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.

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.

[Retrospective assessment of the antidepressants tolerance in the group of patients with diagnosis of depression and different CYP2D6 genotype]. / Retrospektywna ocena tolerancji leczenia lekami przeciwdepresyjnymi u pacjentów z rozpoznaniem depresji, z róznym genotypem CYP2D6.

AIM: The majority of antidepressants undergo the oxidative biotransformation catalysed by cytochrome P-450, particularly by izoenzyme CYP2D6, whose activity is genetically determined. In many cases poor tolerance of antidepressants depends on CYP2D6 activity. The aim of the study was the evaluation of the relationship between the CYP2Dg genotype and the occurrence of side effects during antidepressive pharmacotherapy. METHOD: Eighty nine patients were included into study. During the last episode of depression all included patients were treated with antidepressants, whose metabolism is catalysed mainly by CYP2D6. Based on medical records and patient interview the occurrence of side effects was evaluated. The genetic material was isolated from the patients' saliva. Genotyping of CYP2D6 was performed using the PCR techniques. The most frequent inactive alleles in the Caucasian population, *3 and *4 were identified. Alleles that were not identified as *3 or *4 were stated as active allele *1. RESULTS: Based on retrospective analysis among patients treated with antidepressants during the last episode of depression 42 patients (47.2%) reported severe side effects. Comparing to the group of patients with wide type genotype (*1/*1), in the group with the genotype including at least one inactive allele, side effects occurred significantly more frequently. CONCLUSION: In this group, comparing to the group of patients with wide type genotype, severe side effects that required discontinuation of antidepressants also occurred significantly more frequently.

[Assessment of efficacy and tolerability of mirtazapine treatment of patients with depression]. / Ocena skutecznosci i tolerancji leczenia mirtazapina u pacjentów z rozpoznaniem zaburzen depresyjnych.

The paper presents results of the study on the efficacy and tolerability of mirtazapine treatment of patients with depression. The study was open and conducted in three centers. 65 out- and in-patients with diagnosis of depression was included. 50% reduction of the score in the HAM-D scale was obtained in 57%, according to MADRS scale--in 61% patients. Side effects were reported in 49% patients. The most frequent side effects were: drowsiness, fatigue, anxiety, sleepiness, weight increase, headache. The results of the study are comparable with other mirtazapine studies.

[The relevance of genetically determined polymorphism CYP2D6 in psychopharmacology; the relationship between genotype and phenotype]. / Znaczenie genetycznie uwarunkowanego polimorfizmu CYP2D6 w psychofarmakoterapii; zaleznosc miedzy genotypem CYP2D6 a fenotypem.

Based on literature review the paper presents some clinical aspects of the genetically determined polymorphism of the CYP2D6. One of the main biotransformation processes of psychotropic drugs is oxidation catalysed by enzymes of cytochrome P-450. CYP2D6 is an isoenzyme of cytochrome P-450. Its activity is determined genetically and is characterised by interindividual variability. Genetically determined polymorphism of CYP2D6 is related to mutated alleles that code enzymatic proteins with different activity. Based on individual ability to oxidize drugs by CYP2D6 in population there are four phenotypically different groups: extensive (EM), ultra-rapid (UM), intermediate (IM) and poor metabolizers (PM). Each phenotype is determined by a given genotype. About 6-10% of the Caucasian population is known as PM phenotype. Drugs used in standard doses in this group may reach a markedly higher level in blood, even a toxic level. Compared to the group with EM phenotype persons with PM or IM phenotype are more likely to suffer from side effects that are related to impaired metabolic pathways that are catalyzed by CYP2D6. In the group with UM phenotype (1-7% of population) metabolism is very rapid, thus they need higher doses of psychotropic drugs to reach therapeutic blood level of drug.