Lack of association between a functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene and tardive dyskinesia in schizophrenia.

Tardive dyskinesia (TD) is a common side effect of long-term medication with typical neuroleptics. TD presents itself by abnormal involuntary movements and may lead to a potentially disabling and chronic clinical course. A vast majority of patients suffering from schizophrenia are smokers. Smoking has been reported to induce the activity of the CYP1A2 enzyme, which is an established metabolic pathway within the disposition of antipsychotics. Recently, a C-->A genetic polymorphism in the first intron of the CYP1A2 gene was reported to influence CYP1A2 activity in smokers. Subsequently, a pharmacogenetic study in 85 U.S. patients with schizophrenia (44 smokers, 41 individuals with unknown smoking status) showed the C/C genotype to be associated with higher TD severity (measured by the Abnormal Involuntary Movement Scale, AIMS) than the A/C or A/A genotype. This finding prompted us to investigate whether this effect was also present in a larger German sample of 119 patients with schizophrenia (82 smokers, 37 individuals with unknown smoking status). However, we could not replicate the reported association. The median AIMS scores did not differ between individuals with the A/A, A/C, or C/C genotypes. In an additional analysis, we compared the genotypic and allelic distribution among individuals grouped according to the criteria established by Schooler and Kane [1982: Arch Gen Psychiatry 39:486-487] (persistent TD vs. absent TD). We did not observe a differential genotypic or allelic distribution between the two diagnostic groups. Thus, our results do not support the hypothesis that the C-->A polymorphism in the CYP1A2 gene is involved in the etiology of TD in the German population.

Affective symptomatology in schizophrenia: a risk factor for tardive dyskinesia?

Affective symptomatology has repeatedly been suggested to confer susceptibility to tardive dyskinesia (TD). In our sample of 174 schizophrenic patients a history of depressive symptoms was not associated with the occurrence of TD, whereas manic symptomatology was significantly associated with the absence of TD. Thus, our data suggest that affective symptomatology cannot unambiguously be considered to predispose to TD.

Dopamine D3 receptor variant and tardive dyskinesia.

In the search for genetic factors contributing to tardive dyskinesia, dopamine receptor genes are considered major candidates. The dopamine D3 receptor is of primary interest as dopamine D3 receptor knock-out mice show locomotor hyperactivation resembling extrapyramidal side-effects of neuroleptic treatment. Furthermore, Steen and colleagues (1997) recently reported an association between tardive dyskinesia and a dopamine D3 receptor gene variant. In the present study we tried to replicate this finding. We investigated 157 patients with schizophrenia or schizoaffective disorder receiving long-term neuroleptic medication who never or persistently displayed tardive dyskinesia. As advanced age is a main risk factor for tardive dyskinesia, we also compared older patients with a long duration of schizophrenia not displaying tardive dyskinesia to younger patients with a shorter duration of the illness displaying tardive dyskinesia. However, we found no evidence that the dopamine D3 receptor gene is likely to confer susceptibility to the development of tardive dyskinesia.