Gene polymorphism of dopaminergic, serotoninergic and glutamatergic receptors and tardive dyskinesia in schizophreniaFedorenko, O. Y., Ivanova, S. A. & Loonen, A. J. M. Oct-2016 In : European Neuropsychopharmacology. 26, p. S495-S496 2 p.
Research output: Other research output › Meeting Abstract
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 . 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 . This finding led to the hypothesis that HTR2A and HTR2C activate GABAergic interneurons , 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.
|Number of pages||2|
|State||Published - Oct-2016|
|Event||29th Congress of the European-College-of-Neuropsychopharmacology (ECNP) - Vienna, Austria|
29th Congress of the European-College-of-Neuropsychopharmacology (ECNP)
17/09/2016 → 20/09/2016Vienna, Austria
- atypical antipsychotic agent, dopamine, dopamine 2 receptor, dopamine 3 receptor, dopamine 4 receptor, endogenous compound, n methyl dextro aspartic acid receptor 2A, n methyl dextro aspartic acid receptor 2B, neurotransmitter, serotonin 2A receptor, serotonin 2C receptor, Abnormal Involuntary Movement Scale, adverse drug reaction, basal ganglion, brain cortex, calculation, DNA extraction, dopamine release, dopaminergic activity, gene frequency, gene mutation, genetic susceptibility, genotype, human, interneuron, mesencephalon, meta analysis, physical disability, psychosis, Russian (citizen), side effect, single nucleotide polymorphism, tardive dyskinesia, thinking