Skip to main content Accessibility help

Association between CYP1A2 gene single nucleotide polymorphisms and clinical responses to clozapine in patients with treatment-resistant schizophrenia

  • Anto P. Rajkumar (a1) (a2), B. Poonkuzhali (a3), Anju Kuruvilla (a1), Alok Srivastava (a3), Molly Jacob (a4) and K. S. Jacob (a1)...



Despite clozapine's superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes mandate a clinical need to predict its treatment response. Although cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine, the role of CYP1A2 gene in the clinical response to clozapine is uncertain. Hence, we investigated its association with treatment responses and adverse events of clozapine in TRS.


We evaluated four single nucleotide polymorphisms (SNP) in the CYP1A2 gene, clinical responses and serum clozapine levels in 101 consecutive patients with TRS on stable doses of clozapine. We defined clozapine response a priori and investigated allelic and genotypic associations. We assessed the socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition and disability of the participants, using standard assessment schedules for appropriate multivariate analyses.


Our results revealed that CYP1A2 gene SNP (*1C, *1D, *1E and *1F) were not associated with clozapine treatment response, adverse effects, serum clozapine levels or with disability (p values > 0.10).


As CYP1A2 gene SNP do not help to predict the clinical response to clozapine, routine screening for them prior to start clozapine is currently unwarranted. We suggest future longitudinal genome-wide association studies investigating clinical and pharmacogenetic variables together.


Corresponding author

Dr Anto Praveen Rajkumar Rajamani, Centre for Psychiatric Research, Aarhus University Hospital, 2, Skovagervej, Risskov-8240, Denmark. Tel: +45 7789 3548; Fax: +45 8612 3173; E-mail:


Hide All
1Kane, J, Honigfeld, G, Singer, J, Meltzer, H.Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45:789796.
2Horacek, J, Bubenikova-Valesova, V, Kopecek, Met al.Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs 2006;20: 389409.
3Meltzer, HY, Alphs, L, Green, AIet al.Clozapine treatment for suicidality in schizophrenia: International suicide prevention trial (InterSePT). Arch Gen Psychiatry 2003;60:8291.
4Tandon, R, Fleischhacker, WW.Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment. Schizophr Res 2005;79:145155.
5Remington, G, Saha, A, Chong, SA, Shammi, C.Augmentation strategies in clozapine-resistant schizophrenia. CNS Drugs 2005;19:843872.
6Henderson, DC, Cagliero, E, Gray, Cet al.Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study. Am J Psychiatry 2000;157:975981.
7Chung, C, Remington, G.Predictors and markers of clozapine response. Psychopharmacology (Berl) 2005;179: 317335.
8Pirmohamed, M, Williams, D, Madden, S, Templeton, E, Park, BK.Metabolism and bioactivation of clozapine by human liver in vitro. J Pharmacol Exp Ther 1995;272: 984990.
9Ozdemir, V, Kalow, W, Okey, ABet al.Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C–>A polymorphism in intron 1 of the CYP1A2 gene: effect of grapefruit juice and low-dose fluvoxamine J Clin Psychopharmacol 2001;21:603607.
10Eap, CB, Bender, S, Jaquenoud Sirot, Eet al.Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. J Clin Psychopharmacol 2004;24:214219.
11Djordjevic, N, Ghotbi, R, Jankovic, S, Aklillu, E.Induction of CYP1A2 by heavy coffee consumption is associated with the CYP1A2-163C>A polymorphism. Eur J Clin Pharmacol 2010;66:697703.
12Potkin, SG, Bera, R, Gulasekaram, Bet al.Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 1994;55(Suppl. B):133136.
13Kronig, MH, Munne, RA, Szymanski, Set al.Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 1995;152: 179182.
14Miller, DD, Fleming, F, Holman, TL, Perry, PJ.Plasma clozapine concentrations as a predictor of clinical response: a follow-up study. J Clin Psychiatry 1994;55(Suppl. B): 117121.
15Corchero, J, Pimprale, S, Kimura, S, Gonzalez, FJ.Organization of the CYP1A cluster on human chromosome 15: implications for gene regulation. Pharmacogenetics 2001;11:16.
16Zhou, SF, Wang, B, Yang, LP, Liu, JP.Structure function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev 2010;42:268354.
17Murayama, N, Soyama, A, Saito, Yet al.Six novel nonsynonymous CYP1A2 gene polymorphisms: catalytic activities of the naturally occurring variant enzymes. J Pharmacol Exp Ther 2004;308:300306.
18Soyama, A, Saito, Y, Hanioka, Net al.Single nucleotide polymorphisms and haplotypes of CYP1A2 in a Japanese population. Drug Metab Pharmacokinet 2005;20:2433.
19Sachse, C, Bhambra, U, Smith, Get al.Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol 2003;55:6876.
20Arranz, MJ, Munro, J, Sham, Pet al.Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res 1998;32:9399.
21Souza, RP, de Luca, V, Meltzer, HY, Lieberman, JA, Kennedy, JL.Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia. Pharmacogenet Genomics 2010;20:274276.
22Honigfeld, G, Patin, J.Predictors of response to clozapine therapy. Psychopharmacology (Berl) 1989;99(Suppl): S64S67.
23Honer, WG, Macewan, GW, Kopala, Let al.A clinical study of clozapine treatment and predictors of response in a Canadian sample. Can J Psychiatry 1995;40:208211.
24Umbricht, DS, Wirshing, WC, Wirshing, DAet al.Clinical predictors of response to clozapine treatment in ambulatory patients with schizophrenia. J Clin Psychiatry 2002;63:420424.
25Lieberman, JA, Safferman, AZ, Pollack, Set al.Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 1994;151:17441752.
26Mancama, D, Arranz, MJ, Kerwin, RW.Genetic predictors of therapeutic response to clozapine: current status of research. CNS Drugs 2002;16:317324.
27Arranz, MJ, Munro, J, Birkett, Jet al.Pharmacogenetic prediction of clozapine response. Lancet 2000;355: 16151616.
28Hwang, R, Shinkai, T, De Luca, Vet al.Association study of 12 polymorphisms spanning the dopamine D(2) receptor gene and clozapine treatment response in two treatment refractory/intolerant populations. Psychopharmacology (Berl) 2005;181:179187.
29Lieberman, JA, Kane, JM, Safferman, AZet al.Predictors of response to clozapine. J Clin Psychiatry 1994;55(Suppl. B):126128.
30Gross, A, Joutsiniemi, SL, Rimon, R, Appelber, GB.Clozapine-induced QEEG changes correlate with clinical response in schizophrenic patients: a prospective, longitudinal study. Pharmacopsychiatry 2004;37:119122.
31Swen, JJ, Nijenhuis, M, de Boer, Aet al.Pharmacogenetics: from bench to byte–an update of guidelines. Clin Pharmacol Ther 2011;89:662673.
32Kootstra-Ros, JE, Smallegoor, W, Van der Weide, J.The cytochrome P450 CYP1A2 genetic polymorphisms *1F and *1D do not affect clozapine clearance in a group of schizophrenic patients. Ann Clin Biochem 2005;42:216219.
33Jaquenoud Sirot, E, Knezevic, B, Morena, GPet al.ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol 2009;29:319326.
34Van der Weide, J, Steijns, LS, Van Weelden, MJ.The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. Pharmacogenetics 2003;13:169172.
35Schulte, PF.Risk of clozapine-associated agranulocytosis and mandatory white blood cell monitoring. Ann Pharmacother 2006;40:683688.
36NOVARTIS. Clozaril prescribing information, 2010. URL [accessed on 2 November 2011].
37APA. Diagnostic and statistical manual of mental disorders. 4th edn. Text Revision (DSM-IV-TR). Washington D.C.: American Psychiatric Association, 2000.
38Overall, JE, Gorham, DR.The brief psychiatric rating scale. Psychol Rep 1962;10:799812.
39Guy, W.ECDEU assessment manual for psychopharmacology. Washington, DC: US Department of Health, Education and Welfare, 1976.
40Mioshi, E, Dawson, K, Mitchell, J, Arnold, R, Hodges, JR.The Addenbrooke's Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry 2006;21:10781085.
41WHO. WHODAS II Disability Assessment Schedule: 12-Item interviewer administered version. Geneva: World Health Organization, 2001.
42Pennebaker, JW, Susman, JR.Disclosure of traumas and psychosomatic processes. Soc Sci Med 1988;26:327332.
43Rabinowitz, J, Levine, SZ, Brill, N, Bromet, EJ.The premorbid adjustment scale structured interview (PAS-SI): preliminary findings. Schizophr Res 2007;90:255257.
44Wongsinsup, C, Taesotikul, W, Kaewvichit, S, Sangsrijan, S, Sangsrija, S.Determination of clozapine in human plasma by high – performance liquid chromatography with UV – VIS Detector. CMU J Nat Sci 2010;9:2937.
45Conley, RR, Carpenter, WT Jr, Tamminga, CA.Time to clozapine response in a standardized trial. Am J Psychiatry 1997;154:12431247.
46Buckley, P, Miller, A, Olsen, J, Garver, D, Miller, DD, Csernansky, J.When symptoms persist: clozapine augmentation strategies. Schizophr Bull 2001;27:615628.
47Gauderman, WJ.Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 2002;155:478484.
48Purcell, S, Neale, B, Todd-Brown, Ket al.PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81:559575.
49Semiz, UB, Cetin, M, Basoglu, Cet al.Clinical predictors of therapeutic response to clozapine in a sample of Turkish patients with treatment-resistant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:13301336.
50NCBI-SNP. Reference SNP cluster report: rs762551. Bethesda (MD): National Library of Medicine (US), 2011. URL [accessed on 26 September 2011].
51NCBI-SNP. Reference SNP cluster report: rs35694136. Bethesda (MD): National Library of Medicine (US); 2011. URL [accessed on 26 September 2011].
52Estellat, C, Torgerson, DJ, Ravaud, P.How to perform a critical analysis of a randomised controlled trial. Best Pract Res Clin Rheumatol 2009;23:291303.
53Burns, T.Evolution of outcome measures in schizophrenia. Br J Psychiatry Suppl 2007;50:s1s6.
54Tiwari, AK, Deshpande, SN, Lerer, B, Nimgaonkar, VL, Thelma, BK.Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism Pharmacogenomics J 2007;7:305311.
55Perry, PJ, Bever, KA, Arndt, S, Combs, MD.Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram. Biol Psychiatry 1998;44: 733738.
56Dratcu, L, Grandison, A, Mckay, G, Bamidele, A, Vasudevan, V.Clozapine-resistant psychosis, smoking, and caffeine: managing the neglected effects of substances that our patients consume every day. Am J Ther 2007;14:314318.
57Mcevoy, JP, Freudenreich, O, Wilson, WH.Smoking and therapeutic response to clozapine in patients with schizophrenia. Biol Psychiatry 1999;46:125129.
58de Leon, J, Arranz, MJ, Ruano, G.Pharmacogenetic testing in psychiatry: a review of features and clinical realities. Clin Lab Med 2008;28:599617.
59NCBI-SNP. Reference SNP cluster report: rs2069526. Bethesda (MD): National Library of Medicine (US), 2011. URL [accessed on 26 September 2011].
60NCBI-SNP. Reference SNP cluster report: rs2069514. Bethesda (MD): National Library of Medicine (US), 2011. URL [accessed on 26 September 2011].
61Stefansson, H, Ophoff, RA, Steinberg, Set al.Common variants conferring risk of schizophrenia. Nature 2009;460:744747.
62Sullivan, PF, Kendler, KS, Neale, MC.Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003;60:11871192.
63Prasad, S, Semwal, P, Deshpande, S, Bhatia, T, Nimgaonkar, VL, Thelma, BK.Molecular genetics of schizophrenia: past, present and future. J Biosci 2002;27:3552.
64Jerling, M, Merle, Y, Mentre, F, Mallet, A.Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. Br J Clin Pharmacol 1997;44:447453.


Association between CYP1A2 gene single nucleotide polymorphisms and clinical responses to clozapine in patients with treatment-resistant schizophrenia

  • Anto P. Rajkumar (a1) (a2), B. Poonkuzhali (a3), Anju Kuruvilla (a1), Alok Srivastava (a3), Molly Jacob (a4) and K. S. Jacob (a1)...


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed