The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides recommendations on dosing of amitriptyline and nortriptyline based on patients’ genotype (UM, EM, PM) for CYP2D6 and CYP2C19 isoenzymes.29,30 Pharmacodynamically, several SNPs have been associated with treatment-emergent side effects. SNPs in MDGA2 and 5-HT2A receptor genes were associated with higher rates of sexual dysfunction among Asian patients.31,32
In CGASs, German patients who were T carriers of the tryptophan hydroxylase (TPH2) gene had 3.5 times the rate of treatment-emergent suicidal ideation from treatment with antidepressants.33 By identifying potential adverse effects before treatment initiation, pharmacogenomics testing may improve medication adherence.
Several investigations have demonstrated the potential utility and benefit of pharmacogenomic testing in clinical settings. Hall-Flavin et al compared antidepressant response and remission rates between genetically-guided prescribing and usual care in 227 patients.34 The GeneSight® interpretive report provides prescribers with three levels of recommendations for prescribers (‘use as directed’, ‘use with caution’, and ‘use with increased caution and with more frequent monitoring’).
Patients who received antidepressants based on genetically-guided interpretive reports provided to prescribers had greater response rates and remission after 8 weeks.34 In a retrospective study, patients with MDD who were identified to require monitoring based on their pharmacogenomic testing reports (completed post-hoc) had greater number of medical visits, higher total healthcare costs, greater number of missed days from work and greater number of disability claims compared to those who did not have variations in CYP450 enzymes (CYP2D6, CYP2C19, CYP2C9, CYP1A2).35
Patients with severe mental illness with PM or UM profiles for CYP2D6 enzyme have incurred longer hospitalization stays amounting to $4,000-$6,000.36 Cost-effectiveness studies have shown that pharmacogenomic testing can reduce average cost/resource utilization by 10% to 30%.27, 35-38
Barriers to Implementing Routine Pharmacogenetic Testing
There is sufficient evidence that certain genetic variants play a role in determining response and remission to antidepressants and development or worsening of adverse effects.
The utility of pharmacogenetic testing in routine psychiatric practice is unclear, and currently there is no recommendation to conduct testing prior to initiating antidepressant treatment.39
Before widespread implementation and use of pharmacogenomic testing for antidepressants, several barriers must be overcome such as limited accessibility of cost-effective tests, adequate and timely clinical decision support for prescribers, and trained personnel to provide appropriate education to patients.
Kelly C. Lee, PharmD, MAS, BCPP, is an associate professor of clinical pharmacy at the University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences.
- Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617-27.
- Demyttenaere K, Bruffaerts R, Posada-Villa J, et al. Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. JAMA. 2004;291:2581-90.
- Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64:1465-75.
- Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095-105.
- American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Third Ed. 2010. Available at http://psychiatryonline.org/guidelines.aspx. Accessed on 1/20/15.
- Thase ME. Effectiveness of antidepressants: comparative remission rates. The Journal of Clinical Psychiatry. 2003;64 Suppl 2:3-7.
- Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-17.
- Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
- Kirchheiner J, Seeringer A, Viviani R. Pharmacogenetics in psychiatry–a useful clinical tool or wishful thinking for the future? Curr Pharm Des. 2010;16:136-44.
- Lee KC, Ma JD, Kuo GM. Pharmacogenomics: bridging the gap between science and practice. J Am Pharm Assoc (2003) 2010;50:e1-14; quiz e5-7.
- Singh AB, Bousman CA, Ng C, Berk M. Antidepressant pharmacogenetics. Current Opinion in Psychiatry. 2014;27:43-51.
- Porcelli S, Fabbri C, Serretti A. Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. European Neuropsychopharmacology 2012;22:239-58.
- Risch N, Herrell R, Lehner T, et al. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis. JAMA. 2009;301:2462-71.
- Yoshida K, Ito K, Sato K, et al. Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:383-6.
- Houston JP, Kohler J, Ostbye KM, Heinloth A, Perlis RH. Association of catechol-O-methyltransferase variants with duloxetine response in major depressive disorder. Psychiatry Research. 2011;189:475-7.
- Shi Y, Yuan Y, Xu Z, et al. Genetic variation in the calcium/calmodulin-dependent protein kinase (CaMK) pathway is associated with antidepressant response in females. Journal of Affective Disorders. 2012;136:558-66.
- Montminy M. Transcriptional regulation by cyclic AMP. Annu Rev Biochem. 1997;66:807-22.
- Pilar-Cuellar F, Vidal R, Diaz A, et al. Neural plasticity and proliferation in the generation of antidepressant effects: hippocampal implication. Neural Plast. 2013;2013:537265.
- Niitsu T, Fabbri C, Bentini F, Serretti A. Pharmacogenetics in major depression: a comprehensive meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2013;45:183-94.
- Maddox JC, Levi M, Thompson C. The compliance with antidepressants in general practice. Journal of Psychopharmacology. 1994;8:48-52.
- Overview of Pharmacokinetics. Merck Manual. Available at http://www.merckmanuals.com/professional/clinical_pharmacology/pharmacokinetics/overview_of_pharmacokinetics.html. Accessed on 1/22/15.
- Ereshefsky L, Riesenman C, Lam YW. Serotonin selective reuptake inhibitor drug interactions and the cytochrome P450 system. J Clin Psychiatry. 1996;57 Suppl 8:17-24; discussion 5.
- Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7:257-65.
- Gaedigk A, Gotschall RR, Forbes NS, Simon SD, Kearns GL, Leeder JS. Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allele frequency data. Pharmacogenetics. 1999;9:669-82.
- Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83:234-42.
- Laika B, Leucht S, Heres S, Steimer W. Intermediate metabolizer: increased side effects in psychoactive drug therapy. The key to cost-effectiveness of pretreatment CYP2D6 screening? Pharmacogenomics J. 2009;9:395-403.
- Ruano G, Szarek BL, Villagra D, et al. Length of psychiatric hospitalization is correlated with CYP2D6 functional status in inpatients with major depressive disorder. Biomark Med. 2013;7:429-39.
- Hodgson K, Tansey K, Dernovsek MZ, et al. Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol. 2014;28:133-41.
- Hicks JK, Swen JJ, Thorn CF, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013;93:402-8.
- Leckband SG, Kelsoe JR, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther. 2013;94:324-8.
- Kurose K, Hiratsuka K, Ishiwata K, et al. Genome-wide association study of SSRI/SNRI-induced sexual dysfunction in a Japanese cohort with major depression. Psychiatry Research. 2012;198:424-9.
- Liang CS, Ho PS, Chiang KT, Su HC. 5-HT2A receptor -1438 G/A polymorphism and serotonergic antidepressant-induced sexual dysfunction in male patients with major depressive disorder: a prospective exploratory study. J Sex Med. 2012;9:2009-16.
- Musil R, Zill P, Seemuller F, et al. Genetics of emergent suicidality during antidepressive treatment–data from a naturalistic study on a large sample of inpatients with a major depressive episode. European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology. 2013;23:663-74.
- Hall-Flavin DK, Winner JG, Allen JD, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics 2013;23:535-48.
- Winner J, Allen JD, Altar CA, Spahic-Mihajlovic A. Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Transl Psychiatry. 2013;3:e242.
- Chou WH, Yan FX, de Leon J, et al. Extension of a pilot study: impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness. Journal of Clinical Psychopharmacology. 2000;20:246-51.
- Herbild L, Andersen SE, Werge T, Rasmussen HB, Jurgens G. Does pharmacogenetic testing for CYP450 2D6 and 2C19 among patients with diagnoses within the schizophrenic spectrum reduce treatment costs? Basic Clin Pharmacol Toxicol. 2013;113:266-72.
- Fagerness J, Fonseca E, Hess GP, et al. Pharmacogenetic-guided psychiatric intervention associated with increased adherence and cost savings. Am J Manag Care. 2014;20:e146-56.
- Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors. Genet Med. 2007;9:819-25.