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

The polymorphic isoenzyme CYP2D6 has a major role in the oxidative metabolism of many deal of psychoactive drugs. Its six mutant alleles (null alleles *3, *4, *5, *6, *7 and *8) encode for inactive enzyme molecules. A carrier of two mutant alleles is considered a poor metabolizer phenotype, while a carrier of only one damaged allele is considered an intermediate metabolizer phenotype. The aim of the study was to assess the prevalence of null alleles in a group of psychiatric patients suffering from depression (n=49) and schizophrenia (n=86) in comparison with healthy individuals (n=145) by the method of multiplex allele specific PCR. Only CYP2D6*3,*4 and *6 mutant alleles were found in the study subjects. No significant difference between the depression and control groups was found for allele prevalence, genotype or phenotype distribution (p>0.05). However, a significant difference was observed between schizophrenic patients and controls for allele frequency (p=0.002), genotype distribution (p=0.016), and phenotype prevalence (p=0.018). The odds ratio of 2.542 for 2D6*4 suggested a significant association between this allele and schizophrenia, significantly contributing to poor metabolizer phenotype (odds ratio=5.020). The relationship between CYP2D6 gene polymorphism and side effects in schizophrenic patients undergoing long-term psychoactive drug therapy was investigated. A significant difference was obtained for allele prevalence (p=0.002), genotype (p=0.029), and phenotype (p=0.002) distribution between patients without and with side effects. A relative risk of 2.626 and 5.333 for 2D6*4 and 2D6*6, respectively, and of 7.08 for poor metabolizer phenotype suggested a significant association between the hereditary susceptibility for a particular type of drug metabolism (defect alleles) and side effects. These preliminary results suggest that the CYP2D6 genotyping appears to be useful for predicting risks for side effects of psychoactive drugs in schizophrenic patients, but their usefulness should be further explored.
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PMID:CYP2D6 genotyping in patients on psychoactive drug therapy. 1109 51

The effect of paroxetine or sertraline on steady-state plasma concentrations of clozapine and its major metabolites was studied in 17 patients with schizophrenia or schizoaffective disorder stabilized on clozapine therapy (200-400 mg/day). In order to treat negative symptomatology or concomitant depression, 9 patients received additional paroxetine (20-40mg/day) and 8 patients sertraline (50-100 mg/day). After 3 weeks of paroxetine administration, mean plasma concentrations of clozapine and norclozapine increased significantly by 31% (p<0.01) and by 20% (p<0.05), respectively, while levels of clozapine N-oxide remained almost unchanged. The mean plasma norclozapine/clozapine and clozapine N-oxide/clozapine ratios were not modified during paroxetine treatment. No significant changes in plasma concentrations of clozapine and its major metabolites were observed after 3 weeks of combined therapy with sertraline. Clozapine coadministration with either paroxetine or sertraline was well tolerated. Our findings suggest that the metabolism of clozapine is not affected by sertraline treatment at typical therapeutic doses, while paroxetine, a potent inhibitor of CYP2D6, appears to inhibit the metabolism of clozapine, possibly by affecting pathways other than N-demethylation and N-oxidation. While sertraline may be added safely to patients on maintenance treatment with clozapine, careful clinical observation and monitoring of plasma clozapine levels may be useful whenever paroxetine is coadministered with clozapine.
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PMID:Plasma concentrations of clozapine and its major metabolites during combined treatment with paroxetine or sertraline. 1114 28

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

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

We describe a patient with treatment-resistant schizophrenia who had a duplication in the cytochrome P450IID6 (CYP2D6) gene. This severely ill 71-year-old-woman had responded poorly to several neuroleptics. Molecular genetic study revealed CYP2D6 gene duplication, which results in excessive activity of CYP2D6 that metabolizes various commonly used neuroleptics. The mutation may have contributed to treatment resistance in this case.
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PMID:A patient with treatment-resistant schizophrenia and cytochrome P4502D6 gene duplication. 1194 91

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

The effect of fluoxetine on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was evaluated in 10 patients with schizophrenia or schizoaffective disorder. Patients stabilized on risperidone (4-6 mg/day) received additional fluoxetine (20 mg/day) to treat concomitant depression. One patient dropped out after 1 week due to the occurrence of akathisia associated with markedly increased plasma risperidone concentrations. In the other subjects, mean plasma concentrations of risperidone increased during fluoxetine administration from 12 +/- 9 ng/mL at baseline to 56 +/- 31 at week 4 (p < 0.001), while the levels of 9-OH-risperidone were not significantly affected. After 4 weeks of combined treatment, the levels of the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) increased by 75% (range, 9-204%, p < 0.01) compared with baseline. The mean plasma risperidone/9-OH-risperidone ratio also increased significantly. During the second week of adjunctive therapy, two patients developed Parkinsonian symptoms, which were controlled with anticholinergic medication. These findings indicate that fluoxetine, a potent inhibitor of the cytochrome P450 enzyme CYP2D6 and a less potent inhibitor of CYP3A4, reduces the clearance of risperidone by inhibiting its 9-hydroxylation or alternative metabolic pathways. This interaction may lead to toxic plasma risperidone concentrations. In addition to careful clinical observation, monitoring plasma risperidone levels may be of value in patients given adjunctive therapy with fluoxetine.
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PMID:Inhibition of risperidone metabolism by fluoxetine in patients with schizophrenia: a clinically relevant pharmacokinetic drug interaction. 1217 43


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