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Pharmacogenetics in psychiatry: translating research into clinical practice

Molecular Psychiatry volume 17, pages 760–769 (2012)Cite this article

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Abstract

Pharmacogenetic/pharmacogenomic (PGx) approaches to psychopharmacology aim to identify clinically meaningful predictors of drug efficacy and/or side-effect burden. To date, however, PGx studies in psychiatry have not yielded compelling results, and clinical utilization of PGx testing in psychiatry is extremely limited. In this review, the authors provide a brief overview on the status of PGx studies in psychiatry, review the commercialization process for PGx tests and then discuss methodological considerations that may enhance the potential for clinically applicable PGx tests in psychiatry. The authors focus on design considerations that include increased ascertainment of subjects in the earliest phases of illness, discuss the advantages of drug-induced adverse events as phenotypes for examination and emphasize the importance of maximizing adherence to treatment in pharmacogenetic studies. Finally, the authors discuss unique aspects of pharmacogenetic studies that may distinguish them from studies of other complex traits. Taken together, these data provide insights into the design and methodological considerations that may enhance the potential for clinical utility of PGx studies.

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References

  1. Arranz MJ, de Leon J . Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry 2007; 12: 707–747.

    Article  CAS  PubMed  Google Scholar 

  2. Zhang JP, Malhotra AK . Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol 2011; 7: 9–37.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kato M, Serretti A . Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry 2010; 15: 473–500.

    Article  CAS  PubMed  Google Scholar 

  4. Sturgess JE, George TP, Kennedy JL, Heinz A, Muller DJ . Pharmacogenetics of alcohol, nicotine and drug addiction treatments. Addict Biol 2011; 16: 357–376.

    Article  CAS  PubMed  Google Scholar 

  5. Fleeman N, Dundar Y, Dickson R, Jorgensen A, Pushpakom S, McLeod C et al. Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses. Pharmacogenomics J 2011; 11: 1–14.

    Article  CAS  PubMed  Google Scholar 

  6. Taylor MJ, Sen S, Bhagwagar Z . Antidepressant response and the serotonin transporter gene-linked polymorphic region. Biol Psychiatry 2010; 68: 536–543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. McCarthy MJ, Leckband SG, Kelsoe JR . Pharmacogenetics of lithium response in bipolar disorder. Pharmacogenomics 2010; 11: 1439–1465.

    Article  CAS  PubMed  Google Scholar 

  8. Kapur S, Mamo D . Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1081–1090.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang JP, Lencz T, Malhotra AK . D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am J Psychiatry 2010; 167: 763–772.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Serretti A, Kato M, De Ronchi D, Kinoshita T . Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 2007; 12: 247–257.

    Article  CAS  PubMed  Google Scholar 

  11. Mizutani T . PM frequencies of major CYPs in Asians and Caucasians. Drug Metab Rev 2003; 35: 99–106.

    Article  CAS  PubMed  Google Scholar 

  12. Ulrich S, Lauter J . Comprehensive survey of the relationship between serum concentration and therapeutic effect of amitriptyline in depression. Clin Pharmacokinet 2002; 41: 853–876.

    Article  CAS  PubMed  Google Scholar 

  13. Conley RR . Optimizing treatment with clozapine. J Clin Psychiatry 1998; 59 (Suppl 3): 44–48.

    CAS  PubMed  Google Scholar 

  14. de Leon J, Armstrong SC, Cozza KL . Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics 2006; 47: 75–85.

    Article  PubMed  Google Scholar 

  15. Cichon S, Craddock N, Daly M, Faraone SV, Gejman PV, Kelsoe J et al. Genomewide association studies: history, rationale, and prospects for psychiatric disorders. Am J Psychiatry 2009; 166: 540–556.

    Article  PubMed  Google Scholar 

  16. Uher R, Perroud N, Ng MY, Hauser J, Henigsberg N, Maier W et al. Genome-wide pharmacogenetics of antidepressant response in the GENDEP project. Am J Psychiatry 2010; 167: 555–564.

    Article  PubMed  Google Scholar 

  17. Garriock HA, Kraft JB, Shyn SI, Peters EJ, Yokoyama JS, Jenkins GD et al. A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry 2011; 67: 133–138.

    Article  Google Scholar 

  18. Ising M, Lucae S, Binder EB, Bettecken T, Uhr M, Ripke S et al. A genomewide association study points to multiple loci that predict antidepressant drug treatment outcome in depression. Arch Gen Psychiatry 2009; 66: 966–975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Perlis RH, Smoller JW, Ferreira MA, McQuillin A, Bass N, Lawrence J et al. A genomewide association study of response to lithium for prevention of recurrence in bipolar disorder. Am J Psychiatry 2009; 166: 718–725.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Aberg K, Adkins DE, Bukszar J, Webb BT, Caroff SN, Miller DD et al. Genomewide association study of movement-related adverse antipsychotic effects. Biol Psychiatry 2010; 67: 279–282.

    Article  PubMed  Google Scholar 

  21. Adkins DE, Aberg K, McClay JL, Bukszár J, Zhao Z, Jia P et al. Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Mol Psychiatry 2011; 16: 321–332.

    Article  CAS  PubMed  Google Scholar 

  22. Alkelai A, Greenbaum L, Rigbi A, Kanyas K, Lerer B . Genome-wide association study of antipsychotic-induced parkinsonism severity among schizophrenia patients. Psychopharmacology (Berl) 2009; 206: 491–499.

    Article  CAS  Google Scholar 

  23. McClay JL, Adkins DE, Aberg K, Stroup S, Perkins DO, Vladimirov VI et al. Genome-wide pharmacogenomic analysis of response to treatment with antipsychotics. Mol Psychiatry 2011; 16: 76–85.

    Article  CAS  PubMed  Google Scholar 

  24. McGuire AL, Evans BJ, Caulfield T, Burke W . Science and regulation. Regulating direct-to-consumer personal genome testing. Science (New York, NY) 2010; 330: 181–182.

    Article  CAS  Google Scholar 

  25. Kirchheiner J, Brosen K, Dahl ML, Gram LF, Kasper S, Roots I et al. CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages. Acta Psychiatr Scand 2001; 104: 173–192.

    Article  CAS  PubMed  Google Scholar 

  26. de Leon J . Pharmacogenomics: the promise of personalized medicine for CNS disorders. Neuropsychopharmacology 2009; 34: 159–172.

    Article  CAS  PubMed  Google Scholar 

  27. Malhotra AK, Lencz T, Correll CU, Kane JM . Genomics and the future of pharmacotherapy in psychiatry. Int Rev Psychiatry (Abingdon, England) 2007; 19: 523–530.

    Article  Google Scholar 

  28. Lieberman JA, Phillips M, Gu H, Stroup S, Zhang P, Kong L et al. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology 2003; 28: 995–1003.

    Article  CAS  PubMed  Google Scholar 

  29. Robinson DG, Woerner MG, Alvir JM, Geisler S, Koreen A, Sheitman B et al. Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 1999; 156: 544–549.

    Article  CAS  PubMed  Google Scholar 

  30. Perkins DO, Wyatt RJ, Bartko JJ . Penny-wise and pound-foolish: the impact of measurement error on sample size requirements in clinical trials. Biol Psychiatry 2000; 47: 762–766.

    Article  CAS  PubMed  Google Scholar 

  31. Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009; 41: 816–819.

    Article  CAS  PubMed  Google Scholar 

  32. Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008; 358: 568–579.

    Article  PubMed  Google Scholar 

  33. Hung SI, Chung WH, Liu ZS, Chen CH, Hsih MS, Hui RC et al. Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics 2010; 11: 349–356.

    Article  CAS  PubMed  Google Scholar 

  34. Kazeem GR, Cox C, Aponte J, Messenheimer J, Brazell C, Nelsen AC et al. High-resolution HLA genotyping and severe cutaneous adverse reactions in lamotrigine-treated patients. Pharmacogenet Genomics 2009; 19: 661–665.

    Article  CAS  PubMed  Google Scholar 

  35. Kane J, Honigfeld G, Singer J, Meltzer H . Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–796.

    Article  CAS  PubMed  Google Scholar 

  36. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006; 163: 600–610.

    Article  PubMed  Google Scholar 

  37. Kelly DL, Dixon LB, Kreyenbuhl JA, Medoff D, Lehman AF, Love RC et al. Clozapine utilization and outcomes by race in a public mental health system: 1994-2000. J Clin Psychiatry 2006; 67: 1404–1411.

    Article  CAS  PubMed  Google Scholar 

  38. Athanasiou MC, Dettling M, Cascorbi I, Mosyagin I, Salisbury BA, Pierz KA et al. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry 2011; 72: 458–463.

    Article  CAS  PubMed  Google Scholar 

  39. Parsons B, Allison DB, Loebel A, Williams K, Giller E, Romano S et al. Weight effects associated with antipsychotics: a comprehensive database analysis. Schizophr Res 2009; 110: 103–110.

    Article  PubMed  Google Scholar 

  40. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

    Article  CAS  PubMed  Google Scholar 

  41. Pandina GJ, Aman MG, Findling RL . Risperidone in the management of disruptive behavior disorders. J Child Adolesc Psychopharmacol 2006; 16: 379–392.

    Article  PubMed  Google Scholar 

  42. Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L et al. Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165: 1420–1431.

    Article  PubMed  Google Scholar 

  43. Correll CU, Manu P, Olshanskiy V, Napolitano B, Kane JM, Malhotra AK . Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA 2009; 302: 1765–1773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Reynolds GP, Zhang ZJ, Zhang XB . Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 2002; 359: 2086–2087.

    Article  CAS  PubMed  Google Scholar 

  45. Templeman LA, Reynolds GP, Arranz B, San L . Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet Genomics 2005; 15: 195–200.

    Article  CAS  PubMed  Google Scholar 

  46. Sicard MN, Zai CC, Tiwari AK, Souza RP, Meltzer HY, Lieberman JA et al. Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics 2010; 11: 1561–1571.

    Article  CAS  PubMed  Google Scholar 

  47. Lencz T, Robinson DG, Napolitano B, Sevy S, Kane JM, Goldman D et al. DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet Genomics 2010; 20: 569–572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Julius RJ, Novitsky Jr MA, Dubin WR . Medication adherence: a review of the literature and implications for clinical practice. J Psychiatr Pract 2009; 15: 34–44.

    Article  PubMed  Google Scholar 

  49. Zhang JP, Lencz T, Malhotra AK . Enhancing power in pharmacogenetic studies: maximizing adherence and meta-analytic strategies. Symposium Presented at the Society of Biological Psychiatry Annual Meeting. San Francisco, CA, 13th May 2011.

  50. Velligan DI, Weiden PJ, Sajatovic M, Scott J, Carpenter D, Ross R et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry 2009; 70 (Suppl 4): 1–46; quiz 47-48.

    PubMed  Google Scholar 

  51. Sullivan PF . The psychiatric GWAS consortium: big science comes to psychiatry. Neuron 2010; 68: 182–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ et al. Finding the missing heritability of complex diseases. Nature 2009; 461: 747–753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690–1698.

    Article  CAS  PubMed  Google Scholar 

  54. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 2010; 304: 1821–1830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. De Luca V, Mueller DJ, de Bartolomeis A, Kennedy JL . Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol 2007; 10: 697–704.

    Article  CAS  PubMed  Google Scholar 

  56. Simon GE, Perlis RH . Personalized medicine for depression: can we match patients with treatments? Am J Psychiatry 2010; 167: 1445–1455.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Johnson BA, Ait-Daoud N, Seneviratne C, Roache JD, Javors MA, Wang XQ et al. Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry 2011; 168: 265–275.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Kirchheiner J, Fuhr U, Brockmoller J . Pharmacogenetics-based therapeutic recommendations--ready for clinical practice? Nat Rev Drug Discov 2005; 4: 639–647.

    Article  CAS  PubMed  Google Scholar 

  59. Wu RR, Zhao JP, Jin H, Shao P, Fang MS, Guo XF et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 2008; 299: 185–193.

    CAS  PubMed  Google Scholar 

  60. Lenzini PA, Grice GR, Milligan PE, Dowd MB, Subherwal S, Deych E et al. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. J Thromb Haemost 2008; 6: 1655–1662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the NIH Grants P50MH080173 (to AK Malhotra), P30MH090590 (JM Kane) and R01MH79800-01 (to AK Malhotra).

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Authors and Affiliations

  1. Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA

    A K Malhotra, J-P Zhang & T Lencz

  2. The Feinstein Institute for Medical Research, Manhasset, NY, USA

    A K Malhotra, J-P Zhang & T Lencz

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  1. A K Malhotra
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Correspondence to A K Malhotra.

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Malhotra, A., Zhang, JP. & Lencz, T. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol Psychiatry 17, 760–769 (2012). https://doi.org/10.1038/mp.2011.146

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