Potential biomarkers of tardive dyskinesia:A multiplex analysis of blood serum

Potential biomarkers of tardive dyskinesia: a multiplex analysis of blood serum A.S. Boiko(1), E.G. Kornetova(2), S.A. Ivanova(1), A.J.M. Loonen(3) (1)Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Laboratory of Molecular Genetics and Biochemistry, Tomsk, Russia (2)Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences, Department of Endogenous Disorders, Tomsk, Russia (3)University of Groningen, Groningen Research Institute of Pharmacy, Groningen, The Netherlands Long-term antipsychotic treatment of schizophrenia is associated with the emergence of tardive dyskinesia (TD), a motor syndrome consisting of involuntary and hyperkinetic movements [1]. Pathogenesis of this drug-induced movement disorder is not yet fully established, but may be connected to oxidative stress-related indirect pathway neurotoxicity [2]. Dysregulations in immune, hormonal and neurotrophic systems have been postulated to be one of the mechanisms underlying this form of neurotoxicity [3,4]. Principle aims of translational psychiatric research are searching for biomarkers which can be used to diagnose pathological biochemical processes and to identify molecular targets for treatment as well as development of pharmacogenetic approaches to personalize this therapy. The aim is to study potential endocrine, neurotrophic and immunological markers of tardive dyskinesia in the blood serum of patients with schizophrenia with antipsychotic therapy. Methods: After obtaining approval of the study protocol by the local ethical committee, suitable participants were recruited from psychiatric hospitals. All subjects gave informed consent after proper explanation of the study. TD was assessed cross-sectionally by the use of the Abnormal Involuntary Movement Scale (AIMS) [1,5]. The concentrations of cortisol, brain-derived neurotrophic factor (BDNF), prolactin, cytokines (tumor necrosis factor (TNFa), interleukin 1 (IL-1β), interleukin 3 (IL-3), interleukin 6 (IL-6), interferon gamma (INF-γ) and S100β were measured in blood serum using the MILLIPLEX® MAP panels (Merck, Darmstadt, Germany) by the multiplex analyzer MAGPIX (Luminex, USA). Statistical analyses were performed using SPSS software for Windows. Results were expressed as median and quartile intervals (Me [Q1; Q3]) or mean and standard deviation (M ± SD). Differences were considered significant at p ≤ 0.05. Results: In total 180 patients with schizophrenia, 128 males and 52 females (age 39.2 ± 12.1 years), receiving long-term antipsychotic treatment were included. These patients were divided into two groups: 71 patients with tardive dyskinesia and 109 patients without this movement disorder. A significant (p = 0.04) decrease in BDNF concentration was observed in patients with TD (1.9 [1.01; 2.99] ng/ml) in comparison to patients without TD (2.66 [1.29; 3.89] ng/ml). An increase (p = 0.05) of the serum IL-6 level of patients with TD (5.69 [3.55; 7.4] pg/ml) was detected relative to patients without TD (4.69 [2.82; 6.13] pg/ml). In addition, a statistical trend (p = 0.06) of increased serum S100β concentration was found in TD patients (85.29 ± 5.53 ng/L) compared to patients without this side effect (75.14 ± 2.81 ng/L). No other significant differences were established concerning the other assayed biomarkers. Conclusions: The biological processes that might play a role in the development of TD are not confined to the human brain per se. Hormonal and immune systems are also involved, which may be related to these systems being closely interrelated. Furthermore, these parameters may provide information about risk factors of the movement disorder. Identifying markers that can be used as diagnostics or predictors of treatment response in people with tardive dyskinesia will be an important step towards being able to provide personalized treatment. References [1] Loonen, A.J., van Praag, H.M., 2007. Measuring movement disorders in antipsychotic drug trials: the need to define a new standard. J Clin Psychopharmacol 27, 423–430. [2] Loonen, A.J.M., Ivanova, S.A., 2013. New insights into the mechanism of druginduced dyskinesia. CNS Spectrums 18 (01), 15–20. [3] Wu, J.Q., Chen, D.Ch., Tan, Yu.L., Tan, Sh.P., Hui, L., Lv, M.H., Soares, J.C., Zhang, X.Y., 2015. Altered BDNF is correlated to cognition impairment in schizophrenia patients with tardive dyskinesia. Psychopharmacology 232, 223–232. [4] An, H.M., Tan, Y.L., Shi, J., Wang, Z.R., Soars, J.C., Wu, J.Q., Yang, F.D., Huang, X.F., Zhang, X.Y., 2015. Altered IL-2, IL-6 and IL-8 serum levels in schizophrenia patients with tardive dyskinesia. Schizophr Res 162 (1–3), 261–268. [5] Loonen, A.J.M., Doorschot, C.H., van Hemert, D.A., Oostelbos, M.C., Sijben, A.E., 2001. The schedule for the assessment of drug-induced movement disorders (SADIMoD): inter-rater reliability and construct validity. Int J Neuropsychopharmacol 4, 347–360. Keywords: Biological markers Schizophrenia: clinical Neuroleptics & antipsychotics: clinica

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

Genetic polymorphisms of PIP5K2A and course of schizophrenia

BackgroundSchizophrenia is a severe highly heritable mental disorder. The clinical heterogeneity of schizophrenia is expressed in the difference in the leading symptoms and course of the disease. Identifying the genetic variants that affect clinical heterogeneity may ultimately reveal the genetic basis of the features of schizophrenia and suggest novel treatment targets. PIP5K2A (Phosphatidylinositol-4-Phosphate 5-Kinase Type II Alpha) has been investigated as a potential susceptibility gene for schizophrenia.MethodsIn this work, we studied the possible association between eleven polymorphic variants of PIP5K2A and the clinical features of schizophrenia in a population of 384 white Siberian patients with schizophrenia. Genotyping was carried out on QuantStudio 5 Real-Time PCR System with a TaqMan Validate SNP Genotyping Assay (Applied Biosystems, USA).ResultsPIP5K2A rs8341 (chi (2)=6.559, p=0.038) and rs946961 (chi (2)=5.976, p=0.049) showed significant association with course of schizophrenia (continuous or episodic). The rs8341*CT (OR=1.63, 95% CI: 1.04-2.54) and rs946961*CC (OR=5.17, 95% CI: 1.20-22.21) genotypes were associated with a continuous type of course, while the rs8341*TT genotype (OR=0.53, 95% CI: 0.29-0.97) was associated with an episodic type of course of schizophrenia. Therefore rs8341*TT genotype presumably has protective effect against the more severe continuous course of schizophrenia compared to the episodic one.ConclusionsOur experimental data confirm that PIP5K2A is a genetic factor influencing the type of course of schizophrenia in Siberian population. Disturbances in the phosphatidylinositol pathways may be a possible reason for the transition to a more severe continuous course of schizophrenia

Study of early onset schizophrenia:Associations of GRIN2A and GRIN2B polymorphisms

Background: Schizophrenia is a complex mental disorder with a high heritability. Dysfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptors may be involved in the pathogenesis of schizophrenia. In this study, we examined the contribution of GRIN2A and GRIN2B (Glutamate Ionotropic Receptor NMDA Type Subunit 2A/2B) polymorphisms to the clinical features of schizophrenia, such as the leading symptoms, the type of course, and the age of onset. Methods: A population of 402 Russian patients with schizophrenia from the Siberian region was investigated. Genotyping of seventeen single-nucleotide polymorphisms (SNPs) in GRIN2A and GRIN2B was performed using QuantStudio™ 3D Digital PCR System Life Technologies amplifier using TaqMan Validated SNP Genotyping Assay kits (Applied Biosystems). The results were analyzed using Chi-square and the Fisher’s exact tests. Results: We found an association of GRIN2A rs7206256 and rs11644461 and GRIN2B rs7313149 with the early onset (before the age of 18 years old) schizophrenia. We did not reveal any associations of GRIN2A and GRIN2B polymorphisms with leading (positive vs. negative) symptoms or type of course (continuous vs. episodic) of schizophrenia. Conclusions: In the study, we confirmed the involvement of the GRIN2A and GRIN2B genes in the early onset of schizophrenia in a Russian population of the Siberian region

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 demon-strated 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

Changes in Body Fat and Related Biochemical Parameters Associated With Atypical Antipsychotic Drug Treatment in Schizophrenia Patients With or Without Metabolic Syndrome

Background: Metabolic syndrome (MetS) is a common problem in schizophrenia patients and associated with increased mortality due to cardiovascular disease. Second-generation antipsychotics (SGAs) play an important role in facilitating MetS. Objective: The study aimed to assess weight changes and alterations of indicators of body fat composition and lipid-glucose metabolism induced by reinitiating atypical antipsychotics in patients with schizophrenia when with or without MetS. Methods: After giving informed consent, newly admitted patients with a clinical diagnosis of schizophrenia (ICD-10: F20) and an age between 18 and 55 years were included. MetS was diagnosed according to International Diabetes Federation (IDF) criteria. At entry and after 6 weeks of treatment, anthropometry and biochemical analysis were carried out. Total and visceral fats were measured with the use of non-invasive bioimpedance analysis and subcutaneous fat with calculation of total adipose tissue with the use of caliperometry. Based on biochemical assessments low density (LDL) and very low-density lipoproteins (VLDL), atherogenic index and Homeostatic Model Assessment of Insulin Resistance (IR-HOMA) were calculated. Statistical analysis was conducted using Wilcoxon signed-rank test, Mann-Whitney U-test, and chi-squared test. Differences were considered statistically significant at p < 0.05. Results: A total of 114 patients (59M/55F) with schizophrenia were examined; they were divided into two groups with (n = 43; 37.7%) and without (n = 71; 62.3%) MetS. After a 6-week SGA treatment, only the total fat fold, waist circumference, triglyceride level, and atherogenic index underwent statistically significant changes in patients with MetS. In those without MetS, statistically significant changes across all fat indicators were noted. Also, a significant increase in blood glucose and HOMA-IR parameters, triglyceride, and VLDL levels and atherogenic index was observed in this group. Discussion: The study illustrates the benefits of estimating both anthropometric and biochemical parameters shortly after (re)installing treatment of schizophrenia in order to minimize the risk of MetS development

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

Adipocytokines and Metabolic Syndrome in Patients with Schizophrenia

The adipokines leptin, adiponectin, tumor necrosis factor-alpha (TNF-alpha), 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-alpha 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-alpha, and IL-6. Our results support an important pathophysiological role for leptin more than adiponectin in patients with schizophrenia with MetS