Association of ANKK1 polymorphism with antipsychotic-induced hyperprolactinemia

Objective: Schizophrenia is a severe highly heritable mental disorder. Genetic polymorphisms of dopaminergic pathways are related to pathogenesis of drug response. Hyperprolactinemia (HPRL), a common adverse effect of antipsychotics, is attributed to blockade of dopamine D2 receptors. Ankyrin Repeat and Kinase Domain containing 1 (ANKK1) gene is closely related to Dopamine Receptor D2 type (DRD2) gene functioning. We examined whether the functional polymorphism rs2734849 in the ANKK1 gene is associated with antipsychotic-induced HPRL. Methods: We recruited 446 patients with schizophrenia from among the Russian population of the Siberian region. The polymorphism rs2734849 in the ANKK1 gene was genotyped with The MassARRAY® Analyzer 4 by Agena Bioscience™, using the kit SEQUENOM Consumables iPLEXGold 384. Genotype and allele frequencies were compared between groups of schizophrenia patients with and without HPRL using the χ2 test. Results: A comparison between schizophrenia patients with and without HPRL revealed significantly higher frequency of the C allele of the polymorphic variant rs2734849 in the ANKK1 gene in patients with HPRL as compared to the patients without it (χ2 = 3.70; p =.05; odds ratio [OR] = 1.30 [0.99–1.69]). Conclusion: The functional polymorphism rs2734849 in the ANKK1 gene was associated with HPRL in patients with schizophrenia

5-Hydroxytryptamine Receptors and Tardive Dyskinesia in Schizophrenia

Background Tardive dyskinesia (TD) is a common side effect of antipsychotic treatment. This movement disorder consists of orofacial and limb-truncal components. The present study is aimed at investigating the role of serotonin receptors (HTR) in modulating tardive dyskinesia by genotyping patients with schizophrenia. Methods A set of 29 SNPs of genes of serotonin receptors HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B, and HTR6 was studied in a population of 449 Caucasians (226 females and 223 males) with verified clinical diagnosis of schizophrenia (according to ICD-10: F20). Five SNPs were excluded because of low minor allele frequency or for not passing the Hardy-Weinberg equilibrium test. Affinity of antipsychotics to 5-HT2 receptors was defined according to previous publications. Genotyping was carried out with SEQUENOM Mass Array Analyzer 4. Results Statistically significant associations of rs1928040 of HTR2A gene in groups of patients with orofacial type of TD and total diagnosis of TD was found for alleles, and a statistical trend for genotypes. Moreover, statistically significant associations were discovered in the female group for rs1801412 of HTR2C for alleles and genotypes. Excluding patients who used HTR2A, respectively, HTR2C antagonists changed little to the associations of HTR2A polymorphisms, but caused a major change of the magnitude of the association of HTR2C variants. Due to the low patient numbers, these sub-analyses did not have significant results. Conclusion We found significant associations in rs1928040 of HTR2A and for rs1801412 of X-bound HTR2C in female patients. The associations were particularly related to the orofacial type of TD. Excluding patients using relevant antagonists particularly affected rs1801412, but not rs1928040-related associations. This suggest that rs1801412 is directly or indirectly linked to the functioning of HTR2C. Further study of variants of the HTR2C gene in a larger group of male patients who were not using HTR2C antagonists is necessary in order to verify a possible functional role of this receptor

COMT gene polymorphism and antipsychotic-induced hyperprolactinemia in schizophrenia patients

Hyperprolactinemia (HPRL) is considered to be a frequent and typical adverse drug reaction caused by antipsychotic medications first and foremost due to excessive dopamine D2 receptors blockade. The aim is to study the set of polymorphisms of genes encoding neurotransmitter synthesis and metabolism enzymes COMT, TPH1 and TPH2 in schizophrenia inpatients. A comprehensive examination of 446 schizophrenia inpatients, aged 18-75 years, was conducted. Genotyping of DNA samples in patients with or without HPRL was carried out for 14 polymorphisms of COMT, TPH1, and TPH2 genes. We revealed an association between carriership of the COMT rs165774* G allele and HPRL. As a result of the study, a regression model was designed to predict the risk of developing HPRL in schizophrenia inpatients, taking into account age, gender, and treatment duration, the dosage of drugs in chlorpromazine equivalents as independent covariates and genotypes of the studied polymorphisms

Polymorphisms in the adrenergic neurotransmission pathway impact antidepressant response in depressed patients

Mood disorders are a prevalent mental health disorder. The adrenergic neurotransmission pathway presents an opportunity to determine whether genetic mutations impact antidepressant response. For this study, 163 patients with major depressive disorders were enrolled to measure treatment response using the Hamilton Depression Rating Scale (HAMD-17). More than half of the patients had never been treated with antidepressants previously. Patients were genotyped for 14 SNPs within ADRA1A, SLC6A2, ADRβ1, MAOA and COMT to determine the impact of adrenergic neurotransmission polymorphisms related in antidepressant response. Patients were treated mainly with SSRIs and TCAs. The difference in HAMD-17 scores between the measurement periods were defined as the outcome measure. Multiple linear regression was conducted to determine the association between the genotypes and difference in HAMD-17 across the study period. Covariates of age, sex, antidepressant medication and depression diagnoses were included in the regression. Throughout the study HAMD-17 scores were measured at initiation, at two weeks and at four weeks for each patient. The difference in HAMD-17 scores was found to be 11.2 ​± ​4.4 between initiation and two weeks, 7.8 ​± ​5.3 between two week and four week, and 19.0 ​± ​5.3 throughout the entire study. SLC6A2 rs1532701 homozygous G/G Patients were associated with improved ΔHAMD-17 across week 2–4 and the entire study (B ​= ​7.1, p ​= ​0.002; B ​= ​6.7, p ​= ​0.013) compared to homozygous A/A patients. SLC6A2 rs1532701 homozygous A/G patients were further associated with improved ΔHAMD-17 compared to homozygous A/A patients at week 2–4 (B ​= ​2.8, p ​= ​0.023). Through our investigation, we were able to determine the genes within the adrenergic pathway to investigate further. To further elucidate these findings, replication and combination with other neurotransmitter pathways to better map the mechanism of actions of antidepressant for tailored treatment would be suggested

Preliminary pharmacogenetic study to explore putative dopaminergic mechanisms of antidepressant action

Background: There is sufficient evidence that interference of dopaminergic neurotransmission contributes to the therapeutic effects of antidepressants in unipolar and bipolar depression. Methods: Hamilton depression rating scale (HAMD 17) scores of 163 at least moderately ill patients with major depressive disorders were used to establish treatment response. HAMD 17 score status was measured before initiation, after two weeks, and after four weeks of treatment with various antidepressants. The possible association between response and genotype in a total of 14 variants of dopamine neurotransmission-related proteins was investigated. Results: DRD4 rs11246226 CA heterozygous patients were found with a greater improvement of HAMD 17 score when compared to homozygous C patients during 0–2 weeks and 0–4 weeks. Patients with MAOB rs1799836 heterozygous GA and homozygous A also demonstrated improved scores during 2–4 weeks and 0–4 weeks. Conclusions: The results are preliminary due to the limited population size and the small number of variants. Further research into the involvement of habenular dopamine D4 receptors in the antidepressant response is desirable

Limited Associations Between 5-HT Receptor Gene Polymorphisms and Treatment Response in Antidepressant Treatment-Free Patients With Depression

Major depressive disorder has become a prominent cause of disability, as lifetime prevalence has increased to similar to 15% in the Western world. Pharmacological effects of serotonin (5-hydroxytryptamine, 5-HT) are mediated through 5-hydroxytryptamine receptor (5-HTR) binding. Serotonin regulation of amygdala activity is attained through activation of three 5-HT2 family receptor subtypes, 5-HT2A, 5-HT2B, and 5-HT2C. Specifically, HT2A and the HT2C receptors have similar gross cerebral distribution and function, with higher constitutive activity found in HT2C than in HT2A. We investigated the possible association of 5-HTR gene polymorphisms to specific and non-specific antidepressant treatment responses in treatment-free patients in Siberia. 156 patients, aged between 18-70 years and clinically diagnosed with depressive disorders, were treated with antidepressants for 4 weeks. Patients were genotyped for a subset of 29 SNPs from the following 5-HT Receptor genes: HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B and HTR6. Primary outcome was measured by differences in Hamilton Depression Rating Scale (Delta HAM-D 17) scores between baseline/week two, week two/week four and baseline/week four. Univariate linear regression was initially conducted to determine the 5-HTR SNPs to be studied within the multiple linear regression. Multiple linear regression analyses over the three time periods were conducted for Delta HAM-D 17 with independent factors including: age, gender, depression diagnosis, antidepressant treatment and selected 5-HTR SNPs. We found improved increment HAM-D 17 in patients taking tricyclic antidepressants (0-4 weeks: B = 4.85, p = 0.0002; 0-2 weeks: B = 3.58, p = 0.002) compared to patients taking SSRIs. Over the course of study, significant associations between 5-HT receptors SNPs and antidepressant response were not identified

Association of Cholinergic Muscarinic M4 Receptor Gene Polymorphism with Schizophrenia

Background: Previous studies have linked muscarinic M4 receptors (CHRM4) to schizophrenia. Specifically, the rs2067482 polymorphism was found to be highly associated with this disease. Purpose: To test whether rs2067482 and rs72910092 are potential risk factors for schizophrenia and/or pharmacogenetic markers for antipsychotic-induced tardive dyskinesia. Patients and Methods: We genotyped DNA of 449 patients with schizophrenia and 134 healthy controls for rs2067482 and rs72910092 polymorphisms of the CHRM4 gene with the use of the MassARRAY® System by Agena Bioscience. Mann–Whitney test was used to compare qualitative traits and χ2 test was used for categorical traits. Results: The frequency of genotypes and alleles of rs72910092 did not differ between patients with schizophrenia and control subjects. We did not reveal any statistical differences for both rs2067482 and rs72910092 between schizophrenia patients with and without tardive dyskinesia. The frequency of the C allele of the polymorphic variant rs2067482 was significantly higher in healthy persons compared to patients with schizophrenia (OR=0.51, 95% CI [0.33–0.80]; p=0.003). Accordingly, the CC genotype was found significantly more often in healthy persons compared to patients with schizophrenia (OR=0.49, 95% CI [0.31–0.80]; p=0.010). Conclusion: Our study found the presence of the minor allele (T) of rs2067482 variant being associated with schizophrenia. We argue that the association of rs2067482 with schizophrenia may be via its regulatory effect on some other gene with protein kinase C and casein Kknase substrate in neurons 3 (PACSIN3) as a possible candidate. Neither rs2067482 nor rs72910092 is associated with tardive dyskinesia

Genes of the Glutamatergic System and Tardive Dyskinesia in Patients with Schizophrenia

Background: Tardive dyskinesia (TD) is an extrapyramidal side effect of the long-term use of antipsychotics. In the present study, the role of glutamatergic system genes in the pathogenesis of total TD, as well as two phenotypic forms, orofacial TD and limb-truncal TD, was studied. Methods: A set of 46 SNPs of the glutamatergic system genes (GRIN2A, GRIN2B, GRIK4, GRM3, GRM7, GRM8, SLC1A2, SLC1A3, SLC17A7) was studied in a population of 704 Caucasian patients with schizophrenia. Genotyping was performed using the MassARRAY Analyzer 4 (Agena Bioscience™). Logistic regression analysis was performed to test for the association of TD with the SNPs while adjusting for confounders. Results: No statistically significant associations between the SNPs and TD were found after adjusting for multiple testing. Since three SNPs of the SLC1A2 gene demonstrated nominally significant associations, we carried out a haplotype analysis for these SNPs. This analysis identified a risk haplotype for TD comprising CAT alleles of the SLC1A2 gene SNPs rs1042113, rs10768121, and rs12361171. Nominally significant associations were identified for SLC1A3 rs2229894 and orofacial TD, as well as for GRIN2A rs7192557 and limb-truncal TD. Conclusions: Genes encoding for mGlu3, EAAT2, and EAAT1 may be involved in the development of TD in schizophrenia patients

Genetic Polymorphisms of 5-HT Receptors and Antipsychotic-Induced Metabolic Dysfunction in Patients with Schizophrenia

Background: Antipsychotic-induced metabolic syndrome (MetS) is a multifactorial disease with a genetic predisposition. Serotonin and its receptors are involved in antipsychotic-drug-induced metabolic disorders. The present study investigated the association of nine polymorphisms in the four 5-hydroxytryptamine receptor (HTR) genes HTR1A, HTR2A, HTR3A, and HTR2C and the gene encoding for the serotonin transporter SLC6A4 with MetS in patients with schizophrenia. Methods: A set of nine single-nucleotide polymorphisms of genes of the serotonergic system was investigated in a population of 475 patients from several Siberian regions (Russia) with a clinical diagnosis of schizophrenia. Genotyping was performed and the results were analyzed using chi-square tests. Results: Polymorphic variant rs521018 (HTR2C) was associated with higher body mass index in patients receiving long-term antipsychotic therapy, but not with drug-induced metabolic syndrome. Rs1150226 (HTR3A) was also associated but did not meet Hardy-Weinberg equilibrium. Conclusions: Our results indicate that allelic variants of HTR2C genes may have consequences on metabolic parameters. MetS may have too complex a mechanistic background to be studied without dissecting the syndrome into its individual (causal) components