Piotr Tybura

Influence of DRD2 and ANKK1 genotypes on apomorphine-induced growth hormone (GH) response in alcohol-dependent patients

BACKGROUND D(2) receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail. METHODS Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12. RESULTS Associations (p<0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D(2) receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects. CONCLUSION This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D(2) receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results.

Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients.

BACKGROUND Therapeutic effects of all clinically used antipsychotics are related to the reduction of dopaminergic transmission in the limbic system. The aim of present study was two-fold. First, efficacy of atypical drugs (ziprasidone and olanzapine) against schizophrenia symptoms was compared to that offered by a typical antipsychotic medication, perazine. Second, associations between some dopaminergic genes polymorphisms and therapeutic response to antipsychotics were assessed in the same group of schizophrenia patients. METHODS One hundred ninety one Caucasian patients admitted with exacerbation of paranoid schizophrenia were genotyped for polymorphisms of the DRD2 [the ins/del -141C (rs1799732) and exon 8 (rs 71653615)], DRD2/ANKK1 Taq IA(rs 1800497), DAT1 (the 40 bp VNTR), COMT (rs 4680), and MAOA gene (the 30 bp VNTR in promoter). The patients were randomly assigned to the treatment with perazine, olanzapine or ziprasidone given as monotherapy for 3 months. Treatment efficacy was measured from baseline (T0) to T1 (14 days) and T2 (3 months). A retention rate was also assessed at T1 and T2. RESULTS The three antipsychotics did not differ in terms of reduction of the PANSS score or retention rate at the follow-up. There was no interaction between the investigated polymorphisms and response to the antipsychotic treatment. CONCLUSIONS The present results suggest that: i) there are no major differences in short-term efficacy or effectiveness of atypical (olanzapine, ziprasidone) and typical (perazine) antipsychotic drugs; ii) the studied polymorphisms are not primarily involved in treatment response to antipsychotics in schizophrenia patients.

BDNF rs 6265 polymorphism and COMT rs 4680 polymorphism in deficit schizophrenia in Polish sample

BACKGROUND Deficit schizophrenia (DS) is distinguished from the group of schizophrenic psychoses based on the presence of primary negative symptoms. It differs from nondeficit (NDS) forms of schizophrenia in dimensions such as risk factors, family history, course of illness and neurobiological differences. The aim of the study was assessment of a potential association of the investigated polymorphisms of the brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes with the deficit syndrome in schizophrenia. METHODS A cohort of 200 patients with schizophrenia (81 DS and 119 NDS subjects) and a group of 100 control subjects matched for ethnicity, sex and age were recruited. Somatic and psychometric assessment were conducted as well as structured interview about the influence of adverse biological, family and social factors. Genetic analysis of the BDNF (Val66Met) rs6265 and the COMT (Val158Met) rs4680 polymorphisms was performed. RESULTS We found significant differences between DS and NDS in rs4680 COMT genotype distribution: more homozygous Val/Val were found (31 vs. 17%) in the NDS compared to the DS subgroup. No associations were found between the investigated polymorphisms of the BDNF gene and the presence of schizophrenia either in DS and NDS subgroups. CONCLUSION The analysis of the COMT rs4680 polymorphism in the present DS and NDS study shows that some genetic factors may be relevant in analyzing the reasons for the differentiation of schizophrenic subtypes.

Pharmacogenetics of adverse events in schizophrenia treatment: Comparison study of ziprasidone, olanzapine and perazine

The primary aim of the present study was to assess the possible associations between dopaminergic, serotonergic, and glutamatergic system-related genes and adverse events after antipsychotic treatment in paranoid schizophrenia patients. The second aim of the study was to compare the intensity of these symptoms between atypical (ziprasidone and olanzapine) and typical (perazine) antipsychotic drugs. One-hundred and ninety-one Polish patients suffering from paranoid schizophrenia were genotyped for polymorphisms of DRD2, DAT1, COMT, MAOA, SERT, 5HT2A, and GRIK3. The patients were randomized to treatment with perazine, olanzapine or ziprasidone monotherapy for 3 months. The intensity of side effects (changes in body weights and extrapyramidal symptoms (EPS)) was measured at baseline and after 12 weeks of antipsychotic treatment. After 3 months of therapy, the weight increase was the greatest in the group treated with olanzapine and the least in the group treated with ziprasidone. None of the examined gene polymorphisms was associated with the body weight changes. Perazine treatment was associated with the significantly highest intensity of EPS. None of the examined polymorphisms was associated with the changes in extrapyramidal adverse events after antipsychotic treatment. The selected polymorphisms are not primarily involved in changes in body weights and EPS related to antipsychotic treatment in paranoid schizophrenia patients.

Functional polymorphism of matrix metalloproteinase-9 (MMP9) gene is not associated with schizophrenia and with its deficit subtype

BACKGROUND The deficit subtype of schizophrenia is hypothesized to constitute a pathophysiologically distinct subgroup of schizophrenia patients suffering from enduring, idiopathic negative symptoms and various neuropsychological deficits. Matrix metalloproteinases (MMPs) are extracellularly acting endopeptidases the substrates of which are matrix and adhesion molecules. Recently, MMP9 has been shown to be involved in various forms of synaptic plasticity, learning and memory consolidation. The primary aim of the present study was to evaluate associations between the functional MMP-9 -1562C/T gene polymorphism and the deficit and non-deficit subtypes of schizophrenia. METHODS The study was conducted between 2009 and 2012. Deficit schizophrenia was diagnosed using the SDS. The sample consisted of 468 patients, Caucasians, of Polish descent with ICD 10 diagnosis of schizophrenia: 189 [51% males] were included in a non-deficit subgroup, 279 patients [53% males] were included in a deficit subgroup. The control group consisted of 532 subjects, Caucasians, of Polish descent [51% males]. MMP-9 -1562C/T gene polymorphism was genotyped using the fluorescence resonance energy transfer (FRET) method and the Light Cycler System 2.0. RESULTS The frequencies of genotypes and alleles did not differ between the schizophrenia patients and control group. The deficit and non-deficit patients did not differ in terms of the genotype and allele frequencies. No differences were found in genotype and allele frequencies between the deficit patients and the controls and between the non-deficit patients and the controls. CONCLUSION We found no evidence for the association between the functional MMP-9 -1562C/T gene polymorphism and deficit/non-deficit subtypes of schizophrenia.

Effects of antipsychotics on insight in schizophrenia: results from independent samples of first-episode and acutely relapsed patients.

We aimed to investigate whether antipsychotics differentially impact insight and whether these effects appear because of improvement in psychopathological manifestation in 132 first-episode schizophrenia patients and 201 acutely relapsed schizophrenic patients, who were followed up for 12 weeks. Olanzapine and risperidone were administered to first-episode schizophrenia patients, whereas acutely relapsed schizophrenic patients were treated with olanzapine, perazine and ziprasidone. The Positive And Negative Syndrome Scale (PANSS) was used to assess psychopathology. Insight was assessed using the G12 item of PANSS. Unadjusted mixed-model regression analysis indicated a significant improvement in the PANSS G12 item score in both groups. There were no significant differences between distinct treatment subgroups of patients in terms of improvement in the PANSS G12 item score. After adjustment for the trajectories of changes in symptom dimensions, a decrease in the PANSS G12 item score was because of an improvement in positive, negative and excitement symptoms. A decrease in the PANSS G12 item score was also related to an increase in the severity of depressive symptomatology. Our results indicate that antipsychotics exert similar effects on insight in acute psychosis. These effects are likely because of an improvement in psychopathological manifestation. The improvement in insight might be related to the development of depressive symptoms.

Pharmacogenetics of Adverse Events in Schizophrenia Treatment: Comparison Study of Ziprasidone, Olanzapine and Perazine

The primary aim of the present study was to assess the possible associations between dopaminergic, serotonergic, and glutamatergic system-related genes and adverse events after antipsychotic treatment in paranoid schizophrenia patients. The second aim of the study was to compare the intensity of these symptoms between atypical (ziprasidone and olanzapine) and typical (perazine) antipsychotic drugs. Methods One hundred ninety-one Polish patients suffering from paranoid schizophrenia were genotyped for polymorphisms of DRD2, DAT1, COMT, MAOA, SERT, 5HT2A, and GRIK3. The patients were randomized to treatment with perazine, olanzapine or ziprasidone monotherapy for 3 months. The intensity of side effects (changes in body weights and extrapyramidal symptoms) was measured at baseline and after 12 weeks of antipsychotic treatment. Results After 3 months of therapy, the weight increase was the greatest in the group treated with olanzapine and the least in the group treated with ziprasidone. None of the examined gene polymorphisms was associated with the body weight changes. Perazine treatment was associated with the significantly highest intensity of extrapyramidal symptoms. None of the examined polymorphisms was associated with the changes in extrapyramidal adverse events after antipsychotic treatment. Conclusion The selected polymorphisms are not primarily involved in changes in body weights and extrapyramidal symptoms related to antipsychotic treatment in paranoid schizophrenia patients.

P03-327 - Searching for the genetic markers connected with paranoid schizophrenia and conditioning the treatment efficiency

Aim The aim of the study was to find genetic markers which can influence on susceptibility of paranoid schizophrenia and the treatment efficiency measured by the PANSS. We analyzed genes polymorphisms: DRD2 (Taq 1A, in egzon 8, - 141 C ins/del), DAT, GRIK3, SERT, 5HT2A, MAO-A, COMT. Method One hundred and ninety one patients with the diagnosis of paranoid schizophrenia were recruited as study group. To obtain the diagnosis meeting the criteria to ICD-10 we used the polish version of CIDI - Composite International Diagnostic Interview. Exclusion criteria included serious neurological disorders, major somatic disorders impairing cognitive functions and diagnosed mental impairment. The intensity of psychopathological symptoms was examined using the PANSS. Genomic DNA was extracted from leucocytes using the Millers salting method. Polymorphisms were studied by the PCR method. Statistical analyses were performed by the Statistica computer program, specifically Pearsons chi-square test. Associations between the treatment progress and the genotype were studied by analysis of variance (ANOVA). Results We didn’t find associations between investigated genes polymorphisms and susceptibility of paranoid schizophrenia. Probably, there is no influence of studied polymorphisms on the treatment efficiency. Conclusions No differences were found in the genotypes distribution in investigated genes polymorphisms between the whole schizophrenics and the control group. No association was found between any particular genotype and the effect of antipsychotic treatment.

P03-119 - Pharmacogenetic studies of olanzapine, perazine and ziprasidone in paranoid schizophrenia

Literature data revealed that efficacy and side effects of antipsychotic treatment are influenced by multiple genes interactions. Polymorphic variation is likely to contribute substantially in this matter. Pharmacogenetic studies will help to determine which drug and dosage are best for each individual patient. The aim of our study was to find: 1. Genetic markers influencing susceptibility of paranoid schizophrenia. The polymorphisms of DRD2 (-141C del/ins, Taq1A, egzon8), DAT, 5HT2a, 5HTT_LPR, COMT, MAO A and GRIK3 genes were studied. 2. Relationships between different gene variants and the treatment efficacy measured by the PANSS. The group of 201 patients with paranoid schizophrenia consisted of 95 men (mean age 34) and 105 women (mean age 35). There were no significant differences between the groups according to the studied gender. Males patients had a significantly earlier age of onset but the duration of illness was similar in both gender groups. The patients were treated randomly with perazine, olanzapine or ziprasidone. The control group consist of 230 healthy volunteers ethnically, gender and age matched. Results 1. No differences were found in the allelic distribution in the investigated genes polymorphisms between the whole schizophrenics and the control group. 2. Associations between DAT: A9 allele, DRD2: del 141C allele, DRD2: Taq1A A1 allele, COMT: Met/Met genotype, MAOA: 4VNTR allel (males only) and GRIK3: SER allel with non responding patients were found.