Gene polymorphism of dopaminergic, serotoninergic and glutamatergic receptors and tardive dyskinesia in schizophrenia

Introduction: For over six decades, antipsychotic drugs have remained the mainstay of schizophrenia treatment. Tardive dyskinesia (TD) is a potentially irreversible antipsychotic-induced. movement disorder with a prevalence of about 20-30% in psychiatric patients chronically exposed to antipsychotics. TD can be dissected into two distinct subsyndromes: orofaciolingual (TDof, involves movements of mouth and face) and limb-truncal dyskinesias (TDlt, involves purposeless choreiform movements of trunk and/or limbs) which probably have different genetic liability [1]. TD in schizophrenic patients is associated with poor outcome and TD patients may suffer from more physical or psychological problems. The genetic basis of pathogenesis of TD is thought to be primarily related to dopamine dysregulation. Genes of other neurotransmitter systems are less investigated [2,3]. Aim: Study the association between antipsychotic-induced TD and a set of 43 tag single nucleotide polymorphisms (SNPs) from dopaminergic, serotoninergic and glutamatergic receptors genes GRIN2A, GRIN2B, DRD3, DRD4, and HTR2C in schizophrenic patients in Russian population. Methods: 431 Russian patients with schizophrenia were investigated. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale (AIMS). TD of and TDlt were assessed with AIMS items 1-4 and 5-7, respectively. The DNA extraction and genotyping of 43 polymorphisms of GRIN2A, GRIN2B, DRD3, DRD4, and HTR2C genes were conducted using Veracode Assay according to standard protocols. All calculations were performed in the R statistical environment with the SNPassoc package and basic R functions. Results and Discussion: Significant associations were found between five SNPs encoding three receptors: GRIN2B (rs220599, P = 0.04451), GRIN2A (rs11646587, P = 0.04652; rs7206256, P = 0.03570); rs1345423, P = 0.01043)), DRD3 (rs167770, P = 0.01751) and TDof. Also significant associations were found between six SNPs of two receptors GRIN2A (rs1345423, P = 0.02504; rs7190619, P = 0.04292; rs9788936, P = 0.04020; rs11644461, P = 0.03875), DRD3 (rs963468, P = 0.01533; rs167770, P = 0.012236) and TDlt. Moreover, significant associations were found in four specific SNPs encoding three receptors GRIN2B (rs2192970, P = 0.005411), GRIN2A (rs1345423, P = 0.015210) and DRD3 (rs324035, P = 0.03211; rs167770, P = 0.02197). Only rs1345423 in GRIN2A was significantly associated with overall TD in studied group of schizophrenic patients. No associations between polymorphism of receptors genes DRD4 and HTR2C were revealed. It is thought that TD is primarily related to DA dysregulation. Antipsychotic treatment with both serotoninergic HTR2A and HTR2C antagonists resulted in a lower annual incidence of TD [4]. This finding led to the hypothesis that HTR2A and HTR2C activate GABAergic interneurons [5], within the cerebral cortex, basal ganglia and mesencephalic areas, resulting in decreased dopaminergic activity. Hence, HTR2A and HTR2C antagonism increases dopamine release. Our results do not differ much from those found in relevant meta-analyses, which led us to propose that genetically determined variations of dopamine type 2 receptors and/or dopamine type 2 receptor signaling are unlikely to affect the sensitivity to TD. Conclusion: We suggest that mechanism other than HTR2- induced augmentation of dopamine release is responsible for explaining the lower incidence of TD after treatment with atypical antipsychotics

Association of polymorphism in the dopamine receptors and transporter genes with hyperprolactinemia in patients with schizophrenia

Background: Long-term antipsychotic drug use remains the mainstay of treatment for patients with schizophrenia. However, pharmacotherapy with these drugs is complicated by several troublesome side effects, including hyperprolactinemia (HP). Prolactin secretion is persistently inhibited by dopamine, and antipsychotic drugs are believed to increase prolactin release by blocking dopamine receptors in the pituitary gland. Genetic factors play an important role in the development of antipsychotic induced HP [1, 2]. Genes coding for dopamine receptors and transporters are considered to be responsible for HP in schizophrenia [3]. The present study aimed to investigate the role of polymorph-isms of the dopamine receptors and transporters genes (DRD1, DRD2, SLC6A3) in the pathogenesis of antipsychotic-related HP in patients with schizophrenia. Methods: 431 Russian patients with schizophrenia were examined. The average age of patients was 42.1 ± 1.4 years. Evaluation of serum prolactin level was performed by ELISA using reagents set PRL Test System (USA). Genotyping was carried out on 17 polymorphic variants of the dopamine receptors and transporters genes DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs2550956, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The SPSS sof tware was used for statistical analysis. The Hardy-Weinberg equilibrium (HWE) of genotypic frequencies was tested by the chi-square test. Results: We studied the association between HP and a set of SNPs from DRD1, DRD2 receptor genes and neurotransmitter transporter SLC6A3 in patients from Siberia with a clinical diagnosis of schizophrenia who were treated with classical and/or atypical antipsychotic drugs. All patients with schizophrenia were divided into two groups: those with and without HP. Physiological normal results for the serum prolactin levels are less than 20 ng/ml in men, and less than 25 ng/ml in women. Statistically significant result was obtained for polymorphic variant rs2550956 of the gene SLC6A3 (χ2 = 9.992; p = 0.007), which suggests its involvement in the development of HP. The heterozygous genotype TC of rs2550956 was significantly less common in patients with elevated levels of prolactin and it presumably has protective properties (OR 0.54; 95% CI: 0.36-0.81). We did not find any statistically significant associations for other polymorphisms DRD1 (rs4532, rs936461), DRD2 (rs4245147, rs6279, rs2734842) and SLC6A3 (rs3756450, rs6347, rs2617605, rs3863145, rs250686, rs464049, rs4975646, rs1048953, rs11133767, rs27048, rs40184). The group of dopamine receptors is heterogeneous and only some of them participate in the formation of psychotic symptoms and, accord ingly, in the antipsychotic action of neuroleptics. The effect of neuroleptics on other groups of dopamine receptors leads to the development of different side effects including extrapyramidal disorders [4], and their role is extremely low in the formation of the actual therapeutic response. Conclusion: Our results indicate that genetic variants of SLC6A3 may have functional consequences on the modulation of prolactin secretion. Neurotransmitter systems are involved in the mechanisms of action of antipsychotic drugs; therefore, a further search for genetic markers associated with the development of antipsychotic-related hyperprolactinemia in schizophrenic patients is needed