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
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-
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