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Antipsychotic drug-induced movement disorders in schizophrenics in relation to CYP2D6 genotype

Published online by Cambridge University Press:  02 January 2018

Martin Armstrong*
Affiliation:
Department of Pharmacological Sciences, University of Newcastle upon Tyne
Ann K. Daly
Affiliation:
Department of Pharmacological Sciences, University of Newcastle upon Tyne
Richard Blennerhassett
Affiliation:
Department of Psychiatry, University of Newcastle upon Tyne
Nicol Ferrier
Affiliation:
Department of Psychiatry, University of Newcastle upon Tyne
Jeffrey R. Idle
Affiliation:
Department of Pharmacological Sciences, University of Newcastle upon Tyne
*
Dr Ann K. Daly, Department of Pharmacological Sciences, University of Newcastle upon Tyne, Medical School, Framlington Place, Newcastle upon Tyne NE24HH

Abstract

Background

Approximately 5–10% of Caucasians (poor metabolisers) show impaired metabolism of at least 20 therapeutically important drugs, including a number of commonly used antipsychotic agents, because they lack the cytochrome p450 enzyme CYP2D6. The molecular basis of this defect is now well understood and simple genotyping tests using the polymerase chain reaction (PCR) have been developed.

Method

To determine whether poor metabolisers are more susceptible to acute dystonic reactions and chronic movement disorders associated with the administration of antipsychotic drugs, we determined CYP2D6 genotypes in a group of 76 schizophrenics using previously described methods involving PCR and restriction fragment length polymorphism analysis.

Results

There was no difference in genotype frequencies between the schizophrenics and a normal control population, suggesting that CYP2D6 genotype was not a factor in determining susceptibility to the disease. However, four of the five poor metabolisers compared with 44% of the remaining subjects were suffering from a movement disorder at the time of the study, although because of the small number of poor metabolisers in the group the difference was not statistically significant. Poor metabolisers were not more likely to suffer an acute dystonic reaction.

Conclusions

CYP2D6 genotype is not a determinant of susceptibility to acute dystonic reactions but may be a contributory factor in antipsychotic drug-induced movement disorders including tardive dyskinesia.

Type
Papers
Copyright
Copyright © 1997 The Royal College of Psychiatrists 

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References

Alvan, G., Bechtal, P., Isethus, L., et al (1990) Hydroxylation polymorphisms of debrisoquine and mephanytoin in European populations. European Journal of Cinical Pharmacology 39, 533537.Google ScholarPubMed
American Psychiatric Association (1967) Diagnostic and Statistical Manual of Mental Disorders (3rd edn, revised) (DSM-III-R)-Washington, DC: APA.Google Scholar
Armitage, P. & Berry, G. (1967) Statistical Methods in Medical Research(2nd edn). Oxford: Blackwell Scientific.Google Scholar
Arthur, H., Dahl, M.-L., Siwers, B., et al (1995) Polymorphic drug metabolism in schizophrenic patients with tardive dyskinesia, Journal of Clinical PsychopharmacologY 15, 211216.Google Scholar
Broly, F., Gaodigk, A., Heim, M., et al (1991) Debrisoquine/ sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population. DMA and Cell Biology, 10, 545 558.Google ScholarPubMed
Cholerton, S., Daly, A. K. & Idle, J. R. (1992) The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends in Pharmacological Sciences. 13, 434438.CrossRefGoogle ScholarPubMed
Dahl, M.-L. & Bartilsson, L. (1993) Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics, 3, 6170.CrossRefGoogle ScholarPubMed
Dahl, M.-L. & Bartilsson, L., Johansson, L., Palmertz, M. P., et al (1992) Analysis of the CYP2D6 gene in relation to debrisoquine and desipramine hydroxylation in a Swedish population. Clinical Pharmacology and Therapeutics, 51, 1217.Google Scholar
Dahl-Puustian, M.-L., Liden, A., Alm, C., et al (1989) Analysis of the CYP2D6 gene in relation to debrisoquine and desipramine hydroxylation in a Swedish population. Clinical Pharmacology and Therapeutics, 46, 7881.Google Scholar
Daly, A. K. Armstrong, M., Monkman, S. C., et al (1991) The genetic and metabolic criteria for the assignment of debrisoquine 4-hydroxylation (P450IID6) phenotypes. Pharmacogenetics, i 3341.Google Scholar
Evans, D. A. P. (1993) Genetic Factors in Drug Therapy Cambridge: Cambridge University Press.Google Scholar
Gough, A. C., Miles, J. S., Spurr, N. K., et al (1990) Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347, 773776.CrossRefGoogle ScholarPubMed
Grohman, R., Gunther, W. & Ruther, E. (1983) Adverse effects of psychotrophic drugs. Clinical Psychopharmacology 1 378397.Google Scholar
GUYECDU (1976) Assessment Manual for Psychopharmacology pp. 534 537 Department of Health, Education and WWfare.Google Scholar
Heim, M. & Meyer, U. A. (1990) Genotyping of poor metabolisers by allele-specific PCR amplification. Lancet, ii, 529532.CrossRefGoogle Scholar
Jerling, M., Dahl, M.-L., Aberg-Wistedt, A. et al (1996) The CYP2D6 gencjtype predicts the oral clearance of the neuroleptic agents perphenazine and zulcopenthixol. Clinical Pharmacology and Therapeutics. 59, 423428.CrossRefGoogle Scholar
Lierena, A., Alam, C., Dahl, M. L., et al (1992) Haloperidoi disposition is dependent on debrisoquine hydroxylation phenotype. Therapeutic Drug Monitoring. 14, 9297.Google Scholar
Niznik, H. B., Tyndale, R. F., Sallee, F. R. et al (1990) The dopamine transporter and cytochrome P450IIDI (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins. Archives of Biochemistry and Biophysics. 276, 424432.Google Scholar
Owens, D. G. C., Johnstone, E. C. & Frith, C. D. (1982) Spontaneous involuntary disorders of movement: their prevalence, severity and distribution in chronic schizophrenics with and without treatnnent with neuroleptics. Archives of General Psychiatryi 39, 452461.CrossRefGoogle ScholarPubMed
Spina, E., Campo, G. M., Calandra, S., et al (1992a) Debrisoquine oxidation in an Italian population: a study in healthy subjects and in schizophrenic patients. Pharmacological Research. 25, 4350.Google Scholar
Spina, E., Campo, G. M., Calandra, S., Sturiale, V., & Valvo, S. et al (1992b) Debrisoquine oxidation phenotype and neuroleptic-induced dystonic reactions. Acta Psychiatrica Scandinavica. 96, 364366.CrossRefGoogle Scholar
Vallada, H., Collier, D., Dewson, E., et al (1992) Debnsoquine 4-hydroxylase (CYP2D) locus and possible susceptibility to schizophrenia. Lancet, 340, 181182.CrossRefGoogle ScholarPubMed
Webster, D. D. (1968) Critical analysis of the disability of Parkinsons disease. Modem Treatment, 5, 257282.Google Scholar
Wolf, C. R., Smith, C. A. D., Gough, A. C., et al (1992) Relationship between the debnsoquine hydroxylase polymorphism and cancer susceptibility Carcinogenesis, 13, 10351038.CrossRefGoogle ScholarPubMed
von Bahr, C., Movin, G., Nordin, C., et al (1991) Plasma levels of thioridazine and metabolites are influenced by the debrisoquine hydroxylation phenotype. Clinical Pharmacology and Therapeutics, 49, 234240.CrossRefGoogle Scholar
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