Association between the serotonin 2C receptor gene and tardive dyskinesia in chronic schizophrenia: additive contribution of 5-HT2Cser and DRD3gly alleles to susceptibility.
BACKGROUND
Tardive dyskinesia (TD) is a longterm adverse effect of dopamine receptor blockers. The dopamine D3 receptor gene (DRD3) ser9gly polymorphism has been previously associated with susceptibility to TD. Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extra-pyramidal effects profile of atypical antipsychotic drugs.


OBJECTIVE
To examine the association of a functional polymorphism in the 5-HT2C receptor gene (HT2CR) with TD and the joint contribution of HT2CR and DRD3 to susceptibility.


METHODS
Case control association analysis of allele and genotype frequencies among schizophrenia patients with (n=55) and without TD (n=60), matched for antipsychotic drug exposure and other relevant variables, and normal control subjects (n=97). Parametric analyses of the contribution of 5-HT2Cser and DRD3gly alleles to dyskinesia scores.


RESULTS
We found a significant excess of 5-HT2Cser alleles in schizophrenia patients with TD (27.2%) compared to patients without TD (14.6%) and normal controls (14.2%; chi2=6.4, df 2, P=0.03) which was due to the female patients (chi2=8.6, df 2, P=0.01). Among the female TD patients there was an excess of cys-ser and ser-ser genotypes (chi2= 11.9, df 4, P=0.02). Analysis of covariance (ANCOVA), controlling for age at first antipsychotic treatment, revealed a significant effect of 5-HT2C genotype on orofacial dyskinesia (OFD) scores (F=3.47, df 2, P=.03). In a stepwise multiple regression analysis, 5-HT2C and DRD3 genotype (5-HT2Cser and DRD3gly allele carriage) respectively contributed 4.2% and 4.7% to the variance in OFD scores.


CONCLUSIONS
These findings support a small but significant contribution of the HT2CR and DRD3 to susceptibility to TD, which is additive in nature.
Segman
R H
RH
Department of Psychiatry, Hadassah--Hebrew University Medical Center, Ein Karem, Jerusalem, Israel. sronen@md2.huji.ac.il
Heresco-Levy
U
U
Finkel
B
B
Inbar
R
R
Neeman
T
T
Schlafman
M
M
Dorevitch
A
A
Yakir
A
A
Lerner
A
A
Goltser
T
T
Shelevoy
A
A
Lerer
B
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D017109:Akathisia, Drug-Induced / Q000209:etiology / Q000235:genetics*; D000483:Alleles; D000704:Analysis of Variance; D002908:Chronic Disease; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin / Q000235:genetics*; D012559:Schizophrenia / Q000150:complications / Q000235:genetics*
C493593:DRD3 protein, human; D044405:Receptor, Serotonin, 5-HT2C; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011985:Receptors, Serotonin