Smoking and tardive dyskinesia: lack of involvement of the cyp1a2 gene

Research Paper
Article de recherche
Smoking and tardive dyskinesia:
lack of involvement of the CYP1A2 gene
Siow-Ann Chong, MB BS, MMed; Ene-Choo Tan, PhD;
Chay Hoon Tan, MB BS, MMed, PhD; Mythily, MB BS, MD
Chong, Mythily — Woodbridge Hospital and Institute of Mental Health; EC Tan — Defense Medical Research Institute,Defense Science and Technology Agency; CH Tan — Department of Pharmacology, National University of Singapore, Singapore. Objective: To establish if there is an association between cigarette smoking and tardive dyskinesia (TD) in
patients with schizophrenia and to evaluate the role of the CYP1A2 polymorphism in TD in patients of
Chinese descent. Method: Two-hundred and ninety-one patients diagnosed with schizophrenia according
to DSM-IV criteria were included in the study. Dyskinesia was assessed by the Abnormal Involuntary
Movement Scale and TD by the criteria of Schooler and Kane. Demographic and clinical data and informa-
tion on smoking habits were collected, and patients of Chinese descent with a well established smoking
history were subsequently genotyped for CYP1A2. Results: Forty-three (41.3%) of the 104 patients with a
history of smoking and 52 (27.8%) of the 187 non-smokers were diagnosed with TD. The prevalence of TD
was significantly higher among smokers than non-smokers (χ2 = 5.57, p = 0.018). Logistic regression using
TD as the dependent variable revealed smokers to be at a significantly higher risk for TD (p < 0.005).
Genotyping of smokers of Chinese descent for CYP1A2 polymorphism revealed no significant differences
in the genotypic or allelic distribution between those with and without TD. Conclusions: Consistent with
other studies, the prevalence of TD was significantly higher among smokers than non-smokers; however,
we did not find an association between the C→A genetic polymorphism of CYP1A2 and TD.
Objectif : Déterminer s’il y a un lien entre la fumée de cigarette et la dyskinésie tardive (DT) chez les
patients atteints de schizophrénie et évaluer le rôle du polymorphisme de l’enzyme CYP1A2 chez les
patients d’ascendance chinoise atteints de DT. Méthode : L’étude a porté sur 291 patients chez lesquels
on avait diagnostiqué une schizophrénie selon les critères du DSM-IV. On a évalué la dyskinésie au moyen
de l’échelle de mesure des mouvements involontaires anormaux de la DT selon les critères de Schooler et
Kane. On a recueilli des données démographiques et cliniques, ainsi que des renseignements sur les habi-
tudes de tabagisme, et soumis par la suite à un génotypage pour l’enzyme CYP1A2 les patients d’ascen-
dance chinoise ayant des antécédents bien établis de tabagisme. Résultats : On a diagnostiqué une DT chez
43 (41,3 %) des 104 patients ayant des antécédents de tabagisme et 52 (27,8 %) des 187 non-fumeurs. La
prévalence de la DT était beaucoup plus élevée chez les fumeurs que chez les non-fumeurs (χ2 = 5,57, p =
0,018). Une analyse de régression logistique au cours de laquelle on a utilisé la DT comme variable dépen-
dante a révélé que les fumeurs étaient exposés à un risque beaucoup plus élevé de DT (p < 0,005). Le
génotypage des fumeurs d’ascendance chinoise pour le polymorphisme de l’enzyme CYP1A2 n’a révélé
Correspondence to: Dr. Siow-Ann Chong, Woodbridge Hospital and Institute of Mental Health, 10 Buangkok View, Singapore 539747;
fax 65 3892963; [email protected]
Medical subject headings: China; cytochrome P-450 CYP1A2; dyskinesias; genetic predisposition to disease; movement disorders; schizophrenia; smoking.
J Psychiatry Neurosci 2003;28(3):185-9.
Submitted Mar. 1, 2002Revised Oct. 2, 2002; Dec. 11, 2002Accepted Dec. 17, 2002 J Psychiatry Neurosci 2003;28(3)
aucune différence significative dans la distribution des génotypes ou des allèles entre ceux qui avaient une
DT et ceux qui n’en avaient pas. Conclusions : Comme dans d’autres études, la prévalence de la DT était
beaucoup plus élevée chez les fumeurs que chez les non-fumeurs, mais nous n’avons toutefois pas trouvé
de lien entre le polymorphisme génétique C→A de l’enzyme CYP1A2 et la DT.
Introduction
tion of cigarette smoking with TD in patients withschizophrenia and to examine the role of the CYP1A2 The prevalence of smoking in patients with schizo- polymorphism in TD in patients of Chinese descent.
phrenia has been found to be higher than that of thegeneral population.1–3 It has been suggested that smok- ing may lead to a number of consequences, includingmore severe psychotic symptoms,4 higher dose of anti- Patients were recruited from Woodbridge Hospital, psychotic medication being prescribed5–7 and increased which is the only state psychiatric hospital in Singa- pore and the principal treatment centre for those with The pathophysiology of TD — often viewed as a severe mental illnesses such as schizophrenia. Most severe and stigmatizing movement disorder — patients with schizophrenia are likely to have received remains to be fully elucidated. Postulated risk factors their entire treatment at this hospital, which maintains include age, duration of antipsychotic medication, records from first contact. It is therefore possible to ob- female sex and organic brain damage.11 Genetic factors tain a reasonably detailed lifetime history of patients’ have also been implicated in TD, as suggested by the drug treatment, including the daily dose and the interindividual variation in vulnerability.12 A particular line of investigation has focused on a genetic contribu- Patients in the long-stay wards of Woodbridge Hos- tion to the pharmacodynamic and pharmacokinetic pital who were willing to give informed consent were aspects of antipsychotic medications. These include recruited into the study. We excluded those with neu- genetic association studies of the dopamine (D and D ) rological or medical conditions and patients taking receptors13,14 and cytochrome P450 2D6 (CYP2D6).15–17 medication that could cause dyskinesia (i.e., criterion E Recently, Basile et al18 found an association between a of DSM-IV research criteria for neuroleptic-induced C→A genetic polymorphism of the CYP1A2 gene and TD). Ethnicity of the patients was established by asking TD, with the C/C genotype being associated with patients to state their own ethnicity and their country more severe TD than the A/C or A/A genotypes, and of birth, as well as that of their parents. We converted this effect was more pronounced in patients who dosages of neuroleptic drugs to chlorpromazine equiv- smoked. The authors suggest that CYP1A2, which is alents (CPZ eq) using standard guidelines.20,21 The only present at higher concentrations in the liver than anticholinergic agent used was trihexyphenidyl. All CYP2D6, would assume greater importance in the patients were receiving typical neuroleptics, and none metabolism of antipsychotics after the saturation of had received any atypical agent in the past. The hos- CYP2D6 with long-term antipsychotic treatment. Phar- pital ethics committee approved the study. macokinetic studies that indicate variability in CYP1A2activity occurs only in smokers19 suggest that this poly- morphism would assume functional importance onlyin smokers. This being the case, it would provide a DSM-IV diagnoses were made by a psychiatrist who possible explanation for the association between smok- reviewed medical record data and, where necessary, ing and TD. Basile et al18 proposed another mechanism interviewed the patient. Dyskinesia was assessed by wherein neurotoxic antipsychotic metabolites pro- the Abnormal Involuntary Movement Scale (AIMS),22 duced by alternative metabolic pathways, due to the and extrapyramidal side effects were assessed by the lowered CYP1A2 activity in patients with the C/C Simpson–Angus Rating Scale (SARS).23 Such ratings were undertaken by 3 psychiatrists who were blind to The aims of this study were to establish the associa- the clinical and medical histories of the patients and Rev Psychiatr Neurosci 2003;28(3)
who had jointly assessed a number of patients over 3 manufacturer’s instructions (New England Biolabs, sessions before the start of the study. We established Beverly, Mass.). Resulting products were detected by inter-rater reliability (intraclass correlation) coefficients ethidium bromide staining after electrophoresis on a of 0.86 for the AIMS and 0.82 for the SARS. All patients received 2 ratings, with an interval of at least 3 monthsbetween the ratings. Medications were not changed during the periods of assessment. The criteria used inthe diagnosis of TD were those of Schooler and Kane.24 The Mann–Whitney U test was used to examine the Patients were diagnosed to have TD only when 2 assess- differences between patients with and without TD (as ments fulfilled the criteria of presence of “moderate” the variables were not normally distributed). Differ- abnormal movements in 1 or more body areas or at ences in demographic characteristics, neuroleptic dose, least “mild” movements in 2 or more body areas. Pos- AIMS score and SARS for the various genotypes were itive extrapyramidal side effect status was defined by a determined using the Kruskal–Wallis test. Probability values of 0.05 or less were regarded as statistically The smoking habits of the patients were established significant. Tests for differences of allele frequencies, by interviews and by obtaining corroborative history genotypes and other categorical analysis were per- from the nursing staff; cases where conflicting histories formed using the chi-square test. To control for the were obtained were not included in the study.
influence of other variables, logistic regression was In the second part of the study, which involved applied to the factors associated with TD.
genotyping for the CYP1A2 gene polymorphism, onlypatients of Chinese descent who were smokers were invited to participate. Patients again gave written con-sent for this part of the study.
The main demographic and clinical variables of the291 patients (220 men and 71 women) who were diag- nosed with schizophrenia and agreed to take part inthe study are listed in Table 1. Patient age ranged Venous blood was collected in tubes containing ethyl- from 23 to 83 (mean 52.7, standard deviation [SD] enediaminetetraacetic acid (EDTA) tubes, and genomic 10.3) years. Of these, 288 (99.0%) were of Chinese or- DNA was extracted with QIAamp Blood Kit (Qiagen igin, and 3 (1.0%) were Malays. There was no sex dif- GmbH, Hilden, Germany). The region of interest was ference (χ2 = 0.85, p = 0.35) between those with TD first amplified by polymerase chain reaction (PCR), as and those without TD. Those with TD were signifi- previously described.18 PCR products were incubated cantly older (p < 0.005, Mann–Whitney U test) and with the restriction enzyme Bsp120I according to the receiving a lower daily dose of antipsychotics than Table 1: Clinical and demographic characteristics of 291 patients with schizophrenia
Note: SD = standard deviation; TD = tardive dyskinesia; CPZ mg eqv = chlorpromazine milligram equivalent.
*p < 0.005, Mann–Whitney U test (for all patients with TD v. without; smokers with TD v. without; non-smokers with TD v. without) J Psychiatry Neurosci 2003;28(3)
those without TD (p < 0.005, Mann–Whitney U test). The Although there are also negative reports in the lit- prevalence of TD was significantly higher in smokers erature,7,25,26 the smokers in many of those studies were
than non-smokers (41.3% v. 27.8%, χ2 = 5.5, p = 0.018).
taking significantly higher doses of antipsychotic Among the 104 (35.7%) patients who smoked, there medication, and this could have masked the presence were also significant differences in age and daily antipsychotic dose between those with TD and those Suggested mechanisms for the association of smok- ing and TD include increased dopaminergic activity The distribution of the alleles and genotypes for the from nicotine,27 leading to nigrostriatal hypersensitivity patients who were smokers is presented in Table 2.
to dopamine, and neurotoxicity from the free radicals Testing for Hardy–Weinberg equilibrium showed that in cigarette smoke, causing damage to catecholamin- the genotype frequencies did not deviate significantly ergic neurons in the basal ganglia.28 Smoking also from the frequencies expected under random mating increases the risk of cerebrovascular pathology, which conditions for those with TD (χ2 = 0.19, p = 0.67) and may lead to increased risk of developing TD. those without TD (χ2 = 0.33, p = 0.56). Genotype fre- Consistent with the findings of Schulze et al29 and quencies did not differ significantly (χ2 = 0.90, p = 0.63), Shimoda et al,30 we did not find any difference in the and allele frequencies did not differ significantly (χ2 = genotypic or allelic distribution between patients with 0.38, p = 0.56). The median AIMS score was not sig- and without TD, and there was no significant differ- nificantly different between the 3 genotypes (χ2 = 1.8, ence observed in the mean AIMS scores of the different p = 0.40), and the genotypes did not differ significantly genotypes. However, there were differences in anti- in other demographic or clinical characteristics.
psychotic dose and duration of exposure in patients On performing a logistic regression, with TD as the with and without TD, which could have confounded dependent variable and age, neuroleptic dose, cumula- our results. Smoking-induced CYP1A2 activity may tive exposure to neuroleptics, smoking status and result in lower antipsychotic plasma levels, which may genotype as the independent variables, age (p < 0.05) in turn lead to inadequate control of psychotic symp- and smoking status (p < 0.005) remained indepen- toms and higher dosages of antipsychotics being pre- dently associated with a higher risk of TD, whereas scribed; thus, these patients may eventually be exposed lower daily neuroleptic dose was associated with a to higher plasma antipsychotic levels. In our study, the significantly lower risk of TD (p < 0.005). The odds lower daily antipsychotic dose of those with TD may ratio of developing TD for smokers relative to non- have been due to a deliberate dose reduction after the smokers was 2.7 (95% confidence interval, 1.5–5.0).
diagnosis of TD was made. Conversely, the sig-nificantly higher mean antipsychotic dose taken by Discussion
patients who did not have TD could have maskeddyskinetic movements, although this is unlikely given Consistent with other studies,8,9 we found a significantly that there were no significant differences in the mean higher prevalence of TD in smokers than non-smokers.
A limitation of this study is the lack of a structured Table 2: Genotypic and allelic distribution with relation to
interview to establish our diagnosis of schizophrenia.
tardive dyskinesia (TD) status and AIMS score in 103 patients
Another limitation is that we did not quantify the of Chinese descent who smoked
amount of smoking, which may have confounded our results, because a positive correlation between CYP1A2 activity and amount smoked has been reported.31 Our patients also received a variety of typical antipsy- chotics, with some being prescribed more than 1 type.32 The diversity of antipsychotics is an important consid- eration given that the role of CYP1A2 in the disposition of antipsychotics is limited to a few (i.e., clozapine, Note: AIMS = Abnormal Involuntary Movement Scale; SD = standard deviation.
*Chi-square test.
†Kruskall–Wallis test.
Although we did not find an association between the C→A genetic polymorphism of CYP1A2 and TD, we Rev Psychiatr Neurosci 2003;28(3)
did not investigate the role of the G→A polymor- 18. Basile VS, Ozdemir V, Masellis M, Walker ML, Meltzer HY, phism, which has been associated with decreased Lieberman JA, et al. A functional polymorphism of the cyto-chrome P450 1A2 (CYP1A2) gene: association with tardive activity of CYP1A2 in Japanese subjects.34 Such studies dyskinesia in schizophrenia. Mol Psychiatry 2000;5:410-7.
should, however, be limited to patients who are taking 19. Sachse C, Brockmoller J, Bauer S, Roots I. Functional signifi- antipsychotics that are substrates for CYP1A2.
cance of a C→A polymorphism in intron l of the cytochromeP450 CYP 1A2 gene tested with caffeine. Br J Clin Pharmacol1999;47:445-9.
Competing interests: None declared.
20. American Psychiatric Association. Practice guidelines for the treatment of patients with schizophrenia. Washington: American References
21. Kane JM, Aguglia E, Altamura C, Ayuso Gutierrez JL, Brunello 1. Gopalaswamy AK, Morgan R. Smoking in chronic schizophre- N, Fleischhacker WW, et al. Guidelines for depot antipsychotic nia [letter]. Br J Psychiatry 1986:149:523.
treatment in schizophrenia. Eur Neuropsychopharmacol De Leon J. Smoking and vulnerability for schizophrenia. Schizo- 22. Guy W, editor. ECDEU assessment manual for psychopharmacol- 3. De Leon J, Dadvand M, Canuso C, White AO, Stanilla JK, ogy. Washington: US Department of Health, Education and Simpson GM. Schizophrenia and smoking: an epidemiological survey in a state hospital. Am J Psychiatry 1995;152:453-5.
23. Simpson GM, Angus JWS. Drug-induced extrapyramidal dis- 4. Chong SA, Choo HL. Smoking among Chinese patients with order — a rating scale for extrapyramidal side effects. Acta schizophrenia. Australian N Z J Psychiatry 1996;30:350-3.
Psychiatr Scand Suppl 1970;212:20-7.
5. Masterson E, O’Shea B. Smoking and malignancy in schizo- Schooler N, Kane JM. Research diagnosis for tardive dyskinesia.
phrenia. Br J Psychiatry 1984;145:429-32.
Arch Gen Psychiatry 1982;39:486-7.
6. Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA. Preva- 25. Menza MA, Grossman N, Van Horn M, Cody R, Forman N.
lence of smoking among psychiatric outpatients. Am J Psychia- Smoking and movement disorders in psychiatric patients. Biol 7. Goff DC, Henderson DC, Amico E. Cigarette smoking in 26. Ziedonis DM, Kosten TR, Glazer WM, Frances RJ. Nicotine schizophrenia: relationship to psychopathology and medica- dependence and schizophrenia. Hosp Community Psychiatry tion side effects. Am J Psychiatry 1992;149:1189-94.
8. Binder RL, Kazamatsuri H, Nishimura T, McNiel DE. Smoking 27. Andersson K, Fuxe K, Agnati LF. Effects of single injections of and tardive dyskinesia. Biol Psychiatry 1987;22:1280-2.
nicotine on the ascending dopamine pathways in the rat.
9. Yassa R, Lal S, Korpassy A, Ally J. Nicotine exposure and tar- Evidence for increases of dopamine turnover in the mesostri- dive dyskinesia. Biol Psychiatry 1987;22:67-72.
atal and mesolimbic dopamine neurons. Acta Physiol Scand 10. Nilsson A, Waller L, Rosengren A, Adlerberth A, Wilhelmsen L. Cigarette smoking is associated with abnormal involuntary 28. Cadet JL, Lohr JB, Jeste DV. Free radicals and tardive dyskin- movements in the general male population — a study of men esia. Trends Neurosci 1986;9:107-8.
born in 1933. Biol Psychiatry 1997;41:717-23.
29. Schulze TG, Schumacher J, Muller DJ, Krauss H, Alfter D, 11. Bergen J, Kitchin R, Berry G. Predictors of the course of tar- Maroldt A, et al. Lack of association between a functional dive dyskinesia in patients receiving neuroleptics. Biol Psychia- polymorphism of the cytochrome P450 1A2 (CYP1A2) gene and tardive dyskinesia in schizophrenia. Am J Med Genet 12. Rosengarten H, Schweitzer JW, Friedhoff AJ. Possible genetic factors underlying the pathophysiology of tardive dyskinesia. 30. Shimoda K, Someya T, Morita S, Hirokane G, Yokono A, Taka- Pharmacol Biochem Behav 1994;49:663-7.
hashi S, et al. Lack of impact of CYP1A2 genetic polymor- 13. Chen CH, Wei CF, Koong FJ, Hsiao KJ. Association of TaqI A phism (C/A polymorphism at position 734 in intron 1 and polymorphism of dopamine D receptor gene and tardive G/A polymorphism at position –2964 in the 5’-flanking region dyskinesia in schizophrenia. Biol Psychiatry 1997;41:827-9.
of CYP1A2) on the plasma concentration of haloperidol in 14. Segman R, Neeman T, Hersco-Levy U, Finkel B, Karagichev L, smoking male Japanese with schizophrenia. Prog Neuropsy- Schlafman M, et al. Genotypic association between the do- chopharmacol Biol Psychiatry 2002;26:261-5.
pamine D receptor and tardive dyskinesia in chronic schizo- 31. Kalow W, Tang BK. Caffeine as a metabolic probe: exploration phrenia. Mol Psychiatry 1999;4:247-53.
of the enzyme-inducing effect of cigarette smoking. Clin Phar- 15. Kapitany T, Meszaros K, Lenzinger E, Schindler SD, Barnas C, Fuchs K, et al. Genetic polymorphisms for drug metabolism 32. Chong SA, Sachdev P, Mahendran R, Chua HC. Neuroleptic (CYP2D6) and tardive dyskinesia in schizophrenia. Schizophr and anticholinergic drug use in Chinese patients with schizo- phrenia resident in state psychiatric hospital in Singapore.
16. Arthur H, Dahl ML, Siwers B, Sjoqvist F. Polymorphic drug Australia N Z J Psychiatry 2000;34:988-91.
metabolism in schizophrenic patients with tardive dyskinesia.
33. Cozza KL, Armstrong SC. The cytochrome P450 system. Wash- J Clin Psychopharmacol 1995;15:211-6.
ington: American Psychiatric Publishing Inc.; 2001.
17. Ohmori O, Suzuki T, Kojima H, Shinkai T, Tera T, Mita T, et 34. Nakajima M, Yokoi T, Mizutani M, Kinoshita M, Funayama al. Tardive dyskinesia and debrisoquine 4-hydroxylase M, Kamataki T. Genetic polymorphism in the 5’-flanking (CYP2D6) genotypes in Japanese schizophrenics. Schizophr Res region of human CYP1A2 gene: effect on the CYP1A2 in- ducibility in humans. J Biochem 1999;125:803-8.
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