Pharmacogenetics of Serious Antipsychotic Side Effects

  • Malgorzata Maciukiewicz
  • Venuja Sriretnakumar
  • Daniel J. MüllerEmail author


First- and second-generation antipsychotics are common drugs for treatment of schizophrenia (SCZ). Both classes of drugs have different receptor-binding profiles and affinities that are likely involved in their propensity to cause adverse side effects such as tardive dyskinesia (TD), antipsychotic-induced weight gain (AIWG) and clozapine-induced agranulocytosis (CIA). Apart from clinical and demographic factors (e.g. age, drug exposure, etc.) associated with risk for specific antipsychotic-induced side effects, genetic factors have also been shown to modulate outcome to antispychotic drugs. Notably, some of the studied genetic variants have been shown to have relatively large effect sizes in the risk for specific side effects. Beyond genes involved in drug metabolism (in particular CYP2D6 and CYP1A2), SLC18A2, PIP5K2A, CNR1, DPP6 and HSPG2 gene variants have more recently been found to be associated with TD. Similarly, HTR2C, LEP, MC4R, NDUFS1 and CNR1 genes have been associated with AIWG in at least two independent samples. Finally, variants of the HLA and MPO genes have been associated with CIA. Notably, the first genetic test kits designed to reduce risk of antipsychotic-induced side effects have become available for use in clinical practice. However, the clinical relevance of these gene variants needs further evaluation, and future studies are required to better understand the molecular context of the variants in these side effects.


Tardive Dyskinesia Genetic Association Study Human Leucocyte Antigen Polygenic Risk Score Opioid Growth Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Adkins DE, Aberg K, McClay JL, Bukszar J, Zhao Z, Jia P et al (2011) Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Mol Psychiatry 16(3):321–332PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Al Hadithy AF, Ivanova SA, Pechlivanoglou P, Semke A, Fedorenko O et al (2009) Tardive dyskinesia and DRD3, HTR2A and HTR2C gene polymorphisms in Russian psychiatric inpatients from Siberia. Prog Neuropsychopharmacol Biol Psychiatry 33(3):475–481PubMedCrossRefGoogle Scholar
  3. 3.
    Bakker PR, Al Hadithy AF, Amin N, van Duijn CM, van Os J, van Harten PN (2012) Antipsychotic-induced movement disorders in long-stay psychiatric patients and 45 tag SNPs in 7 candidate genes: a prospective study. PLoS One 7(12):e50970PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    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(5):544–556PubMedCrossRefGoogle Scholar
  5. 5.
    Basile VS, Masellis M, Potkin SG, Kennedy JL (2002) Pharmacogenomics in schizophrenia: the quest for individualized therapy. Hum Mol Genet 11(20):2517–2530PubMedCrossRefGoogle Scholar
  6. 6.
    Boskovic M, Vovk T, Saje M, Goricar K, Dolzan V, Kores Plesnicar B, Grabnar I (2013) Association of SOD2, GPX1, CAT, and TNF genetic polymorphisms with oxidative stress, neurochemistry, psychopathology, and extrapyramidal symptoms in schizophrenia. Neurochem Res 38(2):433–442PubMedCrossRefGoogle Scholar
  7. 7.
    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(2):134–141PubMedCrossRefGoogle Scholar
  8. 8.
    Brandl EJ, Kennedy JL, Muller DJ (2014) Pharmacogenetics of antipsychotics. Can J Psychiatry 59(2):76–88PubMedCentralPubMedGoogle Scholar
  9. 8a.
    Brandl EJ, Tiwari AK, Zai CC, Nurmi EL, Chowdhury NI, Arenovich T, Sanches M, Goncalves VF, Shen JJ, Lieberman JA, Meltzer HY, Kennedy JL, Müller DJ. Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample. Pharmacogenomics J (in press)Google Scholar
  10. 9.
    Calarge CA, Ellingrod VL, Zimmerman B, Acion L, Sivitz WI, Schlechte JA (2009) Leptin gene -2548G/A variants predict risperidone-associated weight gain in children and adolescents. Psychiatr Genet 19(6):320–327PubMedCentralPubMedCrossRefGoogle Scholar
  11. 10.
    Caudle KE, Klein TE, Hoffman JM, Muller DJ, Whirl-Carrillo M, Gong L et al (2014) Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process. Curr Drug Metab 15(2):209–217PubMedCentralPubMedCrossRefGoogle Scholar
  12. 11.
    Chowdhury NI, Remington G, Kennedy JL (2011) Genetics of antipsychotic-induced side effects and agranulocytosis. Curr Psychiatry Rep 13(2):156–165PubMedCrossRefGoogle Scholar
  13. 12.
    Chowdhury NI, Tiwari AK, Souza RP, Zai CC, Shaikh SA, Chen S et al (2013) Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene. Pharmacogenomics J 13(3):272–279PubMedCrossRefGoogle Scholar
  14. 13.
    Czerwensky F, Leucht S, Steimer W (2013) Association of the common MC4R rs17782313 polymorphism with antipsychotic-related weight gain. J Clin Psychopharmacol 33(1):74–79PubMedCrossRefGoogle Scholar
  15. 14.
    de Leon J, Susce MT, Pan RM, Koch WH, Wedlund PJ (2005) Polymorphic variations in GSTM1, GSTT1, PgP, CYP2D6, CYP3A5, and dopamine D2 and D3 receptors and their association with tardive dyskinesia in severe mental illness. J Clin Psychopharmacol 25(5):448–456PubMedCrossRefGoogle Scholar
  16. 15.
    De Luca V, Mueller DJ, de Bartolomeis A, Kennedy JL (2007) Association of the HTR2C gene and antipsychotic induced weight gain: a meta-analysis. Int J Neuropsychopharmacol 10(5):697–704PubMedGoogle Scholar
  17. 16.
    de With SA, Pulit SL, Wang T, Staal WG, van Solinge WW, de Bakker PI, Ophoff RA (2015) Genome-wide association study of lymphoblast cell viability after clozapine exposure. Am J Med Genet B Neuropsychiatr Genet 168(2):116–122CrossRefGoogle Scholar
  18. 17.
    Drozda K, Muller DJ, Bishop JR (2014) Pharmacogenomic testing for neuropsychiatric drugs: current status of drug labeling, guidelines for using genetic information, and test options. Pharmacotherapy 34(2):166–184PubMedCentralPubMedCrossRefGoogle Scholar
  19. 18.
    Ebert T, Midbari Y, Shmilovitz R, Kosov I, Kotler M, Weizman A, Ram A (2014) Metabolic effects of antipsychotics in prepubertal children: a retrospective chart review. J Child Adolesc Psychopharmacol 24(4):218–222PubMedCrossRefGoogle Scholar
  20. 19.
    Ellingrod VL, Bishop JR, Moline J, Lin YC, Miller DD (2007) Leptin and leptin receptor gene polymorphisms and increases in body mass index (BMI) from olanzapine treatment in persons with schizophrenia. Psychopharmacol Bull 40(1):57–62PubMedGoogle Scholar
  21. 20.
    Fedorenko O, Rudikov EV, Gavrilova VA, Boiarko EG, Semke AV, Ivanova SA (2013) Association of (N251S)-PIP5K2A with schizophrenic disorders: a study of the Russian population of Siberia. Zh Nevrol Psikhiatr Im S S Korsakova 113(5):58–61PubMedGoogle Scholar
  22. 21.
    Fedorenko OY, Loonen AJ, Lang F, Toshchakova VA, Boyarko EG, Semke AV, et al. (2015) Association study indicates a protective role of phosphatidylinositol-4-phosphate-5-kinase against tardive dyskinesia. Int J Neuropsychopharmacol 18(6):1–6Google Scholar
  23. 22.
    Fernandez-Ruiz J (2009) The endocannabinoid system as a target for the treatment of motor dysfunction. Br J Pharmacol 156(7):1029–1040PubMedCentralPubMedCrossRefGoogle Scholar
  24. 23.
    Fu Y, Fan CH, Deng HH, Hu SH, Lv DP, Li LH et al (2006) Association of CYP2D6 and CYP1A2 gene polymorphism with tardive dyskinesia in Chinese schizophrenic patients. Acta Pharmacol Sin 27(3):328–332PubMedCrossRefGoogle Scholar
  25. 24.
    Gaedigk A (2013) Complexities of CYP2D6 gene analysis and interpretation. Int Rev Psychiatry 25(5):534–553PubMedCrossRefGoogle Scholar
  26. 25.
    Goncalves VF, Zai CC, Tiwari AK, Brandl EJ, Derkach A, Meltzer HY et al (2014) A hypothesis-driven association study of 28 nuclear-encoded mitochondrial genes with antipsychotic-induced weight gain in schizophrenia. Neuropsychopharmacology 39(6):1347–1354PubMedCentralPubMedCrossRefGoogle Scholar
  27. 26.
    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(6):513–520PubMedCrossRefGoogle Scholar
  28. 27.
    Gregoor JG, van der Weide J, Loovers HM, van Megen HJ, Egberts TC, Heerdink ER (2011) Polymorphisms of the LEP, LEPR and HTR2C gene: obesity and BMI change in patients using antipsychotic medication in a naturalistic setting. Pharmacogenomics 12(6):919–923PubMedCrossRefGoogle Scholar
  29. 28.
    Gunes A, Melkersson KI, Scordo MG, Dahl ML (2009) Association between HTR2C and HTR2A polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. J Clin Psychopharmacol 29(1):65–68PubMedCrossRefGoogle Scholar
  30. 29.
    He S, Tao YX (2014) Defect in MAPK signaling as a cause for monogenic obesity caused by inactivating mutations in the melanocortin-4 receptor gene. Int J Biol Sci 10(10):1128–1137PubMedCentralPubMedCrossRefGoogle Scholar
  31. 30.
    Houston JP, Kohler J, Bishop JR, Ellingrod VL, Ostbye KM, Zhao F et al (2012) Pharmacogenomic associations with weight gain in olanzapine treatment of patients without schizophrenia. J Clin Psychiatry 73(8):1077–1086PubMedCrossRefGoogle Scholar
  32. 31.
    Hsieh CJ, Chen YC, Lai MS, Hong CJ, Chien KL (2011) Genetic variability in serotonin receptor and transporter genes may influence risk for tardive dyskinesia in chronic schizophrenia. Psychiatry Res 188(1):175–176PubMedCrossRefGoogle Scholar
  33. 32.
    Ivanova SA, Toshchakova VA, Filipenko ML, Fedorenko OY, Boyarko EG, Boiko AS et al (2015) Cytochrome P450 1A2 co-determines neuroleptic load and may diminish tardive dyskinesia by increased inducibility. World J Biol Psychiatry 16(3):200–205PubMedCrossRefGoogle Scholar
  34. 33.
    Janno S, Holi M, Tuisku K, Wahlbeck K (2004) Prevalence of neuroleptic-induced movement disorders in chronic schizophrenia inpatients. Am J Psychiatry 161(1):160–163PubMedCrossRefGoogle Scholar
  35. 34.
    Kang SG, Lee HJ, Park YM, Choi JE, Han C, Kim YK et al (2008) Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 32(1):160–163PubMedCrossRefGoogle Scholar
  36. 35.
    Kang SH, Lee JI, Chang AK, Joo YH, Kim CY, Kim SY (2011) Genetic polymorphisms in the HTR2C and peroxisome proliferator-activated receptors are not associated with metabolic syndrome in patients with schizophrenia taking Clozapine. Psychiatry Investig 8(3):262–268PubMedCentralPubMedCrossRefGoogle Scholar
  37. 36.
    Kann O, Kovacs R (2007) Mitochondria and neuronal activity. Am J Physiol Cell Physiol 292(2):C641–C657PubMedCrossRefGoogle Scholar
  38. 37.
    Kao AC, Muller DJ (2013) Genetics of antipsychotic-induced weight gain: update and current perspectives. Pharmacogenomics 14(16):2067–2083PubMedCrossRefGoogle Scholar
  39. 38.
    Kao AC, Rojnic Kuzman M, Tiwari AK, Zivkovic MV, Chowdhury NI, Medved V et al (2014) Methylenetetrahydrofolate reductase gene variants and antipsychotic-induced weight gain and metabolic disturbances. J Psychiatr Res 54:36–42PubMedCrossRefGoogle Scholar
  40. 39.
    Kapur S, Seeman P (2001) Does fast dissociation from the dopamine D(2) receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry 158(3):360–369PubMedCrossRefGoogle Scholar
  41. 40.
    Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000) Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157(4):514–520PubMedCrossRefGoogle Scholar
  42. 41.
    Klemettila JP, Kampman O, Seppala N, Viikki M, Hamalainen M, Moilanen E et al (2015) Association study of the HTR2C, leptin and adiponectin genes and serum marker analyses in clozapine treated long-term patients with schizophrenia. Eur Psychiatry 30(2):296–302PubMedCrossRefGoogle Scholar
  43. 42.
    Knoll N, Jarick I, Volckmar AL, Klingenspor M, Illig T, Grallert H et al (2014) Mitochondrial DNA variants in obesity. PLoS One 9(5):e94882PubMedCentralPubMedCrossRefGoogle Scholar
  44. 43.
    Koning JP, Vehof J, Burger H, Wilffert B, Al Hadithy A, Alizadeh B et al (2012) Association of two DRD2 gene polymorphisms with acute and tardive antipsychotic-induced movement disorders in young Caucasian patients. Psychopharmacology (Berl) 219(3):727–736CrossRefGoogle Scholar
  45. 44.
    Koola MM, Tsapakis EM, Wright P, Smith S, Kerwin Rip RW, Nugent KL, Aitchison KJ (2014) Association of tardive dyskinesia with variation in CYP2D6: is there a role for active metabolites? J Psychopharmacol 28(7):665–670PubMedCrossRefGoogle Scholar
  46. 45.
    Lane HY, Liu YC, Huang CL, Chang YC, Wu PL, Lu CT, Chang WH (2006) Risperidone-related weight gain: genetic and nongenetic predictors. J Clin Psychopharmacol 26(2):128–134PubMedCrossRefGoogle Scholar
  47. 46.
    Leckband SG, Kelsoe JR, Dunnenberger HM, George AL Jr, Tran E, Berger R, Muller DJ et al (2013) Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and carbamazepine dosing. Clin Pharmacol Ther 94(3):324–328PubMedCentralPubMedCrossRefGoogle Scholar
  48. 47.
    Lee HJ, Kang SG (2011) Genetics of tardive dyskinesia. Int Rev Neurobiol 98:231–264PubMedCrossRefGoogle Scholar
  49. 48.
    Lencz T, Robinson DG, Napolitano B, Sevy S, Kane JM, Goldman D, Malhotra AK (2010) DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet Genomics 20(9):569–572PubMedCentralPubMedCrossRefGoogle Scholar
  50. 49.
    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(3):411–425PubMedCrossRefGoogle Scholar
  51. 50.
    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(3):242–266PubMedCrossRefGoogle Scholar
  52. 51.
    Liou YJ, Liao DL, Chen JY, Wang YC, Lin CC, Bai YM, Yu SC, Lin MW, Lai IC (2004) Association analysis of the dopamine D3 receptor gene ser9gly and brain-derived neurotrophic factor gene val66met polymorphisms with antipsychotic-induced persistent tardive dyskinesia and clinical expression in Chinese schizophrenic patients. Neuromolecular Med 5(3):243–251PubMedCrossRefGoogle Scholar
  53. 52.
    Liu H, Wang C, Chen PH, Zhang BS, Zheng YL, Zhang CX et al (2010) Association of the manganese superoxide dismutase gene Ala-9Val polymorphism with clinical phenotypes and tardive dyskinesia in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 34(4):692–696PubMedCrossRefGoogle Scholar
  54. 53.
    Lohmann PL, Bagli M, Krauss H, Muller DJ, Schulze TG, Fangerau H et al (2003) CYP2D6 polymorphism and tardive dyskinesia in schizophrenic patients. Pharmacopsychiatry 36(2):73–78PubMedCrossRefGoogle Scholar
  55. 54.
    Ma X, Maimaitirexiati T, Zhang R, Gui X, Zhang W, Xu G, Hu G (2014) HTR2C polymorphisms, olanzapine-induced weight gain and antipsychotic-induced metabolic syndrome in schizophrenia patients: a meta-analysis. Int J Psychiatry Clin Pract 18(4):229–242PubMedCrossRefGoogle Scholar
  56. 55.
    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(9):904–912PubMedCentralPubMedCrossRefGoogle Scholar
  57. 56.
    Meltzer HY (1999) The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 21(2 Suppl):106S–115SPubMedCrossRefGoogle Scholar
  58. 57.
    Miura I, Zhang JP, Nitta M, Lencz T, Kane JM, Malhotra AK, Yabe H, Correll CU (2014) BDNF Val66Met polymorphism and antipsychotic-induced tardive dyskinesia occurrence and severity: a meta-analysis. Schizophr Res 152(2–3):365–372PubMedCentralPubMedCrossRefGoogle Scholar
  59. 58.
    Miyamoto S, Duncan GE, Marx CE, Lieberman JA (2005) Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 10(1):79–104PubMedCrossRefGoogle Scholar
  60. 59.
    Mulder H, Franke B, van der-Beek van der AA, Arends J, Wilmink FW, Egberts AC, Scheffer H (2007) The association between HTR2C polymorphisms and obesity in psychiatric patients using antipsychotics: a cross-sectional study. Pharmacogenomics J 5:318–324CrossRefGoogle Scholar
  61. 60.
    Muller DJ, Kekin I, Kao AC, Brandl EJ (2013) Towards the implementation of CYP2D6 and CYP2C19 genotypes in clinical practice: update and report from a pharmacogenetic service clinic. Int Rev Psychiatry 25(5):554–571PubMedCrossRefGoogle Scholar
  62. 61.
    Muller DJ, Schulze TG, Knapp M, Held T, Krauss H, Weber T et al (2001) Familial occurrence of tardive dyskinesia. Acta Psychiatr Scand 104(5):375–379PubMedCrossRefGoogle Scholar
  63. 62.
    Muller DJ, Zai CC, Sicard M, Remington E, Souza RP, Tiwari AK et al (2012) Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain. Pharmacogenomics J 12(2):156–164PubMedCrossRefGoogle Scholar
  64. 63.
    Nurmi EL, Spilman SL, Whelan F, Scahill LL, Aman MG, McDougle CJ et al (2013) Moderation of antipsychotic-induced weight gain by energy balance gene variants in the RUPP autism network risperidone studies. Transl Psychiatry 3:e274PubMedCentralPubMedCrossRefGoogle Scholar
  65. 64.
    Opgen-Rhein C, Brandl EJ, Muller DJ, Neuhaus AH, Tiwari AK, Sander T, Dettling M (2010) Association of HTR2C, but not LEP or INSIG2, genes with antipsychotic-induced weight gain in a German sample. Pharmacogenomics 11(6):773–780PubMedCrossRefGoogle Scholar
  66. 65.
    Park YM, Kang SG, Choi JE, Kim YK, Kim SH, Park JY, Kim L, Lee HJ (2011) No evidence for an association between Dopamine D2 receptor polymorphisms and Tardive Dyskinesia in Korean Schizophrenia patients. Psychiatry Investig 8(1):49–54PubMedCentralPubMedCrossRefGoogle Scholar
  67. 66.
    Patsopoulos NA, Ntzani EE, Zintzaras E, Ioannidis JP (2005) CYP2D6 polymorphisms and the risk of tardive dyskinesia in schizophrenia: a meta-analysis. Pharmacogenet Genomics 15(3):151–158PubMedCrossRefGoogle Scholar
  68. 67.
    Perez-Iglesias R, Mata I, Amado JA, Berja A, Garcia-Unzueta MT, Martinez Garcia O et al (2010) Effect of FTO, SH2B1, LEP, and LEPR polymorphisms on weight gain associated with antipsychotic treatment. J Clin Psychopharmacol 30(6):661–666PubMedCrossRefGoogle Scholar
  69. 68.
    Pouget JG, Goncalves VF, Nurmi EL, P.Laughlin C, Mallya KS, McCracken JT et al (2015) Investigation of TSPO variants in schizophrenia and antipsychotic treatment outcomes. Pharmacogenomics 16(1):5–22PubMedCrossRefGoogle Scholar
  70. 69.
    Renou J, De Luca V, Zai CC, Bulgin N, Remington G, Meltzer HY, Lieberman JA, Le Foll B, Kennedy JL (2007) Multiple variants of the DRD3, but not BDNF gene, influence age-at-onset of schizophrenia. Mol Psychiatry 12(12):1058–1060PubMedCrossRefGoogle Scholar
  71. 70.
    Risselada AJ, Vehof J, Bruggeman R, Wilffert B, Cohen D, Al Hadithy AF, Arends J, Mulder H (2012) Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study. Pharmacogenomics J 12(1):62–67PubMedCrossRefGoogle Scholar
  72. 71.
    Rizos EN, Siafakas N, Katsantoni E, Lazou V, Sakellaropoulos K, Kastania A et al (2009) Association of the dopamine D3 receptor Ser9Gly and of the serotonin 2C receptor gene polymorphisms with tardive dyskinesia in Greeks with chronic schizophrenic disorder. Psychiatr Genet 19(2):106–107PubMedCrossRefGoogle Scholar
  73. 72.
    Schwab SG, Knapp M, Sklar P, Eckstein GN, Sewekow C, Borrmann-Hassenbach M et al (2006) Evidence for association of DNA sequence variants in the phosphatidylinositol-4-phosphate 5-kinase IIalpha gene (PIP5K2A) with schizophrenia. Mol Psychiatry 11(9):837–846PubMedCrossRefGoogle Scholar
  74. 73.
    Shams TA, Muller DJ (2014) Antipsychotic induced weight gain: genetics, epigenetics, and biomarkers reviewed. Curr Psychiatry Rep 16(10):473PubMedCrossRefGoogle Scholar
  75. 74.
    Shen J, Ge W, Zhang J, Zhu HJ, Fang Y (2014) Leptin -2548g/a gene polymorphism in association with antipsychotic-induced weight gain: a meta-analysis study. Psychiatr Danub 26(2):145–151PubMedGoogle Scholar
  76. 75.
    Shuman MD, Trigoboff E, Demler TL, Opler LA (2014) Exploring the potential effect of polypharmacy on the hematologic profiles of clozapine patients. J Psychiatr Pract 20(1):50–58. doi: 10.1097/01.pra.0000442937.61575.26 PubMedCrossRefGoogle Scholar
  77. 76.
    Sicard MN, Zai CC, Tiwari AK, Souza RP, Meltzer HY, Lieberman JA, Kennedy JL, Muller DJ (2010) Polymorphisms of the HTR2C gene and antipsychotic-induced weight gain: an update and meta-analysis. Pharmacogenomics 11(11):1561–1571. doi: 10.2217/pgs.10.123 PubMedCrossRefGoogle Scholar
  78. 77.
    Soares-Weiser K, Fernandez HH (2007) Tardive dyskinesia. Semin Neurol 27(2):159–169. doi: 10.1055/s-2007-971169 PubMedCrossRefGoogle Scholar
  79. 78.
    Srisawat U, Reynolds GP, Zhang ZJ, Zhang XR, Arranz B, San L, Dalton CF (2014) Methylenetetrahydrofolate reductase (MTHFR) 677C/T polymorphism is associated with antipsychotic-induced weight gain in first-episode schizophrenia. Int J Neuropsychopharmacol 17(3):485–490PubMedCrossRefGoogle Scholar
  80. 79.
    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(5):1155–1164PubMedCentralPubMedCrossRefGoogle Scholar
  81. 80.
    Tanaka S, Syu A, Ishiguro H, Inada T, Horiuchi Y, Ishikawa M et al (2013) DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia. Pharmacogenomics J 13(1):27–34PubMedCrossRefGoogle Scholar
  82. 81.
    Templeman LA, Reynolds GP, Arranz B, San L (2005) 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 15(4):195–200PubMedCrossRefGoogle Scholar
  83. 82.
    Tiwari AK, Brandl EJ, Weber C, Likhodi O, Zai CC, Hahn MK, Lieberman JA, Meltzer HY, Kennedy JL, Muller DJ (2013) Association of a functional polymorphism in neuropeptide Y with antipsychotic-induced weight gain in schizophrenia patients. J Clin Psychopharmacol 33(1):11–17PubMedCrossRefGoogle Scholar
  84. 83.
    Tiwari AK, Deshpande SN, Rao AR, Bhatia T, Mukit SR, Shriharsh V, Lerer B, Nimagaonkar VL, Thelma BK (2005) Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism. Pharmacogenomics J 5(1):60–69PubMedCrossRefGoogle Scholar
  85. 84.
    Tiwari AK, Need AC, Lohoff FW, Zai CC, Chowdhury NI, Muller DJ et al (2014) Exome sequence analysis of Finnish patients with clozapine-induced agranulocytosis. Mol Psychiatry 19(4):403–405PubMedCrossRefGoogle Scholar
  86. 85.
    Tiwari AK, Zai CC, Likhodi O, Lisker A, Singh D, Souza RP et al (2010) A common polymorphism in the cannabinoid receptor 1 (CNR1) gene is associated with antipsychotic-induced weight gain in Schizophrenia. Neuropsychopharmacology 35(6):1315–1324PubMedCentralPubMedCrossRefGoogle Scholar
  87. 86.
    Tiwari AK, Zai CC, Likhodi O, Voineskos AN, Meltzer HY, Lieberman JA et al (2012) Association study of cannabinoid receptor 1 (CNR1) gene in tardive dyskinesia. Pharmacogenomics J 12(3):260–266PubMedCrossRefGoogle Scholar
  88. 87.
    Tsai A, Liou YJ, Hong CJ, Wu CL, Tsai SJ, Bai YM (2011) Association study of brain-derived neurotrophic factor gene polymorphisms and body weight change in schizophrenic patients under long-term atypical antipsychotic treatment. Neuromolecular Med 13(4):328–333PubMedCrossRefGoogle Scholar
  89. 88.
    Tsai HT, Caroff SN, Miller DD, McEvoy J, Lieberman JA, North KE, Stroup TS, Sullivan PF (2010) A candidate gene study of Tardive dyskinesia in the CATIE schizophrenia trial. Am J Med Genet B Neuropsychiatr Genet 153B(1):336–340PubMedGoogle Scholar
  90. 89.
    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(1):57–66PubMedGoogle Scholar
  91. 90.
    Turbay D, Lieberman J, Alper CA, Delgado JC, Corzo D, Yunis JJ, Yunis EJ (1997) Tumor necrosis factor constellation polymorphism and clozapine-induced agranulocytosis in two different ethnic groups. Blood 89(11):4167–4174PubMedGoogle Scholar
  92. 91.
    Tybura P, Trzesniowska-Drukala B, Bienkowski P, Beszlej A, Frydecka D, Mierzejewski P et al (2014) Pharmacogenetics of adverse events in schizophrenia treatment: comparison study of ziprasidone, olanzapine and perazine. Psychiatry Res 219(2):261–267PubMedCrossRefGoogle Scholar
  93. 92.
    Utsunomiya K, Shinkai T, Sakata S, Yamada K, Chen HI, De Luca V, Hwang R, Ohmori O, Nakamura J (2012) Genetic association between the dopamine D3 receptor gene polymorphism (Ser9Gly) and tardive dyskinesia in patients with schizophrenia: a reevaluation in East Asian populations. Neurosci Lett 507(1):52–56PubMedCrossRefGoogle Scholar
  94. 93.
    van den Bout I, Divecha N (2009) PIP5K-driven PtdIns(4,5)P2 synthesis: regulation and cellular functions. J Cell Sci 122(Pt 21):3837–3850PubMedCrossRefGoogle Scholar
  95. 94.
    Wallace TJ, Zai CC, Brandl EJ, Muller DJ (2011) Role of 5-HT(2C) receptor gene variants in antipsychotic-induced weight gain. Pharmgenomics Pers Med 4:83–93PubMedCentralPubMedGoogle Scholar
  96. 95.
    Wu R, Zhao J, Shao P, Ou J, Chang M (2011) Genetic predictors of antipsychotic-induced weight gain: a case-matched multi-gene study. Zhong Nan Da Xue Xue Bao Yi Xue Ban 36(8):720–723PubMedGoogle Scholar
  97. 96.
    Yang YQ, Sun S, Yu YQ, Li WJ, Zhang X, Xiu MH et al (2011) Decreased serum brain-derived neurotrophic factor levels in schizophrenic patients with tardive dyskinesia. Neurosci Lett 502(1):37–40PubMedCrossRefGoogle Scholar
  98. 97.
    Zai CC, De Luca V, Hwang RW, Voineskos A, Muller DJ, Remington G, Kennedy JL (2007) Meta-analysis of two dopamine D2 receptor gene polymorphisms with tardive dyskinesia in schizophrenia patients. Mol Psychiatry 12(9):794–795PubMedCrossRefGoogle Scholar
  99. 98.
    Zai CC, Tiwari AK, Basile V, de Luca V, Muller DJ, Voineskos AN et al (2010) Oxidative stress in tardive dyskinesia: genetic association study and meta-analysis of NADPH quinine oxidoreductase 1 (NQO1) and Superoxide dismutase 2 (SOD2, MnSOD) genes. Prog Neuropsychopharmacol Biol Psychiatry 34(1):50–56PubMedCrossRefGoogle Scholar
  100. 99.
    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(11):1760–1765PubMedCrossRefGoogle Scholar
  101. 100.
    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(1):96–101PubMedCrossRefGoogle Scholar
  102. 101.
    Zhang XY, Tan YL, Zhou DF, Haile CN, Cao LY, Xu Q, Shen Y, Kosten TA, Kosten TR (2007) Association of clozapine-induced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population. J Clin Psychopharmacol 27(3):246–251PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Malgorzata Maciukiewicz
    • 1
  • Venuja Sriretnakumar
    • 1
    • 2
  • Daniel J. Müller
    • 1
    • 3
    • 4
    Email author
  1. 1.Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental HealthTorontoCanada
  2. 2.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  3. 3.Institute of Medical Science, Faculty of MedicineUniversity of TorontoTorontoCanada
  4. 4.Department of PsychiatryUniversity of TorontoTorontoCanada

Personalised recommendations