Pharmacogenetics of clinical response to risperidone

Pharmacogenomics

Volumn 14, Issue 2, 2013, Pages 177-194

  Llerena, Adrián ^a,b,c   Berecz, Roland ^d   Peñas Lledó, Eva ^a   Süveges, Ágnes ^d   Fariñas, Humberto ^b  

^a UNIVERSITY OF EXTREMADURA   (Spain)

^b CICAB   (Spain)

^c INSTITUTO DE SALUD CARLOS III   (Spain)

^d UNIVERSITY OF DEBRECEN   (Hungary)

Author keywords

biomarkers; clinical outcome; pharmacogenetics; risperidone; side effects

Indexed keywords

AMFEBUTAMONE; BRAIN DERIVED NEUROTROPHIC FACTOR; CARBAMAZEPINE; CATECHOL METHYLTRANSFERASE; CLOZAPINE; CYTOCHROME P450 2D6; CYTOCHROME P450 3A; DNA; DOPAMINE 1 RECEPTOR; DOPAMINE 2 RECEPTOR; DOPAMINE 3 RECEPTOR; DOPAMINE TRANSPORTER; FLUOXETINE; GINKGO BILOBA EXTRACT; LEVOMEPROMAZINE; LITHIUM SALT; MULTIDRUG RESISTANCE PROTEIN 1; OLANZAPINE; PAROXETINE; PROTEIN KINASE B; RISPERIDONE; SEROTONIN 1A RECEPTOR; SEROTONIN 2A RECEPTOR; SEROTONIN 2C RECEPTOR; SEROTONIN 6 RECEPTOR; SEROTONIN 7 RECEPTOR; SEROTONIN RECEPTOR; THIORIDAZINE; UNINDEXED DRUG; VALPROIC ACID;

5 HTTLPR GENE; 5HT2A GENE; 5HT2C GENE; 5HT6 GENE; ABCB1 GENE; AKATHISIA; ANORGASMIA; AUTISM; BDNF GENE; BIPOLAR DISORDER; BODY MASS; CARDIOVASCULAR DISEASE; CEREBROVASCULAR ACCIDENT; CEREBROVASCULAR DISEASE; CHOLESTEROL BLOOD LEVEL; CLINICAL EFFECTIVENESS; CLINICAL PRACTICE; COMT GENE; CONDUCT DISORDER; CYP2D6 GENE; CYP3A GENE; DISORDERS OF CARBOHYDRATE METABOLISM; DRD2 GENE; DRD3 GENE; DRUG BINDING; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DISPOSITION; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG HYDROXYLATION; DRUG INDICATION; DRUG INTERACTION; DRUG METABOLISM; DRUG SAFETY; DRUG SUBSTITUTION; DRUG TRANSFORMATION; DRUG WITHDRAWAL; DYSLIPIDEMIA; DYSTONIA; DYSURIA; EDEMA; ENZYME ACTIVITY; EPISTAXIS; EXTRAPYRAMIDAL SYMPTOM; GALACTORRHEA; GENE; GENE EXPRESSION REGULATION; GENE FUNCTION; GENE INTERACTION; GENETIC ASSOCIATION; GENETIC MARKER; GENETIC POLYMORPHISM; GLAUCOMA; GYNECOMASTIA; HUMAN; HYPERPROLACTINEMIA; HYPERVENTILATION; HYPOPHYSIS TUMOR; HYPOTHERMIA; IATROGENIC DISEASE; ILEUS; INCONTINENCE; JAUNDICE; LOW DRUG DOSE; MANIA; MEDICAL INFORMATION; METABOLIC DISORDER; METABOLIC SYNDROME X; MONOTHERAPY; NEUROLEPTIC MALIGNANT SYNDROME; PANCREATITIS; PARKINSONISM; PHARMACOGENETICS; POLYDIPSIA; PROLACTIN BLOOD LEVEL; REVIEW; RHABDOMYOLYSIS; SCHIZOPHRENIA; SIDE EFFECT; SINGLE DRUG DOSE; SLEEP DISORDERED BREATHING; THROMBOSIS; TREATMENT RESPONSE; WAIST CIRCUMFERENCE; WEIGHT GAIN;

ANTIPSYCHOTIC AGENTS; BIOLOGICAL MARKERS; BIOTRANSFORMATION; CYTOCHROME P-450 CYP2D6; CYTOCHROME P-450 CYP3A; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG INTERACTIONS; GENETIC ASSOCIATION STUDIES; HUMANS; P-GLYCOPROTEIN; PHARMACOGENETICS; POLYMORPHISM, GENETIC; RISPERIDONE;

EID: 84872579272     PISSN: 14622416     EISSN: 17448042     Source Type: Journal    
DOI: 10.2217/pgs.12.201     Document Type: Review

References (152)

1. Cáceres MC, Peñas-Lledó EM, de la Rubia A, LLerena A. Increased use of second generation antipsychotic drugs in primary care: potential relevance for hospitalizations in schizophrenia patients. Eur. J. Clin. Pharmacol. 64(1), 73-76 (2008).
2. Heykants J, Huang ML, Mannens G et al. The pharmacokinetics of risperidone in humans: a summary. J. Clin. Psychiatry 55(Suppl.), 13-17 (1994) (Pubitemid 24179364)
3. Huang M-L, Van Peer A, Woestenborghs R et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects Clin. Pharmacol. Ther. 54(3), 257-268 (1993). (Pubitemid 23294526)
4. Cohen LJ. Risperidone. Pharmacotherapy 14(3), 253-265 (1994). (Pubitemid 24161030)
5. Locatelli I, Kastelic M, Koprivsek J et al. A population pharmacokinetic evaluation of the influence of CYP2D6 genotype on risperidone metabolism in patients with acute episode of schizophrenia. Eur. J. Pharm. Sci. 41(2), 289-298 (2010).
6. Jovanovic N, Bozina N, Lovric M, Medved V, Jakovljevic M, Peles AM. The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naive patients with first-episode schizophrenia treated with risperidone. Eur. J. Clin. Pharmacol. 66(11), 1109-1117 (2010).
7. Xiang Q, Zhao X, Zhou Y, Duan JL, Cui YM. Effect of CYP2D6, CYP3A5, and MDR1 genetic polymorphisms on the pharmacokinetics of risperidone and its active moiety. J. Clin. Pharmacol. 50(6), 659-666 (2010).
8. Riedel M, Schwarz MJ, Strassnig M et al. Risperidone plasma levels, clinical response and side-effects. Eur. Arch. Psychiatry Clin. Neurosci. 255(4), 261-268 (2005). (Pubitemid 41187035)
9. Kakihara S, Yoshimura R, Shinkai K et al. Prediction of response to risperidone treatment with respect to plasma concencentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6. Int. Clin. Psychopharmacol. 20(2), 71-78 (2005). (Pubitemid 40354395)
10. Spina E, Avenoso A, Facciolà G et al. Plasma concentrations of risperidone and 9hydroxyrisperidone during combined treatment with paroxetine. Ther. Drug Monit. 23(3), 223-227 (2001). (Pubitemid 32476548)
11. Darby JK, Pasta DJ, Wilson MG, Herbert J. Long-term therapeutic drug monitoring of risperidone and olanzapine identifies altered steady-state pharmacokinetics: a clinical, two-group, naturalistic study. Clin. Drug Investig. 28(9), 553-564 (2008).
12. Furukori N. Clinical pharmacogenetics in the treatment of schizophrenia. Nihon Shinkei Seishin Yakurigaku Zasshi 30(2), 65-69 (2010).
13. Fleeman N, Dundar Y, Dickson R et al. Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses. Pharmacogenomics J. 11(1), 1-14 (2011).
14. Scordo MG, Spina E, Facciolà G, Avenoso A, Johansson I, Dahl ML. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9hydroxyrisperidone. Psychopharmacology (Berl.) 147(3), 300-305 (1999). (Pubitemid 30010551)
15. Berecz R, Lerena A, de la Rubia A et al. Relationship between risperidone and 9-hydroxy-risperidone plasma concentrations and CYP2D6 enzyme activity in psychiatric patients. Pharmacopsychiatry 35(6), 231-234 (2002). (Pubitemid 36061313)
16. de Leon J, Armstrong SC, Cozza KL. The dosing of atypical antipsychotics. Psychosomatics 46(3), 262-273 (2005). (Pubitemid 40594318)
17. de Leon J, Sandson NB, Cozza KL. A preliminary attempt to personalize risperidone dosing using drug-drug interactions and genetics: part II. Psychosomatics 49(4), 347-361 (2008). (Pubitemid 351905210)
18. Bork J, Rogers T, Wedlund P, de Leon J. A pilot study of risperidone metabolism: the role of cytochrome P450 2D6 and 3A. J. Clin. Psychiatry 60(7), 469-476 (1999). (Pubitemid 29369803)
19. Jover F, Cuadrado JM, Andreu L, Merino J. Reversible coma caused by risperidone-ritonavir interaction. Clin. Neuropharmacol. 25(5), 251-253 (2002). (Pubitemid 35239481)
20. Kohnke MD, Griese EU, Stosser D, Gaertner I, Brath G. Cytochrome P450 2D6 deficiency and its clinical relevance in a patient treated with risperidone. Pharmacopsychiatry 35(3), 116-118 (2002). (Pubitemid 34651919)
21. Spina E, Avenoso A, Scordo MG et al. Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. J. Clin. Psychopharmacol. 22(4), 419-423 (2002). (Pubitemid 34810333)
22. Yagihashi T, Mizuno M, Chino B et al. Effects of the CYP2D6 10 alleles and co-medication with CYP2D6-dependent drugs on risperidone metabolism in patients with schizophrenia. Hum. Psychopharmacol. 24(4), 301-308 (2009).
23. Suzuki Y, Fukui N, Tsuneyama N et al. Effect of the cytochrome P450 2D6 10 allele on risperidone metabolism in Japanese psychiatric patients. Hum. Psychopharmacol. 27(1), 43-46 (2012).
24. Hendset M, Molden E, Refsum H, Hermann M. Impact of CYP2D6 genotype on steady-state serum concentrations of risperidone and 9-hydroxyrisperidone in patients using long-acting injectable risperidone. J. Clin. Psychopharmacol. 29(6), 537-541 (2009).
25. de Leon J, Susce MT, Pan RM, Fairchild M, Koch W, Wedlund PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J. Clin. Psychiatry 66(1), 15-27 (2005).
26. Calarge CA, Miller del D. Predictors of risperidone and 9hydroxyrisperidone serum concentration in children and adolescents. J. Child. Adolesc. Psychopharmacol. 21(2), 163-169 (2011).
27. Guzey C, Aamo T, Spigset O. Risperidone metabolism and the impact of being a cytochrome P450 2D6 ultra-rapid metabolizer. J. Clin. Psychiatry 61(8), 600-601 (2000).
28. Albrecht A, Morena PG, Baumann P, Eap CB. High dose of depot risperidone in a nonresponder schizophrenic patient. J. Clin. Psychopharmacol. 24(6), 673-674 (2004). (Pubitemid 39518669)
29. LLerena A, Kiivet RA. Fixed combinations of neuroleptics with antidepressants: potential risks and estimation of use. Br. J. Clin. Pharmacol. 37(6), 531-532 (1994). (Pubitemid 24197144)
30. Mannheimer B, von Bahr C, Pettersson H, Eliasson E. Impact of multiple inhibitors or substrates of cytochrome P450 2D6 on plasma risperidone levels in patients on polypharmacy. Ther. Drug. Monit. 30(5), 565-569 (2008).
31. Berecz R, Dorado P, De La Rubia A, Cáceres MC, Degrell I, LLerena A. The role of cytochrome P450 enzymes in the metabolism of risperidone and its clinical relevance for drug interactions. Curr. Drug. Targets. 5(6), 573-579 (2004). (Pubitemid 39004432)
32. Prior TI, Baker GB. Interactions between the cytochrome P450 system and the second-generation antipsychotics. J. Psychiatry Neurosci. 28(2), 99-112 (2003). (Pubitemid 36628196)
33. Benazzi F. Gynecomastia with risperidone-fluoxetine combination. Pharmacopsychiatry 32(1), 41 (1999). (Pubitemid 29077264)
34. Raaska K, Raitasuo V, Neuvonen PJ. Therapeutic drug monitoring data: risperidone does not increase serum clozapine concentration. Eur. J. Clin. Pharmacol. 58(9), 587-591 (2002).
35. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome P450 3A: ontogeny and drug disposition. Clin. Pharmacokinet. 37(6), 485-505 (1999). (Pubitemid 30032252)
36. Mahatthanatrakul W, Nontaput T, Ridtitid W, Wongnawa M, Sunbhanich M. Rifampin, a cytochrome P450 3A inducer, decreases plasma concentrations of antipsychotic risperidone in healthy volunteers. J. Clin. Pharm. Ther. 32(2), 161-167 (2007). (Pubitemid 46449707)
37. Spina E, Avenoso A, Facciola G et al. Plasma concentrations of risperidone and 9hydroxyrisperidone: effect of comedication with carbamazepine or valproate. Ther. Drug. Monit. 22(4), 481-485 (2000). (Pubitemid 30622123)
38. Jung SM, Kim KA, Cho HK et al. Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9hydroxyrisperidone in schizophrenic patients. Clin. Pharmacol. Ther. 78(5), 520-528 (2005). (Pubitemid 41698906)
39. Mahatthanatrakul W, Sriwiriyajan S, Ridtitid W et al. Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers. J. Clin. Pharm. Ther. 37(2), 221-225 (2012).
40. Boulton DW, DeVane CL, Liston HL, Markowitz JS. In vitro P-glycoprotein affinity for atypical and conventional antipsychotics. Life Sci. 71(2), 163-169 (2002). (Pubitemid 34595435)
41. Marzolini C, Paus E, Buclin T, Kim RB. Polymorphisms in human MDR1 (Pglycoprotein): recent advances and clinical relevance. Clin. Pharmacol. Ther. 75(1), 13-33 (2004). (Pubitemid 38130115)
42. de León J, Susce MT, Pan RM, Wedlund PJ, Orrego ML, Diaz FJ. A study of genetic (CYP2D6 and ABCB1) and environmental (drug inhibitors and inducers) variables that may influence plasma risperidone levels. Pharmacopsychiatry 40(3), 93-102 (2007). (Pubitemid 46910379)
43. Yoo HD, Lee SN, Kang HA, Cho HY, Lee IK, Lee YB. Influence of ABCB1 genetic polymorphisms on the pharmacokinetics of risperidone in healthy subjects with CYP2D610/10. Br. J. Pharmacol. 164(2b), 433-443 (2011).
44. Mas S, Gassò P, Alvarez S, Parellada E, Bernardo M, Lafuente A. Intuitive pharmacogenetics: spontaneous risperidone dosage is related to CYP2D6, CYP3A5 and ABCB1 genotypes. Pharmacogenomics J.12(3), 255-259 (2012).
45. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs 69(13), 1777-1798 (2009).
46. Xuan J, Zhao X, He G et al. Effects of the dopamine D3 receptor (DRD3) gene polymorphisms on risperidone response: A pharmacogenetic study. Neuropsychopharmacology 33(2), 305-311 (2008). (Pubitemid 350243359)
47. Remington G, Kapur S. D2 and 5-HT2 receptor effects of antipsychotics: bridging basic and clinical findings using PET. J. Clin. Psychiatry 60(Suppl. 10), 15-19 (1999). (Pubitemid 29237171)
48. Regenthal R, Kunstler U, Hesse S, Sabri O, Preiss R. D2 dopamine receptor occupancy, risperidone plasma level and extrapyramidal motor symptoms in previously drug-free schizophrenic patients. Int. J. Clin. Pharmacol. Ther. 43(8), 370-378 (2005). (Pubitemid 41078997)
49. Tauscher J, Kapur S. Choosing the right dose of antipsychotics in schizophrenia: lessons from neuroimaging studies. CNS Drugs 15(9), 671-678 (2001). (Pubitemid 33701934)
50. Abi-Dargham A, Laruelle M, Aghajanian GK, Charney D, Cristal J. The role of serotonin in the pathophysiology and treatment of schizophrenia. J. Neuropsychiatr. Clin. Neuroscience 9(1), 1-17 (1997). (Pubitemid 27075408)
51. Vázquez-Bourgon J, Arranz MJ, Mata I et al. Serotonin transporter polymorphisms and early response to antipsychotic treatment in first episode of psychosis. Psychiatry Res. 175(3), 189-194 (2010).
52. Liperoti R, Onder G, Landi F et al. All-cause mortality associated with atypical and conventional antipsychotics among nursing home residents with dementia: a retrospective cohort study. J. Clin. Psychiatry 70(10), 1340-1347 (2009).
53. Huybrechts KF, Schneeweiss S, Gerhard T et al. Comparative safety of antipsychotic medications in nursing home residents. J. Am. Geriatr. Soc. 60(3), 420-429 (2012).
54. Kales HC, Kim HM, Zivin K et al. Risk of mortality among individual antipsychotics in patients with dementia. Am. J. Psychiatry 169(1), 71-79 (2012).
55. Maher A, Maglione M, Bagley S et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA 306(12), 1359-1369 (2011).
56. Harrison-Woolrych M, Clark DW. Nose bleeds associated with use of risperidone. BMJ 328(7453), 1416 (2004). (Pubitemid 38789197)
57. Morrato EH, Newcomer JW, Kamat S, Baser O, Harnett J, Cuffel B. Metabolic screening after the American Diabetes Association's consensus statement on antipsychotic drugs and diabetes. Diabetes Care 32(6), 1037-1042 (2009).
58. Rummel-Kluge C, Komossa K, Schwarz S et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis. Schizophr. Res. 123(2-3), 225-233 (2010).
59. Lane HY, Liu YC, Huang CL et al. Risperidone-related weight gain: genetic and nongenetic predictors. J. Clin. Psychopharmacol. 26(2), 128-134 (2006).
60. Lett TA, Wallace TJ, Chowdhury NI, Tiwari K, Kennedy JL, Müller DJ. Pharmacogenetics of antipsychotic-induced weight gain: review and clinical implications. Mol. Psychiatry 17(3), 242-246 (2012).
61. Lencz T, Robinson DG, Napolitano B et al. DRD2 promoter region variation predicts antipsychotic-induced weight gain in first episode schizophrenia. Pharmacogenet. Genomics 20(9), 569-572 (2010).
62. Adkins DE, Aberg K, McClay JL et al. Genomewide pharmacogenomic study of metabolic side effects to antipsychotic drugs. Mol. Psychiatry 16(3), 321-332 (2011).
63. Smith RC, Segman RH, Golcer-Dubner T, Pavlov V, Lerer B. Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. Pharmacogenomics J. 8(3), 228-236 (2008). (Pubitemid 351712647)
64. Reynolds GP, Zhang Z, Zhang X. Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am. J. Psychiatry 160(4), 677-679 (2003). (Pubitemid 41079599)
65. Mulder H, Franke B, van der-Beek van der AA et al. The association between HTR2C polymorphisms and obesity in psychiatric patients using antipsychotics: a cross-sectional study. Pharmacogenomics J. 7(5), 318-324 (2007). (Pubitemid 47471309)
66. Mulder H, Cohen D, Scheffer H et al. HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. J. Clin. Psychopharmacol. 29(1), 16-20 (2009).
67. Bai YM, Chen TT, Liou YJ, Hong CJ, Tsai SJ. Association between HTR2C polymorphisms and metabolic syndrome in patients with schizophrenia treated with atypical antipsychotics. Schizophr. Res. 125(2-3), 179-186 (2011).
68. Correia CT, Almeida JP, Santos PE et al. Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions. Pharmacogenomics J. 10(5), 418-430 (2010).
69. Kato D, Kawanishi C, Kishida I et al. Effects of CYP2D6 polymorphisms on neuroleptic malignant syndrome. Eur. J. Clin. Pharmacol. 63(11), 991-996 (2007). (Pubitemid 47561803)
70. Ochi S, Kawasoe K, Abe M et al. A case study: neuroleptic malignant syndrome with risperidone and CYP2D6 gene variation. Gen. Hosp. Psychiatry 33(6), 1-2 (2011).
71. Kuzman MR, Medved V, Bozina N, Grubišin J, Jovanovic N, Sertic J. Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic-induced metabolic disturbances in female patients with schizophrenia. Pharmacogenomics J. 11(1), 35-44 (2011).
72. Mulder H, Cohen D, Scheffer H et al. HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. J. Clin. Psychopharmacol. 29(1), 16-20 (2009).
73. Gassó P, Mas S, Bernardo M, Alvarez S, Parellada E, Lafuente A. A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J. 9(6), 404-410 (2009).
74. Hoffmeyer S, Burk O, von Richter O et al. Functional polymorphisms of the human multidrug-resistance gene. multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc. Natl Acad. Sci. USA 97(7), 3473-3478 (2000). (Pubitemid 30183327)
75. Ito S, Ieiri I, Tanabe M, Suzuki A, Higuchi S, Otsubo K. Polymorphism of the ABC transporter genes, MDR1, MRP1 and MRP2/cMOAT, in healthy Japanese subjects. Pharmacogenetics 11(2), 175-184 (2001). (Pubitemid 32216128)
76. Greenbaum L, Strous RD, Kanyas K et al. Association of the RGS2 gene with extrapyramidal symptoms induced by treatment with antipsychotic medication. Pharmacogenet. Genomics 17(7), 519-528 (2007). (Pubitemid 46905218)
77. Szarfman A, Tonning JM, Levine JG, Doraiswamy PM. Atypical antipsychotics and pituitary tumors: a pharmacovigilance study. Pharmacotherapy 26(6), 748-758 (2006). (Pubitemid 43807626)
78. Shinkai T, De Luca V, Utsunomiya K et al. Functional polymorphism of the human multidrug resistance gene (MDR1) and polydipsia-hyponatremia in schizophrenia. Neuromolecular Med. 10(4), 362-367 (2008).
79. Wang L, Fang C, Zhang A et al. The 1019 C/G polymorphism of the 5-HT(1)A receptor gene is associated with negative symptom response to risperidone treatment in schizophrenia patients. J. Psychopharmacol. 22(8), 904-909 (2008).
80. Schotte A, Janssen PF, Gommeren W et al. Risperidone compared with new and reference antipsychotic drugs: in-vitro and in-vivo receptor binding. Psychopharmacology (Berl.) 124(1-2), 57-73 (1996). (Pubitemid 26112775)
81. Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors: focus on newer-generation compounds. Life Sci. 68(1), 29-39 (2000).
82. Arranz MJ, Rivera M, Munro JC. Pharmacogenetics of response to antipsychotics in patients with schizophrenia. CNS Drugs 25(11), 933-969 (2011).
83. Yasui-Furukori N, Tsuchimine S, Saito M et al. Comparing the influence of dopamine D2 polymorphisms and plasma drug concentrations on the clinical response to risperidone. J. Clin. Psychopharmacol. 31(5), 633-637 (2011).
84. Xing Q, Qian X, Li H et al. The relationship between the therapeutic response to risperidone and the dopamine D2 receptor polymorphism in Chinese schizophrenia patients. Int. J. Neuropsychopharmacol. 10(5), 631-637 (2007). (Pubitemid 47517516)
85. 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 163(3), 529-531 (2006). (Pubitemid 44469398)
86. Ikeda M, Yamanouchi Y, Kinoshita Y et al. Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first-episode schizophrenia. Pharmacogenomics 9(10), 1437-1443 (2008).
87. Dolzan V, Plesnicar BK, Serretti A et al. Polymorphisms in dopamine receptor DRD1 and DRD2 genes and psychopathological and extrapyramidal symptoms in patients on long-term antipsychotic treatment. Am. J. Med. Genet. B Neuropsychiatr. Genet. 44B(6), 809-815 (2007). (Pubitemid 47417211)
88. Lane HY, Lee CC, Chang YC et al. Effects of dopamine D2 receptor Ser311Cys polymorphism and clinical factors on risperidone efficacy for positive and negative symptoms and social function. Int. J. Neuropsychopharmacol. 7(4), 461-470 (2004).
89. Yamanouchi Y, Iwata N, Suzuki T, Kitajima T, Ikeda M, Ozaki N. Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J. 3(6), 356-361 (2003). (Pubitemid 38072174)
90. Suzuki M, Hurd YL, Sokoloff P, Schwartz JC, Sedvall G. D3 dopamine receptor mRNA is widely expressed in the human brain. Brain Res. 779(1-2), 58-74 (1998). (Pubitemid 28039940)
91. Schwartz JC, Diaz J, Pilon C, Sokoloff P. Possible implications of the dopamine D(3) receptor in schizophrenia and in antipsychotic drug actions. Brain Res. Brain Res. Rev. 31(2-3), 277-287 (2000). (Pubitemid 30136182)
92. Bressan RA, Erlandsson K, Jones HM, Mulligan RS, Ell PJ, Pilowsky LS. Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J. Clin. Psychopharmacol. 23(1), 5-14 (2003). (Pubitemid 36164419)
93. Stone JM, Bressan RA, Erlandsson K et al. Non-uniform blockade of intrastriatal D2/D3 receptors by risperidone and amisulpride. Psychopharmacology (Berl.) 180(4), 664-669 (2005). (Pubitemid 41317862)
94. Sokoloff P, Andrieux M, Besancon R et al. Pharmacology of human dopamine D3 receptor expressed in a mammalian cell line: comparison with D2 receptor. Eur. J. Pharmacol. 225(4), 331-337 (1992).
95. Schmauss C, Haroutunian V, Davis KL, Davidson M. Selective loss of dopamine D3 -type receptor mRNA expression in parietal and motor cortices of patients with chronic schizophrenia. Proc. Natl Acad. Sci. USA 90(19), 8942-8946 (1993). (Pubitemid 23306427)
96. Gurevich EV, Bordelon Y, Shapiro RM, Arnold SE, Gur RE, Joyce JN. Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch. Gen. Psychiatry 54(3), 225-232 (1997). (Pubitemid 27132051)
97. Graff-Guerrero A, Mamo D, Shammi CM et al. The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study with [11C]-(+)-PHNO. Arch. Gen. Psychiatry 66(6), 606-615 (2009).
98. Mizrahi R, Agid O, Borlido C et al. Effects of antipsychotics on D3 receptors: a clinical PET study in first episode antipsychotic naive patients with schizophrenia using [11C]-(+)-PHNO. Schizophr. Res. 131(1-3), 63-68 (2011).
99. Witkin J, Gasior M, Acri J et al. Atypical antipsychotic-like effects of the dopamine D3 receptor agonist, (+)-PD 128,907. Eur. J. Pharmacol. 347(2-3), R1-R3 (1998). (Pubitemid 28234481)
100. Fink-Jensen A. Novel pharmacological approaches to the treatment of schizophrenia. Dan. Med. Bull. 47, 151-167 (2000). (Pubitemid 30426526)
101. Kim B, Choi EY, Kim CY, Song K, Joo YH. Could HTR2A T102C and DRD3 Ser9Gly predict clinical improvement in patients with acutely exacerbated schizophrenia? Results from treatment responses to risperidone in a naturalistic setting. Hum. Psychopharmacol. 23(1), 61-67 (2008). (Pubitemid 351166069)
102. Lane HY, Hsu SK, Liu YC, Chang YC, Huang CH, Chang WH. Dopamine D3 receptor Ser9Gly polymorphism and risperidone response. J. Clin. Psychopharmacol. 25(1), 6-11 (2005).
103. Vehof J, Burger H, Wilffert B et al. Clinical response to antipsychotic drug treatment: Association study of polymorphisms in six candidate genes. Eur. Neuropsychopharmacol. 22(9), 625-631 (2012).
104. Szekeres G, Kéri S, Juhász A et al. Role of dopamine D3 receptor (DRD3) and dopamine transporter (DAT) polymorphism in cognitive dysfunctions and therapeutic response to atypical antipsychotics in patients with schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 124B(1), 1-5 (2004). (Pubitemid 38031583)
105. Reynolds GP, Yao Z, Zhang X, Sun J, Zhang Z. Pharmacogenetics of treatment in first-episode schizophrenia: D3 and 5-HT2C receptor polymorphisms separately associate with positive and negative symptom response. Eur. Neuropsychopharmacol. 15(2), 143-151 (2005). (Pubitemid 40193419)
106. Le François B, Czesak M, Steubl D, Albert PR. Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology 55(6), 977-985 (2008).
107. Ichikawa J, Ishii H, Bonaccorso S, Fowler WL, O'Laughlin IA, Meltzer HY. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J. Neurochem. 76(5), 1521-1531 (2001). (Pubitemid 32198256)
108. Diaz-Mataix L, Scorza MC, Bortolozzi A, Toth M, Celada P, Artigas F. Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J. Neurosci. 25(47), 10831-10843 (2005). (Pubitemid 41692613)
109. Mössner R, Schuhmacher A, Kühn KU et al. Functional serotonin 1A receptor variant influences treatment response to atypical antipsychotics in schizophrenia. Pharmacogenet. Genomics 19(1), 91-94 (2009).
110. Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 27(7), 1159-1172 (2003). (Pubitemid 37464960)
111. Lane HY, Chang YC, Chiu CC, Chen ML, Hsieh MH, Chang WH. Association of risperidone treatment response with a polymorphism in the 5HT (2A) receptor gene. Am. J. Psychiatry 159(9), 1593-1595 (2002).
112. Angelucci F, Bernardini S, Gravina P et al. Delusion symptoms and response to antipsychotic treatment are associated with the 5-HT2A receptor polymorphism (102T/C) in Alzheimer's disease: a 3-year follow-up longitudinal study. J. Alzheimers. Dis. 17(1), 203-211 (2009).
113. Bonhaus DW, Weinhardt KK, Taylor M et al. RS-102221: a novel high affinity and selective, 5-HT2C receptor antagonist. Neuropharmacology 36(4-5), 621-629 (1997). (Pubitemid 27272107)
114. Tecott LH, Sun LM, Akana SF et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374(6522), 542-546 (1995).
115. Smith SR, Weissman NJ, Anderson CM et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N. Engl. J. Med. 363(3), 245-256 (2010).
116. Lane HY, Lin CC, Huang CH, Chang YC, Hsu SK, Chang WH. Risperidone response and 5-HT6 receptor gene variance: genetic association analysis with adjustment for nongenetic confounders. Schizophr. Res. 67(1), 63-70 (2004).
117. Pouzet B, Didriksen M, Arnt J. Effects of the 5-HT(6) receptor antagonist, SB-271046, in animal models for schizophrenia. Pharmacol. Biochem. Behav. 71(4), 635-643 (2002). (Pubitemid 34219214)
118. Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM. Molecular cloning, characterization, and localization of a high-affinity serotonin receptor (5-HT7) activating cAMP formation. Proc. Natl Acad. Sci. USA 90(18), 8547-8551 (1993). (Pubitemid 23277706)
119. Wei Z, Wang L, Xuan J et al. Association analysis of serotonin receptor 7 gene (HTR7) and risperidone response in Chinese schizophrenia patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 33(3), 547-551 (2009).
120. Veenstra-Vanderweele J, Anderson GM, Cook EH. Pharmacogenetics and the serotonin system: initial studies and future directions. Eur. J. Pharmacol. 410(2-3), 165-181 (2000). (Pubitemid 32008142)
121. Kraft JB, Slager SL, McGrath PJ, Hamilton SP. Sequence analysis of the serotonin transporter and associations with antidepressant response. Biol. Psychiatry 58(5), 374-381 (2005). (Pubitemid 41219705)
122. Mata I, Arranz MJ, Patiño A et al. Serotonergic polymorphisms and psychotic disorders in populations from north Spain. Am. J. Med. Genet. B Neuropsychiatr. Genet. 126B(1), 88-94 (2004). (Pubitemid 38420128)
123. Arranz MJ, de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol. Psychiatry 12(8), 707-747 (2007). (Pubitemid 47172693)
124. Dolzan V, Serretti A, Mandelli L, Koprivsek J, Kastelic M, Plesnicar BK. Acute antipyschotic efficacy and side effects in schizophrenia: association with serotonin transporter promoter genotypes. Prog. Neuropsychopharmacol. Biol. Psychiatry 32(6), 1562-1566 (2008).
125. Wang L, Yu L, He G et al. Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients. Neurosci. Lett. 414(1), 1-4 (2007). (Pubitemid 46241633)
126. Korte M, Carrol P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc. Natl Acad. Sci. USA 92(19), 8856-8860 (1995).
127. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381(6584), 706-709 (1996). (Pubitemid 26196571)
128. Shoval G, Weizman A. The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Eur. Neuropsychopharmacol. 15(3), 319-329 (2005). (Pubitemid 40487736)
129. Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 411(6833), 86-89 (2001). (Pubitemid 32428194)
130. Pröschel M, Saunders A, Roses AD, Müller CR. Dinucleotide repeat polymorphism at the human gene for brain-derived neurotrophic factor (BDNF). Hum. Mol. Genet. 1(5), 353 (1992).
131. Cargill M, Altshuler D, Ireland J et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes Nat. Genet. 22(3), 231-238 (1999). (Pubitemid 29297248)
132. Kunugi H, Ueki A, Otsuka M et al. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease. Mol. Psychiatry 6(1), 83-86 (2001). (Pubitemid 32096070)
133. Ribasés M, Gratacós M, Armengol L et al. Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. Mol. Psychiatry 8(8), 745-751 (2003). (Pubitemid 36976432)
134. Krebs MO, Guillin O, Bourdell MC et al. Brain derived neurotrophic factor (BDNF) gene variants association with age at onset and therapeutic response in schizophrenia. Mol. Psychiatry 5(5), 558-562 (2000).
135. Anttila S, Illi A, Kampman O, Mattila KM, Lehtimäki T, Leinonen E. Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics. J. Neural. Transm. 112(7), 885-890 (2005). (Pubitemid 40869077)
136. Zhang XY, Tan YL, Zhou DF et al. Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics. J. Psychiatr. Res. 41(12), 997-1004 (2007). (Pubitemid 47304448)
137. Egan MF, Kojima M, Callicott JH et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112(2), 257-269 (2003). (Pubitemid 36144114)
138. Chen CC, Huang TL. Effects of antipsychotics on the serum BDNF levels in schizophrenia. Psychiatry Res. 189(3), 327-330 (2011).
139. Yoshimura R, Hori H, Sugita A et al. Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-hydroxypnenylglycol (MHPG) levels, but did not alter plasma brain-derived neurotrophic factor (BDNF) levels in schizophrenic patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 31(5), 1072-1077 (2007). (Pubitemid 46810098)
140. Szczepankiewicz A, Skibinska M, Czerski PM et al. No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia. Schizophr. Res. 76(2-3), 187-193 (2005). (Pubitemid 40804765)
141. Xu M, Li S, Xing Q et al. Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study. Eur. J. Hum. Genet. 18(6), 707-712 (2010).
142. Egan MF, Goldberg TE, Kolachana BS et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl Acad. Sci. USA 98(12), 6917-6922 (2001). (Pubitemid 32538317)
143. Kang CY, Xu XF, Shi ZY, Yang JZ, Liu H, Xu HH. Interaction of catechol-O-methyltransferase (COMT) Val108/158 Met genotype and risperidone treatment in Chinese Han patients with schizophrenia. Psychiatry Res. 176(1), 94-95 (2010).
144. Lane HY, Liu YC, Huang CL et al. RGS4 polymorphisms predict clinical manifestations and responses to risperidone treatment in patients with schizophrenia. J. Clin. Psychopharmacol. 28(1), 64-68 (2008).
145. Xing Q, Gao R, Li H et al. Polymorphisms of the ABCB1 gene are associated with the therapeutic response to risperidone in Chinese schizophrenia patients. Pharmacogenomics 7(7), 987-993 (2006). (Pubitemid 44644778)
146. Kastelic M, Koprivšek J, Plesnicar BK et al. MDR1 gene polymorphisms and response to acute risperidone treatment. Prog. Neuropsychopharmacol. Biol. Psychiatry 34(2), 387-392 (2010).
147. Méary A, Brousse G, Jamain S et al. Pharmacogenetic study of atypical antipsychotic drug response: involvement of the norepinephrine transporter gene. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B(4), 491-494 (2008). (Pubitemid 351830809)
148. Wei Z, Wang L, Zhang M et al. A pharmacogenetic study of risperidone on histamine H3 receptor gene (HRH3) in Chinese Han schizophrenia patients. J. Psychopharmacol. 26(6), 813-818 (2012).
149. Ikeda M, Tomita Y, Mouri A et al. 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(3), 263-269 (2010).
150. Zhao QZ, Liu BC, Zhang J et al. Association between a COMT polymorphism and clinical response to risperidone treatment: a pharmacogenetic study. Psychiatr. Genet. 22(6), 298-299 (2012).
151. EMA. Risperdal (2008). www.emea.europa.eu/ema/index. jsp?curl=pages/ medicines/human/referrals/Risperdal/human-referral-000022.jsp (Accessed 30 August 2012)
152. US FDA. Risperdal (2012). www.accessdata.fda.gov/drugsatfda-docs/lab el/2012/020272s065,020588s053,021444s04 1lbl.pdf (Accessed 30 August 2012)