Cell Adhesion Molecules in Schizophrenia Patients with Metabolic Syndrome.

Metabolic syndrome (MetS) is a common comorbidity of schizophrenia and significantly shortens life expectancy of the patients. Intercellular (ICAM), vascular (VCAM), and neural (NCAM) cell adhesion molecules (CAMs) mediate neuroinflammatory processes, and their soluble forms (e.g., sICAM) in plasma are present in parallel with their cell-bound forms. In this study, their serum levels were examined in 211 white Siberian patients with paranoid schizophrenia (82 patients with and 129 without MetS according to the 2005 International Diabetes Federation criteria). Serum levels of CAMs were determined with Magpix and Luminex 200 (Luminex, Austin, TX, USA) using xMAP Technology. The level of sICAM-1 was significantly higher and that of sVCAM-1 significantly lower in patients with MetS compared to patients without MetS. Levels of NCAM did not differ between the groups. More pronounced Spearman's correlations between CAMs, age, duration of schizophrenia, and body-mass index were observed among patients without MetS than among patients with MetS. Our results are consistent with MetS's being associated with endothelial dysfunction along with other components of inflammation. Through these endothelial components of peripheral inflammatory processes, MetS might induce intracerebral neuroinflammatory changes, but further investigation is needed to confirm this.

The Role of Glutamatergic Gene Polymorphisms in the Clinical Phenotypes of Schizophrenia.

BACKGROUND: Personal variations in genetic risk for schizophrenia relate to its phenotypic heterogeneity-both in disorder development and clinical manifestations. Abnormal glutamatergic neurotransmitter system functioning is integrated in the pathogenesis of schizophrenia. METHODS: A sample of 805 Russian schizophrenia patients from the Siberian Federal region was investigated. We examined the association of 39 single nucleotide polymorphisms in eight genes (GRIN2A, GRIN2B, SLC1A2, SLC1A3, SLC17A7, GRM3, GRM7, and GRM8) involved in the glutamatergic system with the development of clinical heterogeneity of schizophrenia. The MassARRAY Analyzer 4 was used for genotyping. RESULTS: GRIN2A rs11644461, rs8057394 and GRIN2B rs7313149 are associated with the continuous type of schizophrenia. The GRIN2A rs8057394*G allele is a relative risk factor (p = 0.019) for developing the continuous type of schizophrenia. We found a nominally significant association between negative symptoms of schizophrenia and SLC17A7 rs62126236. The SLC17A7 rs62126236*T allele has a protective effect (p = 0.039) against predominant negative symptoms in schizophrenia. The total Positive and Negative Syndrome Scale (PANSS) scores were significantly associated with GRIN2A rs9788936 after adjusting for multiple testing (p = 0.001). CONCLUSIONS: In this study the contribution of the glutamatergic gene polymorphisms to the clinical heterogeneity of schizophrenia has been demonstrated.

Cytokines as Potential Biomarkers of Clinical Characteristics of Schizophrenia.

Immune activation plays a major role in the pathogenesis of schizophrenia, as confirmed by many studies, systematic reviews, and meta-analyses. The important role of neuroinflammation in the formation of the relation between impaired neurobiological processes and schizophrenia psychopathology is being actively discussed. We quantified serum concentrations of 22 cytokines in 236 patients with schizophrenia and 103 mentally and somatically healthy individuals by a multiplex assay. We found higher TGF-α (p = 0.014), IFN-γ (p = 0.036), IL-5 (p < 0.001), IL-6 (p = 0.047), IL-8 (p = 0.005), IL-10 (p <0.001), IL-15 (p = 0.007), IL-1RA (p = 0.007), and TNF-α (p < 0.001) levels in patients with schizophrenia than in healthy individuals. Subgroup analysis revealed a much greater number of statistically significant differences in cytokine levels among females than among males. Patients with a continuous course of schizophrenia showed statistically significantly higher levels of IL-12p70 (p = 0.019), IL-1α (p = 0.046), and IL-1ß (p = 0.035) compared with patients with an episodic course. Most cytokines were positively correlated with positive, general, and total PANSS scores. In patients with a duration of schizophrenia of 10 years or more, the level of IL-10 was higher than that in patients with a disease duration of 5 years or less (p = 0.042). Thus, an imbalance in cytokines was revealed in patients with schizophrenia, depending on sex and clinical characteristics of the disease.

Metabolic Hormones in Schizophrenia Patients with Antipsychotic-Induced Metabolic Syndrome.

Metabolic syndrome (MetS) is a common complication of schizophrenia that is quite exacerbated by long-term use of (atypical) antipsychotics. The mechanism of MetS has neuronal, neuroendocrine, and neuroimmunological components and shows some overlap with those of aspects of schizophrenia. We examined 195 patients with schizophrenia (90 with and 105 without MetS) for the association of serum levels of ghrelin, insulin, and leptin with metabolic abnormalities. Serum glucose levels and lipid profiles were routinely measured with colorimetric enzymatic methods and hormone levels with multiplex analyzers. Leptin levels were highly significantly increased (p < 0.001) in people with MetS (9.966 [5.882; 21.496] vs. 6.35 [2.005; 11.753], Me [Q1; Q3]) and ghrelin levels were actually significantly decreased (p = 0.045). Insulin levels did not differ significantly between those with and without MetS (p = 0.162). In Spearman's correlation analysis between the hormone levels, body characteristics, and biochemical parameters, significant correlations were seen somewhat more often in people without MetS than in those with MetS and also less often for ghrelin than for the other hormones. We conclude that evidence exists for a role in the development of MetS especially for leptin, but that less is supporting a role for ghrelin.

Levels of Acylcarnitines and Branched-Chain Amino Acids in Antipsychotic-Treated Patients with Paranoid Schizophrenia with Metabolic Syndrome.

Several studies have shown that patients with schizophrenia are at high risk for metabolic syndrome (MetS) and bioenergetic dysfunction. Because acylcarnitines are involved in bioenergetic pathways and reflect the functioning of mitochondria, we hypothesized that these compounds are biomarkers of MetS in schizophrenia. The aim of this work was to quantify acylcarnitines and branched-chain amino acids in patients with schizophrenia comorbid with MetS. The study included 112 patients with paranoid schizophrenia treated with antipsychotics. Among them, 39 subjects met criteria of MetS. Concentrations of 30 acylcarnitines and three amino acids in dry serum spots were measured by liquid chromatography coupled with tandem mass spectrometry. MetS patients were found to have higher levels of valeryl carnitine (C5), leucine/isoleucine, and alanine as compared with patients without MetS, indicating possible participation of these compounds in the pathogenesis of metabolic disorders in schizophrenia. In patients with paranoid schizophrenia with or without MetS, lower levels of carnitines C10, C10:1, C12, and C18 were recorded as compared with the healthy individuals (n = 70), implying deterioration of energy metabolism. We believe that this finding can be explained by effects of antipsychotic medication on an enzyme called carnitine-palmitoyl transferase I.

Immunoglobulins G of Patients with Schizophrenia Protects from Superoxide: Pilot Results.

This study aimed to evaluate the superoxide dismutase (SOD) activity of IgG in patients with schizophrenia. After signing informed consent, we included 67 patients with schizophrenia (34 people with acute schizophrenia and 33 individuals were on outpatient treatment in therapeutic remission) and 14 healthy volunteers. IgGs from blood serum were isolated by affinity chromatography. SOD activity of antibodies was determined spectrophotometrically. We have shown for the first time that IgGs from patients with schizophrenia have SOD activity and this activity is an intrinsic property of antibodies. The maximum increase in SOD activity was registered in the group of patients in therapeutic remission compared with acute schizophrenia (p = 0.005) and in healthy individuals (p = 0.001). Based on the data of inhibitory analysis using a specific SOD inhibitor enzyme, triethylenetetramine (TETA), we can assume that the mechanism of the SOD activity of IgG is similar to the mechanism of classical enzyme catalysis. According to the kinetic analysis, the affinity of the IgGs to the substrate is higher than that of the classical SOD enzyme.

The Gender-Specific Association of DRD2 Polymorphism with Metabolic Syndrome in Patients with Schizophrenia.

BACKGROUND: Metabolic syndrome is widespread in patients with schizophrenia receiving long-term antipsychotic therapy. Dopamine D2 receptors play an important role in mediating both the therapeutic actions of antipsychotics and their side effects. The present study examined the association of two polymorphisms of the DRD2 gene with metabolic syndrome in patients with schizophrenia. METHODS: We examined 517 patients from several regions of Siberia (Russia) with a clinical diagnosis of schizophrenia. Genotyping of two single nucleotide polymorphisms rs1799732 and rs4436578 of the dopamine D2 receptor gene (DRD2) was performed in a population of 471 patients. The results were analyzed using chi-square tests. RESULTS: Functional polymorphism rs1799732 of the DRD2 gene is associated with drug-induced metabolic syndrome in women with schizophrenia. CONCLUSIONS: Our results show that the DRD2 gene may be involved in the pathogenesis of metabolic disorders in patients with schizophrenia. Further analysis of possible genetic markers will allow for personalized treatment with minimal side effects and optimal efficacy. This which seems relevant in light of the recent focus on improving the quality of life and ensuring a high level of social adaptation of patients with schizophrenia.

Gene Polymorphisms of Hormonal Regulators of Metabolism in Patients with Schizophrenia with Metabolic Syndrome.

BACKGROUND: Metabolic syndrome (MetS) is a common complication of long-term treatment of persons with schizophrenia taking (atypical) antipsychotics. In this study, we investigated the existence of an association with polymorphisms of genes for four hormones that regulate energy metabolism. METHODS: We recruited 517 clinically admitted white patients (269M/248F) with a verified diagnosis of schizophrenia (ICD-10) and with a stable physical condition. Participants were classified for having or not having MetS and genotyped for 20 single-nucleotide polymorphisms (SNPs) in the genes encoding insulin-induced gene 2 (INSIG2), ghrelin (GHRL), leptin (LEP), and leptin receptor (LEPR). RESULTS: The 139 patients (26.9%) with MetS were significantly more likely to be women, older, and ill longer, and had a larger body mass index (BMI). Four polymorphisms (rs10490624, rs17587100, rs9308762, and rs10490816) did not meet the Hardy-Weinberg equilibrium (HWE) criterion and were excluded. Only genotypes and alleles of the rs3828942 of LEP gene (chi2 = 7.665, p = 0.022; chi2 = 5.136, p = 0.023) and the genotypes of the rs17047718 of INSIG2 gene (chi2 = 7.7, p = 0.021) had a significant association with MetS. CONCLUSIONS: The results of our study suggest that the LEP and INSIG2 genes play a certain causal role in the development of MetS in patients with schizophrenia.

Search for Possible Associations of FTO Gene Polymorphic Variants with Metabolic Syndrome, Obesity and Body Mass Index in Schizophrenia Patients.

PURPOSE: Metabolic syndrome (MetS) is characterized by abdominal obesity, hyperglycaemia, dyslipidaemia and hypertension. FTO gene has been implicated in the pathogenesis of obesity, but the available scientific data concerning their relationship to antipsychotic drug-induced obesity and metabolic syndrome is still incomplete and inconsistent, which indicates that continuing the investigation of this gene's role is necessary. PATIENTS AND METHODS: In the present study, 517 patients with schizophrenia underwent antipsychotic drug treatment, and two groups were identified: patients with MetS and without MetS. Genotyping of 6 SNPs in the FTO gene was performed, and the results analyzed using R-programme. RESULTS: We performed a statistical analysis to identify possible associations of the frequencies of genotypes and alleles of the studied polymorphisms with the presence of metabolic syndrome in schizophrenia patients, with the presence of abdominal obesity, and with an increased body mass index. The rs7185735 polymorphism did not meet the Hardy-Weinberg criterion and was excluded. After correcting for differences in age, gender and duration of illnesses, none of the variants was shown to be related to metabolic syndrome or abdominal obesity, but rs9939609, rs1421085, rs3751812 and rs8050136 were associated with body mass index. CONCLUSION: The present study provides additional support for these SNP's roles as a pharmacogenetic biomarker that may become useful in the framework of the personalized medicine approach.

Comparative Characteristics of the Metabolic Syndrome Prevalence in Patients With Schizophrenia in Three Western Siberia Psychiatric Hospitals.

Objective: The purpose of this study was to compare the prevalence of MetS and the associated sociodemographic, clinical, and pharmacotherapeutic characteristics of patients with schizophrenia in three psychiatric hospitals in the West Siberian region. Methods: Patients with a clinical diagnosis of schizophrenia (ICD-10: F20) and an age between 18 and 60 years were included in the study after giving informed consent. Metabolic syndrome was diagnosed according to the International Diabetes Federation criteria. This research was carried out at three Western Siberian psychiatric hospitals in Kemerovo, Tomsk, and Omsk. The study population included respectively 94, 131, and 91 inpatients with schizophrenia. We carried out schizophrenia symptoms assessment by PANSS, antipsychotic therapy evaluation, anthropometry, and biochemical analysis. Statistical Analysis included the Shapiro-Wilk test, non-parametric Kruskal-Wallis H-test for independent samples, Mann-Whitney U-test for independent samples, the chi-square test, stepwise multiple regression analyses. The level of significance was p < 0.05. Results: The metabolic syndrome prevalence was higher among patients in Tomsk (36.6%), compared with Kemerovo (20.2%, p = 0.008) or Omsk (18.7%, p = 0.004), mainly due to the high prevalence of abdominal obesity, while men from Tomsk were more susceptible to this condition than men from other regions (p < 0.05). Patients from Omsk had the highest severity schizophrenia symptoms according to PANSS, and patients from Tomsk had the lowest severity of positive symptoms according to PANSS. Patients from Tomsk had the minimum duration of antipsychotic therapy compared with the patient from Kemerovo (p = 0.017) and from Omsk (p = 0.000019), but most patients from Tomsk received second-generation atypical antipsychotics, while patients from Omsk received mainly conventional antipsychotics (p = 0.0001). Multiple regression analysis showed that metabolic syndrome associated with schizophrenia duration and body mass index, although the association was not so strong (adjusted R 2 = 0.2435, p < 0.0001). Discussion: The study illustrates that in different psychiatric hospitals within the same region, the prevalence of metabolic syndrome in patients with schizophrenia can vary significantly, which dictates the need to look for opportunities to minimize the risk of its occurrence, taking into account the experience of each hospital.

Global hypomyelination of the brain white and gray matter in schizophrenia: quantitative imaging using macromolecular proton fraction.

Myelin deficiency is commonly recognized as an important pathological feature of brain tissues in schizophrenia (SZ). In this pilot study, global myelin content abnormalities in white matter (WM) and gray matter (GM) of SZ patients were non-invasively investigated using a novel clinically-targeted quantitative myelin imaging technique, fast macromolecular proton fraction (MPF) mapping. MPF maps were obtained from 23 healthy subjects and 31 SZ patients using a clinical 1.5T magnetic resonance imaging (MRI) scanner. Mean MPF in WM and GM was compared between the healthy control subjects and SZ patients with positive and negative leading symptoms using the multivariate analysis of covariance. The SZ patients had significantly reduced MPF in GM (p < 0.001) and WM (p = 0.02) with the corresponding relative decrease of 5% and 3%, respectively. The effect sizes for the myelin content loss in SZ relative to the control group were 1.0 and 1.5 for WM and GM, respectively. The SZ patients with leading negative symptoms had significantly lower MPF in GM (p < 0.001) and WM (p = 0.003) as compared to the controls and showed a significant MPF decrease in WM (p = 0.03) relative to the patients with leading positive symptoms. MPF in WM significantly negatively correlated with the disease duration in SZ patients (Pearson's r = -0.51; p = 0.004). This study demonstrates that chronic SZ is characterized by global microscopic brain hypomyelination of both WM and GM, which is associated with the disease duration and negative symptoms. Myelin deficiency in SZ can be detected and quantified by the fast MPF mapping method.

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.

Amino Acid and Acylcarnitine Levels in Chronic Patients with Schizophrenia: A Preliminary Study.

Amino acids and acylcarnitines play an important role as substrates and intermediate products in most of pathways involved in schizophrenia development such as mitochondrial dysfunction, inflammation, lipid oxidation, DNA damage, oxidative stress, and apoptosis. It seems relevant to use an integrated approach with 'omics' technology to study their contribution. The aim of our study was to investigate serum amino acid and acylcarnitine levels in antipsychotics-treated patients with chronic schizophrenia compared with healthy donors. We measured serum levels of 15 amino acids and 30 acylcarnitines in 37 patients with schizophrenia and 36 healthy donors by means of tandem mass spectrometry. In summary, patients with chronic schizophrenia had an altered concentration of a few amino acids and acylcarnitines in comparison to the healthy probands. Further research is needed to assess and understand the identified changes.

A genome-wide association study identifies a gene network associated with paranoid schizophrenia and antipsychotics-induced tardive dyskinesia.

In the present study we conducted a genome-wide association study (GWAS) in a cohort of 505 patients with paranoid schizophrenia (SCZ), of which 95 had tardive dyskinesia (TD), and 503 healthy controls. Using data generated by the PsychENCODE Consortium (PEC) and other bioinformatic databases, we revealed a gene network, implicated in neurodevelopment and brain function, associated with both these disorders. Almost all these genes are in gene or isoform co-expression PEC network modules important for the functioning of the brain; the activity of these networks is also altered in SCZ, bipolar disorder and autism spectrum disorders. The associated PEC network modules are enriched for gene ontology terms relevant to the brain development and function (CNS development, neuron development, axon ensheathment, synapse, synaptic vesicle cycle, and signaling receptor activity) and to the immune system (inflammatory response). Results of the present study suggest that orofacial and limbtruncal types of TD seem to share the molecular network with SCZ. Paranoid SCZ and abnormal involuntary movements that indicate the orofacial type of TD are associated with the same genomic loci on chromosomes 3p22.2, 8q21.13, and 13q14.2. The limbtruncal type of TD is associated with a locus on chromosome 3p13 where the best functional candidate is FOXP1, a high-confidence SCZ gene. The results of this study shed light on common pathogenic mechanisms for SCZ and TD, and indicate that the pathogenesis of the orofacial and limbtruncal types of TD might be driven by interacting genes implicated in neurodevelopment.

Adipocytokines and Metabolic Syndrome in Patients with Schizophrenia.

The adipokines leptin, adiponectin, tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) might be associated with metabolic syndrome (MetS) in patients with schizophrenia. In the present study, we attempted to confirm the results of previous reports and assessed their MetS-related correlation with body fat composition and biochemical parameters. We measured in 46 patients with schizophrenia and MetS serum levels of adiponectin insulin, leptin, TNF-α and IL-6 and compared these levels to those of patients with schizophrenia without MetS. The MetS patients had significantly increased leptin levels and leptin/adiponectin ratios, as well as decreased adiponectin levels. Leptin levels correlated with several metabolic parameters, both in patients with and without MetS, including body fat percentage, total fat fold, and body mass index (BMI). Patients without abnormal MetS components had lower levels of leptin and leptin/adiponectin ratios compared with patients who had one or two MetS components. Leptin/adiponectin ratios were higher in patients who had four rather than three MetS components. Multiple regression analysis revealed multiple associations for leptin but only one for adiponectin, TNF-α, and IL-6. Our results support an important pathophysiological role for leptin more than adiponectin in patients with schizophrenia with MetS.

Body Fat Parameters, Glucose and Lipid Profiles, and Thyroid Hormone Levels in Schizophrenia Patients with or without Metabolic Syndrome.

In this study, we aim to investigate associations between body fat parameters, glucose and lipid profiles, thyroid-stimulating hormone (TSH), and thyroid hormones (THs) levels in Tomsk-region schizophrenia patients depending upon the presence or absence of metabolic syndrome (MetS). A total of 156 psychiatric inpatients with schizophrenia who had been treated with antipsychotics for at least six months before entry were studied: 56 with and 100 without MetS. Reference groups consisted of general hospital inpatients with MetS and without schizophrenia (n = 35) and healthy individuals (n = 35). Statistical analyses were performed using the Mann-Whitney U-test, chi-square test, Spearman's rank correlation coefficient, multiple regression analyses, and descriptive statistics. Patients with schizophrenia and MetS had significantly higher levels of free triiodothyronine (FT3) and thyroxine (FT4) compared to schizophrenia patients without MetS (3.68 [3.25; 5.50] vs. 3.24 [2.81; 3.66], p = 0.0001, and 12.68 [10.73; 15.54] vs. 10.81 [9.76; 12.3], p = 0.0001, in pmol/L, respectively). FT3 maintained an association with MetS (p = 0.0001), sex (p = 0.0001), age (p = 0.022), and high-density lipoproteins (p = 0.033). FT4 maintained an association with MetS (p = 0.0001), sex (p = 0.001), age (p = 0.014), and glucose (p = 0.009). The data obtained showed body fat parameters, glucose and lipid profiles, and THs levels in Western-Siberian schizophrenia patients depending on MetS presence or absence.

Igg-Dependent Hydrolysis of Myelin Basic Protein of Patients with Different Courses of Schizophrenia.

The level hydrolysis of myelin basic protein (MBP) by IgG in patients with schizophrenia was studied depending on the clinical features and course of the disease. The patients were grouped according to type of schizophrenia and type of disease course. We found that IgGs isolated and purified from sera of schizophrenia patients' blood hydrolyses human MBP, and the level of this hydrolysis significantly exceeds that of healthy individuals. Detection of protease activity corresponding only to intact IgGs in polyacrylamide gel fragments, together with data of gel filtration of antibodies under conditions of "acid shock" (concordance of optical density profile of IgG with profile of MBP-hydrolyzing activity) and with the absence of any other proteins and bands in gradient SDS-PAGE and in PVDF membrane provides direct evidence that the IgGs from the schizophrenia patients have MBP-hydrolyzing activity. The antibodies-specific proteolytic activity of patients with acute schizophrenia (1.026 [0.205; 3.372] mg MBP/mg IgG/h) significantly exceeds the activity of IgG in patients in remission (0.656 [0.279; 0.873] mg MBP/mg IgG/h) and in healthy individuals (0.000 [0.00; 0.367] mg MBP/mg IgG/h). When comparing the specific activity in patients with different types of disease course, we have found that patients with a continuous course of paranoid schizophrenia (1.810 [0.746; 4.101 mg MBP/mg IgG/h]) had maximal activity values. It can be assumed that the increase in the activity of MBP-hydrolyzing antibodies is due to the activation of humoral immunity in acute schizophrenia.

Cortisol and DHEAS Related to Metabolic Syndrome in Patients with Schizophrenia.

BACKGROUND: Both dehydroepiandrosterone (DHEAS) and cortisol are secreted by the adrenal glands and may modulate metabolic syndrome (MetS), which often affects the health of patients with schizophrenia. The relationship between the serum levels of these hormones and MetS has not been established. PURPOSE: In this pilot study, we investigated the serum levels in schizophrenia patients with and without MetS and compared them with those in healthy volunteers. PATIENTS AND METHODS: After obtaining informed consent, 110 patients with acute paranoid schizophrenia were recruited directly after admission to the Mental Health Research Institute. The control group consisted of 51 persons reported on questioning to be mentally and somatically healthy. Blood samples to prepare serum were drawn after an 8-h overnight fast during one of the first days of admission. Serum cortisol and DHEAS concentrations were quantified by enzyme-linked immunosorbent assay. RESULTS: A total of 42 patients had MetS and 68 patients were without MetS. The cortisol blood level was significantly (p = 0.012) higher in schizophrenia patients without MetS in comparison to healthy controls, while patients with schizophrenia and a MetS have significantly (p = 0.014) lower DHEAS levels than healthy volunteers. These differences could, however, exclusively be attributed to female participants. Analysis of covariance adjusted for gender and age demonstrated a significant relationship between age and DHEAS levels (F = 9.512, р = 0.003). CONCLUSION: Lower DHEAS serum levels in relationship to MetS become evident in women, but not in men, and have age differences as a confounding factor.

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 χ 2 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.

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.