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

The study of dopamine receptor genes in patients with schizophrenia

Background: Schizophrenia is a severe mental disorder, usually treated with long-term anti-dopaminergic therapy. Although several theories have been lanced, pathophysiology of schizophrenia has not yet been elucidated. Identifying genetic factors contributing to development of schizophrenia would be of considerable interest for personalizing treatment [1]. Most studies in the field of pharmacogenetics of schizophrenia are based on the study of receptor candidate genes or secondary messengers (pharmacodynamic components) and that of drug metabolizing enzymes (pharmacokinetic components), or suspected loci to the disease schizophrenia (pathogenetic components). An important role in personalization of treatment is played by the suitability of drugs targeting dopamine receptors [2]. Objective: to investigate role of 28 SNP's of dopamine receptor genes DRD1, DRD2, DRD2/ANKK1, DRD3, DRD4 as a potential markers of schizophrenia in patients of Russian population. Methods: Fourhundred and seventy (470) patients with schizophrenia and 127 healthy controls were investigated. Mean age was 42.1 ± 12.4 for patients, for healthy group is 38.5 ± 13.2 years. Mean duration of disease was 13 years for schizophrenic patients. The inclusion criteria were a clinical diagnosis of schizophrenia, according to the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10: F20), and age 18–75 years old. We used the standard phenol-chloroform method for isolation DNA from whole peripheral blood. Genotyping was carried out on 28 SNPs of dopamine receptors (rs6275, rs1801028, rs4245147, rs134655, rs6277, rs1076560, rs2283265, rs179997, rs6279, rs1076562, rs2734842, rs4532, rs936461, rs2734849, rs11721264, rs167770, rs3773678, rs963468, rs7633291, rs2134655, rs9817063, rs324035, rs1800828, rs167771, rs6280, rs1587756, rs3758653, rs11246226). We were employed the MassARRAY® Analyzer 4 (Agena Bioscience™) and using the kit iPLEX Gold 384. Statistical analysis was carried out with SPSS software, release 17. Statistical significance of tested associations was considered for significance at a P-value less than 0.05. Results: This study was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki 1975, revised in Fortaleza, Brazil, 2013), established for experiments involving humans. We recruited patients from three psychiatric hospitals located in the Tomsk, Kemerovo, and Chita oblasts (regions) of Siberia, Russia. Healthy control group was recruited from the same region with identical characteristics, comparable in gender and age. The distribution of genotypes of studied genes corresponded to the Hardy-Weinberg equilibrium. We got statistically significant results for alleles of polymorphic variant rs3773678 of DRD3 receptor gene (c2 = 4.940, p = 0.030). We found that allele C are significantly associated with protective effect (odds ratio is 0.53 [95% CI: 0.30 - 0.94]) and allele T are significantly associated with predisposing effect on the development of schizophrenia (odds ratio is 1.88 [95% CI: 1.07 - 3.29]). Conclusion: According to literature data polymorphisms of dopamine receptors genes play important role in the therapy of schizophrenia. A polymorphic variant of one dopamine receptor gene has been identified, whose alleles have predisposing and protective effects for patients in the pathogenesis of schizophrenia. Acknowledgement: This work was supported by the comprehensive program of fundamental scientific research of the SB RAS ``Interdisciplinary Integrated Studies'' (2018-2020), project No. 3

Association between prolactin gene polymorphism (-1149 G/T) and hyperprolactinemia in anti-psychotic treated patients with schizophrenia

Hyperprolactinemia (HPRL) is a classical side effect of anti-psychotic drugs. Extrapituitary prolactin (PRL) production is regulated by an alternative promoter, which contains the functional single nucleotide polymorphism – 1149 G/T (rs134,1239) in prolactin gene. We examined whether this polymorphism is associated with hyperprolactinemia in patients with schizophrenia. The experimental group comprised 443 patients with schizophrenia. The control group comprised 126 healthy persons. The PRL concentration was measured in serum using the AccuBind ELISA Microwells kit. The functional polymorphism – 1149 G/T (rs134,1239) of the PRL gene was genotyped using the The MassARRAY® system. Genotype and allele frequencies were compared using χ2 test. A total of 227 patients suffered from HPRL (98 males/129 females) according to the criteria of hyperprolactinemia. The frequency of genotypes and alleles in patients with schizophrenia did not differ from those in control subjects. A comparison between patients with schizophrenia with and without hyperprolactinemia revealed that the frequency of G allele in patients with hyperprolactinemia is significantly higher than in patients without hyperprolactinemia (χ2 = 7.25; P = 0.007; OR = 1.44 [1.10–1.89]). Accordingly, the genotype GG was found to be more often in patients with hyperprolactinemia than without it (χ2 = 9.49; P = 0.009). A significant association of the polymorphic variant rs134,1239 with the development of hyperprolactinemia in patients with schizophrenia treated with anti-psychotic drugs was revealed. Therefore, the serum concentration of prolactin in anti-psychotic treatment patients with schizophrenia may also give an indication of the activity of gene regulating extrapituitary prolactin expression.The study was supported by the Russian Science Foundation, Grant 14-35-00023.Disclosure of interestThe authors have not supplied their declaration of competing interest.</jats:sec

Biomarkers of depressive disorders:A multiplex analysis of blood serum

Depressive disorders are a great burden for individual patients and society. Blood-based biomarkers are regarded as a feasible option for investigation of depressive disorders. Several potential biomarkers for depression were selected. We studied the following serum markers: cortisol, melatonin, brain-derived neurotrophic factor (BDNF), prolactin, insulin-like growth factor 1 (IGF-1), β-endorphin, orexin A. The patient sample consisted of 78 persons with depressive disorders. Patients were divided into two groups: 46 patients with a first depressive episode and 32 patients with recurrent depressive disorder. Control group consisted of 71 healthy individuals of corresponding age and sex. All markers were measured in serum using MILLIPLEX® MAP panels (Merck, Darmstadt, Germany) by analyzer MAGPIX (Luminex, USA). Statistical analyses were performed using SPSS software. Results were expressed as median and quartile intervals [Q1–Q3]. There was a significant increase of serum concentrations of cortisol (663.69 [467.5–959.49] nmol/L, Р &lt; 0.001) and melatonin (66.31 [33.6–132.59] pg/mL, P = 0.029) in patients compared with the control group (526.1 [367,24–654,7] nmol/L and 45.11 [27.47–73.47] pg/mL). In addition, correlations were found between potential biomarkers, clinical indicators and treatment response measured by applying the Hamilton Depression rating scale and the Clinical Global Impression rating scales. A significant correlation was found between the concentration of prolactin and high response to pharmacotherapy (r = –0.267, P = 0.029). Identifying biomarkers that can be used as diagnostics or predictors of treatment response in people with depressive disorders will be an important step towards being able to provide personalized treatment.Disclosure of interestThe work is supported by the project of Russian Foundation of Basic Research No 14-04-01157a.</jats:sec

Monolithic stirrer reactor: The selective lactose oxidation in liquid phase over Au/Al2O3 nanostructured catalysts

The performance of rotating metallic monolith stirrer reactor was studied for selective lactose oxidation in liquid phase at 65 °C, atmospheric pressure and with air as oxidant agent. The Au/AlOdeposition on metallic substrates was performed by wash-coating, producing catalyst coating thicknesses between 5 and 20 μm. Monoliths with different configuration (channel size between 0.36 and 1.06 mm) were used as stirrer blades in a batch reactor. Internal and external mass transfer limitations were observed during liquid phase lactose oxidation. For stirring rates equal or higher than 600 rpm there were no important external diffusional restrictions and this was also independent of the monolith configuration. Coating with thickness higher than 15 μm presents loss of catalyst effectiveness due to internal diffusional restrictions. Excellent stability in the catalytic tests was obtained after three regeneration-reaction cycles. Regeneration was carried out at 400 °C in air flow. Gold particle size distribution in the monolith washcoat, determined by TEM before and after reaction, was homogeneous with a medium size of around 5 nm. This is in agreement with the very good reproducibility and stability obtained in the catalytic tests. After calcination at 500 °C, some sintering and a heterogeneous distribution of metal particle size was observed, accompanied by a slight loss in catalyst activity. It is concluded that metallic monolith stirrer reactors are a promising application for selective lactose oxidation in liquid phase