Matej Kastelic

Acute antipyschotic efficacy and side effects in schizophrenia : Association with serotonin transporter promoter genotypes

BACKGROUND The serotonin transporter (5-HTT) plays an important role in serotonergic neurotransmission. In the present study, we investigated the effects of the 44 bp insertion/deletion polymorphism in the promoter region of 5-HTT gene (5-HTTLPR) on symptomatology of psychosis and clinical response to antipsychotic drugs. METHODS In total 56 patients acutely treated with haloperidol or risperidone either for the first episode of schizophrenia, schizophreniform or schizoaffective disorders, or for the relapse of these psychotic disorders after tapering their maintenance treatment, were genotyped for the 5-HTTLPR L and S alleles and for the new A/G functional variant within the L alelle (La/g). Psychopathological symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) and with Clinical Global Impression (CGI) twice: at 8-12 days after the first dose of antipsychotic and after 4 weeks. Extrapyramidal side effects were assessed with the Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS). RESULTS Age, body mass index (BMI), illness duration, drug type and dosage were considered as covariates when analysing association with genetic variants as they were associated with baseline or final BPRS and CGI scores and/or extrapyramidal side effects. 5-HTTLPR was not associated with baseline and final BPRS and CGI scores or with the CGI% reduction. However, the 5-HTTLPR S allele was associated with a lower improvement in BPRS scores (P=0.022) and this effect was even stronger after pooling subjects with S or Lg containing alleles (P=0.006). We did not observe any effect of 5-HTTLPR on acute antipsychotics side effects. CONCLUSION Present result supports a contribution of serotonin system to neuroleptics efficacy for the treatment of schizophrenia. The analysis of the La/g functional variant may significantly improve the predictive power of 5-HTTLPR genotyping and represent a step further towards the development of the personalized antipsychotic treatment.

MDR1 gene polymorphisms and response to acute risperidone treatment

Polymorphic multidrug resistant protein 1 (MDR1) transports drugs against a concentration gradient across the blood-brain barrier and reduces their accumulation in the brain. MDR1 may therefore influence antipsychotic brain availability contributing to inter-individual differences in treatment response and adverse effects, regardless of plasma concentrations. In the present study we investigated the influence of two common MDR1 polymorphisms on the improvement of psychopathological symptoms and occurrence of extrapyramidal side effects (EPS) in Slovenian schizophrenia patients acutely treated with risperidone. A total of 59 clinically well defined patients with first episode schizophrenia spectrum disorders or after tapering their maintenance treatment were genotyped for MDR1 C3435T and G2677T/A. Steady-state plasma concentrations of risperidone active moiety (sum of risperidone and the 9-hydroxyrisperidone) were determined. G2677T/A and C3435T genotypes were not associated to psychopathological symptoms, efficacy of treatment and risk for parkinsonism. Marginal associations with akathisia (p=0.039 and p=0.042, respectively) and dystonia (p=0.013 and p=0.034, respectively) were observed for both G2677T/A and C3435T genotypes. However, higher AIMS and BARS scores were observed only in heterozygous carriers of G2677T/A and C3435T polymorphisms and there was no tendency of gene-dose effect. The present study does not suggest a major influence of MDR1 G2677T/A and C3435T polymorphisms on treatment response during short-term risperidone therapy in patients with schizophrenia or schizoaffective disorder.

A population pharmacokinetic evaluation of the influence of CYP2D6 genotype on risperidone metabolism in patients with acute episode of schizophrenia

The objective of this prospective study was to characterize the metabolism of risperidone to (+)- and (-)-9-hydroxyrisperidone in vivo and to evaluate the influence of CYP2D6 genotype. A population pharmacokinetic modeling approach was used to estimate the interindividual variability of the pharmacokinetic parameters in 50 hospitalized patients with acute episode of schizophrenia. CYP2D6 genotype remarkably influenced the formation clearances of the risperidone metabolites, while creatinine clearance was related to the plasma clearance of 9-hydroxyrisperidone. CYP2D6 genotype was also associated with the average plasma concentration of risperidone active moiety (a sum of all three active compounds). In comparison to the patients with CYP2D6*1/*1 genotype, average steady-state plasma concentration of risperidone active moiety was 3.3- and 1.6-fold higher in poor metabolizers (both alleles nonfunctional; CYP2D6*3 or *4) and intermediate metabolizers (one nonfunctional allele and one allele for diminished enzyme activity; CYP2D6*10 or *41), respectively. Additionally, average plasma concentration of risperidone active moiety was higher in the patients with dystonia (p=0.0066) and parkinsonism (p=0.046). The results of this study imply the potential role of CYP2D6 genotyping in personalizing risperidone therapy in patients with schizophrenia to reduce the incidence of adverse extrapyramidal symptoms.

Genetic Variability Testing of Neurodevelopmental Genes in Schizophrenic Patients

This study investigated the associations between single nucleotide polymorphisms in the neurodevelopmental Disrupted In Schizophrenia 1 (DISC1), neuregulin 1 (NRG1), brain-derived neurotrophic factor (BDNF) and NOTCH4 genes and the clinical symptoms and the occurrence of treatment-resistant schizophrenia in the Slovenian population. We included 138 schizophrenia patients, divided into treatment-responsive and treatment-resistant group and 94 healthy blood donors. All subjects were genotyped for eight polymorphisms (DISC1 rs6675281, DISC1 rs821616, NRG1 rs3735781, NRG1 rs3735782, NRG1 rs10503929, NRG1 rs3924999, BDNF rs6265, NOTCH rs367398) and investigated for associations with clinical variables. NOTCH4 rs367398 AA/AG was significantly associated with worse Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) score. NOTCH4 rs367398 was not statistically significantly associated with the occurrence of treatment-resistant schizophrenia after the correction for multiple testing. Our data indicate that NOTCH4 polymorphism can influence clinical symptoms in Slovenian patients with schizophrenia.

Genetic Variability in CYP2E1 and Catalase Gene Among Currently and Formerly Alcohol-Dependent Male Subjects

AIMS The present study explored whether specific single-nucleotide polymorphisms in alcohol metabolic pathway are associated with alcohol dependence or alcohol-related psychopathological symptoms. METHODS Three groups of male unrelated subjects were included: 101 currently alcohol-dependent patients, 100 formerly alcohol-dependent subjects and 97 healthy controls. The following questionnaires were implemented: AUDIT, Zung Depression and Anxiety scale, Brief Social Phobia Scale, Yale-Brown Obsessive Compulsive Scale, Obsessive Compulsive Drinking Scale and Buss-Durkee Hostility Inventory. All the subjects were genotyped for CYP2E1 c.-1053C>T and CAT c.-262C>T. RESULTS Statistically significant differences in the distribution of genotypes and alleles for CAT c.-262C>T polymorphism were observed among the three investigated groups. We observed a higher frequency of CAT -262T allele in alcohol-dependent subjects (OR = 1.74, 95% CI = 1.164-2.610). Among currently dependent patients CAT -262T allele carriers had higher AUDIT scores (P = 0.023), while CYP2E1-1053T allele carriers had significantly higher YBOCS-obsession subscale scores (P = 0.005) and Zung Anxiety Scale scores (P = 0.011). CONCLUSIONS Our findings suggest that the CAT c.-262C>T genetic polymorphism influences the susceptibility to alcohol dependence and severity of alcohol dependence, while CYP2E1 c.-1053C>T polymorphism influences the expression of obsessive-compulsive and anxiety symptoms.

Influence of 5-HT1A and 5-HTTLPR genetic variants on the schizophrenia symptoms and occurrence of treatment-resistant schizophrenia

This study aimed to explore the influence of two genetic polymorphisms of the 5-hydroxytryptamine 1A receptor (5-HT1A) and solute carrier family 6, member 4 (SLC6A4) genes on the clinical symptoms and treatment resistance in Slovenian patients with schizophrenia. A total of 138 patients with schizophrenia were evaluated using the Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Clinical Global Impression, and Global Assessment of Functioning. Based on the selected criteria, 94 patients were included in the treatment-responsive and 44 in the treatment-resistant group. All subjects and 94 controls were genotyped for the 5-HT1A rs6295 and 5-HTTLPR polymorphisms. There were no statistically significant differences in the frequencies of these polymorphisms between the patients with schizophrenia and the control group and between the treatment-resistant and treatment-responsive group of schizophrenia patients. Polymorphisms rs6295 and 5-HTTLPR had an influence on the Global Assessment of Functioning scale score, while 5-HTTLPR also had an influence on the total score of the negative subscale within the Positive and Negative Syndrome Scale. Although we found no effect on progression toward the treatment-resistant schizophrenia, our data suggest that the rs6295 and 5-HTTLPR polymorphisms can influence some clinical symptoms in schizophrenia.

Genetic variability in tryptophan hydroxylase 2 gene in alcohol dependence and alcohol-related psychopathological symptoms.

Heritability plays an important role in the development and expression of alcohol dependence. The present genetic association study explored the role of TPH2 polymorphisms and their haplotypes to investigate its role in alcohol dependence and comorbid psychopathological symptoms. The sample included 101 subjects currently diagnosed as alcohol abusers, 100 abstinent alcohol-dependent subjects and 97 healthy controls. Subjects were genotyped for TPH2 rs4570625, rs1843809, rs7305115, rs4290270. TPH2 genotypes were not associated with alcohol dependence, but GGAA haplotype was less common (p=0.038) and GTAA and GGGT were more common (p=0.011 and p=0.021, respectively), in currently dependent patients compared to controls. Exploratory analysis of genotypes in currently dependent patients showed that rs1843809 was associated with depressive and aggressive traits (p=0.045 and p=0.001, respectively), rs4290270 with depressive and anxiety traits (p=0.040 and p=0.025, respectively) and rs4570625 with aggressive traits (p=0.011). In abstinent subjects rs1843809 genotype was associated with traits of social anxiety (p=0.003). Only association between rs1843809 and the BDHI score (p=0.001) and associations between GTAA haplotype and Zung Anxiety Scale and BDHI score (p=0.001 and p<0.001, respectively), in currently dependent patients remained significant after applying the Bonferronis correction. Our findings support a potential role of TPH2 in alcohol dependence. TPH2 genetic variability may be also associated with anxiety and aggression traits in alcohol dependent subjects.

Alcohol Dependence and Genetic Variability in the Serotonin Pathway among Currently and Formerly Alcohol-Dependent Males

Background: Genes involved in the serotonin pathway may determine the susceptibility to alcohol dependence and its severity. The present study explored whether specific polymorphisms in the serotonin pathway could be associated with alcohol dependence or alcohol-related psychopathological symptoms. Methods: The cohort comprised 101 currently and 100 formerly alcohol-dependent males, as well as 97 male healthy blood donors. The following questionnaires were employed: the Alcohol Use Disorders Identification Test, the Zung Depression and Anxiety Scale, the Brief Social Phobia Scale, the Yale-Brown Obsessive Compulsive Scale and Obsessive Compulsive Drinking Scale, and the Buss-Durkee Hostility Inventory. Subjects were genotyped for bi- and triallelic SLC6A4 5-HTTLPR,HTR1A rs6295, and HTR1B rs13212041. Results: Statistical differences in bi- and triallelic SLC6A4 5-HTTLPR genotype distribution were observed between the 3 groups investigated (p = 0.008 and p = 0.023, respectively); however, no gene-dose effect was observed. The severity of the alcohol problems was higher in currently alcohol-dependent subjects with the 5-HTTLPR LL (p = 0.039) and L′L′ genotypes (p = 0.027). Formerly dependent subjects with the 5-HTTLPR S′S′ genotype showed more social anxiety, depressive, and anxiety traits (p = 0.009, p = 0.006, and p = 0.036, respectively). Healthy controls with the 5-HTTLPR SS genotype showed more traits of social anxiety (p = 0.020). Conclusions: Our findings suggest that bi- and triallelic SLC6A4 5-HTTLPR has some effects on the severity of alcohol dependence. Triallelic 5-HTTLPR was associated with social anxiety, anxiety, and depressive traits in alcohol-dependent subjects.