N. Bokhan

DNA-hydrolysing activity of IgG antibodies from the sera of patients with schizophrenia

It is believed that damage to the membranes of brain cells of schizophrenia (SCZ) patients induces the formation of autoantigens and autoantibodies. Nevertheless, the importance of immunological changes leading to the loss of tolerance to self-antigens in the genesis of SCZ has not been established. The MALDI mass spectra of the IgG light chains of 20 healthy donors were relatively homogeneous and characterized by one peak with only one maximum. In contrast to the healthy donors, the MALDI mass spectra of IgG light chains corresponding to 20 SCZ patients demonstrated, similarly to 20 autoimmune systemic lupus erythematosus (SLE) patients, two maxima of a comparable intensity. In addition, the MALDI spectra of the IgG light chains of five SLE and four SCZ patients contained a small additional brightly pronounced peak with remarkably lower molecular mass compared with the main one. DNase autoantibodies (abzymes) can be found in the blood of patients with several autoimmune diseases, while the blood of healthy donors or patients with diseases without a significant disturbance of the immune status does not contain DNase abzymes. Here, we present the first analysis of anti-DNA antibodies and DNase abzymes in the sera of SCZ patients. Several strict criteria have been applied to show that the DNase activity is an intrinsic property of IgGs from the sera of SCZ patients. The sera of approximately 30% of SCZ patients displayed a higher content of antibodies (compared with 37% of SLE) interacting with single- and double-stranded DNA compared with healthy donors. Antibodies with DNase activity were revealed in 80% of the patients. These data indicate that some SCZ patients may show signs of typical autoimmune processes to a certain extent.

Association Study Indicates a Protective Role of Phosphatidylinositol-4-Phosphate-5-Kinase against Tardive Dyskinesia

Background: Tardive dyskinesia is a disorder characterized by involuntary muscle movements that occur as a complication of long-term treatment with antipsychotic drugs. It has been suggested to be related to a malfunctioning of the indirect pathway of the motor part of the cortical-striatal-thalamic-cortical circuit, which may be caused by oxidative stress-induced neurotoxicity. Methods: The purpose of our study was to investigate the possible association between phosphatidylinositol-4-phosphate-5-kinase type IIa (PIP5K2A) function and tardive dyskinesia in 491 Caucasian patients with schizophrenia from 3 different psychiatric institutes in West Siberia. The Abnormal Involuntary Movement Scale was used to assess tardive dyskinesia. Individuals were genotyped for 3 single nucleotide polymorphisms in PIP5K2A gene: rs10828317, rs746203, and rs8341. Results: A significant association was established between the functional mutation N251S-polymorphism of the PIP5K2A gene (rs10828317) and tardive dyskinesia, while the other 2 examined nonfunctional single nucleotide polymorphisms were not related. Conclusions: We conclude from this association that PIP5K2A is possibly involved in a mechanism protecting against tardive dyskinesia-inducing neurotoxicity. This corresponds to our hypothesis that tardive dyskinesia is related to neurotoxicity at striatal indirect pathway medium-sized spiny neurons.

Dehydroepiandrosterone sulphate as a putative protective factor against tardive dyskinesia

BACKGROUND Tardive dyskinesia (TD) is a potentially irreversible consequence of long term treatment with antipsychotic drugs which is according to a well-known theory believed to be related to oxidative stress induced neurotoxicity. Dehydroepiandrosterone (DHEA) is an endogenous antioxidant with neuroprotective activity. The biosynthesis of DHEA depends upon the activity of cytochrome P450c17α (CYP17). The gene that encodes for CYP17 has a (T34C) single nucleotide polymorphism which enhances CYP17 transcription and expression. OBJECTIVE To test the hypothesis that carriership of a more active CYP17 variant would result in higher DHEA(S) levels and protect against neurotoxicity which results in orofaciolingual TD (TDof), limb-truncal TD (TDlt) or both (TDsum). METHOD Tardive dyskinesia was assessed cross-sectionally in 146 Caucasian psychiatric inpatients from Siberia. RESULTS Patients who are carriers of the Cyp17 genotype CC have less chance of developing TD compared to patients who are carriers of the Cyp17 genotypes TC or TT (p<0.05). However, these carriers have significant lower circulating DHEAS levels compared to carriers of the Cyp17 genotypes TC and TT (p<0.05). Conversely, carriers of the CYP17 T-allele have significant elevated DHEAS levels. After correcting for gender and age no significant relationship between Cyp17 genotype CC, the T-allelle and the C-allele and the DHEAS concentration of patients was observed. CONCLUSIONS Although an association between the CYP17 CC genotype and TD is indicated, our findings do not support the hypothesis that this is mediated through increased DHEA(S) levels. We believe that the relationship between this polymorphism and neuroprotective effects of steroids is more complex and cannot be elucidated without taking the posttranslational regulation of the enzyme into account.

Neurosteroids Dehydroepiandrosterone and Its Sulfate in Individuals with Personality Disorders Convicted of Serious Violent Crimes

We studied blood serum levels of neurosteroids, dehydroepiandrosterone and its sulfate, in individuals with personality disorders convicted of serious violent crimes. The data were compared with that of a group of mentally and physically healthy persons convicted of acquisitive crimes, and with that of the control group. Significant increase in DHEA in both groups of convicts in comparison with the control was shown. The level of dehydroepiandrosterone sulfate remained unchanged. Increased dehydroepiandrosterone level in the convicted individuals with personality disorders is probably more associated with detention stress than directly with psychopathology or criminal aggression.

Identification of 5-hydroxytryptamine receptor gene polymorphisms modulating hyperprolactinaemia in antipsychotic drug-treated patients with schizophrenia

Abstract Objectives: Hyperprolactinaemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 subtype receptors in the pituitary gland. Although dopamine is considered the primary factor inhibiting prolactin release, the activity of prolactin-producing lactotrophs is also regulated by the secretagogues thyrotrophin releasing hormone, vasoactive intestinal polypeptide and serotonin (5-hydroxytryptamine; 5-HT). Methods: We describe the association between HPRL and a set of 29 SNPs from 5-HT receptor genes HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B and HTR6 in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) who were treated with classical and/or atypical antipsychotic drugs. Results: None of the studied autosomal markers were found to be associated with HPRL. However, a significant association was established between various HTR2C polymorphisms and HPRL. Conclusions: This study revealed an association between HPRL and X-chromosome haplotypes comprised of the rs569959 and rs17326429 polymorphisms.

Cytochrome P450 1A2 co-determines neuroleptic load and may diminish tardive dyskinesia by increased inducibility

Abstract Objectives. The aim of this study was to investigate a possible association between tardive dyskinesia (TD) and CYP1A2 (*1F, -163C>А, rs762551) polymorphism in Russian psychiatric inpatients. Methods. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale (AIMS). Orofacial and limb-truncal dyskinesia were assessed with AIMS 1–4 and 5–7, respectively. Standard protocols were applied for genotyping. Analysis of covariance (ANCOVA) was used to compare the mean AIMS scores for each of the genotypic classes. Results. A total of 319 Caucasian patients from West Siberia with schizophrenia and 117 healthy volunteers were investigated. No significant differences between the patients and the controls in genotype frequencies were found. Analysis of covariance (ANCOVA) with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates showed that limb-truncal, but not orofacial TD, is associated with CYP1A2 (−163C>, rs762551) polymorphism (F = 3.27, P = 0.039). Patients with the C/C genotype had a higher mean AIMS 5–7 score than those with the A/C or the A/A genotype. Conclusions. Our results support the hypothesis that not only with clozapine, but also with other classical and atypical antipsychotics, smoking may decrease plasma levels; this is most extensively expressed in carriers of the CYP1A2*1F (-163C> A) polymorphism.

Association of Cytokine Production with Hormone Level and Sensory Responses during the Formation of Psychoactive Drug Addiction in Men

We performed immunophysiological examination of 144 men aged 17–25 years, patients with psychoactive substance dependence, episodic psychoactive drug users, and conditionally healthy individuals. Associations of proinflammatory cytokine production with age, sex, hormone levels, and olfactory and nociceptive indices were revealed in cases of psychoactive drug use and formation of addiction. Predictive models based on the use of androstenone aversion, pressure algometry testing, and immunological parameters were proposed.

1581 – Steroid hormones levels in alcohol dependent patients under conditions of social isolation

According to literature data, steroid hormones are involved in development of aggressive behavior. In addition, it is shown that alcoholism is associated with alterations in the activity of hypothalamic-pituitary-adrenal axis during chronic alcohol consumption and in withdrawal period as well. Objective The research aims to investigate the correlations between steroid hormones level alterations and aggression level among alcoholic patients under conditions of social isolation. Material and methods Serum levels of cortisol and testosterone were measured in alcohol dependent males with aggressive behavior (n=60) and in alcohol-dependent non-aggressive males (n=27) being under conditions of social isolation. The control group consisted of 24 alcoholic patients during alcohol withdrawal. The hormone serum levels were measured with ELISA method. Statistical processing of results was carried out with software package SPSS for Windows. Results In comparison with the control group, increase of cortisol concentration in patients under conditions of social isolation has been observed. Patients with aggressive behavior have shown the trend toward cortisol level increase as against nonaggressive alcohol-dependent males. Concentration of testosterone in the investigated groups did not differ from the one of control group. Conclusions Increase of cortisol level in the investigated groups is apparently a consequence of influence of the factor of social isolation, but also it might be associated with aggressiveness tendency of alcoholic patients. Steroid hormones may play a significant role in aggressive behavior of alcohol-dependent patients in the conditions of social isolation.

Association of polymorphic variants of PIP5K2A and HTR2C genes with response to antidepressant therapy of patients with a current depressive episode

AIM To study the association between polymorphisms of PIP5K2A and HTR2C genes and response to antidepressant therapy in patients with a current depressive episode. MATERIAL AND METHODS The study included 222 patients (168 women and 54 men) with a current depressive episode. The assessment of the severity of the current depressive episode and the efficacy of treatment was performed using the Hamilton depression scale (HDRS-17) and the Clinical global impression scale (CGI-S, CGI-I). The association of treatment efficacy with PIP5K2A polymorphisms rs10430590, rs10828317 and HTR2C polymorphisms rs6318, rs569959, rs3813929, rs12858300 was studied. RESULTS AND CONCLUSION Polymorphisms rs10828317 and rs10430590 in the PIP5K2A gene were associated with the CGI-S total score at day 28 of therapy. Polymorphism rs6318 in the HTR2C gene was associated with response to antidepressant therapy followed by clinical improvement of patients with current depressive episode on the 28th day of antidepressant therapy.

Dried blood spot analysis for therapeutic drug monitoring of Clozapine

BACKGROUND Schizophrenia is a psychiatric disorder that affects approximately 0.4%-1% of the population worldwide. Diagnosis of schizophrenia is based primarily on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Clozapine is an antipsychotic drug that is mainly used in the treatment of schizophrenia patients who are refractory or intolerant to at least 2 other antipsychotics. Due to the high variability in pharmacokinetics of clozapine, therapeutic drug monitoring (TDM) is highly recommended for clozapine therapy. OBJECTIVE To develop and clinically validate a novel sampling method using dried blood spot (DBS) to support TDM of clozapine and norclozapine. METHODS From June 2014 to September 2014, 15 schizophrenia patients (18-55 years) treated with clozapine were included. Plasma, DBS samples made from venous samples (VDBS), and finger prick DBS (DBS) samples were obtained before administration and 2, 4, 6, and 8 hours after clozapine intake. The study was repeated in 6 Russian patients for external validation. Passing-Bablok regression and Bland-Altman analysis were used to compare the DBS, VDBS, and plasma results for clozapine and norclozapine. RESULTS The DBS validation results showed good linearity over the concentration time curve measured for clozapine and norclozapine. The accuracy and between- and within-day precision variation values were within accepted ranges. Different blood spot volumes and hematocrit values had no significant influence on the results. The DBS samples were stable at 20°C and 37°C for 2 weeks and at -20°C for 2 years. The mean clozapine and norclozapine DBS/plasma ratios were, respectively, 0.80 (95% CI, 0.76 to 0.85) and 1.063 (95% CI, 1.027 to 1.099) in Dutch patients. The mean clozapine DBS/DPS ratio in Russian patients was 0.70 (95% CI, 0.64 to 0.76). CONCLUSION DBS analysis is a reliable tool for blood sampling and performing TDM of clozapine and norclozapine in daily practice and substantially extends the opportunities for TDM of clozapine.