Skip to main content
SpringerLink
Log in

Pharmacogenomics of Antipsychotic Drugs

  • Schizophrenia and Other Psychotic Disorders (J Csernansky, Section Editor)
  • Published:
Current Treatment Options in Psychiatry Aims and scope Submit manuscript

Opinion statement

Pharmacogenomic research of antipsychotic drug (APD) response continued to produce interesting findings in the past few years. Several genetic markers have been shown to be reliably associated with APD responses including efficacy and drug-induced adverse reactions. For APD treatment response, DRD2 has been shown to predict symptom reduction and APD efficacy. For APD-induced weight gain, a recent meta-analysis supports the associations with HTR2C and MC4R variants, as well as several other genetic markers. For clozapine-induced agranulocytosis, an independent sample has confirmed the association with HLA-DQB1. In addition, a multi-marker combination approach has been studied to increase the predictive power for APD response. However, these markers’ sensitivity and specificity are not high enough to be used in routine clinical practice. They may have some value in certain situations such as treatment refractory cases, and they need to be used in conjunction with other clinical predictors. Due to the polygenetic nature of drug response, the new polygenetic risk score method appears promising in combining many genetic markers in predicting clinical response. The current review focused on pharmacodynamic genes (i.e., drug target), and did not touch upon pharmacokinetic genes such as cytochrome P450 genes (e.g., CYP2D6), which have been shown to influence APD response especially adverse reactions. Future research should use a multi-marker approach to combine both pharmacodynamic and pharmacokinetic genes, as well as known clinical factors, to increase the predictive power for APD clinical response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest published recently have been highlighted as: •    Of importance ••    Of major importance

  1. Zhang JP. The benefits of antipsychotic drugs: symptom control and improved quality of life. In: Manu P, Flanagan RJ, Ronaldson KJ, editors. Life threatening effects of antipsychotic drugs. London: Elsevier; 2016. p. 295–309.

    Chapter  Google Scholar 

  2. Insel TR. Next-generation treatments for mental disorders. Sci Transl Med. 2012;4(155):155–19.

    Article  Google Scholar 

  3. Kirchheiner J, Fuhr U, Brockmoller J. Pharmacogenetics-based therapeutic recommendations—ready for clinical practice? Nat Rev Drug Discov. 2005;4(8):639–47.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang JP, Malhotra AK. Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol. 2011;7(1):9–37.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zhang JP, Malhotra AK. Pharmacogenetics of antipsychotics: recent progress and methodological issues. Expert Opin Drug Metab Toxicol. 2013;9(2):183–91.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang J-P, Malhotra AK. Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol. 2011;7(1):9–37.

    Article  PubMed  PubMed Central  Google Scholar 

  7. •• Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7. This was the largest genome-wide association study of schizophrenia risk to date. It found 108 genomic loci that were significantly associated with schizophrenia, and some of the loci are related to antipsychotic drug targets, such as the dopamine D2 receptor gene and genes in the glutmate system.

    Article  Google Scholar 

  8. • Zhang JP, Robinson DG, Gallego JA, et al. Association of a schizophrenia risk variant at the DRD2 locus with antipsychotic treatment response in first-episode psychosis. Schizophr Bull. 2015;41(6):1248–55. This was the first study to find the functional significance of the schizophrenia risk variant at DRD2 locus. The findings suggested that DRD2 genetic variants were predictive of antipsychotic drug response.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lencz T, Robinson DG, Xu K, et al. DRD2 promoter region variation as a predictor of sustained response to antipsychotic medication in first-episode schizophrenia patients. Am J Psychiatry. 2006;163(3):529–31.

    Article  PubMed  Google Scholar 

  10. 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(7):763–72.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Huang E, Maciukiewicz M, Zai CC, et al. Preliminary evidence for association of genome-wide significant DRD2 schizophrenia risk variant with clozapine response. Pharmacogenomics. 2016;17(2):103–9.

    Article  CAS  PubMed  Google Scholar 

  12. McEvoy JP, Lieberman JA, Stroup TS, 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(4):600–10.

    Article  PubMed  Google Scholar 

  13. Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012;37(1):4–15.

    Article  CAS  PubMed  Google Scholar 

  14. Stevenson JM, Reilly JL, Harris MS, et al. Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes. Transl Psychiatry. 2016;6:e739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ramasamy A, Trabzuni D, Guelfi S, et al. Genetic variability in the regulation of gene expression in ten regions of the human brain. Nat Neurosci. 2014;17(10):1418–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Taylor DL, Tiwari AK, Lieberman JA, et al. Genetic association analysis of N-methyl-D-aspartate receptor subunit gene GRIN2B and clinical response to clozapine. Hum Psychopharmacol. 2016;31(2):121–34.

    Article  CAS  PubMed  Google Scholar 

  17. Caroff SN, Campbell EC. Drug-induced extrapyramidal syndromes: implications for contemporary practice. Psychiatr Clin North Am. 2016;39(3):391–411.

    Article  PubMed  Google Scholar 

  18. Robinson DG, Gallego JA, John M, et al. A randomized comparison of aripiprazole and risperidone for the acute treatment of first-episode schizophrenia and related disorders: 3-month outcomes. Schizophr Bull. 2015;41(6):1227–36.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry. 2007;12(8):707–47.

    Article  CAS  PubMed  Google Scholar 

  20. de Leon J, Susce MT, Pan RM, Fairchild M, Koch WH, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66(1):15–27.

    Article  PubMed  Google Scholar 

  21. Kobylecki CJ, Jakobsen KD, Hansen T, Jakobsen IV, Rasmussen HB, Werge T. CYP2D6 genotype predicts antipsychotic side effects in schizophrenia inpatients: a retrospective matched case-control study. Neuropsychobiology. 2009;59(4):222–6.

    Article  CAS  PubMed  Google Scholar 

  22. •• Mas S, Gasso P, Ritter MA, Malagelada C, Bernardo M, Lafuente A. Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: multilocus interaction in the mTOR pathway. Eur Neuropsychopharmacol. 2015;25(1):51–9. This was the first study to find significant gene-gene interactions in the mTOR pathway in predicting extrapyramidal side effects of antipsychotic drugs.

    Article  CAS  PubMed  Google Scholar 

  23. Feyder M, Bonito-Oliva A, Fisone G. L-DOPA-induced dyskinesia and abnormal signaling in striatal medium spiny neurons: focus on dopamine D1 receptor-mediated transmission. Front Behav Neurosci. 2011;5:71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Santini E, Feyder M, Gangarossa G, Bateup HS, Greengard P, Fisone G. Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism. J Biol Chem. 2012;287(33):27806–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mas S, Gasso P, Lafuente A, et al. Pharmacogenetic study of antipsychotic induced acute extrapyramidal symptoms in a first episode psychosis cohort: role of dopamine, serotonin and glutamate candidate genes. Pharmacogenomics J. 2016;16(5):439–45.

    Article  CAS  PubMed  Google Scholar 

  26. Tritsch NX, Ding JB, Sabatini BL. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature. 2012;490(7419):262–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zai CC, Tiwari AK, Mazzoco M, et al. Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia. J Psychiatr Res. 2013;47(11):1760–5.

    Article  PubMed  Google Scholar 

  28. Tsai HT, Caroff SN, Miller del D, et al. A candidate gene study of tardive dyskinesia in the CATIE schizophrenia trial. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(1):336–40.

    CAS  PubMed  Google Scholar 

  29. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686–96.

    CAS  PubMed  Google Scholar 

  30. Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med. 2011;17(2):97–107.

    Article  CAS  PubMed  Google Scholar 

  31. Pramyothin P, Khaodhiar L. Metabolic syndrome with the atypical antipsychotics. Current opinion in endocrinology, diabetes, and obesity. 2010.

  32. •• Zhang JP, Lencz T, Zhang RX, et al. Pharmacogenetic associations of antipsychotic drug-related weight gain: a systematic review and meta-analysis. Schizophr Bull. 2016;42(6):1418–37. This was the largest pharmacogenetic meta-analysis of antipsychotic-induced weight gain. It found several genes that were significantly associated with weight gain, providing directions fro future research

    Article  PubMed  Google Scholar 

  33. Reynolds GP, Zhang ZJ, Zhang XB. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet. 2002;359(9323):2086–7.

    Article  CAS  PubMed  Google Scholar 

  34. Malhotra AK, Correll CU, Chowdhury NI, et al. Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry. 2012;69(9):904–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ioannidis JP, Boffetta P, Little J, et al. Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol. 2008;37(1):120–32.

    Article  PubMed  Google Scholar 

  36. Malhotra AK, Zhang JP, Lencz T. Pharmacogenetics in psychiatry: translating research into clinical practice. Mol Psychiatry. 2012;17(8):760–9.

    Article  CAS  PubMed  Google Scholar 

  37. • Yu H, Wang L, Lv L, et al. Genome-wide association study suggested the PTPRD polymorphisms were associated with weight gain effects of atypical antipsychotic medications. Schizophr Bull. 2016;42(3):814–23. This was a large study to find genome-wide significant signals in antipsychotic-induced weight gain

    Article  PubMed  Google Scholar 

  38. Uetani N, Kato K, Ogura H, et al. Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice. EMBO J. 2000;19(12):2775–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maruthur NM, Gribble MO, Bennett WL, et al. The pharmacogenetics of type 2 diabetes: a systematic review. Diabetes Care. 2014;37(3):876–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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(9):789–96.

    Article  CAS  PubMed  Google Scholar 

  41. Meltzer HY. Treatment-resistant schizophrenia--the role of clozapine. Curr Med Res Opin. 1997;14(1):1–20.

    Article  CAS  PubMed  Google Scholar 

  42. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382(9896):951–62.

    Article  CAS  PubMed  Google Scholar 

  43. Kane JM, Leucht S, Carpenter D, Docherty JP. The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. The Journal of clinical psychiatry. 2003;64(Suppl 12):5–19.

    PubMed  Google Scholar 

  44. Honigfeld G, Arellano F, Sethi J, Bianchini A, Schein J. Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry. The Journal of clinical psychiatry. 1998;59(Suppl 3):3–7.

    PubMed  Google Scholar 

  45. Hsuanyu Y, Dunford HB. Oxidation of clozapine and ascorbate by myeloperoxidase. Arch Biochem Biophys. 1999;368(2):413–20.

    Article  CAS  PubMed  Google Scholar 

  46. Lieberman JA, Yunis J, Egea E, Canoso RT, Kane JM, Yunis EJ. HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry. 1990;47(10):945–8.

    Article  CAS  PubMed  Google Scholar 

  47. Goldstein JI, Jarskog LF, Hilliard C, et al. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles. Nat Commun. 2014;5:4757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Athanasiou MC, Dettling M, Cascorbi I, et al. Candidate gene analysis identifies a polymorphism in HLA-DQB1 associated with clozapine-induced agranulocytosis. J Clin Psychiatry. 2011;72(4):458–63.

    Article  CAS  PubMed  Google Scholar 

  49. •• Legge SE, Hamshere ML, Ripke S, et al. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia. Mol Psychiatry 2016. This was a large genome-wide association study of clozapine-induced neutropenia. It replicated a previous finding on HLA-DQB1 and also found a new independent signal.

  50. Manu P, Sarvaiya N, Rogozea LM, Kane JM, Correll CU. Benign ethnic neutropenia and clozapine use: a systematic review of the evidence and treatment recommendations. J Clin Psychiatry. 2016;77(7):e909–16.

    Article  PubMed  Google Scholar 

  51. Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005;10(1):79–104.

    Article  CAS  PubMed  Google Scholar 

  52. Miyamoto S, Miyake N, Jarskog LF, Fleischhacker WW, Lieberman JA. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry. 2012;17(12):1206–27.

    Article  CAS  PubMed  Google Scholar 

  53. Weiss ST, McLeod HL, Flockhart DA, et al. Creating and evaluating genetic tests predictive of drug response. Nat Rev Drug Discov. 2008;7(7):568–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ramanan VK, Shen L, Moore JH, Saykin AJ. Pathway analysis of genomic data: concepts, methods, and prospects for future development. Trends Genet. 2012;28(7):323–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang L, Jia P, Wolfinger RD, Chen X, Zhao Z. Gene set analysis of genome-wide association studies: methodological issues and perspectives. Genomics. 2011;98(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  56. Cordell HJ. Detecting gene-gene interactions that underlie human diseases. Nat Rev Genet. 2009;10(6):392–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Volpi S, Potkin SG, Malhotra AK, Licamele L, Lavedan C. Applicability of a genetic signature for enhanced iloperidone efficacy in the treatment of schizophrenia. J Clin Psychiatry. 2009;70(6):801–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY, USA

    Jian-Ping Zhang MD, PhD & Anil K. Malhotra MD

  2. Division of Psychiatry Research, Zucker Hillside Hospital, Northwell Health, 75-59 263rd Street, Glen Oaks, NY, 11004, USA

    Jian-Ping Zhang MD, PhD & Anil K. Malhotra MD

Authors
  1. Jian-Ping Zhang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anil K. Malhotra MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jian-Ping Zhang MD, PhD or Anil K. Malhotra MD.

Ethics declarations

Conflict of interest

Dr. Zhang reports grants from National Institute of Mental Health, Brain and Behavior Research Foundation, and Genomind Inc., during the conduct of the study.

Dr. Malhotra reports personal fees from Genomind, Takeda Pharma, and Forum Pharma, outside the submitted work.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Schizophrenia and Other Psychotic Disorders

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, JP., Malhotra, A.K. Pharmacogenomics of Antipsychotic Drugs. Curr Treat Options Psych 4, 127–138 (2017). https://doi.org/10.1007/s40501-017-0113-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40501-017-0113-1

Keywords

Search

Navigation