A. Semke

Tardive dyskinesia and DRD3, HTR2A and HTR2C gene polymorphisms in Russian psychiatric inpatients from Siberia.

BACKGROUND Pharmacogenetics of tardive dyskinesia and dopamine D3 (DRD3), serotonin 2A (HTR2A), and 2C (HTR2C) receptors has been examined in various populations, but not in Russians. PURPOSE To investigate the association between orofaciolingual (TDof) and limb-truncal dyskinesias (TDlt) and Ser9Gly (DRD3), -1438G>A (HTR2A), and Cys23Ser (HTR2C) polymorphisms in Russian psychiatric inpatients from Tomsk, Siberia. METHODS In total, 146 subjects were included. Standard protocols were applied for genotyping. TDof and TDlt were assessed with AIMS items 1-4 and 5-7, respectively. Two-part model, logistic and log-normal regression analyses were applied to assess different variables (e.g., allele-carriership status, age, gender, and medication use). RESULTS TDlt, but not TDof, exhibited an association with Ser9Gly and Cys23Ser (with 9Gly and 23Ser alleles exhibiting opposite effects). However, -1438G>A was not associated with TDof and Dlt. CONCLUSIONS This is the first pharmacogenetic report on tardive dyskinesia in Russians. Subject to further replication, our findings extend and support the available data.

NMDA receptor genotypes associated with the vulnerability to develop dyskinesia

Dyskinesias are involuntary muscle movements that occur spontaneously in Huntingtons disease (HD) and after long-term treatments for Parkinsons disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three conditions originate from different neuronal pathways that converge on overstimulation of the motor cortex. We hypothesized that the same variants of the N-methyl-D-aspartate receptor gene that were previously associated with the age of dyskinesia onset in HD were also associated with the vulnerability for TD and not LID. Genotyping patients with LID and TD revealed, however, that these two variants were dose-dependently associated with susceptibility to LID, but not TD. This suggested that LID, TD and HD might arise from the same neuronal pathways, but TD results from a different mechanism.

Missense polymorphisms in three oxidative-stress enzymes (GSTP1, SOD2, and GPX1) and dyskinesias in Russian psychiatric inpatients from Siberia

Neuronal degeneration due to oxidative stress (OS) has been proposed as a mechanism for tardive dyskinesia (TD) pathogenesis. Cellular defense mechanisms against OS may involve detoxification enzymes (e.g., glutathione peroxidase‐1, GPX1; superoxide dismutase‐2, SOD2 [also commonly known as MnSOD]; and glutathione S‐transferase P1, GSTP1). Several pharmacogenetic studies have examined TD and OS in different ethnic groups, but not in Russians. Here we report the association between orofaciolingual (TDof) and limb‐truncal dyskinesias (TDlt) and polymorphisms of GSTP1 (Ile105Val), MnSOD (Ala‐9Val), and GPX1 (Pro197Leu) genes in 146 Russian inpatients from Siberia. We applied AIMS instrument to rate dyskinesias. Two‐part model analyses, logistic and multivariate parametric regressions were applied to assess the effects of different variables (e.g., genotype, age, gender, and medication use). Our analyses do not suggest that Pro197Leu (GPX1) is associated with TD. However, our analyses suggest that the 105Val‐allele of Ile105Val (GSTP1) may be associated with a lower risk and a severity of TDof and TDlt and that Ile105Val pharmacogenetics may be different in Slavonic Caucasians from that in American Caucasians. Furthermore, we find evidence for an association between Ala‐9Val (MnSOD) and TDof, but not TDlt. Subject to further replication, our findings extend the available knowledge on the pharmacogenetics of TD and oxidative stress. Copyright

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.

No involvement of the adenosine A2A receptor in tardive dyskinesia in Russian psychiatric inpatients from Siberia

The adenosine A2A receptor forms a heteromeric complex with the striatal dopamine D2 receptor. We examined whether a specific polymorphism in adenosine A2A receptor (2592 C/Tins) is associated with tardive dyskinesia.

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.

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.

Prolactin gene polymorphism (− 1149 G/T) is associated with hyperprolactinemia in patients with schizophrenia treated with antipsychotics

BACKGROUND Antipsychotic drugs can cause hyperprolactinemia. However, hyperprolactinemia was also observed in treatment-naive patients with a first schizophrenic episode. This phenomenon might be related to the role of prolactin as a cytokine in autoimmune diseases. Extrapituitary prolactin production is regulated by an alternative promoter, which contains the functional single nucleotide polymorphism -1149 G/T (rs1341239). We examined whether this polymorphism was associated with hyperprolactinemia in patients with schizophrenia. METHOD We recruited 443 patients with schizophrenia and 126 healthy controls. The functional polymorphism -1149 G/T (rs1341239) in the prolactin gene was genotyped with multiplexed primer extension, combined with MALDI-TOF mass spectrometry. Genotype and allele frequencies were compared between groups with the χ2 test and logistic regression models adjusting for covariates. RESULTS 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 significantly higher frequency of the G allele in patients with hyperprolactinemia than in patients without it (χ2=7.25; p=0.007; OR=1.44 [1.10-1.89]). Accordingly, patients with hyperprolactinemia carried the GG genotype more frequently than patients without hyperprolactinemia (χ2=9.49; p=0.009). This association remained significant after adjusting the estimates for such covariates as sex, age, duration of the diseases and the dose of chlorpromazine equivalents. CONCLUSION This study revealed a significant association between the polymorphic variant rs1341239 and the development of hyperprolactinemia in patients with schizophrenia. The serum prolactin concentration in patients with schizophrenia treated with antipsychotics may provide an indication of the activity of the gene that regulates extrapituitary prolactin production which is believed to play a role in the immune system.