Hostname: page-component-78c5997874-t5tsf Total loading time: 0 Render date: 2024-11-13T01:03:47.558Z Has data issue: false hasContentIssue false
  • English
  • Français

Variability in Response to Clozapine: Potential Role of Cytochrome P450 1A2 and the Dopamine D4 Receptor Gene

Published online by Cambridge University Press:  07 November 2014

Vura Özdemir ,
Mario Masellis ,
Vincenzo S. Basile ,
Werner Kalow ,
Herbert Y. Meltzer ,
Jeffrey A. Lieberman  and
James L. Kennedy
Get access Rights & Permissions [Opens in a new window]

Abstract

Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patieents There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the free plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, investigated the (G)n mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.

Type
Feature Articles
Information
CNS Spectrums , Volume 4 , Issue 6: Molecular Genetics: Part Two , June 1999 , pp. 30 - 34, 47-56
Copyright
Copyright © Cambridge University Press 1999

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1.Lieberman, JA. Maximizing clozapine therapy: managing side effects. J Clin Psychiatry. 1998;59(suppl 3):38–43.Google ScholarPubMed
2.Kane, JM. Schizophrenia. N Engl J Med. 1996;334: 34–41.CrossRefGoogle ScholarPubMed
3.Lieberman, JA. Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale and hypothesis. J Clin Psychiatry. 1996;57(suppl 11):68–71.Google ScholarPubMed
4.Meltzer, HY. Atypical antipsychotic drugs. In: Bloom, FE, Kupfer, DJ, eds. Psyche-pharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:1277–1286.Google Scholar
5.Jann, MW, Grimsley, SR, Gray, EC, Chang, WH. Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet. 1993;24:161–176.CrossRefGoogle ScholarPubMed
6.Collins, EJ, Lalonde, P, Jones, BD, et al.Clozapine in the treatment of refractory schizophrenia: Canadian policies and clinical guidelines. Can J Psychiatry. 1992;37:482–496.CrossRefGoogle ScholarPubMed
7.Baldessarini, RJ, Frankenburg, FR. Clozapine. A novel antipsychotic agent. N Engl J Med. 1991;324:746–754.Google ScholarPubMed
8.Miller, DD. The clinical use of clozapine plasma concentrations in the management of treatment-refractory schizophrenia. Ann Clin Psychiatry. 1996;8:99–109.CrossRefGoogle ScholarPubMed
9.Meltzer, HY, Cola, PA. The pharmacoeconomics of clozapine: a review. J Clin Psychiatry. 1994;55(suppl B):161–165.Google ScholarPubMed
10.Sheiner, LB. Learning versus confirming in clinical drug development. Clin Pharmacol Ther. 1997;61:275–291.CrossRefGoogle ScholarPubMed
11.Sheiner, LB. Clinical pharmacology and the choice between theory and empiricism. Clin Pharmacol Ther. 1989;46:605–615.CrossRefGoogle ScholarPubMed
12.Kalow, W. Pharmacogenetics in biological perspective. Pharmacol Rev. 1997;49:369–379.Google ScholarPubMed
13.Llerena, A, Cobaleda, J, Martinez, C, Benitez, J. Interethnic differences in drug metabolism: influence of genetic and environmental factors on debrisoquine hydroxylation phenotype. Eur J Drug Metab Pharmacokinet. 1996;21:129–138.CrossRefGoogle ScholarPubMed
14.Bertilsson, L. Geographical/interracial differences in polymorphic drug oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet. 1995;29:192–209.CrossRefGoogle ScholarPubMed
15.Weber, WW. Influence of heredity on human sensitivity to environmental chemicals. Environ Mol Mutagen. 1995;25(suppl 26):102–114.CrossRefGoogle ScholarPubMed
16.Llerena, A, Herraiz, AG, Cobaleda, J, Johansson, I, Dahl, ML. Debrisoquin and mephenytoin hydroxylation phenotypes and CYP2D6 genotype in patients treated with neuroleptic and antidepressant agents. Clin Pharmacol Ther. 1993;54:606–611.CrossRefGoogle ScholarPubMed
17.Reidenberg, MM. Trends in clinical pharmacokinetics. Clin Pharmacokinet. 1993;24:1–9.CrossRefGoogle ScholarPubMed
18.Okey, AB. Enzyme induction in the cytochrome P-450 system. Pharmacol Ther. 1990;45:241–298.CrossRefGoogle ScholarPubMed
19.Greenblatt, DJ, Harmatz, JS, von Moltke, LL, Shader, RI. Pharmacokinetics and pharmacodynamics. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press; 1995:849–858.Google Scholar
20.Rowland, M, Tozer, TN, eds. Clinical Pharmacokinetics. Concepts and Applications. 3rd ed. Philadelphia, Pa: Williams & Wilkins; 1995.Google Scholar
21.Sindrup, SH, Brøsen, K. The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics. 1995;5:335–346.CrossRefGoogle ScholarPubMed
22.Gonzalez, FJ. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci. 1992;13:346–352.CrossRefGoogle ScholarPubMed
23.Omura, T, Sato, R. The carbon monoxide-binding pigment of liver microsomes. 1. Evidence for its hemoprotein nature. J Biol Chem. 1964;239:2370–2378.CrossRefGoogle Scholar
24.Omura, T, Sato, R. The carbon monoxide-binding pigment of liver microsomes. 2. Solubilization, purification, and properties. J Biol Chem. 1964;239:2379–2385.CrossRefGoogle Scholar
25.Guengerich, FP. Catalytic selectivity of human cytochrome P450 enzymes: relevance to drug metabolism and toxicity. Toxicol Lett. 1994;70:133–138.CrossRefGoogle ScholarPubMed
26.Nelson, DR, Koymans, L, Kamataki, T, et al.P450 super-family: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 1996;6:1–42.CrossRefGoogle Scholar
27.Nebert, DW, Adesnik, M, Coon, MJ, et al.The P450 gene superfamily. Recommended nomenclature. DNA. 1987;6:1–11.CrossRefGoogle ScholarPubMed
28.Nebert, DW, Nelson, DR, Adesnik, M, et al.The P450 gene superfamily. Update on the naming of new genes and nomenclature of chromosomal loci. DNA. 1989;8: 1–13.CrossRefGoogle Scholar
29.Nebert, DW, Nelson, DR, Coon, MJ, et al.The P450 super-family: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol. 1991;10: 1–14.CrossRefGoogle Scholar
30.Nelson, DR, Kamataki, T, Waxman, DJ, et al.The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names, and nomenclature. DNA Cell Biol. 1993;12:1–51.CrossRefGoogle ScholarPubMed
31.Shimada, T, Yamazaki, H, Mimura, M, et al.Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994;270:414–423.Google ScholarPubMed
32.Fleischhacker, WW, Hummer, M, Kurz, M, et al.Clozapine dose in the United States and Europe: implications for therapeutic and adverse effects. J Clin Psychiatry. 1994;(suppl B):78–81.Google ScholarPubMed
33.Freeman, DJ, Oyewumi, LK. Will routine therapeutic drug monitoring have a place in clozapine therapy? Clin Pharmacokinet. 1997;32:93–100.CrossRefGoogle ScholarPubMed
34.Compendium of Pharmaceuticals and Specialties. Clozaril Monograph. Canadian Pharmacists Association; Ottawa, Ontario; 1994:262–264.Google Scholar
35.Cheng, YF, Lundberg, T, Bondesson, U, Lindstrom, L, Gabrielsson, J. Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin Pharmacol. 1988;34:445–449.CrossRefGoogle ScholarPubMed
36.Choc, MG, Hsuan, F, Honigfeld, G, et al.Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients. Pharm Res. 1990;7:347–351.CrossRefGoogle ScholarPubMed
37.Choc, MG, Lehr, RG, Hsuan, F, et al.Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res. 1987;4:402–405.CrossRefGoogle ScholarPubMed
38.Potkin, SG, Bera, R, Gulasekaram, B, et al.Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry. 1994;55(suppl B):133–136.Google ScholarPubMed
39.Ozdemir, V, Posner, P, Collins, EJ, et al.CYP1A2 activity predicts clozapine steady state concentration in schizophrenic patients [abstract]. Clin Pharmacol Ther. 1999;65:175.CrossRefGoogle Scholar
40.Carrillo, JA, Herraiz, AG, Ramos, SI, Benitez, J. Effects of caffeine withdrawal from the diet on the metabolism of clozapine in schizophrenic patients. J Clin Psychopharmacol. 1998;18:311–316.CrossRefGoogle Scholar
41.Byerly, MJ, DeVane, CL. Pharmacokinetics of clozapine and risperidone: a review of recent literature. J Clin Psychopharmacol. 1996;16:177–187.CrossRefGoogle ScholarPubMed
42.Dain, JG, Nicoletti, J, Ballard, F. Biotransformation of clozapine in humans. Drug Metab Dispos. 1997;25: 603–609.Google ScholarPubMed
43.Kuoppamäki, M, Syvälahti, E, Hietala, J. Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists. Eur J Pharmacol. 1993;245:179–182.CrossRefGoogle ScholarPubMed
44.Young, CD, Meltzer, HY, Deutch, AY. Effects of desmethylclozapine on Fos protein expression in the forebrain: in vivo biological activity of the clozapine metabolite. Neuropsychopharmacology. 1998;19:99–103.CrossRefGoogle ScholarPubMed
45.Chang, WH, Lin, SK, Lane, HY, et al.Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients. Prog Neuropychopharmacol Biol Psychiatry. 1998;22:723–739.CrossRefGoogle ScholarPubMed
46.Kalow, W, Bertilsson, L. Interethnic factors affecting drug response. Adv Drug Res. 1994;25:1–53.Google Scholar
47.Kalow, W. Interethnic variation of drug metabolism. Trends Pharmacol Sci. 1991;12:102–107.CrossRefGoogle ScholarPubMed
48.Lin, K-M, Poland, RE, Wan, Y-JY, Smith, MW, Lesser, IM. The evolving science of pharmacogenetics: clinical and ethnic perspectives. Psychopharmacol Bull. 1996;32:205–217.Google ScholarPubMed
49.Lin, K-M, Poland, RE, Nuccio, I, et al.A longitudinal assessment of haloperidol doses and serum concentrations in Asians and Caucasian schizophrenic patients. Am J Psychiatry. 1989;146:1307–1311.Google ScholarPubMed
50.Lin, K-M, Poland, RE, Lau, JK, Rubin, RT. Haloperidol and prolactin concentrations in Asians and Caucasians. J Clin Psychopharmacol. 1988;8:195–201.CrossRefGoogle ScholarPubMed
51.Chong, SA, Tan, CH, Khoo, YM, et al.Clinical evaluation and plasma clozapine concentrations in Chinese patients with schizophrenia. Ther Drug Monit. 1997;19:219–223.CrossRefGoogle ScholarPubMed
52.Matsuda, KT, Cho, MC, Lin, KM, Smith, MW, Young, AS, Adams, JA. Clozapine dosage, serum levels, efficacy, and side-effect profiles: a comparison of Korean-American and Caucasian patients. Psychopharmacol Bull. 1996;32:253–257.Google ScholarPubMed
53.Lin, KM, Anderson, D, Poland, RE. Ethnicity and psychopharmacology: bridging the gap. Psychiatr Clin North Am. 1995;18:635–647.CrossRefGoogle ScholarPubMed
54.Bell, R, McLaren, A, Galanos, J, Copolov, D. The clinical use of plasma clozapine levels. Aust N Z J Psychiatry. 1998;32:567–574.CrossRefGoogle ScholarPubMed
55.VanderZwaag, C, McGee, M, McEvoy, JP, Freudenreich, O, Wilson, WH, Cooper, TB. Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry. 1996;153:1579–1584.Google ScholarPubMed
56.Kronig, MH, Munne, RA, Szymanski, S, et al.Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry. 1995;152:179–182.Google ScholarPubMed
57.Miller, 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):117–121.Google ScholarPubMed
58.Piscitelli, SC, Frazier, JA, McKenna, K, et al.Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response. J Clin Psychiatry. 1994;55(suppl B):94–97.Google ScholarPubMed
59.Hasegawa, M, Gutierrez-Esteinou, R, Way, L, Meltzer, HY. Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking. J Clin Psychopharmacol. 1993;13:383–390.CrossRefGoogle ScholarPubMed
60.Perry, P, Miller, D, Arndt, S, Cadoret, R. Clozapine and norclozapine plasma concentrations and clinical response in treatment-refractory schizophrenics. Am J Psychiatry. 1991;148:231–235.Google Scholar
61.Meltzer, HY. Clozapine: is another view valid? Am J Psychiatry. 1995;152:821–825.Google ScholarPubMed
62.Fang, J, Coutts, RT, McKenna, KF, Baker, GB. Elucidation of individual P cytochrome 450 enzymes involved in the metabolism of clozapine. Naunyn Schmiedeberg's Arch Pharmacol. 1998;358:592–599.CrossRefGoogle Scholar
63.Eiermann, B, Engel, G, Johansson, I, Zanger, UM, Bertilsson, L. The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine. Br J Clin Pharmacol. 1997;44:439–446.CrossRefGoogle Scholar
64.Linnet, K, Olesen, OV. Metabolism of clozapine by cDNA-expressed human cytochrome P450 enzymes. Drug Metab Dispos. 1997;25:1379–1382.Google ScholarPubMed
65.Pirmohamed, M, Williams, D, Madden, S, Templeton, E, Park, BK. Metabolism and bioactivation of clozapine by human liver in vitro. J Pharmacol Exp Ther. 1995;272:984–990.Google ScholarPubMed
66.Fischer, V, Vogels, B, Maurer, G, Tynes, RE. The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P450 2D6. J Pharmacol Exp Ther. 1992;260:1355–1360.Google ScholarPubMed
67.Shader, RI, Greenblatt, DJ. Clozapine and fluvoxamine, a curious complexity. J Clin Psychopharmacol. 1998;18:101–102.CrossRefGoogle ScholarPubMed
68.Tugnait, M, Hawes, EM, McKay, G, Rettie, AE, Haining, RL, Midha, KK. N-oxygenation of clozapine by flavin-containing monooxygenase. Drug Metab Dispos. 1997;25:524–527.Google ScholarPubMed
69.Kalow, W, Tang, BK. Caffeine as a metabolic probe: Exploration of the enzyme-inducing effects of cigarette smoking. Clin Pharmacol Ther. 1991;49:44–48.CrossRefGoogle ScholarPubMed
70.Schmider, J, Greenblatt, DJ, von Moltke, LL, Shader, RI. Relationship of in vitro data on drug metabolism to in vivo pharmacokinetics and drug interactions: implications for diazepam disposition in humans. J Clin Psychopharmacol. 1996;16:267–272.CrossRefGoogle ScholarPubMed
71.Bertilsson, L, Carrillo, JA, Dahl, ML, et al.Clozapine disposition covaries with CYP1A2 activity determined by a caffeine test. 1994. Br J Clin Pharmacol. 1994;38: 471–473.CrossRefGoogle Scholar
72.Kashuba, AD, Nafziger, AN, Kearns, GL, et al.Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping. Clin Pharmacol Ther. 1998;64:257–268.CrossRefGoogle Scholar
73.Rasmussen, BB, Nielsen, TL, Brøsen, K. Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. Pharmacol Toxicol. 1998;83:240–245.CrossRefGoogle Scholar
74.Preskorn, SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet. 1997;32(suppl 1):1–21.CrossRefGoogle ScholarPubMed
75.Wetzel, H, Anghelescu, I, Szegedi, A, et al.Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study. J Clin Psychopharmacol. 1998;18:2–9.CrossRefGoogle ScholarPubMed
76.Armstrong, SC, Stephans, JR. Blood clozapine levels elevated by fluvoxamine: potential for side effects and lower clozapine dosage [letter]. J Clin Psychiatry. 1997;58:499.CrossRefGoogle ScholarPubMed
77.Taylor, D. Pharmacokinetic interactions involving clozapine. Br J Psychiatry. 1997;171:109–112.CrossRefGoogle ScholarPubMed
78.Hiemke, C, Weigmann, H, Härtter, S, Dahmen, N, Wetzel, H, Müller, H. Elevated levels of clozapine in serum after addition of fluvoxamine. J Clin Psychopharmacol. 1994;14:279–281.CrossRefGoogle ScholarPubMed
79.Jerling, M, Lindstrom, L, Bondesson, U, Bertilsson, L. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit. 1994;16:368–374.CrossRefGoogle Scholar
80.Bender, S, Eap, CB. Very high cytochrome P4501A2 activity and nonresponse to clozapine. Arch Gen Psychiatry. 1998;55:1048–1050.CrossRefGoogle ScholarPubMed
81.Dahl, ML, Llerena, A, Bondesson, U, Lindstrom, L, Bertilsson, L. Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. Br J Clin Pharmacol. 1994;37:71–74.CrossRefGoogle ScholarPubMed
82.Arranz, MJ, Dawson, E, Shaikh, S, et al.Cytochrome P4502D6 genotype does not determine response to clozapine. Br J Clin Pharmacol. 1995;39:417–420.CrossRefGoogle Scholar
83.Raaska, K, Neuvonen, PJ. Serum concentrations of clozapine and N-desmethylclozapine are unaffected by the potent CYP3A4 inhibitor itraconazole. Eur J Clin Pharmacol. 1998;54:167–170.CrossRefGoogle ScholarPubMed
84.Cohen, LG, Chesley, S, Eugenio, L, Flood, JG, Fisch, J, Goff, DC. Erythromycin-induced clozapine toxic reaction. Arch Intern Med. 1996;156:675–677.CrossRefGoogle ScholarPubMed
85.Kalow, W, Tang, BK, Endrenyi, L. Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics. 1998;8:283–289.Google ScholarPubMed
86.Tang, BK, Kalow, W. Assays for CYP1A2 by testing in vivo metabolism of caffeine in humans. Methods Enzymol. 1996;272:124–131.CrossRefGoogle ScholarPubMed
87.Tang, BK, Zhou, Y, Radar, D, Kalow, W. Caffeine as a probe for CYP1A2 activity: potential influence of renal factors on urinary phenotypic trait measurements. Pharmacogenetics. 1994;4:117–124.CrossRefGoogle ScholarPubMed
88.Kalow, W, Tang, BK. The use of caffeine for enzyme assays: a critical appraisal. Clin Pharmacol Ther. 1993;53:503–514.CrossRefGoogle ScholarPubMed
89.Kalow, W, Tang, BK. Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clin Pharmacol Ther. 1991;50:508–519.CrossRefGoogle ScholarPubMed
90.Kashuba, AD, Bertino, JS Jr, Kearns, GL, et al.Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping. Clin Pharmacol Ther. 1998;63:540–551.CrossRefGoogle ScholarPubMed
91.Kail, MA, Vang, O, Clausen, J. Effects of dietary broccoli on human drug metabolising activity. Cancer Lett. 1997;114:169–170.CrossRefGoogle Scholar
92.Kail, MA, Vang, O, Clausen, J. Effects of dietary broccoli on human in vivo drug metabolizing enzymes: evaluation of caffeine, oestrone and chlorzoxazone metabolism. Carcinogenesis. 1996;17:793–9.CrossRefGoogle Scholar
93.Sinha, R, Rothman, N, Brown, ED, et al.Pan-fried meat containing high levels of heterocyclic aromatic amines but low levels of polycyclic aromatic hydrocarbons induces cytochrome P4501A2 activity in humans. Cancer Res. 1994;54:6154–6159.Google ScholarPubMed
94.Fuhr, U, Klittich, K, Staib, AH. Inhibitory effect of grapefruit juice and the active component naringenin on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol. 1993;35:431–436.CrossRefGoogle Scholar
95.Masimirembwa, CM, Beke, M, Hasler, JA, Tang, BK, Kalow, W. Low CYP1A2 activity in rural Shona children of Zimbabwe. Clin Pharmacol Ther. 1995;57:25–31.CrossRefGoogle ScholarPubMed
96.O'Connell, MB, Frye, R, Peter, JV. Effect of conjugated estrogen replacement therapy on CYP activity. Clin Pharmacol Ther. 1997;61:226.Google Scholar
97.Sarich, T, Kalhorn, T, Magee, S, et al.The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin. Clin Pharmacol Ther. 1997;62:21–28.Google ScholarPubMed
98.Rost, KL, Brosicke, H, Heinemeyer, G, Roots, I. Specific and dose-dependent enzyme induction by omeprazole in human beings. Hepatology. 1994;20:1204–1212.CrossRefGoogle ScholarPubMed
99.Bertilsson, L, Lou, YQ, Du, YL, et al.Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther. 1992;51:388–397.CrossRefGoogle ScholarPubMed
100.Jurima, M, Inaba, T, Kadar, D, Kalow, W. Genetic polymorphism of mephenytoin p(4')-hydroxylation: difference between Orientals and Caucasians. Br J Clin Pharmacol. 1985;19:483–487.CrossRefGoogle ScholarPubMed
101.Nakamura, K, Goto, F, Ray, WA, et al.Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther. 1985;38:402–408.CrossRefGoogle ScholarPubMed
102.Ashby, CR, Wang, RY. Pharmacological actions of the atypical antipsychotic drag clozapine: a review. Synapse. 1996;24:349–394.3.0.CO;2-D>CrossRefGoogle Scholar
103.Farde, L, Nordstrom, AL, Wiesel, FA, Pauli, S, Halldin, C, Sedvall, G. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry. 1992;49:538–544.CrossRefGoogle ScholarPubMed
104.Nordstrom, AL, Farde, L, Nyberg, S, Karlsson, P, Halldin, C, Sedvall, G. D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry. 1995;152:1444–1449.Google ScholarPubMed
105.Miller, RJ, Hiley, CR. Anti-muscarinic properties of neuroleptics and drag-induced Parkinsonism. Nature. 1974;248:596–597.CrossRefGoogle Scholar
106.Snyder, SH, Greenberg, D, Yamumura, HI. Antischizophrenic drugs: affinity for muscarinic cholinergic receptor sites in the brain predicts extrapyramidal effects. J Psychiatr Res. 1974;11: 91–95.CrossRefGoogle ScholarPubMed
107.Kinon, BJ, Lieberman, JA. Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology (Beri). 1996;124:2–34.CrossRefGoogle ScholarPubMed
108.Meltzer, HY, Matsubara, S, Lee, J-C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exper Ther. 1989;251:238–246.Google ScholarPubMed
109.Meltzer, HY, Fatemi, SH. The role of serotonin in schizophrenia and the mechanism of action of anti-psychotic drugs. In: Kane, JM, Moller, H-J, Awouters, F, eds. Serotonergic Mechanisms in Antipsychotic Treatment. New York, NY: Marcel Dekker; 1996:77–107.Google Scholar
110.Meltzer, HY. An overview of the mechanism of action of clozapine. J Clin Psychiatry. 1994;55(suppl B):47–52.Google ScholarPubMed
111.Van Tol, HH, Bunzow, JR, Guan, HC, et al.Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991;350:610–614.CrossRefGoogle ScholarPubMed
112.Seeman, P. Dopamine receptor sequences: therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharmacology. 1992;7:261–284.Google ScholarPubMed
113.Seeman, P, Van Tol, HHM. Deriving the therapeutic concentrations for clozapine and haloperidol: the apparent dissociation constant of a neuroleptic at the dopamine D2 or D4 receptor varies with the affinity of the competing radioligand. Eur J Pharmacol. 1995;291:59–66.CrossRefGoogle ScholarPubMed
114.Sanyal, S, Van Tol, HHM. Review. The role of dopamine D4 receptors in schizophrenia and antipsychotic action. J Psychiatr Res. 1997;31:219–232.CrossRefGoogle ScholarPubMed
115.Paterson, AD, Sunohara, GA, Kennedy, JL. Dopamine D4 receptor gene: novelty or nonsense?Neuropsychopharmacology. In press.Google Scholar
116.Shaikh, S, Collier, D, Kerwin, RW, et al.Dopamine D4 receptor subtypes and response to clozapine [letter]. Lancet. 1993;341:116.CrossRefGoogle ScholarPubMed
117.Shaikh, S, Collier, DA, Sham, P, et al.Analysis of clozapine response and polymorphisms of the dopamine D4 receptor gene (DRD4) in schizophrenic patients. Am J Med Genet. 1995;60:541–545.CrossRefGoogle ScholarPubMed
118.Rao, PA, Piekar, D, Gejman, PV, Ram, A, Gershon, ES, Gelernter, J. Allelic variation in the D4 dopamine receptor (DRD4) gene does not predict response to clozapine. Arch Gen Psychiatry. 1994;51:912–917.CrossRefGoogle Scholar
119.Badri, F, Masellis, M, Petronis, A, et al.Genetic studies of dopamine and serotonin system genes in clinical response to clozapine [abstract]. Am J Hum Genet. 1996;57:1358.Google Scholar
120.Rietschel, M, Naber, D, Oberlander, H, et al.Efficacy and side-effects of clozapine: testing for association with allelic variation in the dopamine D4 receptor gene. Neuropsychopharmacology. 1996;15(5):491–496.CrossRefGoogle ScholarPubMed
121.Kohn, Y, Ebstein, RP, Heresco Levy, U, et al.Dopamine D4 receptor gene polymorphisms: relation to ethnicity, no association with schizophrenia and response to clozapine in Israeli subjects. Eur Neuropsychopharmacol. 1997;7:39–43.CrossRefGoogle ScholarPubMed
122.Hebebrand, J, Nothen, MM, Ziegler, A, et al.Nonreplication of linkage disequilibrium between the dopamine D4 receptor locus and Tourette syndrome [letter]. Am J Hum Genet. 1997;61:238–239.CrossRefGoogle ScholarPubMed
123.LaHoste, GJ, Swanson, JM, Wigal, SB, et al.Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry. 1996;1:121–124.Google ScholarPubMed
124.Swanson, JM, Sunohara, GA, Kennedy, JL, et al.Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach. Mol Psychiatry. 1998;3:38–41.CrossRefGoogle Scholar
125.Sunohara, GA, Kennedy, JL. The dopamine D4 receptor gene and neuropsychiatrie disorders. In: Savage, LM, ed. Dopaminergic Disorders: Novel Approaches for Drug Discovery and Development. IBC Library Series. Southborough, Mass: IBC;1998:29–42.Google Scholar
126.Masellis, M, Basile, V, Meltzer, HY, et al.Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients. Neuropsychopharmacology. 1998;19:123–132.CrossRefGoogle ScholarPubMed
127.Arranz, MJ, Munro, J, Sham, P, et al.Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response. Schizophr Res. 1998;32:93–99.CrossRefGoogle ScholarPubMed
128.Rietschel, M, Kennedy, JL, Macciardi, FM, DeLisi, L, Meltzer, HY, and the Consensus Group for Outcome Measures in Psychoses for Pharmacogenetic Studies. Pharmacogenetics in psychosis: the first consensus conference. Schuophr Res. In press.Google Scholar