Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antipsychotic response to clozapine varies markedly among patients with schizophrenia. The disposition of clozapine is dependent, in part, on the cytochrome P-450 (CYP) 1A2 enzyme in vivo. In theory, a very high CYP1A2 activity may lead to subtherapeutic concentrations and treatment resistance to clozapine. This prospective case study evaluates the clinical significance of ultrarapid CYP1A2 activity and a recently discovered single nucleotide (C --> A) polymorphism in intron 1 of the CYP1A2 gene (CYP1A2*F) for treatment resistance to clozapine. In addition, we describe the effect of grapefruit juice or low-dose fluvoxamine (25-50 mg/d) coadministration on clozapine and active metabolite norclozapine steady-state plasma concentration and antipsychotic response.
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PMID:Treatment-resistance to clozapine in association with ultrarapid CYP1A2 activity and the C-->A polymorphism in intron 1 of the CYP1A2 gene: effect of grapefruit juice and low-dose fluvoxamine. 1176 9

The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of haloperidol (HAL) in 40 male smokers with schizophrenia was investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position -2964 in the 5'-flanking region of CYP1A2 were identified by polymerase chain-reaction-restricted fragment length polymorphism method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A (n = 21), A/C (n = 14) and C/C (n = 5) genotypes (one-way analysis of variance: 63.1 +/- 18.5, 47.8 +/- 12.5 and 50.8 +/- 15.1 ng/ml/mg/kg, respectively, F(2,37) = 2.556, P = .09). Regarding G/A polymorphism at position -2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G (n = 24) and G/A (n = 15) (two-tailed t test: G/G and G/A = 51.2 +/- 16.6 and 59.0 +/- 17.6 ng/ml/mg/kg, respectively, df = 28, P = .22). The present study suggests that the genotyping of CYP1A2 cannot predict the steady state plasma levels of HAL in male smoking schizophrenics.
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PMID:Lack of impact of CYP1A2 genetic polymorphism (C/A polymorphism at position 734 in intron 1 and G/A polymorphism at position -2964 in the 5'-flanking region of CYP1A2) on the plasma concentration of haloperidol in smoking male Japanese with schizophrenia. 1181 2

Antipsychotic drugs are used for the treatment of schizophrenia and other related psychotic disorders. The antipsychotics currently available include older or classical compounds and newer or atypical agents. Most antipsychotic drugs are highly lipophilic compounds and undergo extensive metabolism by cytochrome P450 (CYP) enzymes in order to be excreted. There is a wide interindividual variability in the biotransformation of antipsychotic drugs, resulting in pronounced differences in steady-state plasma concentrations and, possibly, in therapeutic and toxic effects, during treatment with fixed doses. Many classical and some newer antipsychotics are metabolized to a significant extent by the polymorphic CYP2D6, which shows large interindividual variation in activity. Other CYPs, especially CYP1A2 and CYP3A4, also contribute to the interindividual variability in the kinetics of antipsychotics and occurrence of drug interactions. No relationship between CYP2D6 genotype or activity and therapeutic effects of classical antipsychotic drugs has been found in the few studies performed. On the other hand, some investigations suggest that poor metabolizers (PMs) of CYP2D6 would be more prone to over-sedation and, possibly, Parkinsonism during treatment with classical antipsychotics, while other studies, mostly retrospective, have been negative or inconclusive. For the newer antipsychotics, such data are lacking. To date, CYP2D6 phenotyping and genotyping appear, therefore, to be clinically useful for dose predicting only in special cases and for a limited number of antipsychotics, while their usefulness in predicting clinical effects must be further explored.
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PMID:Cytochrome P450 polymorphisms and response to antipsychotic therapy. 1197 42

There is strong evidence to suggest that genetic variation plays an important role in inter-individual differences in medication response and toxicity. The rapidly evolving disciplines of pharmacogenetics and pharmacogenomics seek to uncover this genetic variation in order to predict treatment outcomes. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up-individualized therapy. Pharmacogenomic studies utilize genomic technologies to identify chromosomal areas of interest and novel putative drug targets, while pharmacogenetic strategies rely on studying sequence variations in candidate genes suspected of affecting drug response or toxicity. The candidate gene variants that affect function of the gene or its protein product have the highest priority for investigation. This review will provide demonstrative examples of functional candidate gene variants studied in a variety of antipsychotic response phenotypes in the treatment of schizophrenia. Serotonin and dopamine receptor gene variants in clozapine response will be examined, and in the process the need for sub-phenotypes will be pointed out. Our recent pharmacogenetic studies of the subphenotype of neurocognitive functioning following clozapine treatment and the dopamine D(1) receptor gene (DRD1) will be presented, highlighting our novel neuroimaging data via [(18)F]fluoro-2-deoxy-D-glucose (FDG) metabolism position emission tomography (PET) that demonstrates hypofunctioning of several brain regions in patients with specific dopamine D(1) genotype. Preliminary candidate gene studies investigating the side-effect of clozapine-induced weight gain are also presented. The antipsychotic adverse reaction of tardive dyskinesia and its association with the dopamine D(3) receptor will be critically examined, as well as the added influence of antipsychotic metabolism via the cytochrome P450 1A2 gene (CYP1A2 ). Results that delineate the putative gene-gene interaction between DRD3 and CYP1A2 are also presented. We have also utilized FDG-PET subphenotyping to demonstrate increased brain region activity in patients who have the dopamine D(3) genotype that confers increased risk for antipsychotic induced tardive dyskinesia. The merits and weaknesses of neuroimaging technologies as applied to pharmacogenetic analyses are discussed. To the extent that the above data become more widely verified and replicated, the field of psychiatry will move closer to clinically meaningful tests that will be useful in deciding the best drug for each individual patient.
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PMID:Pharmacogenomics in schizophrenia: the quest for individualized therapy. 1235 88

Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% ( < 0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed ( > 0.05). Fluvoxamine concentrations were 48 +/- 26 ng/mL on week 1 and 83 +/- 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications.
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PMID:Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects. 1235 74

N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100) has been developed to treat subjects with schizophrenia. This drug is mainly excreted in the form of oxidative metabolites. In the present study, identification of p450 forms involved in the metabolism was carried out using human livers and intestinal microsomes (HLM and HIM). Eadie-Hofstee plots for NE-100 disappearance in HLM were biphasic, thus indicating the involvement of at least two p450 forms. The metabolism of NE-100 was mediated with recombinant CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A significant correlation was observed between activities of NE-100 metabolism and dextromethorphan O-demethylation (a specific activity for CYP2D6) or testosterone 6beta-hydroxylation (a specific activity for CYP3A4) in HLM. The activity of NE-100 metabolism was inhibited by approximately 80% by an anti-CYP2D6 antibody and only by quinidine among the p450-selective inhibitors at a low substrate concentration (0.1 microM). In contrast, with a high substrate concentration (10 microM), the activity was inhibited by an anti-CYP3A4 antibody and by ketoconazole. On the other hand, in HIM, the Eadie-Hofstee plots for NE-100 disappearance were monophasic, and the metabolism was strongly inhibited by an anti-CYP3A4 antibody and by ketoconazole but not by other inhibitors used. These results strongly suggest that NE-100 has different profiles regarding metabolism between liver and intestine. During absorption, NE-100 is mainly metabolized by CYP3A4 in the intestine and thereafter by CYP2D6 in the liver in the presence of therapeutic doses.
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PMID:Differences in cytochrome P450 forms involved in the metabolism of N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride (NE-100), a novel sigma ligand, in human liver and intestine. 1248 54

Since 1989, several novel antipsychotic drugs have become available for use including clozapine, risperidone, olanzapine, quetiapine and ziprasidone. These agents represent a substantial improvement in the treatment of schizophrenia and related disorders and are considered to have a favourable adverse effect profile relative to traditional antipsychotics. Nonetheless, in rare cases, people have died as a result of taking atypical antipsychotic drugs at therapeutic and supratherapeutic doses. Toxic doses of atypical antipsychotics are highly variable: some patients have died while taking therapeutic doses and others have survived massive overdoses. Toxicity may be increased by coingestion of other agents, particularly drugs with similar metabolic pathways. Atypical antipsychotics are metabolised predominantly by cytochrome p450 (CYP) isoenzymes, particularly CYP1A2 (clozapine and olanzapine), CYP3A4 (clozapine, quetiapine and ziprasidone) and CYP2D6 (olanzapine and risperidone). Concurrent prescription of other drugs that inhibit these isoenzymes may increase the probability of adverse events in patients taking atypical antipsychotics. Deaths due to atypical antipsychotic toxicity are often related to cardiovascular complications, but pulmonary, neurological, endocrine and gastrointestinal complications have also caused fatalities. Prevention and management of atypical antipsychotic overdose are of increased clinical relevance as prescription of these drugs increases.
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PMID:Fatalities associated with therapeutic use and overdose of atypical antipsychotics. 1266 90

Clozapine is an effective atypical antipsychotic drug applied in the treatment of resistant schizophrenia. The drug is mainly metabolized by cytochrome P-450 (CYP) enzymes especially the isozyme CYP1A2. Remarkably, the effective dosage varies widely among patients, making it necessary to individualize drug therapy with clozapine. The explanation for dosage variation may be differences in drug metabolism, and more specifically of CYP1A2 activity. This study is aimed at determining to what extent variability in clozapine dose can be explained by pharmacokinetic (PK) factors and more specifically by CYP1A2 activity in effectively treated psychiatric patients. In 22 evaluable patients with a schizophrenic disorder chronically using clozapine, the CYP1A2 activity and the clozapine clearance were estimated. For calculation of the pharmacokinetic parameters of clozapine, population PK software based upon Bayesian analysis was used. Caffeine clearance was estimated with the paraxanthine/caffeine ratio and served as estimate of CYP1A2 activity.A significant linear relationship was found between the clozapine dose and clozapine clearance (R: 0.71; P<0.05), whereas no relationship was found between clozapine dosage and clozapine serum trough concentration. Moreover, individual caffeine and clozapine clearances were found to be significantly related (R: 0.62; P<0.05) as were clozapine dose per kg body weight and P/C mol ratio (R: 0.44; P<0.05). We conclude that CYP1A2 activity is an important determinant of the variability of effective clozapine doses in psychiatric patients.
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PMID:CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients. 1465 89

The purpose of the present study was to assess the impact of smoking on the metabolism of psychotropic drugs in a group of patients with schizophrenia, by measuring CYP1A2 activity. This activity was assessed by the molar ratio (MR) of caffeine metabolites in urine [(AFMU+1U+1X)/17U] and saliva (17X/137X). Participants were 40 patients with schizophrenia: 30 current cigarette smokers and 10 nonsmokers. The two groups (smokers and nonsmokers) differed significantly in their ratio of men to women (83% men and 17% women were among smokers compared with 50% men and 50% women nonsmokers). No other group differences were found regarding age, level of education, PANSS, extrapyramidal symptoms, age of symptoms onset, antipsychotic doses (chloropromazine equivalents), and anticholinergic drug used. Smokers had significant higher MR in urine (P<0.001) as well as in saliva (P=0.001) than nonsmokers, suggesting a higher activity of CYP1A2 dependent on smoking. When gender was used as a covariate, the differences between the two groups remained significant for MR. Cigarette smoking may be a factor influencing the plasma levels of antipsychotics that metabolized through CYP1A2. Clinicians should weight the possibility that smoking and the subsequent modulation of antipsychotic metabolism may be the main reason of treatment resistance. Furthermore, any attempt to reduce or cease smoking in patients with schizophrenia necessitates close monitoring of drug doses, because untoward adverse effects may emerge.
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PMID:Smoking impact on CYP1A2 activity in a group of patients with schizophrenia. 1465 85

The population of Japanese smokers has decreased; however, the prevalence of smokers among psychiatric patients has been reported to be as high as 80% in schizophrenic patients. Although the impact of smoking on the pharmacokinetics of antipsychotics has been reported, results have been controversial. At first, the impact of smoking on plasma haloperidol (HAL) concentrations was investigated in Japanese male schizophrenic inpatients treated with HAL per os. Smokers had approximately 20% lower HAL concentrations/daily dose of HAL/kg body weight than non-smokers. The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of HAL in male smokers with schizophrenia was also investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position--2964 in the 5'-flanking region of CYP1A2 were identified by the PCR-RFLP method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A, A/C and C/C genotypes. Regarding G/A polymorphism at position--2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G and G/A.
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PMID:[Effect of smoking on pharmacokinetics of antipsychotics]. 1516 12


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