimately result in hypersensitivity reactions such as Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis. He shared study findings in which almost all of the carriers of the HLA-B*1502 allele developed SJS with carbamazepine use.4 This led to a change in the boxed warning for carbamazepine in 2007 which now recommends screening for the presence of this allele in genetically at-risk populations. These findings also led to the development of the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for HLA-B genotype and carbamazepine dosing.5 CPIC is an NIH funded endeavor which provides information on pharmacogenetic drug-gene pairs and helps providers understand how to apply pharmacogenetic information to clinical practice through the publication of guidelines.

Drug Metabolism

There is evidence that CYP450 genetic variations are associated with altered drug metabolism for medications such as phenytoin (CYP2C9), tricyclic antidepressants (CYP2D6/CYP2C19), and selective serotonin reuptake inhibitors (SSRI) (CYP2D6/CYP2C19) and CPIC guidelines can assist clinicians in choosing the most appropriate medication when pharmacogenomic results are available.6 For example, Dr. Bishop noted there is a strong recommendation to select a medication other than paroxetine for patients who are CYP2D6 ultra-rapid metabolizers whereas alternative therapy to citalopram and escitalopram should be considered for CYP2C19 ultra-rapid, rapid, and poor metabolizers (moderate recommendation). He also pointed out that while not included in CPIC guidelines yet, there are multiple medications (e.g. aripiprazole, atomoxetine, iloperidone, perphenazine, risperidone, valproic acid, venlafaxine, and vortioxetine) that have drug-gene recommendations in product labeling.

Outcomes and Limitations

Dr. Bishop described how results from one study showed how pharmacogenetic testing in psychiatry had the potential to reduce average cost over time by reducing length of hospital stays.7 This may be due to the ability to determine the optimal medication and dose more quickly and/or avoidance of toxicities. Results from another study suggested that pharmacogenomic guided treatment of major depressive disorder may be more beneficial than unguided treatment (although there may have been some bias on the part of the investigators).8 While pharmacogenomic results are a valuable tool, it should be noted that these results alone will not result in 100% clinical response and prevention of adverse reactions.9 Age, disease states, pharmacokinetic factors, and environment are all important pieces of the puzzle.

Why Integrate Pharmacogenomics into Patient Care?

Value-based care places greater emphasis on outcomes and preventative care. It is estimated that two million hospitalized individuals each year experience an adverse drug reaction (ADR) with 100,000 deaths attributed to ADRs.10 Dr. Bishop also presented data from a study published in JAMA Psychiatry in 2014 which estimated 90,000 patients visit the emergency department annually due to psychiatric drug-induced adverse events.11 Using pharmacogenomics testing, one could preemptively identify those at risk for an ADR. Similarly, a provider could use the same results to help optimize drug selection as approximately 20 to 50% of psychiatric patients fail their initial pharmacotherapy regimen.12 Genetic testing is being used more frequently with the majority of providers using this information in their practices and/or agreeing that it will become the common standard of practice in psychiatric pharmacotherapy.13 Therefore it is important for all pharmacists to be aware of the possible clinical applications of these results.

Pharmacogenomic Resources

Multiple resources are available for providers to obtain CPIC guidelines and learn more about how genetic test results can be used to optimize drug therapy.

Clinical Pharmacogenetics Implementation Consortium (CPIC) https://cpicpgx.org/
Pharmacogenomics Knowledgebase http://www.pharmgkb.org
FDA Drug Insert http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm
Genetic Testing Registry http://www.ncbi.nlm.nih.gov/gtr/
National Guideline Clearinghouse http://www.guideline.gov/

Take Home Messages

  • Pharmacogenomic testing can be used, along with other information, to make decisions about medications that are individualized to the patient.
  • In the future, it is likely that providers will be able to uniformly and systematically apply this approach to all patients to improve patient care and treatment outcomes.
  • Pharmacogenomics is a growing field and it is critical that all neuropsychiatric pharmacists have the knowledge necessary to apply these concepts in the clinical setting.

References

  1. Meyer UA. Timeline: Pharmacogenetics – five decades of therapeutic lessons from genetic diversity. Nat Rev Genet. 2004;5(9):669- 676. DOI: 10.1038/nrg1428 .
  2. Crews KR, Hicks JK, Pui C-H, Relling MV, Evans WE. Pharmacogenomics and Individualized Medicine: Translating Science Into Practice. Clin Pharmacol Ther. 2012;. DOI: 10.1038/clpt.2012.120 .
  3. Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Human Leukocyte Antigen-B Genotype and Allopurinol Dosing. Clin Pharmacol Ther. 2013;93(2):153- 158. DOI: 10.1038/clpt.2012.209 .
  4. Chung W-H, Hung S-I, Hong H-S, Hsih M-S, Yang L-C, Ho H-C, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486. DOI: 10.1038/428486a . PubMed PMID: 15057820 .
  5. Leckband SG, Kelsoe JR, Dunnenberger HM, George AL, Tran E, Berger R, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther. 2013;94(3):324-8. DOI: 10.1038/clpt.2013.103 . PubMed PMID: 23695185 .
  6. Hicks JK, Bishop JR, Sangkuhl K, Muller DJ, Ji Y, Leckband SG 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(2):127‐34.
  7. Gardner KR, Brennan FX, Scott R, Lombard J. The Potential Utility of Pharmacogenetic Testing in Psychiatry. Psychiatry J. 2014;20141220142016512023(151156912):1- 6. DOI: 10.1155/2014/730956 .
  8. Hall-Flavin DK, Winner JG, Allen JD, Carhart JM, Proctor B, Snyder KA, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics. 2013;23(10):535-48. DOI: 10.1097/FPC.0b013e3283649b9a . PubMed PMID: 24018772 .
  9. Preskorn SH, Hatt CR. How pharmacogenomics (PG) are changing practice: implications for prescribers, their patients, and the healthcare system (PG series part I). J Psychiatr Pract. 2013;19(2):142-9. DOI: 10.1097/01.pra.0000428559.01953.73 . PubMed PMID: 23507814 .
  10. Lazarou J, Pomeranz BH, Corey PN. Incidence of Adverse Drug Reactions in Hospitalized Patients. JAMA. 1998;279(15):1200. DOI: 10.1001/jama.279.15.1200 .
  11. Hampton LM, Daubresse M, Chang H-Y, Alexander GC, Budnitz DS. Emergency department visits by adults for psychiatric medication adverse events. Jama Psychiatry. 2014;71(9):1006-14. DOI: 10.1001/jamapsychiatry.2014.436 . PubMed PMID: 25006837 .
  12. Barak Y, Swartz M, Baruch Y. Venlafaxine or a second SSRI: Switching after treatment failure with an SSRI among depressed inpatients: a retrospective analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(7):1744-7. DOI: 10.1016/j.pnpbp.2011.06.007 . PubMed PMID: 21722691 .
  13. Walden LM, Brandl EJ, Changasi A, Sturgess JE, Soibel A, Notario JFD, et al. Physicians' opinions following pharmacogenetic testing for psychotropic medication. Psychiatry Res. 2015;229(3):913-8. DOI: 10.1016/j.psychres.2015.07.032 . PubMed PMID: 26298505 .

 

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