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Pharmacogenetics of Antipsychotic Treatment in Schizophrenia

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Pharmacogenomics in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1175))

Abstract

Antipsychotics are the mainstay treatment for schizophrenia. There is large variability between individuals in their response to antipsychotics, both in efficacy and adverse effects of treatment. While the source of interindividual variability in antipsychotic response is not completely understood, genetics is a major contributing factor. The identification of pharmacogenetic markers that predict antipsychotic efficacy and adverse reactions is a growing area of research, and holds the potential to replace the current trial-and-error approach to treatment selection in schizophrenia with a personalized medicine approach.

In this chapter, we provide an overview of the current state of pharmacogenetics in schizophrenia treatment. The most promising pharmacogenetic findings are presented for both antipsychotic response and commonly studied adverse reactions. The application of pharmacogenetics to schizophrenia treatment is discussed, with an emphasis on the clinical utility of pharmacogenetic testing and directions for future research.

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References

  1. Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 158:360–369

    CAS  PubMed  Google Scholar 

  2. Perkins DO, Gu H, Boteva K, Lieberman JA (2005) Relationship between duration of untreated psychosis and outcome in first-episode schizophrenia: a critical review and meta-analysis. Am J Psychiatry 162:1785–1804

    PubMed  Google Scholar 

  3. Youssef H, Lyster G, Youssef F (1989) Familial psychosis and vulnerability to tardive dyskinesia. Int Clin Psychopharmacol 4:323–328

    CAS  PubMed  Google Scholar 

  4. Muller DJ, Schulze TG, Knapp M, Held T, Krauss H, Weber T et al (2001) Familial occurrence of tardive dyskinesia. Acta Psychiatr Scand 104:375–379

    CAS  PubMed  Google Scholar 

  5. Vojvoda D, Grimmell K, Sernyak M, Mazure CM (1996) Monozygotic twins concordant for response to clozapine. Lancet 347:61

    CAS  PubMed  Google Scholar 

  6. Mata I, Madoz V, Arranz MJ, Sham P, Murray RM (2001) Olanzapine: concordant response in monozygotic twins with schizophrenia. Br J Psychiatry 178:86

    CAS  PubMed  Google Scholar 

  7. Gebhardt S, Theisen FM, Haberhausen M, Heinzel-Gutenbrunner M, Wehmeier PM, Krieg JC et al (2010) Body weight gain induced by atypical antipsychotics: an extension of the monozygotic twin and sib pair study. J Clin Pharm Ther 35:207–211

    CAS  PubMed  Google Scholar 

  8. Hamburg MA, Collins FS (2010) The path to personalized medicine. N Engl J Med 363:301–304

    CAS  PubMed  Google Scholar 

  9. Lavedan C, Licamele L, Volpi S, Hamilton J, Heaton C, Mack K et al (2009) Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Mol Psychiatry 14:804–819

    CAS  PubMed  Google Scholar 

  10. Ikeda M, Tomita Y, Mouri A, Koga M, Okochi T, Yoshimura R et al (2010) Identification of novel candidate genes for treatment response to risperidone and susceptibility for schizophrenia: integrated analysis among pharmacogenomics, mouse expression, and genetic case–control association approaches. Biol Psychiatry 67:263–269

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Malhotra AK, Correll CU, Chowdhury NI, Muller DJ, Gregersen PK, Lee AT et al (2012) Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry 69:904–912

    CAS  PubMed  Google Scholar 

  13. Syu A, Ishiguro H, Inada T, Horiuchi Y, Tanaka S, Ishikawa M et al (2010) Association of the HSPG2 gene with neuroleptic-induced tardive dyskinesia. Neuropsychopharmacology 35:1155–1164

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Guengerich FP (2008) Cytochrome P450 and chemical toxicology. Chem Res Toxicol 21:70–83

    CAS  PubMed  Google Scholar 

  15. Moons T, de Roo M, Claes S, Dom G (2011) Relationship between P-glycoprotein and second-generation antipsychotics. Pharmacogenomics 12:1193–1211

    CAS  PubMed  Google Scholar 

  16. Cacabelos R, Hashimoto R, Takeda M (2011) Pharmacogenomics of antipsychotics efficacy for schizophrenia. Psychiatry Clin Neurosci 65:3–19

    CAS  PubMed  Google Scholar 

  17. Ravyn D, Ravyn V, Lowney R, Nasrallah HA (2013) CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence. Schizophr Res 149:1–14

    PubMed  Google Scholar 

  18. Sim SC, Ingelman-Sundberg M (2010) The human cytochrome P450 (CYP) allele nomenclature website: a peer-reviewed database of CYP variants and their associated effects. Hum Genomics 4:278–281

    CAS  PubMed Central  PubMed  Google Scholar 

  19. U.S. Food and Drug Administration (2013) Table of pharmacogenomic biomarkers in drug labels. http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

  20. Perera V, Gross AS, Polasek T, Qin Y, Rao G, Forrest A et al (2013) Considering CYP1A2 phenotype and genotype for optimizing the dose of olanzapine in the management of schizophrenia. Expert Opin Drug Metab Toxicol 9:1115–1137

    CAS  PubMed  Google Scholar 

  21. Rasmussen BB, Brix TH, Kyvik KO, Brosen K (2002) The interindividual differences in the 3-demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors. Pharmacogenetics 12:473–478

    CAS  PubMed  Google Scholar 

  22. Ingelman-Sundberg M (2004) Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedebergs Arch Pharmacol 369:89–104

    CAS  PubMed  Google Scholar 

  23. Ozdemir V, Kalow W, Tang BK, Paterson AD, Walker SE, Endrenyi L et al (2000) Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics 10:373–388

    CAS  PubMed  Google Scholar 

  24. Amirimani B, Ning B, Deitz AC, Weber BL, Kadlubar FF, Rebbeck TR (2003) Increased transcriptional activity of the CYP3A4*1B promoter variant. Environ Mol Mutagen 42:299–305

    CAS  PubMed  Google Scholar 

  25. Zochowska D, Wyzgal J, Paczek L (2012) Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients. Ann Transplant 17:36–44

    PubMed  Google Scholar 

  26. Kohlrausch FB, Gama CS, Lobato MI, Belmonte-de-Abreu P, Callegari-Jacques SM, Gesteira A et al (2008) Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics. Pharmacogenet Genomics 18:599–609

    CAS  PubMed  Google Scholar 

  27. Wong M, Evans S, Rivory LP, Hoskins JM, Mann GJ, Farlow D et al (2005) Hepatic technetium Tc 99m-labeled sestamibi elimination rate and ABCB1 (MDR1) genotype as indicators of ABCB1 (P-glycoprotein) activity in patients with cancer. Clin Pharmacol Ther 77:33–42

    CAS  PubMed  Google Scholar 

  28. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV et al (2007) A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528

    CAS  PubMed  Google Scholar 

  29. Jafari S, Fernandez-Enright F, Huang XF (2012) Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects. J Neurochem 120:371–384

    CAS  PubMed  Google Scholar 

  30. Reynolds GP (2012) The pharmacogenetics of antipsychotic treatment. Handb Exp Pharmacol 213–239

    Google Scholar 

  31. Blanc O, Brousse G, Meary A, Leboyer M, Llorca PM (2010) Pharmacogenetic of response efficacy to antipsychotics in schizophrenia: pharmacodynamic aspects. Review and implications for clinical research. Fundam Clin Pharmacol 24:139–160

    CAS  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  34. Arinami T, Gao M, Hamaguchi H, Toru M (1997) A functional polymorphism in the promoter region of the dopamine D2 receptor gene is associated with schizophrenia. Hum Mol Genet 6:577–582

    CAS  PubMed  Google Scholar 

  35. Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E et al (2006) The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 5:25–43

    CAS  PubMed  Google Scholar 

  36. Joyce JN, Gurevich EV (1999) D3 receptors and the actions of neuroleptics in the ventral striatopallidal system of schizophrenics. Ann N Y Acad Sci 877:595–613

    CAS  PubMed  Google Scholar 

  37. Jeanneteau F, Funalot B, Jankovic J, Deng H, Lagarde JP, Lucotte G et al (2006) A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor. Proc Natl Acad Sci U S A 103:10753–10758

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Hwang R, Zai C, Tiwari A, Muller DJ, Arranz MJ, Morris AG et al (2010) Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant. Pharmacogenomics J 10:200–218

    CAS  PubMed  Google Scholar 

  39. Bantick RA, Deakin JF, Grasby PM (2001) The 5-HT1A receptor in schizophrenia: a promising target for novel atypical neuroleptics? J Psychopharmacol 15:37–46

    CAS  PubMed  Google Scholar 

  40. Reynolds GP, Arranz B, Templeman LA, Fertuzinhos S, San L (2006) Effect of 5-HT1A receptor gene polymorphism on negative and depressive symptom response to antipsychotic treatment of drug-naive psychotic patients. Am J Psychiatry 163:1826–1829

    PubMed  Google Scholar 

  41. Wang L, Fang C, Zhang A, Du J, Yu L, Ma J et al (2008) The –1019C/G polymorphism of the 5-HT1A receptor gene is associated with negative symptom response to risperidone treatment in schizophrenia patients. J Psychopharmacol 22:904–909

    CAS  PubMed  Google Scholar 

  42. Mossner R, Schuhmacher A, Kuhn KU, Cvetanovska G, Rujescu D, Zill P et al (2009) Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia. Pharmacogenet Genomics 19:91–94

    PubMed  Google Scholar 

  43. Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD et al (2003) Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23:8788–8799

    CAS  PubMed  Google Scholar 

  44. Aghajanian GK, Marek GJ (1999) Serotonin and hallucinogens. Neuropsychopharmacology 21:16S–23S

    CAS  PubMed  Google Scholar 

  45. Arranz MJ, Munro J, Sham P, Kirov G, Murray RM, Collier DA et al (1998) Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res 32:93–99

    CAS  PubMed  Google Scholar 

  46. Polesskaya OO, Aston C, Sokolov BP (2006) Allele C-specific methylation of the 5-HT2A receptor gene: evidence for correlation with its expression and expression of DNA methylase DNMT1. J Neurosci Res 83:362–373

    CAS  PubMed  Google Scholar 

  47. Parsons MJ, D'Souza UM, Arranz MJ, Kerwin RW, Makoff AJ (2004) The -1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity. Biol Psychiatry 56:406–410

    CAS  PubMed  Google Scholar 

  48. Hazelwood LA, Sanders-Bush E (2004) His452Tyr polymorphism in the human 5-HT2A receptor destabilizes the signaling conformation. Mol Pharmacol 66:1293–1300

    CAS  PubMed  Google Scholar 

  49. Bunzel R, Blumcke I, Cichon S, Normann S, Schramm J, Propping P et al (1998) Polymorphic imprinting of the serotonin-2A (5-HT2A) receptor gene in human adult brain. Brain Res Mol Brain Res 59:90–92

    CAS  PubMed  Google Scholar 

  50. Lieberman JA, Mailman RB, Duncan G, Sikich L, Chakos M, Nichols DE et al (1998) Serotonergic basis of antipsychotic drug effects in schizophrenia. Biol Psychiatry 44:1099–1117

    CAS  PubMed  Google Scholar 

  51. Veenstra-VanderWeele J, Anderson GM, Cook EHJ (2000) Pharmacogenetics and the serotonin system: initial studies and future directions. Eur J Pharmacol 410:165–181

    CAS  PubMed  Google Scholar 

  52. Lappalainen J, Long JC, Virkkunen M, Ozaki N, Goldman D, Linnoila M (1999) HTR2C Cys23Ser polymorphism in relation to CSF monoamine metabolite concentrations and DSM-III-R psychiatric diagnoses. Biol Psychiatry 46:821–826

    CAS  PubMed  Google Scholar 

  53. Greenberg BD, Tolliver TJ, Huang SJ, Li Q, Bengel D, Murphy DL (1999) Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 88:83–87

    CAS  PubMed  Google Scholar 

  54. Arranz MJ, Munro J, Birkett J, Bolonna A, Mancama D, Sodhi M et al (2000) Pharmacogenetic prediction of clozapine response. Lancet 355:1615–1616

    CAS  PubMed  Google Scholar 

  55. Wang L, Yu L, He G, Zhang J, Zhang AP, Du J et al (2007) Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients. Neurosci Lett 414:1–4

    CAS  PubMed  Google Scholar 

  56. Dolzan V, Serretti A, Mandelli L, Koprivsek J, Kastelic M, Plesnicar BK (2008) Acute antipyschotic efficacy and side effects in schizophrenia: association with serotonin transporter promoter genotypes. Prog Neuropsychopharmacol Biol Psychiatry 32:1562–1566

    CAS  PubMed  Google Scholar 

  57. Arranz MJ, Bolonna AA, Munro J, Curtis CJ, Collier DA, Kerwin RW (2000) The serotonin transporter and clozapine response. Mol Psychiatry 5:124–125

    CAS  PubMed  Google Scholar 

  58. Tsai SJ, Hong CJ, Yu YW, Lin CH, Song HL, Lai HC et al (2000) Association study of a functional serotonin transporter gene polymorphism with schizophrenia, psychopathology and clozapine response. Schizophr Res 44:177–181

    CAS  PubMed  Google Scholar 

  59. Kaiser R, Tremblay PB, Schmider J, Henneken M, Dettling M, Muller-Oerlinghausen B et al (2001) Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia. Mol Psychiatry 6:179–185

    CAS  PubMed  Google Scholar 

  60. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6:243–250

    CAS  PubMed  Google Scholar 

  61. Illi A, Mattila KM, Kampman O, Anttila S, Roivas M, Lehtimaki T et al (2003) Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia. J Clin Psychopharmacol 23:429–434

    CAS  PubMed  Google Scholar 

  62. Illi A, Kampman O, Hanninen K, Anttila S, Mattila KM, Katila H et al (2007) Catechol-O-methyltransferase val108/158met genotype and response to antipsychotic medication in schizophrenia. Hum Psychopharmacol 22:211–215

    CAS  PubMed  Google Scholar 

  63. Woodward ND, Jayathilake K, Meltzer HY (2007) COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr Res 90:86–96

    PubMed  Google Scholar 

  64. Weickert TW, Goldberg TE, Mishara A, Apud JA, Kolachana BS, Egan MF et al (2004) Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry 56:677–682

    CAS  PubMed  Google Scholar 

  65. Bertolino A, Caforio G, Blasi G, Rampino A, Nardini M, Weinberger DR et al (2007) COMT Val158Met polymorphism predicts negative symptoms response to treatment with olanzapine in schizophrenia. Schizophr Res 95(1–3):253–255

    PubMed  Google Scholar 

  66. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R et al (1998) Association of a human G-protein beta3 subunit variant with hypertension. Nat Genet 18:45–48

    CAS  PubMed  Google Scholar 

  67. Muller DJ, De Luca V, Sicard T, King N, Hwang R, Volavka J et al (2005) Suggestive association between the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia. Eur Neuropsychopharmacol 15:525–531

    PubMed  Google Scholar 

  68. Kohlrausch FB, Salatino-Oliveira A, Gama CS, Lobato MI, Belmonte-de-Abreu P, Hutz MH (2008) G-protein gene 825C>T polymorphism is associated with response to clozapine in Brazilian schizophrenics. Pharmacogenomics 9:1429–1436

    CAS  PubMed  Google Scholar 

  69. Ujike H, Nomura A, Morita Y, Morio A, Okahisa Y, Kotaka T et al (2008) Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: a cohort study. J Clin Psychiatry 69:1416–1422

    CAS  PubMed  Google Scholar 

  70. Bishop JR, Ellingrod VL, Moline J, Miller D (2006) Pilot study of the G-protein beta3 subunit gene (C825T) polymorphism and clinical response to olanzapine or olanzapine-related weight gain in persons with schizophrenia. Med Sci Monit 12:BR47–BR50

    CAS  PubMed  Google Scholar 

  71. Anttila S, Kampman O, Illi A, Rontu R, Lehtimaki T, Leinonen E (2007) Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach. BMC Psychiatry 7:22

    PubMed Central  PubMed  Google Scholar 

  72. Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32

    CAS  PubMed  Google Scholar 

  73. Nurjono M, Lee J, Chong SA (2012) A review of brain-derived neurotrophic factor as a candidate biomarker in schizophrenia. Clin Psychopharmacol Neurosci 10:61–70

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL et al (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24:4401–4411

    CAS  PubMed  Google Scholar 

  75. Chiaruttini C, Vicario A, Li Z, Baj G, Braiuca P, Wu Y et al (2009) Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation. Proc Natl Acad Sci U S A 106:16481–16486

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Zhang JP, Lencz T, Geisler S, DeRosse P, Bromet EJ, Malhotra AK (2013) Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia. Schizophr Res 146:285–288

    PubMed Central  PubMed  Google Scholar 

  77. Zai GC, Zai CC, Chowdhury NI, Tiwari AK, Souza RP, Lieberman JA et al (2012) The role of brain-derived neurotrophic factor (BDNF) gene variants in antipsychotic response and antipsychotic-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 39:96–101

    CAS  PubMed  Google Scholar 

  78. Anttila S, Illi A, Kampman O, Mattila KM, Lehtimaki T, Leinonen E (2005) Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics. J Neural Transm 112:885–890

    CAS  PubMed  Google Scholar 

  79. Hong CJ, Yu YW, Lin CH, Tsai SJ (2003) An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients. Neurosci Lett 349:206–208

    CAS  PubMed  Google Scholar 

  80. Li M, Luo XJ, Xiao X, Shi L, Liu XY, Yin LD et al (2011) Allelic differences between Han Chinese and Europeans for functional variants in ZNF804A and their association with schizophrenia. Am J Psychiatry 168:1318–1325

    PubMed  Google Scholar 

  81. Riley B, Thiselton D, Maher BS, Bigdeli T, Wormley B, McMichael GO et al (2010) Replication of association between schizophrenia and ZNF804A in the Irish case–control study of schizophrenia sample. Mol Psychiatry 15:29–37

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Xiao B, Li W, Zhang H, Lv L, Song X, Yang Y et al (2011) To the editor: association of ZNF804A polymorphisms with schizophrenia and antipsychotic drug efficacy in a Chinese Han population. Psychiatry Res 190:379–381

    CAS  PubMed  Google Scholar 

  83. Zhang J, Wu X, Diao F, Gan Z, Zhong Z, Wei Q et al (2012) Association analysis of ZNF804A (zinc finger protein 804A) rs1344706 with therapeutic response to atypical antipsychotics in first-episode Chinese patients with schizophrenia. Compr Psychiatry 53:1044–1048

    PubMed  Google Scholar 

  84. Mossner R, Schuhmacher A, Wagner M, Lennertz L, Steinbrecher A, Quednow BB et al (2012) The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms. Eur Arch Psychiatry Clin Neurosci 262:193–197

    PubMed  Google Scholar 

  85. Cramer JA, Rosenheck R (1998) Compliance with medication regimens for mental and physical disorders. Psychiatr Serv 49:196–201

    CAS  PubMed  Google Scholar 

  86. Kampman O, Laippala P, Vaananen J, Koivisto E, Kiviniemi P, Kilkku N et al (2002) Indicators of medication compliance in first-episode psychosis. Psychiatry Res 110:39–48

    PubMed  Google Scholar 

  87. Citrome L, Holt RI, Walker DJ, Hoffmann VP (2011) Weight gain and changes in metabolic variables following olanzapine treatment in schizophrenia and bipolar disorder. Clin Drug Investig 31:455–482

    CAS  PubMed  Google Scholar 

  88. Lett TA, Wallace TJ, Chowdhury NI, Tiwari AK, Kennedy JL, Muller DJ (2012) Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol Psychiatry 17:242–266

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  90. Zhang JP, Malhotra AK (2013) Pharmacogenetics of antipsychotics: recent progress and methodological issues. Expert Opin Drug Metab Toxicol 9:183–191

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Hill MJ, Reynolds GP (2011) Functional consequences of two HTR2C polymorphisms associated with antipsychotic-induced weight gain. Pharmacogenomics 12:727–734

    CAS  PubMed  Google Scholar 

  92. Wallace TJ, Zai CC, Brandl EJ, Muller DJ (2011) Role of (5-HT2C) receptor gene variants in antipsychotic-induced weight gain. Pharmgenomics Pers Med 4:83–93

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Trevaskis JL, Butler AA (2005) Double leptin and melanocortin-4 receptor gene mutations have an additive effect on fat mass and are associated with reduced effects of leptin on weight loss and food intake. Endocrinology 146:4257–4265

    CAS  PubMed  Google Scholar 

  94. Czerwensky F, Leucht S, Steimer W (2013) MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain? Int J Neuropsychopharmacol 16:2103–2109

    CAS  PubMed  Google Scholar 

  95. Czerwensky F, Leucht S, Steimer W (2013) Association of the common MC4R rs17782313 polymorphism with antipsychotic-related weight gain. J Clin Psychopharmacol 33:74–79

    CAS  PubMed  Google Scholar 

  96. Meyre D, Delplanque J, Chevre JC, Lecoeur C, Lobbens S, Gallina S et al (2009) Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nat Genet 41:157–159

    CAS  PubMed  Google Scholar 

  97. Brandl EJ, Frydrychowicz C, Tiwari AK, Lett TA, Kitzrow W, Buttner S et al (2012) Association study of polymorphisms in leptin and leptin receptor genes with antipsychotic-induced body weight gain. Prog Neuropsychopharmacol Biol Psychiatry 38:134–141

    CAS  PubMed  Google Scholar 

  98. Hoffstedt J, Eriksson P, Mottagui-Tabar S, Arner P (2002) A polymorphism in the leptin promoter region (−2548G/A) influences gene expression and adipose tissue secretion of leptin. Horm Metab Res 34:355–359

    CAS  PubMed  Google Scholar 

  99. Waterhouse EG, Xu B (2013) The skinny on brain-derived neurotrophic factor: evidence from animal models to GWAS. J Mol Med (Berl) 91:1241–1247

    CAS  Google Scholar 

  100. Beckers S, Peeters A, Zegers D, Mertens I, Van Gaal L, Van Hul W (2008) Association of the BDNF Val66Met variation with obesity in women. Mol Genet Metab 95:110–112

    CAS  PubMed  Google Scholar 

  101. Lane HY, Liu YC, Huang CL, Chang YC, Wu PL, Lu CT et al (2006) Risperidone-related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol 26:128–134

    CAS  PubMed  Google Scholar 

  102. Zhang XY, Zhou DF, Wu GY, Cao LY, Tan YL, Haile CN et al (2008) BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology 33:2200–2205

    CAS  PubMed  Google Scholar 

  103. Margolese HC, Chouinard G, Kolivakis TT, Beauclair L, Miller R, Annable L (2005) Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: incidence and management strategies in patients with schizophrenia. Can J Psychiatry 50:703–714

    PubMed  Google Scholar 

  104. Schooler NR, Kane JM (1982) Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry 39(4):486–487

    CAS  PubMed  Google Scholar 

  105. Guy W (1976) The clinical global impression scale. In: ECDEU assessment manual for psychopharmacology – revised. US Department of Health, Education, and Welfare, Public Health Service, ADHMHA, NIMH Psychopharmacology Research Branch, Rockville, MD, pp 218–222

    Google Scholar 

  106. Lee HJ, Kang SG (2011) Genetics of tardive dyskinesia. Int Rev Neurobiol 98:231–264

    CAS  PubMed  Google Scholar 

  107. Muller DJ, Shinkai T, De Luca V, Kennedy JL (2004) Clinical implications of pharmacogenomics for tardive dyskinesia. Pharmacogenomics J 4:77–87

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  109. Loonen AJ, Ivanova SA (2013) New insights into the mechanism of drug-induced dyskinesia. CNS Spectr 18:15–20

    PubMed  Google Scholar 

  110. Zai CC, De Luca V, Hwang RW, Voineskos A, Muller DJ, Remington G et al (2007) Meta-analysis of two dopamine D2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients. Mol Psychiatry 12(9):794–795

    CAS  PubMed  Google Scholar 

  111. Pohjalainen T, Rinne JO, Nagren K, Lehikoinen P, Anttila K, Syvalahti EK et al (1998) The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 3:256–260

    CAS  PubMed  Google Scholar 

  112. Ritchie T, Noble EP (2003) Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res 28:73–82

    CAS  PubMed  Google Scholar 

  113. Bakker PR, van Harten PN, van Os J (2008) Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions. Mol Psychiatry 13:544–556

    CAS  PubMed  Google Scholar 

  114. Steen VM, Lovlie R, MacEwan T, McCreadie RG (1997) Dopamine D3-receptor gene variant and susceptibility to tardive dyskinesia in schizophrenic patients. Mol Psychiatry 2:139–145

    CAS  PubMed  Google Scholar 

  115. Basile VS, Masellis M, Badri F, Paterson AD, Meltzer HY, Lieberman JA et al (1999) Association of the MscI polymorphism of the dopamine D3 receptor gene with tardive dyskinesia in schizophrenia. Neuropsychopharmacology 21:17–27

    CAS  PubMed  Google Scholar 

  116. Bakker PR, van Harten PN, van Os J (2006) Antipsychotic-induced tardive dyskinesia and the Ser9Gly polymorphism in the DRD3 gene: a meta analysis. Schizophr Res 83:185–192

    PubMed  Google Scholar 

  117. Tsai HT, North KE, West SL, Poole C (2010) The DRD3 rs6280 polymorphism and prevalence of tardive dyskinesia: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet 153B:57–66

    CAS  PubMed  Google Scholar 

  118. Zai CC, Tiwari AK, De Luca V, Muller DJ, Bulgin N, Hwang R et al (2009) Genetic study of BDNF, DRD3, and their interaction in tardive dyskinesia. Eur Neuropsychopharmacol 19:317–328

    CAS  PubMed  Google Scholar 

  119. Lerer B, Segman RH, Tan EC, Basile VS, Cavallaro R, Aschauer HN et al (2005) Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype. Int J Neuropsychopharmacol 8:411–425

    CAS  PubMed  Google Scholar 

  120. Zai CC, Tiwari AK, Muller DJ, De Luca V, Shinkai T, Shaikh S et al (2010) The catechol-O-methyl-transferase gene in tardive dyskinesia. World J Biol Psychiatry 11:803–812

    PubMed  Google Scholar 

  121. Harrison PJ, Tunbridge EM (2008) Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33:3037–3045

    CAS  PubMed  Google Scholar 

  122. Greenbaum L, Alkelai A, Zozulinsky P, Kohn Y, Lerer B (2012) Support for association of HSPG2 with tardive dyskinesia in Caucasian populations. Pharmacogenomics J 12:513–520

    CAS  PubMed  Google Scholar 

  123. Tsai HT, Caroff SN, Miller DD, McEvoy J, Lieberman JA, North KE et al (2010) A candidate gene study of tardive dyskinesia in the CATIE schizophrenia trial. Am J Med Genet B Neuropsychiatr Genet 153B:336–340

    CAS  PubMed  Google Scholar 

  124. Zai CC, Tiwari AK, Mazzoco M, de Luca V, Muller DJ, Shaikh SA et al (2013) Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia. J Psychiatr Res 47:1760–1765

    PubMed  Google Scholar 

  125. Armstrong MJ, Miyasaki JM (2012) Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease: report of the guideline development subcommittee of the American Academy of Neurology. Neurology 79:597–603

    PubMed Central  PubMed  Google Scholar 

  126. Alvir JM, Lieberman JA, Safferman AZ, Schwimmer JL, Schaaf JA (1993) Clozapine-induced agranulocytosis. Incidence and risk factors in the United States. N Engl J Med 329:162–167

    CAS  PubMed  Google Scholar 

  127. Uetrecht J, Zahid N, Tehim A, Fu JM, Rakhit S (1997) Structural features associated with reactive metabolite formation in clozapine analogues. Chem Biol Interact 104:117–129

    CAS  PubMed  Google Scholar 

  128. Gerson SL, Meltzer H (1992) Mechanisms of clozapine-induced agranulocytosis. Drug Saf 7(Suppl 1):17–25

    PubMed  Google Scholar 

  129. Grunder G, Hippius H, Carlsson A (2009) The 'atypicality' of antipsychotics: a concept re-examined and re-defined. Nat Rev Drug Discov 8:197–202

    PubMed  Google Scholar 

  130. Meltzer HY (2012) Clozapine: balancing safety with superior antipsychotic efficacy. Clin Schizophr Relat Psychoses 6:134–144

    PubMed  Google Scholar 

  131. Yunis JJ, Corzo D, Salazar M, Lieberman JA, Howard A, Yunis EJ (1995) HLA associations in clozapine-induced agranulocytosis. Blood 86:1177–1183

    CAS  PubMed  Google Scholar 

  132. Amar A, Segman RH, Shtrussberg S, Sherman L, Safirman C, Lerer B et al (1998) An association between clozapine-induced agranulocytosis in schizophrenics and HLA-DQB1*0201. Int J Neuropsychopharmacol 1:41–44

    CAS  PubMed  Google Scholar 

  133. Dettling M, Cascorbi I, Roots I, Mueller-Oerlinghausen B (2001) Genetic determinants of clozapine-induced agranulocytosis: recent results of HLA subtyping in a non-Jewish Caucasian sample. Arch Gen Psychiatry 58:93–94

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  135. Tiwari, A.K., Need, A.C., Lohoff, F.W., Zai, C.C., Chowdhury, N.I., Muller, D.J., et al. (2013) Exome sequence analysis of Finnish patients with clozapine-induced agranulocytosis. Mol Psychiatry Advance online publication.

    Google Scholar 

  136. Chowdhury NI, Remington G, Kennedy JL (2011) Genetics of antipsychotic-induced side effects and agranulocytosis. Curr Psychiatry Rep 13:156–165

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  138. Muller DJ, Brandl EJ, Hwang R, Tiwari AK, Sturgess JE, Zai CC et al (2012) The AmpliChip® CYP450 test and response to treatment in schizophrenia and obsessive compulsive disorder: a pilot study and focus on cases with abnormal CYP2D6 drug metabolism. Genet Test Mol Biomarkers 16:897–903

    PubMed  Google Scholar 

  139. Dunbar L, Butler R, Wheeler A, Pulford J, Miles W, Sheridan J (2012) Clinician experiences of employing the AmpliChip® CYP450 test in routine psychiatric practice. J Psychopharmacol 26:390–397

    PubMed  Google Scholar 

  140. Winner J, Allen JD, Altar CA, Spahic-Mihajlovic A (2013) Psychiatric pharmacogenomics predicts health resource utilization of outpatients with anxiety and depression. Transl Psychiatry 3:e242

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Hall-Flavin DK, Winner JG, Allen JD, Jordan JJ, Nesheim RS, Snyder KA et al (2012) Using a pharmacogenomic algorithm to guide the treatment of depression. Transl Psychiatry 2:e172

    CAS  PubMed Central  PubMed  Google Scholar 

  142. McKnight C, Guirgis H, Votolato N (2011) Clozapine rechallenge after excluding the high-risk clozapine-induced agranulocytosis genotype of HLA-DQB1 6672G>C. Am J Psychiatry 168:1120

    PubMed  Google Scholar 

  143. Gershon ES, Alliey-Rodriguez N (2013) New ethical issues for genetic counseling in common mental disorders. Am J Psychiatry 170:968–976

    PubMed  Google Scholar 

  144. Relling MV, Klein TE (2011) CPIC: clinical pharmacogenetics implementation consortium of the pharmacogenomics research network. Clin Pharmacol Ther 89:464–467

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF et al (2012) Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 92:414–417

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Altman RB (2011) Pharmacogenomics: "noninferiority" is sufficient for initial implementation. Clin Pharmacol Ther 89:348–350

    CAS  PubMed  Google Scholar 

  147. Mrazek DA, Lerman C (2011) Facilitating clinical implementation of pharmacogenomics. JAMA 306:304–305

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  149. Volpi S, Potkin SG, Malhotra AK, Licamele L, Lavedan C (2009) Applicability of a genetic signature for enhanced iloperidone efficacy in the treatment of schizophrenia. J Clin Psychiatry 70:801–809

    CAS  PubMed  Google Scholar 

  150. Tunis SR, Stryer DB, Clancy CM (2003) Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 290:1624–1632

    CAS  PubMed  Google Scholar 

  151. Muller DJ, De Luca V, Kennedy JL (2003) Overview: towards individualized treatment in schizophrenia. Drug Dev Res 60:75–94

    Google Scholar 

  152. Hiemke C, Pfuhlmann B (2012) Interactions and monitoring of antipsychotic drugs. Handb Exp Pharmacol 212:241–265

    PubMed  Google Scholar 

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Pouget, J.G., Müller, D.J. (2014). Pharmacogenetics of Antipsychotic Treatment in Schizophrenia. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology, vol 1175. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0956-8_14

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