Association of the MscI Polymorphism of the Dopamine D3 Receptor Gene with Tardive Dyskinesia in Schizophrenia

Abstract

In 112 schizophrenic patients previously treated with typical neuroleptics, we investigated the putative role of the dopamine D3 receptor gene (DRD3) in tardive dyskinesia (TD). Patients were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS) and were subsequently genotyped for the MscI polymorphism that identifies a serine to glycine substitution in DRD3. A modified analysis of covariance model, which incorporated several clinical risk factors for TD, was utilized to detect differences in TD severity among the various genotypic groups. The glycine allele of DRD3 was found to be associated with typical neuroleptic-induced TD (F[2,95] ϭ 8.25, p Ͻ .0005). Higher mean AIMS scores were found in patients homozygous for the glycine variant of the DRD3 gene, as compared to both heterozygous and serine homozygous patients. Although replication is necessary, this finding supports a role for the dopamine D3 receptor inSchizophrenia is a common and devastating neuropsychiatric syndrome afflicting approximately 1% of the human population (APA 1994). Although there are no cures, neuroleptic medications are frequently used to alleviate the psychosis. One of the major drawbacks to chronic treatment with typical neuroleptic drugs is the possible development of severe extrapyramidal side effects, such as pseudoparkinsonism, acute dystonia, akathisia, and tardive dyskinesia (TD). TD is a motor disorder characterized by abnormal involuntary movements of the orofacial musculature (Caligiuri et al. 1988), particularly in the jaw, lips, and tongue. Choreoathetoid movements of the extremities and/or trunk involvement may occur as well (Weinhold et al. 1981). TD occurs in predisposed individuals during or following cessation of prolonged typical neuroleptic treatment (Gerlach and Casey 1984). Schooler and Kane (1982) outline various subtypes of TD, including probable TD, masked TD, transient TD, withdrawal TD, persistent TD, and masked persistent TD. Atypical antipsychotics have a lower occurrence of extrapyramidal side effects and rarely cause TD. Recent studies have shown that clozapine may ameliorate TD symptoms Received July 6, 1998; revised October 27, 1998; accepted November 10, 1998. 18 V.S. Basile et al. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 1 (Buchanan 1995;Kane et al. 1993;Lieberman et al. 1991;Ranjan and Meltzer 1996;Wilson 1992). However, clozapine's use is limited by its lack of efficacy in some patients and its propensity to induce agranulocytosis. Although the mechanism of TD remains unknown, it has been postulated that an overactivity of dopaminergic neurotransmission in the basal ganglia may play a crucial role in the manifestation of TD (Tarsy and Baldessarini 1977).The dopamine overactivity hypothesis for TD is supported by the clinical pharmacology of TD, because dopamine agonists increase TD severity, whereas, dopamine antagonists reduce the symptoms (Wolfe and Mosnaim 1988). The hypothesis speculates that TD results from chronic neuroleptic blockade of dopamine D2-like re...

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

“…The severity of TD has also been observed to increase with age in conformity with other reports. 4,11,22 However, severity of TD was higher among males compared to females in our study, which is in contrast to other reports. 23,24 This may be due to sampling variation or may reflect a variation unique to Indian population.…”

Age and the relationship of dopamine D3, serotonin 2C and serotonin 2A receptor genes to abnormal involuntary movements in chronic schizophrenia

“…This was not true of DRD3 which, intriguingly, was found to be associated with TD by our group 4 and by Basile et al 5 and is a widely although not universally replicated genetic association with TD. [9][10][11] On the other hand, there was a significant age effect of HTR2A for which there was a disparity between our findings 2 and those of Basile et al 3 As noted, the sample examined by Basile et al 3 was two decades younger, on average, than our sample.…”

“…This disparity contrasts with similar findings of the two groups in the same patient samples in regard to association of the dopamine D3 receptor gene (DRD3) with TD. 4,5 Among the demographic and clinical factors that have been associated with individual susceptibility to TD, age is the most consistently reported. In a prospective study, Jeste et al 6 found the cumulative incidence of TD in patients who initiated treatment with antipsychotic drugs after the age of 45, to be 60% after 3 years.…”

Clinical implications of pharmacogenomics for tardive dyskinesia

“…In order to shed light on these controversial results, recently, Lerer et al 6 performed a combined analysis including data from 780 patients from six research centers, dividing patients into eight groups based on their population origin. Most of the data have been published previously either in peer reviewed journals [43][44][45][46][47] or in abstract form 48,49 (see Table 2 for more details). The authors applied stepwise logistic regression, and confounding effects of group, age and gender were taken into account.…”

“…The two genetic variants DRD3 Ser9Gly (Steen et al 43 ) and CYP1A2 C734A (presented in our additive, co-recessive model of interaction as mentioned above) were published (Basile et al 33,44 ) without Genetics of tardive dyskinesia DJ Müller et al protecting the potential intellectual property. In our academic culture, it is commonplace to publicize our findings rapidly to promote replication and wide use of the information.…”