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)

The introduction of the atypical antipsychotics clozapine, risperidone, olanzapine, quetiapine and sertindole for the treatment of schizophrenia has coincided with an increased awareness of the potential of drug-drug interactions, particularly involving the cytochrome P450 (CYP) enzymes. The current literature describing the pharmacokinetics of the metabolism of these agents, including their potential to influence the metabolism of other medications, is reviewed. Clozapine appears to be metabolized primarily by CYP1A2 and CYP3A4, with additional contributions by CYP2C19 and CYP2D6. In addition, clozapine may inhibit the activity of CYP2C9 and CYP2C19, and induce CYP1A, CYP2B and CYP3A. Risperidone is metabolized by CYP2D6, and possibly CYP3A4. In vitro data indicate that olanzapine is metabolized by CYP1A2 and CYP2D6. Quetiapine is metabolised by CYP3A4 and sertindole by CYP2D6. There is, however, a general paucity of in vivo data regarding the metabolism of the atypical antipsychotics, indicating a need for further research in this area.
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PMID:Drug metabolism and atypical antipsychotics. 1042 90

Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated. The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers. After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and alpha 1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4'-N-glucuronides, 4'-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4'-N-desmethylolanzapine is correlated with the clearance of olanzapine. Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations. Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations. Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.
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PMID:Olanzapine. Pharmacokinetic and pharmacodynamic profile. 1051 17

Patients display significant differences in response to therapeutic agents which may be caused by a variety of factors. Among them, genetic components presumably play a major role. Pharmacogenetics is the field of research that attempts to unravel the relationship between genetic variation affecting drug metabolism (pharmacokinetic level) or drug targets (pharmacodynamic level) and interindividual differences in pharmacoresponse. In schizophrenia, pharmacokinetic studies have shown the role of genetic variants of the cytochrome P450 enzymes CYP2D6, CYP2C19, and CYP2C9 in the metabolism of neuroleptic drugs. At the level of the drug target, variants of the dopamine D3 and D4, and 5-HT2A and 5-HT2C receptors have been examined. A general problem of pharmacogenetic studies in schizophrenia is the high number of controversial findings which may be related to the lack of standardized phenotype definition. Recently, guidelines for an exact and comparable phenotype characterization have been proposed and will aid in designing and evaluating pharmacogenetic studies in the future. The final goal of pharmacogenetic studies-making a prediction of drug response at the level of the individual patient-will require a simultaneous look at a large number of response-determining genetic variants by applying the tools of pharmacogenomics, e.g. large-scale Single Nucleotide Polymorphism (SNP) detection and genotyping.
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PMID:Pharmacogenetics of schizophrenia. 1081 9

Quetiapine, a dibenzothiazepine derivative, is a atypical antipsychotic which has greater in vitro binding affinity for serotonin 5-HT2 receptors than for dopamine D2 receptors. Quetiapine effectively treats both the positive and the negative symptoms of schizophrenia and is also associated with an incidence of extrapyramidal symptoms no greater than placebo across the entire dose range. In addition, it does not cause persistent hyperprolactinaemia. Quetiapine is associated with high levels of patient acceptability and satisfaction, which may result from its combination of efficacy and relatively benign adverse effect profile. The drug is well tolerated and has a low propensity to cause adverse events both during acute and long term treatment in the adult populations. The adverse effect profile of quetiapine makes the drug advantageous for patient populations who are susceptible to the adverse effects of drugs. Indeed, preliminary data show quetiapine to be very well tolerated in the elderly. Overdoses of quetiapine of up to 20g have been reported; however, with appropriate management in an intensive care setting there have been no reported fatalities. Quetiapine is metabolised by the cytochrome P450 3A4 isoenzyme, and the dose may need to be adjusted if quetiapine is co-administered with drugs which affect the activity of this isoenzyme. Overall, quetiapine has a favourable risk-benefit profile that should make it a valuable first-line agent in the treatment of schizophrenia.
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PMID:Quetiapine: a review of its safety in the management of schizophrenia. 1105 Dec 17

Quetiapine fumarate ('Seroquel') is a newly introduced atypical antipsychotic with demonstrated efficacy in the treatment of positive and negative symptoms of schizophrenia. It is extensively metabolized, predominantly by cytochrome P450 3A4. Therefore, concurrent administration of drugs that induce or inhibit this enzyme may affect quetiapine pharmacokinetics. This study demonstrated that the potent cytochrome P450 enzyme-inducer phenytoin did indeed have a marked effect on the metabolism of quetiapine, resulting in a 5-fold increase in clearance when administered concomitantly to patients with DSM-IV-diagnosed schizophrenia, schizoaffective disorder, or bipolar disorder. These results indicate that dosage adjustment of quetiapine may be necessary when the two drugs are given concurrently and that caution may be required when administering other drugs that inhibit or induce cytochromes, particularly P450 3A4.
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PMID:The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of quetiapine. 1119 55

Individual schizophrenic patients are sometimes reported to benefit from unusually high doses of neuroleptics. Such patients may have poor drug penetration into the brain or ultra-rapid metabolism. Alternately, very high doses may be required to induce occupancy of 5-HT(2) receptors, which have been suggested as mediators of atypical effects. Five schizophrenic patients treated with high doses of fluphenazine decanoate (100-250 mg/wk) and adjunct medications were examined with positron emission tomography and [(11)C]raclopride to measure D(2) receptor occupancy and [(11)C]NMSP to measure 5-HT(2) receptor occupancy. All patients were rated globally as 'markedly' to 'severely' ill and had high scores on all subscales of the Positive and Negative Syndrome Scale for schizophrenia. However, according to retrospective clinical evaluation, there was improved social function and reduced distress following high-dose treatment, an effect that deteriorated after previous explorative dose reduction. Extrapyramidal symptoms were modest. D(2) receptor occupancy was very high (89-97%). 5-HT(2) receptor occupancy was also high (76-105%). Plasma concentrations of fluphenazine were 5-37 nm. No patient had a cytochrome P450 CYP2D6 genotype associated with ultra-rapid drug metabolism. The findings suggest almost complete saturation of D(2) receptors, and do not support poor drug availability in the brain as the basis of the apparent high-dose requirement. The high 5-HT(2) receptor occupancy may have contributed to the apparent clinical improvement and modest degree of EPS. However, it is likely that the treatment used also induced occupancy of other neuroreceptors.
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PMID:D(2)- and 5-HT(2) receptor occupancy in high-dose neuroleptic-treated patients. 1128 52

Risperidone, an atypical antipsychotic drug, is widely used in the treatment of psychoses associated with schizophrenia, Alzheimer's disease, and other psychiatric disorders. Polypharmacology is a necessary condition for the optimal treatment of many patients with comorbid psychiatric and medical illness. One concern raised by the widespread use of multiple concurrent pharmacotherapies is the potential for drug-drug interactions to adversely affect patient outcome. Accordingly, the biomedical literature was reviewed for reports of drug interactions involving risperidone, and the clinical significance of each report was evaluated. Additionally, the potential for risperidone to participate in drug interactions was evaluated by considering the drug's pharmacokinetic properties. Controlled studies and case reports indicate that risperidone has a low potential for metabolic drug interactions. Drugs that inhibit cytochrome P450 (CYP) 2D6 or induce or inhibit CYP3A4 may alter risperidone plasma concentrations, but the clinical significance of such interactions seems to be minimal. Adherence to a few guidelines for the design of dosage regimens should limit the effect of drug-drug interactions on patient status and contribute to optimal pharmacotherapy with risperidone.
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PMID:An evaluation of risperidone drug interactions. 1147 25

Debrisoquine 4-hydroxylase (CYP2D6) is one of the cytochrome P450 enzyme families that metabolize many compounds. Polymorphic activities of debrisoquine 4-hydroxylase were suggested to be associated with some complex diseases, such as cancer and Parkinson's disease. Schizophrenia is also a complex disorder, and hence we are interested in understanding if the CYP2D6 gene is a susceptibility gene for schizophrenia in Chinese. We determined the genotype and allele frequencies of four molecular variants of CYP2D6 gene (i.e. 188C/T, 1934G/A, 2938C/T and 4268C/G) in 162 Chinese schizophrenic patients and 94 non-psychotic control subjects from Taiwan. No significant differences of allele or genotype frequencies of three polymorphisms (i.e. 188T/C, 2938C/T and 4268C/G) were detected between patients and control subjects. The 1934A allele, which accounts for the majority of poor metabolizers in Caucasians, was not detected in either patients or control subjects, indicating that the 1934A allele is very rare in Chinese. Our data suggest that the CYP2D6 gene may not be a susceptibility gene for schizophrenia in Chinese schizophrenic patients.
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PMID:Debrisoquine 4-hydroxylase (CYP2D6) genetic polymorphisms and susceptibility to schizophrenia in Chinese patients from Taiwan. 1170 57

Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and endometrial, prostate, and breast cancer. Available data indicate that the protective effect of a later age at menarche is limited to mutant CYP 17 allele carriers. Among women with the Polycystic Ovary (PCO) syndrome, mutant CYP 17 alleles are sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for breast cancer, advanced disease stage, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase (COMT) allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to estrogen metabolising genes as strong hereditary determinants of the susceptibility to benign and malignant conditions.
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PMID:Genetic modeling of estrogen metabolism as a risk factor of hormone-dependent disorders. 1195 95

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


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