Recent Progress in Pharmacogenomics of Antipsychotic Drug Response

  • Jian-Ping Zhang
  • Anil K. Malhotra
Genetic Disorders (F Goes, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetic Disorders


Purpose of Review

Pharmacogenomics (PGx) of antipsychotic drug response is an active area of research in the past few years. We reviewed recent PGx studies with an emphasis of development of new methodologies and new research directions.

Recent Findings

Traditional candidate gene approach continues to generate evidence to support the associations of antipsychotic response with genes coding for drug targets such as DRD2. Genome-wide association studies have found a few novel genes that may be associated with drug efficacy and adverse events. Recent application of polygenic risk score makes it possible to combine many genetic variants to predict clinical response. Finally, epigenetic research including DNA methylation is emerging and promises new findings that potentially can be applied in clinical practice.


New methodologies may advance PGx closer to clinical application. Multiple genes and epigenomic markers can be used in prediction of clinical phenotypes.


Pharmacogenomics Antipsychotics Schizophrenia Treatment response Adverse reactions 


Compliance with Ethical Standards

Conflict of Interest

Jian-Ping Zhang declares no conflict of interest.

Anil K. Malhotra has received consultancy fees from Genomind, Inc., Concert Pharma, and Biogen. Dr. Malhotra is an advisory board member and receives stock options from InformedDNA.

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.


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

  1. 1.
    Kahn RS, Sommer IE, Murray RM, et al. Schizophrenia. Nat Rev Dis Primers. 2015;1:15067.CrossRefPubMedGoogle Scholar
  2. 2.
    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.CrossRefGoogle Scholar
  3. 3.
    Zhang JP, Gallego JA, Robinson DG, Malhotra AK, Kane JM, Correll CU. Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2013;16(6):1205–18.CrossRefPubMedGoogle Scholar
  4. 4.
    Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IPM, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet. 2008;371(9618):1085–97.CrossRefPubMedGoogle Scholar
  5. 5.
    Robinson DG, Gallego JA, John M, Petrides G, Hassoun Y, Zhang JP, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Leucht S, Arbter D, Engel RR, Kissling W, Davis JM. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry. 2009;14(4):429–47.CrossRefPubMedGoogle Scholar
  7. 7.
    Kirchheiner J, Fuhr U, Brockmoller J. Pharmacogenetics-based therapeutic recommendations—ready for clinical practice? Nat Rev Drug Discov. 2005;4(8):639–47.CrossRefPubMedGoogle Scholar
  8. 8.
    • Zhang J-P, Malhotra AK. Pharmacogenetics and antipsychotics: therapeutic efficacy and side effects prediction. Expert Opin Drug Metab Toxicol. 2011;7(1):9–37. This is a comprehensive review of pharmacogenetics of antipsychotic drugs.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zhang JP, Malhotra AK. Pharmacogenetics of antipsychotics: recent progress and methodological issues. Expert Opin Drug Metab Toxicol. 2013;9(2):183–91.CrossRefPubMedGoogle Scholar
  10. 10.
    Kapur S, Mamo D. Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuro-Psychopharmacol Biol Psychiatry. 2003;27(7):1081–90.CrossRefGoogle Scholar
  11. 11.
    Zhang JP, Robinson DG, Gallego JA, John M, Yu J, Addington J, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Schizophrenia Working Group of the Psychiatric Genomics C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421–7.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Moghaddam B, Javitt D. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology. 2012;37(1):4–15.CrossRefPubMedGoogle Scholar
  16. 16.
    Stevenson JM, Reilly JL, Harris MS, et al. Antipsychotic pharmacogenomics in first episode psychosis: a role for glutamate genes. Transl Psychiatry. 2016;6:e739.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Taylor DL, Tiwari AK, Lieberman JA, Potkin SG, Meltzer HY, Knight J, 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.CrossRefPubMedGoogle Scholar
  19. 19.
    Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686–96.PubMedGoogle Scholar
  20. 20.
    Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med. 2011;17(2):97–107.CrossRefPubMedGoogle Scholar
  21. 21.
    •• 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 is the latest comprehensive review and meta-analysis of genetic basis of antipsychotic drug induced weight gain.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    Malhotra AK, Correll CU, Chowdhury NI, Müller DJ, Gregersen PK, Lee AT, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ioannidis JP, Boffetta P, Little J, O'Brien TR, Uitterlinden AG, Vineis P, et al. Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol. 2008;37(1):120–32.CrossRefPubMedGoogle Scholar
  25. 25.
    McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet. 2008;9(5):356–69.CrossRefPubMedGoogle Scholar
  26. 26.
    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(12):1209–23.CrossRefPubMedGoogle Scholar
  27. 27.
    Clark SL, Souza RP, Adkins DE, Åberg K, Bukszár J, McClay JL, et al. Genome-wide association study of patient-rated and clinician-rated global impression of severity during antipsychotic treatment. Pharmacogenet Genomics. 2013;23(2):69–77.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Brandl EJ, Tiwari AK, Zai CC, Nurmi EL, Chowdhury NI, Arenovich T, et al. Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample. Pharmacogenomics J. 2016;16(4):352–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Li Q, Wineinger NE, Fu DJ, et al. Genome-wide association study of paliperidone efficacy. Pharmacogenet Genomics. 2016.Google Scholar
  30. 30.
    • 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 GWAS found a novel gene that may be associated with antipsychoti-induced weight gain.CrossRefPubMedGoogle Scholar
  31. 31.
    Uetani N, Kato K, Ogura H, Mizuno K, Kawano K, Mikoshiba K, et al. Impaired learning with enhanced hippocampal long-term potentiation in PTPdelta-deficient mice. EMBO J. 2000;19(12):2775–85.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Li J, Yoshikawa A, Brennan MD, Ramsey TL, Meltzer HY. Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes. Schizophr Res. 2017.Google Scholar
  33. 33.
    Kane JM, Leucht S, Carpenter D, Docherty JP. The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry. 2003;64(Suppl 12):5–19.PubMedGoogle Scholar
  34. 34.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    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(4):458–63.CrossRefPubMedGoogle Scholar
  37. 37.
    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.CrossRefPubMedGoogle Scholar
  38. 38.
    •• 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 study applied a novel gene-gene interaction and gene pathway analysis to exmaine antipsychotic induced adverse events.CrossRefPubMedGoogle Scholar
  39. 39.
    Mas S, Gasso P, Lafuente A. Applicability of gene expression and systems biology to develop pharmacogenetic predictors; antipsychotic-induced extrapyramidal symptoms as an example. Pharmacogenomics. 2015;16(17):1975–88.CrossRefPubMedGoogle Scholar
  40. 40.
    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.CrossRefPubMedGoogle Scholar
  41. 41.
    Caroff SN, Campbell EC. Drug-induced extrapyramidal syndromes: Implications for Contemporary Practice. Psychiatr Clin North Am. 2016;39(3):391–411.CrossRefPubMedGoogle Scholar
  42. 42.
    Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol Psychiatry. 2007;12(8):707–47.CrossRefPubMedGoogle Scholar
  43. 43.
    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.CrossRefPubMedGoogle Scholar
  44. 44.
    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.CrossRefPubMedGoogle Scholar
  45. 45.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Tritsch NX, Ding JB, Sabatini BL. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature. 2012;490(7419):262–6.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Zai CC, Tiwari AK, Mazzoco M, de Luca V, Müller DJ, Shaikh SA, et al. Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia. J Psychiatr Res. 2013;47(11):1760–5.CrossRefPubMedGoogle Scholar
  49. 49.
    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.PubMedGoogle Scholar
  50. 50.
    Euesden J, Lewis CM, O'Reilly PF. PRSice: polygenic risk score software. Bioinformatics. 2015;31(9):1466–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748–52.PubMedGoogle Scholar
  52. 52.
    Huang J, Perlis RH, Lee PH, Rush AJ, Fava M, Sachs GS, et al. Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression. Am J Psychiatry. 2010;167(10):1254–63.CrossRefPubMedGoogle Scholar
  53. 53.
    Ruderfer DM, Charney AW, Readhead B, Kidd BA, Kähler AK, Kenny PJ, et al. Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach. Lancet Psychiatry. 2016;3(4):350–7.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    • Frank J, Lang M, Witt SH, Strohmaier J, Rujescu D, Cichon S, et al. Identification of increased genetic risk scores for schizophrenia in treatment-resistant patients. Mol Psychiatry. 2015;20(2):150–1. This is one of the first studies to use polygeneic risk scores to investigate treatment refractory schizophrenia.CrossRefPubMedGoogle Scholar
  55. 55.
    Wimberley T, Gasse C, Meier SM, Agerbo E, MacCabe JH, Horsdal HT. Polygenic risk score for schizophrenia and treatment-resistant schizophrenia. Schizophr Bull. 2017;43(5):1064–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Petronis A. Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature. 2010;465(7299):721–7.CrossRefPubMedGoogle Scholar
  57. 57.
    Grayson DR, Guidotti A. The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology. 2013;38(1):138–66.CrossRefPubMedGoogle Scholar
  58. 58.
    Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16(1):33–41.CrossRefPubMedGoogle Scholar
  59. 59.
    Klengel T, Binder EB. FKBP5 allele-specific epigenetic modification in gene by environment interaction. Neuropsychopharmacology. 2015;40(1):244–6.CrossRefPubMedGoogle Scholar
  60. 60.
    Boks MP, de Jong NM, Kas MJ, et al. Current status and future prospects for epigenetic psychopharmacology. Epigenetics : Off J DNA Methylation Soc. 2012;7(1):20–8.CrossRefGoogle Scholar
  61. 61.
    Melka MG, Castellani CA, Laufer BI, Rajakumar RN, O'Reilly R, Singh SM. Olanzapine induced DNA methylation changes support the dopamine hypothesis of psychosis. J Mol Psychiatry. 2013;1(1):19.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Dong E, Nelson M, Grayson DR, Costa E, Guidotti A. Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation. Proc Natl Acad Sci U S A. 2008;105(36):13614–9.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Aberg KA, Xie LY, McClay JL, et al. Testing two models describing how methylome-wide studies in blood are informative for psychiatric conditions. Epigenomics. 2013;5(4):367–77.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Petronis A, Gottesman II, Kan P, et al. Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance? Schizophr Bull. 2003;29(1):169–78.CrossRefPubMedGoogle Scholar
  65. 65.
    Walton E, Hass J, Liu J, Roffman JL, Bernardoni F, Roessner V, et al. Correspondence of DNA methylation between blood and brain tissue and its application to schizophrenia research. Schizophr Bull. 2016;42(2):406–14.CrossRefPubMedGoogle Scholar
  66. 66.
    Tang H, Dalton CF, Srisawat U, Zhang ZJ, Reynolds GP. Methylation at a transcription factor-binding site on the 5-HT1A receptor gene correlates with negative symptom treatment response in first episode schizophrenia. Int J Neuropsychopharmacol. 2013:1–5.Google Scholar
  67. 67.
    Kinoshita M, Numata S, Tajima A, Yamamori H, Yasuda Y, Fujimoto M, et al. Effect of clozapine on DNA methylation in peripheral leukocytes from patients with treatment-resistant schizophrenia. Int J Mol Sci. 2017;18(3)Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PsychiatryHofstra Northwell School of MedicineHempsteadUSA
  2. 2.Division of Psychiatry Research, Zucker Hillside HospitalNorthwell HealthGlen OaksUSA
  3. 3.Center for Psychiatric NeuroscienceFeinstein Institute for Medical ResearchManhassetUSA

Personalised recommendations