| 1 | Eur. J. Clin. Pharmacol. 2000 Nov 56: 585-9 |
|---|---|
| PMID | 11151749 |
| Title | Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia. |
| Abstract | A possible pharmacokinetic interaction between a CYP1A2 inhibitor, ciprofloxacin, and clozapine was studied in schizophrenia patients with stable clozapine treatment. A randomised double-blind cross-over study design with two phases was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 250 mg ciprofloxacin or placebo twice daily (b.i.d.) for 7 days. The phases were separated by a 7-day wash-out period. Serum concentrations of clozapine and its main metabolite N-desmethylclozapine were measured during both phases before the first dose on day 1 and on days 3 and 8. Ciprofloxacin increased mean serum concentration of clozapine and N-desmethylclozapine by 29% (P < 0.01) and 31% (P < 0.05), respectively. There was a significant positive correlation (r = 0.90, P < 0.01) between the individual concentrations of serum ciprofloxacin and the increase in concentrations of clozapine plus N-desmethylclozapine. The increase in serum clozapine concentrations correlated significantly (r = 0.89, P < 0.01) with the ratios of N-desmethylclozapine to clozapine concentrations. Even a low dose of ciprofloxacin can moderately increase serum concentrations of clozapine and N-desmethylclozapine. A probable mechanism of interaction is an inhibition of CYP1A2 enzyme by ciprofloxacin. The possibility of clinically significant interaction should be considered, especially when higher doses of ciprofloxacin are used concomitantly with clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Mol. Psychiatry 2000 Jul 5: 410-7 |
| PMID | 10889552 |
| Title | A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia. |
| Abstract | Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | Ther Drug Monit 2000 Jun 22: 245-9 |
| PMID | 10850389 |
| Title | Effect of a genetic polymorphism of CYP1A2 inducibility on the steady state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. |
| Abstract | The effect of a genetic polymorphism of inducibility of cytochrome P450 (CYP) 1A2 on the steady state plasma concentrations (Css) of haloperidol and reduced haloperidol was studied to clarify if these Css are dependent on the CYP1A2 activity. The subjects were 101 Japanese schizophrenic inpatients receiving oral haloperidol 12 mg/d. The Css of haloperidol and reduced haloperidol were measured in duplicate by high performance liquid chromatographic method, and were corrected to the mean body weight. A point mutation from guanine (wild-type) to adenine (mutated-type) at position -2964 in the 5'-flanking region of CYP1A2 gene was identified by polymerase chain reaction (PCR)-fragment length polymorphism method. Based on the present results, i.e., significant effects of CYP2D6 genotypes on the Css of haloperidol and reduced haloperidol, analyses were separately performed in two groups, i.e., patients with 0 mutated allele of the CYP2D6 (41 cases) and those with 1 or 2 mutated alleles (60 cases). Subjects in each CYP2D6 genotype group consisted of 4 subgroups according to smoking habit and the presence of the mutated allele of the CYP1A2. Neither the Css of haloperidol nor that of reduced haloperidol significantly differed among the 4 subgroups in either CYP2D6 genotype group. The present study thus suggests that the CYP1A2 activity does not play an important role in controlling the Css of haloperidol or reduced haloperidol. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Eur. J. Clin. Pharmacol. 2000 Nov 56: 585-9 |
| PMID | 11151749 |
| Title | Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia. |
| Abstract | A possible pharmacokinetic interaction between a CYP1A2 inhibitor, ciprofloxacin, and clozapine was studied in schizophrenia patients with stable clozapine treatment. A randomised double-blind cross-over study design with two phases was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 250 mg ciprofloxacin or placebo twice daily (b.i.d.) for 7 days. The phases were separated by a 7-day wash-out period. Serum concentrations of clozapine and its main metabolite N-desmethylclozapine were measured during both phases before the first dose on day 1 and on days 3 and 8. Ciprofloxacin increased mean serum concentration of clozapine and N-desmethylclozapine by 29% (P < 0.01) and 31% (P < 0.05), respectively. There was a significant positive correlation (r = 0.90, P < 0.01) between the individual concentrations of serum ciprofloxacin and the increase in concentrations of clozapine plus N-desmethylclozapine. The increase in serum clozapine concentrations correlated significantly (r = 0.89, P < 0.01) with the ratios of N-desmethylclozapine to clozapine concentrations. Even a low dose of ciprofloxacin can moderately increase serum concentrations of clozapine and N-desmethylclozapine. A probable mechanism of interaction is an inhibition of CYP1A2 enzyme by ciprofloxacin. The possibility of clinically significant interaction should be considered, especially when higher doses of ciprofloxacin are used concomitantly with clozapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Ther Drug Monit 2000 Jun 22: 245-9 |
| PMID | 10850389 |
| Title | Effect of a genetic polymorphism of CYP1A2 inducibility on the steady state plasma concentrations of haloperidol and reduced haloperidol in Japanese patients with schizophrenia. |
| Abstract | The effect of a genetic polymorphism of inducibility of cytochrome P450 (CYP) 1A2 on the steady state plasma concentrations (Css) of haloperidol and reduced haloperidol was studied to clarify if these Css are dependent on the CYP1A2 activity. The subjects were 101 Japanese schizophrenic inpatients receiving oral haloperidol 12 mg/d. The Css of haloperidol and reduced haloperidol were measured in duplicate by high performance liquid chromatographic method, and were corrected to the mean body weight. A point mutation from guanine (wild-type) to adenine (mutated-type) at position -2964 in the 5'-flanking region of CYP1A2 gene was identified by polymerase chain reaction (PCR)-fragment length polymorphism method. Based on the present results, i.e., significant effects of CYP2D6 genotypes on the Css of haloperidol and reduced haloperidol, analyses were separately performed in two groups, i.e., patients with 0 mutated allele of the CYP2D6 (41 cases) and those with 1 or 2 mutated alleles (60 cases). Subjects in each CYP2D6 genotype group consisted of 4 subgroups according to smoking habit and the presence of the mutated allele of the CYP1A2. Neither the Css of haloperidol nor that of reduced haloperidol significantly differed among the 4 subgroups in either CYP2D6 genotype group. The present study thus suggests that the CYP1A2 activity does not play an important role in controlling the Css of haloperidol or reduced haloperidol. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | J Clin Psychopharmacol 2001 Dec 21: 603-7 |
| PMID | 11763009 |
| Title | 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. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | J. Biochem. Biophys. Methods 2001 Jan 47: 151-7 |
| PMID | 11179771 |
| Title | Pharmacogenetic assessment of antipsychotic-induced movement disorders: contribution of the dopamine D3 receptor and cytochrome P450 1A2 genes. |
| Abstract | Tardive dyskinesia (TD) is characterized by involuntary movements predominantly in the orofacial region and develops in approximately 20% of patients during long-term treatment with typical antipsychotics. The high prevalence of TD and its disabling and potentially irreversible clinical course is an important shortcoming for treatment with typical antipsychotics. The studies presented in this article evaluate the role of single nucleotide polymorphisms in dopamine D3 receptor (DRD3) and CYP1A2 genes for propensity to develop TD in patients with schizophrenia. In theory, a combined pharmacogenetic analysis of pharmacokinetic and pharmacodynamic targets for antipsychotics should improve our ability to identify subpopulations that differ in drug safety profile. This information may in turn contribute to the design of more efficient clinical trials and thus expedite the development and regulatory approval of newer antipsychotic compounds. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Am. J. Med. Genet. 2001 Aug 105: 498-501 |
| PMID | 11496364 |
| Title | Lack of association between a functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene and tardive dyskinesia in schizophrenia. |
| Abstract | Tardive dyskinesia (TD) is a common side effect of long-term medication with typical neuroleptics. TD presents itself by abnormal involuntary movements and may lead to a potentially disabling and chronic clinical course. A vast majority of patients suffering from schizophrenia are smokers. Smoking has been reported to induce the activity of the CYP1A2 enzyme, which is an established metabolic pathway within the disposition of antipsychotics. Recently, a C-->A genetic polymorphism in the first intron of the CYP1A2 gene was reported to influence CYP1A2 activity in smokers. Subsequently, a pharmacogenetic study in 85 U.S. patients with schizophrenia (44 smokers, 41 individuals with unknown smoking status) showed the C/C genotype to be associated with higher TD severity (measured by the Abnormal Involuntary Movement Scale, AIMS) than the A/C or A/A genotype. This finding prompted us to investigate whether this effect was also present in a larger German sample of 119 patients with schizophrenia (82 smokers, 37 individuals with unknown smoking status). However, we could not replicate the reported association. The median AIMS scores did not differ between individuals with the A/A, A/C, or C/C genotypes. In an additional analysis, we compared the genotypic and allelic distribution among individuals grouped according to the criteria established by Schooler and Kane [1982: Arch Gen Psychiatry 39:486-487] (persistent TD vs. absent TD). We did not observe a differential genotypic or allelic distribution between the two diagnostic groups. Thus, our results do not support the hypothesis that the C-->A polymorphism in the CYP1A2 gene is involved in the etiology of TD in the German population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | J Clin Psychopharmacol 2001 Aug 21: 398-407 |
| PMID | 11476124 |
| Title | CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite steady-state concentrationin patients with schizophrenia. |
| Abstract | Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | J Clin Psychiatry 2001 Oct 62: 812-7 |
| PMID | 11816871 |
| Title | Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability. |
| Abstract | Grapefruit juice can inhibit the gastrointestinal activity of cytochrome P450 (CYP) 3A4, while its effect on CYP1A2 remains controversial. Several grapefruit juice bioflavonoids also modulate the activity of the drug transporter P-glycoprotein in the gut and in the blood-brain barrier. Both CYP1A2 and CYP3A4 are involved in clozapine metabolism. This study investigated the effects of repeated ingestion of grapefruit juice on multiple-dose pharmacokinetics and pharmacodynamics of clozapine in schizophrenic patients. Clozapine therapy was initiated for fifteen treatment-resistant schizophrenic inpatients (DSM-IV criteria). The doses were individually titrated from day -35 to day -15 and then kept unchanged from day -14 to day 49. Regular-strength grapefruit juice (250 mL) was coadministered b.i.d. with each clozapine dose from day 15 to day 28. Plasma levels of clozapine and its main metabolites (norclozapine and clozapine N-oxide) were obtained, and clinical efficacy and safety assessments were completed prior to juice administration (days 0, 7, and 14), during the coadministration (days 17, 21, and 28), and after cessation of the juice (days 35, 42, and 49). After reaching steady states, plasma concentrations of clozapine and its metabolites and Positive and Negative Syndrome Scale scores were not significantly altered by the effect of grapefruit juice ingestion. The Clinical Global Impressions scale scores, Calgary Depression Scale scores, and side effect profiles (by the Extrapyramidal Symptom Rating Scale, the UKU Side Effect Rating Scale, and thorough examinations including electrocardiography and electroencephalography) also remained constant during the study. Consumption of regular-strength grapefruit juice, 250 mL b.i.d., for 14 days did not significantly impact clozapine metabolism, clinical efficacy, or tolerability. One reason is that enzymes other than CYP3A4 also mediate clozapine disposition. Also, grapefruit juice inhibits CYP3A4 in the gut, but not in the liver. The preliminary results also suggest that clozapine is unlikely to be a P-glycoprotein substrate. Further rigorous studies are necessary to reconfirm these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | J Clin Psychopharmacol 2002 Oct 22: 502-6 |
| PMID | 12352274 |
| Title | Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Curr Opin Investig Drugs 2002 Jul 3: 1073-80 |
| PMID | 12186270 |
| Title | New antipsychotic agents for schizophrenia: pharmacokinetics and metabolism update. |
| Abstract | The so-called atypical antipsychotics undergo extensive metabolism, except for amisulpride, which is substantially excreted unchanged. Risperidone is oxidized by CYP2D6/CYP3A4 and iloperidone is reduced by cytosolic enzymes, although CYP1A2, CYP2E1 and CYP3A4 are involved as well. Olanzapine is both conjugated and oxidized (mainly by CYP1A2), while quetiapine and zotepine primarily undergo CYP3A4-mediated oxidation. Ziprasidone pathways include aldehyde oxidase-mediated reduction and CYP3A4-mediated oxidation. The main metabolites of risperidone, zotepine and possibly perospirone and ziprasidone contribute to the parent drug's effect. Information is limited, however, on some promising antipsychotics in the pipeline. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Hum. Mol. Genet. 2002 Oct 11: 2517-30 |
| PMID | 12351588 |
| Title | Pharmacogenomics in schizophrenia: the quest for individualized therapy. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Pharmacogenomics 2002 Mar 3: 201-18 |
| PMID | 11972442 |
| Title | Cytochrome P450 polymorphisms and response to antipsychotic therapy. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2002 Feb 26: 261-5 |
| PMID | 11817502 |
| Title | 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. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2002 Feb 26: 261-5 |
| PMID | 11817502 |
| Title | 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. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Drug Metab. Dispos. 2003 Jan 31: 60-6 |
| PMID | 12485954 |
| Title | 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. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | J Psychiatry Neurosci 2003 May 28: 185-9 |
| PMID | 12790158 |
| Title | Smoking and tardive dyskinesia: lack of involvement of the CYP1A2 gene. |
| Abstract | To establish if there is an association between cigarette smoking and tardive dyskinesia (TD) in patients with schizophrenia and to evaluate the role of the CYP1A2 polymorphism in TD in patients of Chinese descent. Two-hundred and ninety-one patients diagnosed with schizophrenia according to DSM-IV criteria were included in the study. Dyskinesia was assessed by the Abnormal Involuntary Movement Scale and TD by the criteria of Schooler and Kane. Demographic and clinical data and information on smoking habits were collected, and patients of Chinese descent with a well established smoking history were subsequently genotyped for CYP1A2. Forty-three (41.3%) of the 104 patients with a history of smoking and 52 (27.8%) of the 187 non-smokers were diagnosed with TD. The prevalence of TD was significantly higher among smokers than non-smokers (chi2 = 5.57, p = 0.018). Logistic regression using TD as the dependent variable revealed smokers to be at a significantly higher risk for TD (p < 0.005). Genotyping of smokers of Chinese descent for CYP1A2 polymorphism revealed no significant differences in the genotypic or allelic distribution between those with and without TD. Consistent with other studies, the prevalence of TD was significantly higher among smokers than non-smokers; however, we did not find an association between the C --> A genetic polymorphism of CYP1A2 and TD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Eur J Pharm Sci 2003 Dec 20: 451-7 |
| PMID | 14659489 |
| Title | CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | CNS Drugs 2003 -1 17: 307-24 |
| PMID | 12665390 |
| Title | Fatalities associated with therapeutic use and overdose of atypical antipsychotics. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Eur J Pharm Sci 2003 Dec 20: 451-7 |
| PMID | 14659489 |
| Title | CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Pharmacogenetics 2003 Mar 13: 169-72 |
| PMID | 12618594 |
| Title | The effect of smoking and cytochrome P450 CYP1A2 genetic polymorphism on clozapine clearance and dose requirement. |
| Abstract | Clozapine is an atypical antipsychotic drug that is metabolized to a major extent by the cytochrome P450 enzyme CYP1A2. Smoking is a potent inducer of CYP1A2 enzyme activity, resulting in significant lower clozapine serum concentrations in smokers compared with non-smokers, upon a given dose. Recently, a single nucleotide polymorphism identified at position 734 of the CYP1A2 gene, was reported to affect the inducibility of the enzyme. Because this polymorphism in relation to smoking behaviour may be relevant in treatment with clozapine, we studied the effect of CYP1A2 genotype on clozapine clearance and dose requirement in a group of 80 smoking and non-smoking schizophrenic patients on long-term clozapine therapy. Clozapine serum concentration and CYP1A2 genotype had been determined routinely by high-performance liquid chromatography and polymerase chain reaction analyses, respectively. In smokers, the clozapine serum concentration corrected for dose (C/D ratio) was on average 2.5 times lower compared with non-smokers, indicating an enhanced clearance. The mean required maintenance doses of clozapine for smokers and non-smokers were 382 mg/day and 197 mg/day, respectively (P < 0.01). Neither among smokers, nor among non-smokers mean C/D ratios and daily doses did vary significantly between patients with the different CYP1A2 genotypes. The results show that clozapine clearance and daily dose requirement are strongly associated with smoking behaviour, while the CYP1A2 genetic polymorphism seems to have no significant clinical effect. Dosage adjustment based on smoking behaviour would be of value in order to lower the incidence of non-therapeutic serum drug levels and, consequently, intoxication or inadequate antipsychotic response. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 23 | J Clin Pharmacol 2004 Dec 44: 1385-90 |
| PMID | 15545309 |
| Title | Dose-dependent alternations in the pharmacokinetics of olanzapine during coadministration of fluvoxamine in patients with schizophrenia. |
| Abstract | Olanzapine, an atypical antipsychotic agent, is a substrate of the cytochrome P4501A2 (CYP1A2) enzyme. Administration of a potent CYP1A2 inhibitor (eg, fluvoxamine) may alter the pharmacokinetics of olanzapine. This study investigated the pharmacokinetic interactions between olanzapine and fluvoxamine in patients with schizophrenia. Ten male smokers were administrated a single dose of olanzapine 10 mg at baseline, followed by 2 weeks of fluvoxamine 50 mg/day and another 2 weeks of fluvoxamine 100 mg/day. Olanzapine 10 mg was given at day 10 during each fluvoxamine treatment. After pretreatment with fluvoxamine, the area under the curve, maximal plasma concentration, and half-time of olanzapine were significantly increased by 30% to 55%, 12% to 64%, and 25% to 32%, respectively. Volume of distribution and apparent clearance were significantly reduced by 4% to 26% and 26% t O 38%, respectively, after administration of fluvoxamine. Increases in area under the plasma concentration-time curve from time 0 to infinity appear to be dose dependent. Presumably, altered olanzapine pharmacokinetics are attributed to the inhibition of CYP1A2. Patients treated with the combination of olanzapine and fluvoxamine should be monitored carefully. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 24 | Nihon Shinkei Seishin Yakurigaku Zasshi 2004 Apr 24: 67-70 |
| PMID | 15164612 |
| Title | [Effect of smoking on pharmacokinetics of antipsychotics]. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 25 | Nihon Shinkei Seishin Yakurigaku Zasshi 2004 Apr 24: 67-70 |
| PMID | 15164612 |
| Title | [Effect of smoking on pharmacokinetics of antipsychotics]. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 26 | Psychiatr. Genet. 2004 Dec 14: 209-13 |
| PMID | 15564895 |
| Title | Genetic association analysis of functional polymorphisms in the cytochrome P450 1A2 (CYP1A2) gene with tardive dyskinesia in Japanese patients with schizophrenia. |
| Abstract | Recent studies have revealed positive associations between tardive dyskinesia (TD) and genetic polymorphisms of several cytochrome P450 (CYP) subfamilies that are involved in pharmacokinetic process of antipsychotic drugs. In the present study, we analyzed the relationship between TD and two polymorphisms of the CYP1A2 gene, 734C/A and -2964G/A, in a sample of Japanese patients with schizophrenia. We studied 199 Japanese patients with schizophrenia. We used the Abnormal Involuntary Movement Scale to evaluate TD. Two polymorphisms of the CYP1A2 gene, 734C/A and -2964 G/A were genotyped by means of polymerase chain reaction and restriction fragment length polymorphism analysis. Neither the 734C/A nor the -2964G/A polymorphism was associated with TD [734C/A genotype: chi2=0.02, degrees of freedom (df)=2, P=1.00; allele: chi2=0.02, df=1, P=0.89; -2964G/A genotype: chi2=0.21, df=2, P=0.90; allele: chi2=0.15, df=1, P=0.70]. In addition, CYP1A2 haplotype was associated with TD (chi2=0.24, df=3, P=0.97). Furthermore, in both the subgroup of smokers and the subgroup of patients receiving high-dosage antipsychotics (chlorpromazine equivalent >1000 mg), neither the 734C/A nor the -2964G/A polymorphism was associated with TD. We did not find significant associations between the 734C/A and -2964G/A polymorphisms of CYP1A2 gene and TD in Japanese patients with schizophrenia. Our results suggest that these CYP1A2 gene polymorphisms may not contribute to TD susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 27 | J Clin Psychiatry 2004 Aug 65: 1138-43 |
| PMID | 15323601 |
| Title | Variables associated with high olanzapine dosing in a state hospital. |
| Abstract | Olanzapine has a U.S. Food and Drug Administration-approved dosing range of 10 to 20 mg/day but is often used at doses exceeding this range. Olanzapine is largely metabolized by cytochrome P450 (CYP) 1A2. Smoking, which induces CYP1A2, is expected to increase clearance of olanzapine by 40%; however, dosage adjustment in smokers is not currently recommended. Additionally, female gender is expected to reduce clearance by 30%. Many institutions target high-dose olanzapine prescribers in an effort to reduce unnecessary drug costs. However, factors such as smoking or gender may necessitate increased doses. A retrospective review of all patients receiving olanzapine during an inpatient stay at a state psychiatric hospital in Kentucky during 2001 was conducted. Demographic information and smoking status were collected for all patients. Olanzapine doses of > 20 mg/day were considered high doses. Nine percent (48/522) of olanzapine patients were prescribed high doses. The percentages were similar in women and men (10% vs. 9%, p =.69) and in smokers and nonsmokers (9% vs. 9%, p =.82). Moreover, the mean maximum olanzapine dose was also similar in men and women (15.4 +/- 7.2 vs. 14.9 +/- 7.3 mg/day, p =.51). The odds of receiving a high dose of olanzapine were increased 2.1 for patients with a schizophrenia spectrum diagnosis (DSM-IV schizophrenia or other psychotic disorder). The odds of receiving a high dose of olanzapine were increased with each incremental increase in length of stay (intermediate length of stay [8-60 days], OR = 5.6; long-term length of stay [> 60 days], OR = 12.0, relative to acute length of stay [< 8 days]). Neither gender nor smoking status was associated with receiving a high dose of olanzapine. The association of increased length of stay with high dose suggests that treatment resistance may be an important factor in receiving high daily doses of olanzapine. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 28 | J Clin Psychopharmacol 2004 Apr 24: 214-9 |
| PMID | 15206669 |
| Title | Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. |
| Abstract | Clozapine (CLO), an atypical antipsychotic, depends mainly on cytochrome P450 1A2 (CYP1A2) for its metabolic clearance. Four patients treated with CLO, who were smokers, were nonresponders and had low plasma levels while receiving usual doses. Their plasma levels to dose ratios of CLO (median; range, 0.34; 0.22 to 0.40 ng x day/mL x mg) were significantly lower than ratios calculated from another study with 29 patients (0.75; 0.22 to 2.83 ng x day/mL x mg; P < 0.01). These patients were confirmed as being CYP1A2 ultrarapid metabolizers by the caffeine phenotyping test (median systemic caffeine plasma clearance; range, 3.85; 3.33 to 4.17 mL/min/kg) when compared with previous studies (0.3 to 3.33 mL/min/kg). The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the -164C > A mutation (CYP1A2*1F) in intron 1, which confers a high inducibility of CYP1A2 in smokers, is the most likely explanation for their ultrarapid CYP1A2 activity. A marked (2 patients) or a moderate (2 patients) improvement of the clinical state of the patients occurred after the increase of CLO blood levels above the therapeutic threshold by the increase of CLO doses to very high values (ie, up to 1400 mg/d) or by the introduction of fluvoxamine, a potent CYP1A2 inhibitor, at low dosage (50 to 100 mg/d). Due to the high frequency of smokers among patients with schizophrenia and to the high frequency of the -164C > A polymorphism, CYP1A2 genotyping could have important clinical implications for the treatment of patients with CLO. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 29 | Eur Neuropsychopharmacol 2004 Jan 14: 39-44 |
| PMID | 14659985 |
| Title | Smoking impact on CYP1A2 activity in a group of patients with schizophrenia. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 30 | Xenobiotica 2005 Jun 35: 549-60 |
| PMID | 16192107 |
| Title | Inhibitory effects of psychotropic drugs on mexiletine metabolism in human liver microsomes: prediction of in vivo drug interactions. |
| Abstract | Mexiletine, an anti-arrhythmic agent, is used for the control of ventricular arrhythmias and for neuropathic pain from cancer or diabetes mellitus. It is sometimes used together with psychotropic drugs in patients with depression, schizophrenia or sleep disorder. It is metabolized mainly by cytochrome P450 (CYP) 2 D 6 and, to a minor extent, by CYP1A2. To predict possible drug interactions between mexiletine and psychotropic drugs, the inhibitory effects of 14 psychotropic drugs (phenytoin, carbamazepine, fluvoxamine, paroxetine, fluoxetine, citalopram, sertraline, imipramine, desipramine, haloperidol, thioridazine, olanzapine, etizolam, and quazepam) on mexiletine metabolism in human liver microsomes were determined. Fluoxetine (Ki=0.6+/- 0.1 microM), sertraline (Ki=7.6+/- 0.8 microM) and desipramine (Ki=3.2+/- 0.5 microM) competitively inhibited the mexiletine p-hydroxylation in human liver microsomes. Thioridazine (Kis=0.5+/- 0.2 microM; Kii =3.6+/-1.6 microM) and paroxetine (Kis=1.7+/- 0.7 microM; Kii=3.6+/- 0.9 microM) exhibited a mixed-type inhibition (competitive and non-competitive) toward mexiletine p-hydroxylation in human liver microsomes. The changes of the in vivo clearance of mexiletine by the psychotropic drugs were predicted by 1+(I/Ki) using the in vitro Ki and unbound inhibitor concentrations in liver. The values were calculated as 2.4 for paroxetine, 5.5 for fluoxetine, 1.1 for sertraline, 2.8 for desipramine and 2.2 for thioridazine. In addition, paroxetine exhibited a mechanism-based inactivation with Ki=0.7 microM and Kinact=0.15 min(-1). The present study predicted the possibility of drug interactions between mexiletine and paroxetine, fluoxetine, desipramine, and thioridazine in clinical use. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 31 | Ann. Clin. Biochem. 2005 May 42: 216-9 |
| PMID | 15949157 |
| Title | The cytochrome P450 CYP1A2 genetic polymorphisms *1F and *1D do not affect clozapine clearance in a group of schizophrenic patients. |
| Abstract | The atypical antipsychotic drug clozapine is metabolized by CYP1A2. The activity of CYP1A2 is highly variable and is among others dependent on smoking habits. Certain genotypes of CYP1A2 have been associated with increased inducibility/activity of CYP1A2. However, the relevance of genotyping for these mutations in a clinical setting has not yet been demonstrated. In this study, the CYP1A2 *1F, *1C and *1D genotypes of 58 schizophrenic patients on clozapine treatment were correlated with clozapine serum concentrations corrected for dose and weight or concentration/dosage ratios. The allele frequency of *1F and *1D was 67% and 6%, respectively. With an allele frequency of 1%, the occurrence of *1C was very low. Multivariate analysis of variance did not reveal any significant correlations between CYP1A2 genotypes and clozapine clearance in these subjects, although a possible effect of the *1D allele cannot be excluded in this study. Although this study was performed using samples from a limited number of patients, routine genotyping of CYP1A2 *1F, *1C or *1D polymorphisms for their effect on metabolic capacity is, at least in Caucasians, not yet indicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 32 | Pharm World Sci 2005 Feb 27: 20-30 |
| PMID | 15861931 |
| Title | Pharmacogenetics as a tool in the therapy of schizophrenia. |
| Abstract | This review summarises the present knowledge of associations between pharmacogenetics and therapeutic efficacy and side effects of antipsychotics to enable pharmacists to judge the applicability for a more tailor made therapy in patients with schizophrenia. Polymorphisms of Cytochrome P450 isoenzymes and neurotransmitter receptors involved in the efficacy and side effects of antipsychotics are highlighted in this review. A search was performed in Medline and EMBASE for the period 1995-August 2002. Also relevant references from the selected papers were incorporated. Poor metabolism with respect to CYP2D6 seems to be related with more pronounced extrapyramidal symptoms and more specifically with a higher incidence of tardive dyskinesia. The C/C-genotype for CYP1A2 results in smokers in a reduction of enzyme activity, but an effect on the incidence of tardive dyskinesia is controversial. For dopamine D2 receptors the effect of the -141C Ins/Del polymorphism on efficacy is not clear yet, although the Taq I polymorphism is associated with greater improvement of positive, but not negative symptoms in acute psychosis. The Gly9-allele of the dopamine D3 receptor is associated with the response to clozapine, but in studies in which the choice of antipsychotics is not restricted, the role of this polymorphism is unclear. The reverse is applicable to the dopamine D(4.2/4.7) polymorphism. For the 5-HT2A receptor the His452Tyr polymorphism is associated with response to clozapine, the 102 T/C polymorphism leads to equivocal results. The polymorphism studied for 5-HT5A, 5-HT6, alpha1A- and alpha2A-receptors give no clear associations with the response to clozapine. The polymorphism studied of the dopamine D2 and D4 receptor are not related to extrapyramidal adverse effects and side effects, respectively. The 9Gly-variant of the dopamine D3 receptor, the 102C-variant, but not the His452Tyr polymorphism of the 5-HT2A-receptor and the 23Ser-variant (for females only) of the 5-HT2C receptor seem to increase the susceptibility to tardive dyskinesia. Weight gain induced by antipsychotics seems to be associated with the -759C-allele of the 5-HT2C receptor. The results show the first careful steps toward application of pharmacogenetics in a more individualised, tailor-made, pharmacotherapy. A pre-condition seems to be a multifactorial approach, as can be expected for multifactorial processes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 33 | Pharmacogenomics J. 2005 -1 5: 60-9 |
| PMID | 15505641 |
| Title | Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism. |
| Abstract | Understanding the pharmacogenetic basis of developing iatrogenic disorders such as Tardive Dyskinesia (TD) has significant clinical implications. CYP1A2, an inducible gene of the cytochrome P450 family of genes, has been suggested to contribute to the metabolism of typical antipsychotics in subjects with schizophrenia on long-term treatment, and has been considered as a potential candidate gene for development of TD. In this study, we have investigated the significance of CYP1A2 gene polymorphisms in TD susceptibility among chronic schizophrenia sufferers (n=335) from north India. TD was diagnosed in approximately 29% (96/335) of these subjects. Of the 96 TD positives, 28 had been treated with typical antipsychotics alone, 23 with atypical antipsychotics alone and 45 patients had received both classes of drugs during the course of their illness. Out of the six SNPs tested, CYP1A2(*)2, (*)4, (*)5, (*)6 were found to be monomorphic in our population. CYP1A2(*)1C and CYP1A2(*)1F were polymorphic and were analyzed in the study sample. Since these two allelic variants lead to lesser inducibility among smokers, the smoking status of TD patients was also considered for all subsequent analysis. We observed increased severity of TD among TD-Y smokers, who were carriers of CYP1A2(*)1C (G>A) variant allele and had received only typical antipsychotic drugs (F(1,8)=9.203, P=0.016). No significant association of CYP1A2(*)1F with TD was observed irrespective of the class of drug they received or their smoking status. However, we found a significant association of CYP1A2(*)1F with schizophrenia (chi(2)=6.572, df=2, P=0.037). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 34 | Neuromolecular Med. 2006 -1 8: 381-8 |
| PMID | 16775389 |
| Title | Association study between functional polymorphisms in the cytochrome P450 1A2 and 2D6 genes and polydipsia in schizophrenia. |
| Abstract | The underlying pathophysiology of polydipsia in schizophrenia is poorly understood. Several studies, however, have suggested that there might be a genetic predisposition to polydipsia. In the present study, using a case-control sample that is independent from the previous family sample, we examined a possible association between polydipsia and functional polymorphisms in the genes of cytochrome P450 (CYP) 1A2 and 2D6, primarily important enzymes to the pharmacokinetics of antipsychotic drugs. Japanese patients with schizophrenia (63 polydipsics and 78 nonpolydipsics) were genotyped for two functional polymorphisms, the 734C/A polymorphism in the CYP1A2 gene and the 2D6*10 allele of the CYP2D6 gene. Neither of the polymorphisms was found to be associated with polydipsia nor was any evidence found that the two polymorphisms have an additive effect on the liability to polydipsia. Our results suggest that the CYP1A2 and CYP2D6 polymorphisms are not likely to play a major role in the development of polydipsia in schizophrenia, although further studies testing other alleles of CYP1A2 and CYP2D6 using different ethnic populations are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 35 | Acta Pharmacol. Sin. 2006 Mar 27: 328-32 |
| PMID | 16490169 |
| Title | Association of CYP2D6 and CYP1A2 gene polymorphism with tardive dyskinesia in Chinese schizophrenic patients. |
| Abstract | To investigate the possible association of the CYP2D6 gene C100T polymorphism and the CYP1A2 gene C163A polymorphism with tardive dyskinesia (TD) in Chinese patients with schizophrenia. The recruited schizophrenic patients were assessed with the Abnormal Involuntary Movement Scale (AIMS), and divided into groups with TD (n=91) and without TD (n=91) according to the AIMS score. Polymorphisms of the CYP2D6 and CYP1A2 genes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). No allele frequencies deviated from Hardy-Weinberg equilibrium. No significant differences in genotypes frequencies of the CYP2D6 C100T polymorphism were observed between patients with TD and without TD (Chi2=4.078, P>0.05), but patients with TD had a significant excess of the T allele compared with those without TD (Chi2=4.28, P<0.05). Moreover, the frequency of the CYP1A2 C allele in patients with TD was significantly higher than that in those without TD (Chi2=6.38, P<0.05). An association between TD and the CYP2D6 100T and CYP1A2 163C alleles was observed. Additionally, there were no differences in the mean AIMS scores among different genotypes in TD patients as a group or in smokers. The results of logistic regression analysis demonstrated that mean age and duration of illness were risk factors for TD, but not sex, cumulative exposure to neuroleptic drugs in years, CYP2D6 or CYP1A2 genotype. The C100T polymorphism of the CYP2D6 gene and the C163A polymorphism of the CYP1A2 gene may be associated with neuroleptic drug-induced tardive dyskinesia in Chinese patients with schizophrenia. However, genetic factors have a weaker association with susceptibility to TD compared with mean age and duration of illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 36 | Acta Pharmacol. Sin. 2006 Mar 27: 328-32 |
| PMID | 16490169 |
| Title | Association of CYP2D6 and CYP1A2 gene polymorphism with tardive dyskinesia in Chinese schizophrenic patients. |
| Abstract | To investigate the possible association of the CYP2D6 gene C100T polymorphism and the CYP1A2 gene C163A polymorphism with tardive dyskinesia (TD) in Chinese patients with schizophrenia. The recruited schizophrenic patients were assessed with the Abnormal Involuntary Movement Scale (AIMS), and divided into groups with TD (n=91) and without TD (n=91) according to the AIMS score. Polymorphisms of the CYP2D6 and CYP1A2 genes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). No allele frequencies deviated from Hardy-Weinberg equilibrium. No significant differences in genotypes frequencies of the CYP2D6 C100T polymorphism were observed between patients with TD and without TD (Chi2=4.078, P>0.05), but patients with TD had a significant excess of the T allele compared with those without TD (Chi2=4.28, P<0.05). Moreover, the frequency of the CYP1A2 C allele in patients with TD was significantly higher than that in those without TD (Chi2=6.38, P<0.05). An association between TD and the CYP2D6 100T and CYP1A2 163C alleles was observed. Additionally, there were no differences in the mean AIMS scores among different genotypes in TD patients as a group or in smokers. The results of logistic regression analysis demonstrated that mean age and duration of illness were risk factors for TD, but not sex, cumulative exposure to neuroleptic drugs in years, CYP2D6 or CYP1A2 genotype. The C100T polymorphism of the CYP2D6 gene and the C163A polymorphism of the CYP1A2 gene may be associated with neuroleptic drug-induced tardive dyskinesia in Chinese patients with schizophrenia. However, genetic factors have a weaker association with susceptibility to TD compared with mean age and duration of illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 37 | Eur. J. Clin. Pharmacol. 2006 Dec 62: 1049-53 |
| PMID | 17089108 |
| Title | The effect of variable cigarette consumption on the interaction with clozapine and olanzapine. |
| Abstract | Cigarette smoking has been shown in several studies to induce the metabolism of the cytochrome P4501A2 (CYP1A2) substrates clozapine and olanzapine. The aim of the present study was to investigate the dose-dependent effect of cigarette smoking on serum concentrations of these drugs in a naturalistic setting. In 73 schizophrenic patients recruited from psychiatric nursing homes, patient characteristics, smoking habits, drug dosing and serum concentrations of clozapine (n=33) and olanzapine (n=40) were registered. Concentration to dose (C/D) ratios of clozapine and olanzapine in non-smokers and subgroups of smokers were compared. Fifty-nine patients (80%) were smokers and these were stratified into the following groups according to smoking habits: 1-6 (n=0), 7-12 (n=13), 13-19 (n=18) and >or=20 (n=28) cigarettes daily. While the mean ratio was twice as high in non-smokers compared to smokers for both drugs (p<0.01), the C/D ratios of clozapine and olanzapine were not significantly different between the subgroups of smokers (p >0.15). Absolute serum concentrations were also higher in non-smokers compared to smokers: 50% for clozapine (p=0.058) and 67% for olanzapine (p<0.01). A daily consumption of 7-12 cigarettes is probably sufficient for maximum induction of clozapine and olanzapine metabolism. A 50% lower starting dose of both drugs in non-smokers seems rational to avoid side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 38 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Aug 31: 1297-302 |
| PMID | 17611010 |
| Title | Functional polymorphisms of the cytochrome P450 1A2 (CYP1A2) gene and prolonged QTc interval in schizophrenia. |
| Abstract | CYP1A2 is an important inducible enzyme involved in the metabolism of antipsychotics. This study examined two functional polymorphisms in the gene as potential markers in predicting prolongation of QTc interval in patients treated with antipsychotics. QT intervals were measured by 12-lead electrocardiography (ECG) for patients with a DSM-IV diagnosis of schizophrenia. Genomic DNA extracted from venous blood were genotyped for the two polymorphisms by PCR-RFLP. Statistically significant result for CYP1A2(*)1F was noted for all patients receiving chlorpromazine equivalent doses of above 300 mg and also for a further subgroup on antipsychotics known to be CYP1A2 substrates (p=0.007, mean QTc in ms for A/A: 395.5+/-15.1, A/C: 425.7+/-25.1, C/C: 427.3+/-20.7). For CYP1A2(*)1C, there was no statistically significant association between genotypes and mean QTc interval. Overall, there was a trend of those with the C allele of the CYP1A2(*)1F polymorphism having longer QTc intervals. The results of this study suggest that the CYP1A2(*)1F polymorphism may contribute to the risk of developing prolonged QT-interval in patients who are treated with higher doses of antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 39 | Pharmacogenomics J. 2007 Oct 7: 305-11 |
| PMID | 16969362 |
| Title | Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism. |
| Abstract | Tardive dyskinesia (TD) is an iatrogenic disorder observed in approximately 20-30% of schizophrenia patients on long-term treatment with typical antipsychotic drugs. CYP1A2 is involved in the metabolism of atypical antipsychotic drugs such as clozapine and olanzapine. It is not directly involved in the metabolism of typical antipsychotic drugs, but gains importance when the schizophrenia patients are under long-term chronic treatment, acting as a low-affinity high-capacity metabolizing enzyme. In this study, we have completely sequenced the coding region to ascertain the presence of common coding polymorphisms and their role if any in susceptibility to TD and schizophrenia. Four previously reported polymorphisms, CYP1A2*1F (intron A), rs2472304 & rs3743484 (intron D) and rs2470890 (CYP1A2 1545 C>T) in exon 7 were identified. We further investigated whether the CYP1A2 1545 C>T polymorphism has any role to play in susceptibility to TD and in schizophrenia per se. Association of this single nucleotide polymorphism with TD (P=0.03) and schizophrenia (P=0.04) was observed, but was rendered insignificant after corrections for multiple comparisons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 40 | DNA Cell Biol. 2007 Aug 26: 527-31 |
| PMID | 17688403 |
| Title | Association of serotonin 2A receptor and lack of association of CYP1A2 gene polymorphism with tardive dyskinesia in a Turkish population. |
| Abstract | The aim of this study was to investigate the possible association of serotonin 2A receptor gene (HTR2A) -1438 G/A polymorphism and CYP1A2 gene 163C/A polymorphism with tardive dyskinesia (TD) in a Turkish population. A total of 47 patients with persistent TD, 80 patients who were consistently without TD, and 100 healthy controls were included in this study. The polymorphic regions of -1438 G/A polymorphism of HTR2A receptor gene (rs6311) and 163C/A of CYP1A2 (rs762551) gene were amplified using polymerase chain reaction (PCR), followed by digestion with restriction enzymes MspI and Bsp1201. Genotype and allele frequencies were calculated by the chi(2)-test. Crude and adjusted odds ratios (ORs) were estimated, and 95% confidence intervals (CIs) were computed by multivariate logistic regression analysis. The genotype and allele frequencies of HTR2A and CYP1A2 gene were similar in schizophrenia with TD, schizophrenia without TD, and healthy controls. The logistic regression analysis showed that cumulative exposure to antipsychotic drugs for every year (p = 0.003; OR = 1.15; CI = 1.07-1.23), and AA genotype of HTR2A gene (p = 0.0258; OR = 4.34; CI = 1.19-15.81) are risk factors for TD. The same logistic regression model showed no association between CYP1A2 polymorphism and TD. The results of the present study seem to indicate that HTR2A gene polymorphism influences the tendency to express TD following prolonged antipsychotic drug exposure in Turkish schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 41 | Psychiatry Res 2008 Dec 161: 275-83 |
| PMID | 19000940 |
| Title | Correlates of response to Olanzapine in a North Indian Schizophrenia sample. |
| Abstract | Olanzapine is widely used for the treatment of schizophrenia and is considered a first line medication in India. Along with other factors, the variation in response and side effects to this agent may be accounted for by genetic differences among patients. Olanzapine was administered for 6 weeks to Indian subjects with schizophrenia or schizoaffective disorder (DSM-IV, n=130), as part of an open label study. Intent-to-treat analysis was performed, and 10 polymorphic markers from seven genes (dopamine D1, D2, D3 and D4 receptors, serotonin 2A receptor and the drug-metabolizing enzymes (CYP1A2 and CYP2D6)), together with demographic and clinical variables, were analyzed as potential predictors of response. Olanzapine was efficacious, but significant weight gain was noted. Baseline weight and a 120 bp deletion polymorphism at the dopamine receptor D4 (DRD4) gene were associated with changes in symptom scores. Predictable covariates of treatment response were also noted. These results merit replicate studies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 42 | Pharmacogenomics 2008 Sep 9: 1285-306 |
| PMID | 18781856 |
| Title | Genetic underpinnings of tardive dyskinesia: passing the baton to pharmacogenetics. |
| Abstract | Manifestation of tardive dyskinesia (TD) among schizophrenia subjects on long-term antipsychotic treatment with typical drugs has been a clinical concern. Despite its association with extrapyramidal symptoms, typical drugs are still routinely prescribed globally though marginally superior atypical drugs have long been available. The genetic component in the etiology of TD is well documented. Search for these determinants has led to a few consensus associations of CYP2D6 *10, CYP1A2*1F, DRD2 Taq1A (rs1800497), DRD3 Ser9Gly (rs6280) and MnSOD Ala9Val (rs4880) variants with TD. However, translation of these observations into the clinic has not been achieved so far. This review discusses the salient features of TD etiopathology, current status of TD genetics, interactions between genetic and nongenetic factors, some major drawbacks, challenges and expected focus in TD research over the next decade, with emphasis on pharmacogenetics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 43 | Ther Drug Monit 2008 Feb 30: 35-40 |
| PMID | 18223460 |
| Title | The relationship between the response of clinical symptoms and plasma olanzapine concentration, based on pharmacogenetics: Juntendo University Schizophrenia Projects (JUSP). |
| Abstract | The monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms of UGT1A4, CYP1A2, and CYP2D6 genes have on plasma olanzapine concentration, as well as the effects of plasma olanzapine concentrations on Japanese schizophrenic patients' clinical symptoms. The subjects included 51 chronic schizophrenic patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 44 | Ther Drug Monit 2008 Feb 30: 35-40 |
| PMID | 18223460 |
| Title | The relationship between the response of clinical symptoms and plasma olanzapine concentration, based on pharmacogenetics: Juntendo University Schizophrenia Projects (JUSP). |
| Abstract | The monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms of UGT1A4, CYP1A2, and CYP2D6 genes have on plasma olanzapine concentration, as well as the effects of plasma olanzapine concentrations on Japanese schizophrenic patients' clinical symptoms. The subjects included 51 chronic schizophrenic patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 45 | Br J Clin Pharmacol 2009 Oct 68: 574-9 |
| PMID | 19843060 |
| Title | In vitro and in vivo evaluation of the inhibition potential of risperidone toward clozapine biotransformation. |
| Abstract | To study the impact of risperidone (RISP) on clozapine (CLZ) biotransformation in vitro in microsomal fractions containing varying expression of CYP oxidases and in vivo in patients. Human liver microsomes (n= 11) were assessed for expression of CYPs 1A2, 2D6 and 3A4, because these enzymes mediate RISP and CLZ oxidation. Inhibition of CLZ oxidation by RISP was assessed. Plasma CLZ elimination was estimated in patients with schizophrenia who received either CLZ alone or the CLZ-RISP combination (n= 10 per group). (i) The CYP3A4 and CYP1A2 inhibitors ketoconazole and fluvoxamine inhibited CLZ oxidation to varying extents in individual microsomal fractions. (ii) RISP did not inhibit CLZ oxidation, regardless of variations in CYP expression. (iii) RISP co-administration did not impair CLZ clearance. No evidence was found for CYP-mediated inhibitory or pharmacokinetic interactions between RISP and CLZ. Occasional literature reports of such interactions may involve other pathways that participate in CLZ disposition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 46 | Ther Drug Monit 2009 Apr 31: 239-46 |
| PMID | 19307938 |
| Title | A high-throughput assay using liquid chromatography-tandem mass spectrometry for simultaneous in vivo phenotyping of 5 major cytochrome p450 enzymes in patients. |
| Abstract | The phenotyping cocktail is a practical approach for phenotyping of cytochrome P450 (CYP) enzymes in vivo. In this study, a liquid chromatography-tandem mass spectrometry method using a dual-extraction approach was developed and validated to quantify 5 selective substrates and their metabolites for the simultaneous phenotyping CYPs 1A2, 2C19, 2C9, 2D6, and 3A4 in patient blood samples. The assay was applied in a pilot study of 11 patients with schizophrenia. Five blood samples were collected before and at 1, 2, 4, and 6 hours after administration of a phenotyping cocktail consisting of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam. The method successfully quantitated the CYP enzyme activities without serious side effects in patients. The ratios of metabolite to parent area under the concentration-time curve values were calculated over the 6-hour postdosage to reflect CYP2D6, CYP3A4, and CYP2C9 activities. The ratios of metabolite to parent plasma concentrations were calculated at 4-hour postdosage for CYP1A2 and at 4- or 6-hour postdose for CYP2C19, respectively. The plasma concentration of midazolam at 4 hours was also estimated as another phenotyping index for CYP3A4 activity. The simultaneous assay of all these analytes in a single matrix (plasma) will increase the feasibility of CYP phenotyping in patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 47 | Yao Xue Xue Bao 2009 Jul 44: 785-92 |
| PMID | 19806921 |
| Title | [Population pharmacokinetics research of clozapine in Chinese schizophrenic patients]. |
| Abstract | The goal of this study is to investigate the population pharmacokinetics of oral given clozapine in Chinese schizophrenic patients and to identify possible relationships between population parameters and covariates including demography factors and CYP1A2 genetic polymorphism, so as to create the population pharmacokinetics model to guide individual clinical delivery. Details of drug dosage history, sampling time and concentration of 626 data points from 183 patients were collected retrospectively. The 183 patients were randomly allocated either to the index group (n = 168) or to the validation group (n = 15). Population pharmacokinetic data analysis was performed using the nonlinear mixed-effects model (NONMEM) program on the index group. The values of apparent clearance (CL/F), apparent volume of distribution (V/F) and the constant of absorption rate were estimated. A number of covariates including demographic index, coadministration of other drugs and CYP1A2 genotypes were evaluated statistically for their influence on these parameters. The final population model related clearance with day-dose/BSA (DBSA) and smoke habit (SMOK). Predictive performance of the final model evaluated with the validation group showed insignificant bias between observed and model predicted concentrations. Typical value of CL/F (non-smoking group), V/F and the constant of absorption rate were 28.5 L x h(-1) (5.05%), 1 290 L (16.7%) and 2.26 h(-1) (fixed), inter-patient variability (CV) in CL/F and V/F was) 42.2% and 10.0%, respectively. It was observed that the values of CL/F in the two smoking groups were higher than that in the non-smoking group. The residual variability (SD) between observed and model-predicted concentrations was 45.8 microg x L(-1). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 48 | J Clin Psychopharmacol 2010 Dec 30: 737-9 |
| PMID | 21057239 |
| Title | Development of asymptomatic pancreatitis with paradoxically high serum clozapine levels in a patient with schizophrenia and the CYP1A2*1F/1F genotype. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 49 | Pharmacogenomics 2010 Dec 11: 1725-31 |
| PMID | 21142916 |
| Title | Xenobiotic metabolizing and transporter genes: gene-gene interactions in schizophrenia and related disorders. |
| Abstract | In this study we explored possible epistasis between CYP2D6 (*3, *4, *5, *6 and *1xN), CYP3A5 (*3), CYP1A2 (*1C and *1F) and ABCB1 (G2677T) in schizophrenia and related disorders. A total of 344 patients diagnosed with schizophrenia and related disorders, and 484 healthy controls participated in the present study. We analyzed gene-gene interactions by multifactor dimensionality reduction. A four-way model including ABCB1 G2677T, CYP3A5*3, CYP1A2*1F and CYP2D6*4 variants had the best overall performances (accuracy: 0.573) and a crossvalidation consistency of 10/10 (permutation testing p < 0.004). Our results suggest a significant involvement of CYPs and transporters in brain metabolism and homeostasis, and provide evidence of gene-gene interactions among xenobiotic metabolizing and transporter genes in the context of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 50 | Xenobiotica 2010 Nov 40: 721-9 |
| PMID | 20937004 |
| Title | In vitro assessment of metabolic drug?drug interaction potential of AZD2624, neurokinin-3 receptor antagonist, through cytochrome P(450) enzyme identification, inhibition, and induction studies. |
| Abstract | AZD2624 was pharmacologically characterized as a NK3 receptor antagonist intended for treatment of schizophrenia. The metabolic drug-drug interaction potential of AZD2624 was evaluated in in vitro studies. CYP3A4 and CYP3A5 appeared to be the primary enzymes mediating the formation of pharmacologically active ketone metabolite (M1), whereas CYP3A4, CYP3A5, and CYP2C9 appeared to be the enzymes responsible for the formation of the hydroxylated metabolite (M2). The apparent K(m) values were 1.5 and 6.3 µM for the formation of M1 and M2 in human liver microsomes, respectively. AZD2624 exhibited an inhibitory effect on microsomal CYP3A4/5 activities with apparent IC(50) values of 7.1 and 19.8 µM for midazolam and testosterone assays, respectively. No time-dependent inactivation of CYP3A4/5 activity (midazolam 1'-hydroxylation) by AZD2624 was observed. AZD2624 demonstrated weak to no inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AZD2624 was not an inducer of CYP1A2 or CYP2B6. Although AZD2624-induced CYP3A4 activity in hepatocytes, the potential of AZD2624 to cause inductive drug interactions of this enzyme was low at relevant exposure concentration. Together with targeted low efficacious concentration, the results of this study demonstrated AZD2624 has a relatively low metabolic drug-drug interaction potential towards co-administered drugs. However, metabolism of AZD2624 might be inhibited when co-administrated with potent CYP3A4/5 inhibitors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 51 | Eur. J. Clin. Pharmacol. 2010 May 66: 465-74 |
| PMID | 20143052 |
| Title | Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure--an impact similar to male gender or smoking in schizophrenic patients. |
| Abstract | The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia. A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine. In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 52 | Eur. J. Clin. Pharmacol. 2010 May 66: 465-74 |
| PMID | 20143052 |
| Title | Carriers of the UGT1A4 142T>G gene variant are predisposed to reduced olanzapine exposure--an impact similar to male gender or smoking in schizophrenic patients. |
| Abstract | The impact of the UGT1A4, CYP1A2, and MDR1 genetic variants on olanzapine plasma levels, in relation to those of other individual factors, such as gender, smoking status, body weight, and age, was investigated in patients with schizophrenia. A total of 121 patients were recruited from psychosis-specialized outpatient departments in Stockholm County. Olanzapine plasma concentrations were determined by high-performance liquid chromatography. Genotyping was carried out by PCR-restriction fragment length polymorphism or minisequencing, and haplotypes were analyzed using specialized computer software on population genetics. Multiple regression analysis was performed to investigate the combined effect of patient characteristics and genotypes/haplotypes on daily dose-corrected plasma concentrations of olanzapine. In addition to , the results indicate that inter-patient differences in olanzapine exposure were explained by the known factor of time of sampling from last dose intake and by the following individual factors in order of relative impact: (1) male gender, (2) carrier of the UGT1A4 142T>G single nucleotide polymorphism (SNP), and (3) smoking. Each of these three factors predicted a decrease in daily dose-corrected plasma concentrations of 35, 25, and 21%, respectively. In contrast, age, body weight, and MDR1 or CYP1A2 haplotype did not have a significant impact. At 12 h after dose intake, the regression model predicted a 5.1-fold higher olanzapine plasma level in a non-smoking female patient who did not carry the UGT1A4 142T>G SNP compared to a smoking man treated with the same dose but heterozygous for UGT1A4 142T>G SNP. Whether these combined genetic and environmental factors influence the risk of therapeutic failure remains to be established. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 53 | Pharmacogenomics J. 2010 Feb 10: 20-9 |
| PMID | 19636338 |
| Title | Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome. |
| Abstract | Psychiatric pharmacotherapy with olanzapine is commonplace. We investigated the influence of CYP1A2*1F (-163A, rs762551) and serotonergic polymorphisms on olanzapine serum concentrations and clinical outcome in a naturalistic clinical setting. Included were 124 Caucasian psychiatric inpatients treated with olanzapine for at least 4 weeks with steady-state serum concentrations available for 73 patients. The CYP1A2*1F polymorphism was reported to affect the inducibility of CYP1A2. In our study population, CYP1A2*1F/*1F genotype alone resulted in a 22% reduction of dose-/body weight-normalized olanzapine serum concentrations compared to homo- and heterozygote carriers of CYP1A2*1A (both groups without inducers). This effect was independent of the well-known effect of inducing agents (here tobacco smoke and carbamazepine which led to on average 28% lower concentrations in CYP1A2*1A carriers and 26% lower concentrations in CYP1A2*1F/*1F carriers). Consistently, patients with the CYP1A2*1F/*1F genotype taking inducers had 22% lower concentrations compared to CYP1A2*1A carriers taking inducers. The influence of genotype alone remained significant after Bonferroni's post hoc test. Higher olanzapine concentrations were significantly correlated with better improvement of paranoid and depressive symptoms in patients with schizophrenic disorders (Spearman's r=0.5, P=0.026 and P=0.006, respectively). No relationship between serum concentrations and the side effects (DOTES) score was detected. However, patients with the 5-HTR2A intron 2 (rs7997012) AA genotype suffered from more pronounced side effects compared to carriers of the GA or GG genotype (P=0.018 and P=0.002). Short-term weight gain under olanzapine therapy was significantly lower for 5-HTR2C -759 T-allele carriers (P=0.011). Our data suggest that the CYP1A2*1F/*1F genotype exhibits a significant influence on olanzapine concentrations independent of other inducing factors. Thus, CYP1A2*1F genotyping may be useful for clinical treatment decisions given the fact that olanzapine serum concentrations correlated with treatment response. Side effects and weight gain, however, seem to be more influenced by serotonergic polymorphisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 54 | Psychiatry Clin. Neurosci. 2011 Feb 65: 3-19 |
| PMID | 21265934 |
| Title | Pharmacogenomics of antipsychotics efficacy for schizophrenia. |
| Abstract | Central nervous system disorders are the third greatest health problem in developed countries, and schizophrenia represents some of the most disabling ailments in young individuals. There is an abuse and/or misuse of antipsychotics, and recent advances in pharmacogenomics pose new challenges for the clinical management of this complex disorder. schizophrenia is a multi-factorial/polygenic complex disorder in which hundreds of different genes are potentially involved, leading to the phenotypic expression of the disease in conjunction with epigenetic and environmental phenomena. Consequently, structural and functional genomic changes induce proteomic and metabolomic defects associated with the disease phenotype. Disease-related genomic profiles and genetic variants in genes involved in drug metabolism are responsible for drug efficacy and safety. About 20% of Caucasians are defective in CYP2D6 enzymes, which participate in the metabolism of 25-30% of central nervous system drugs. Approximately 40% of antipsychotics are substrates of CYP2D6 enzymes, 23% are substrates of CYP3A4, and 18% are substrates of CYP1A2. In order to achieve a mature discipline of pharmacogenomics of schizophrenia it would be effective to accelerate: (i) the education of physicians and the public in the use of genomic screening in daily clinical practice; (ii) the standardization of genetic testing for major categories of drugs; (iii) the validation of pharmacogenomic procedures according to drug category and pathology; (iv) the regulation of ethical, social, and economic issues; and (v) the incorporation of pharmacogenomic procedures of drugs in development and drugs on the market in order to optimize therapeutics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 55 | J Clin Psychopharmacol 2011 Feb 31: 4-9 |
| PMID | 21192135 |
| Title | High correlation between serum and cerebrospinal fluid olanzapine concentrations in patients with schizophrenia or schizoaffective disorder medicating with oral olanzapine as the only antipsychotic drug. |
| Abstract | The primary aim of the present study was to investigate the relationship between steady state serum and cerebrospinal fluid (CSF) concentrations of olanzapine (OLA) and its metabolite 4'-N-desmethylolanzapine (DMO) in patients with schizophrenia or schizoaffective disorder treated with oral OLA as the only antipsychotic drug. The influence of smoking, gender, age, as well as polymorphisms in cytochrome P450 CYP2D6, CYP1A2, and ABCB1 genes on the serum and CSF drug levels was also analyzed. Thirty-seven white outpatients (10 smokers and 27 nonsmokers) were included. From 29 of them, CSF was collected successfully. A strong correlation (Spearman rank correlation [rs] = 0.93; P < 0.05) was found between serum and CSF concentrations of OLA and a somewhat weaker correlation (rs = 0.5; P < 0.05) between those of DMO. The CSF concentrations of OLA and DMO were on average 12% and 16% of those in serum. Extensive metabolizers of CYP2D6 had higher (P < 0.05) daily doses than poor metabolizers when the influence of smoking was taken into account. Smokers had lower (P < 0.01) concentration-to-dose ratios of OLA in serum (mean, 2.23 ng/mL per mg vs 3.32 ng/mL per mg) and CSF (0.27 ng/mL per mg vs 0.41 ng/mL per mg) than nonsmokers. The concentration-to-dose ratio for serum DMO decreased with increasing age (rs = -0.41; P < 0.05). Carriers of ABCB1 1236T/2677T/3435T haplotype had higher serum (mean, 37.7 ng/mL vs 22.5 ng/mL; P = 0.035) and CSF (4.7 ng/mL vs 2.6 ng/mL; P = 0.018) OLA concentrations than patients without this haplotype. The present study shows a strong correlation between serum and CSF concentrations of OLA, indicating that concentrations of OLA in serum reflect those in CSF. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 56 | CNS Neurosci Ther 2011 Oct 17: 541-65 |
| PMID | 20718829 |
| Title | Genomics and pharmacogenomics of schizophrenia. |
| Abstract | schizophrenia (SCZ) is among the most disabling of mental disorders. Several neurobiological hypotheses have been postulated as responsible for SCZ pathogenesis: polygenic/multifactorial genomic defects, intrauterine and perinatal environment-genome interactions, neurodevelopmental defects, dopaminergic, cholinergic, serotonergic, gamma-aminobutiric acid (GABAergic), neuropeptidergic and glutamatergic/N-Methyl-D-Aspartate (NMDA) dysfunctions, seasonal infection, neuroimmune dysfunction, and epigenetic dysregulation. SCZ has a heritability estimated at 60-90%. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single nucleotide polymorphisms (SNPs) in microRNA genes, mitochondrial DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are major substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are major substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. About 10-20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6+CYP2C19+CYP2C9 genes. The pharmacogenomic response of SCZ patients to conventional psychotropic drugs also depends on genetic variants associated with SCZ-related genes. Consequently, the incorporation of pharmacogenomic procedures both to drugs in development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system (CNS) disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 57 | PLoS ONE 2012 -1 7: e36561 |
| PMID | 22615781 |
| Title | Candidate gene-based association study of antipsychotic-induced movement disorders in long-stay psychiatric patients: a prospective study. |
| Abstract | Four types of antipsychotic-induced movement disorders: tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia, subtypes of TD (orofacial and limb truncal dyskinesia), subtypes of parkinsonism (rest tremor, rigidity, and bradykinesia), as well as a principal-factor of the movement disorders and their subtypes, were examined for association with variation in 10 candidate genes (PPP1R1B, BDNF, DRD3, DRD2, HTR2A, HTR2C, COMT, MnSOD, CYP1A2, and RGS2). Naturalistic study of 168 white long-stay patients with chronic mental illness requiring long-term antipsychotic treatment, examined by the same rater at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. The authors genotyped 31 SNPs, associated with movement disorders or schizophrenia in previous studies. Genotype and allele frequency comparisons were performed with multiple regression methods for continuous movement disorders. VARIOUS SNPS REACHED NOMINAL SIGNIFICANCE: TD and orofacial dyskinesia with rs6265 and rs988748, limb truncal dyskinesia with rs6314, rest tremor with rs6275, rigidity with rs6265 and rs4680, bradykinesia with rs4795390, akathisia with rs4680, tardive dystonia with rs1799732, rs4880 and rs1152746. After controlling for multiple testing, no significant results remained. The findings suggest that selected SNPs are not associated with a susceptibility to movement disorders. However, as the sample size was small and previous studies show inconsistent results, definite conclusions cannot be made. Replication is needed in larger study samples, preferably in longitudinal studies which take the fluctuating course of movement disorders and gene-environment interactions into account. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 58 | Psychiatry Res 2012 Dec 200: 1014-7 |
| PMID | 22901441 |
| Title | Association between CYP1A2 polymorphisms and clozapine-induced adverse reactions in patients with schizophrenia. |
| Abstract | We investigated the relationships between common polymorphisms in CYP1A2 (CYP1A2(?)1C and (?)1F), CYP1A2-mRNA levels in circulating lymphocytes and clozapine(CLZ)-induced adverse drug reactions (ADRs) in 34 patients. Patients with ADRs had a higher frequency of CYP1A2 low activity allele combinations (8/12; 67%) and lower CYP1A2-mRNA levels than patients without ADRs (6/22; 27%, P=0.019). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 59 | Int Clin Psychopharmacol 2012 Mar 27: 121-4 |
| PMID | 22113252 |
| Title | Interaction of St John's wort (Hypericum perforatum) with clozapine. |
| Abstract | St John's wort (Hypericum perforatum) is notorious for its ability to induce the enzymes of the P450 system. Especially, it induces CYP1A2 and CYP3A4, enzymes that are closely involved in the metabolism of clozapine. We present a patient with schizophrenia, who was stable on a fixed dose with stable plasma level of clozapine, and who deteriorated after she started self-medicating with St John's wort. The reduced plasma clozapine level and the psychiatric condition normalized after the withdrawal of St John's wort. It is possible that, beside the induction of P450-enzymes, the induction of P-glycoprotein by St John's wort aggravated psychiatric deterioration of the patient. Physicians should be alert to patients self-medicating with over-the-counter medicines, especially when these medicines can lower clozapine concentrations below the therapeutic range. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 60 | J Clin Psychopharmacol 2012 Aug 32: 441-8 |
| PMID | 22722500 |
| Title | Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response. |
| Abstract | Pharmacogenetic studies on clozapine (CLZ) have provided meaningful insights but have shown redundancies owing to wide interindividual variability and insufficient replication. The present study was designed to validate hitherto suggested candidate genes on CLZ pharmacokinetics and pharmacodynamics and explore new markers through an integrative study. Based on a literature review, a total of 127 variations in 27 candidate genes were selected and analyzed. Ninety-six schizophrenic patients of Korean ethnicity with constant CLZ dosing were recruited, and information on body weight and smoking habits was gathered, as well as plasma drug levels and treatment responses. Among the pharmacokinetic-related single nucleotide polymorphisms, rs2069521 and rs2069522 in CYP1A2 for CLZ/(dose/weight) and norclozapine/(dose/weight) and rs1135840 in CYP2D6 for norclozapine/CLZ showed borderline associations that were insignificant after correction for multiple testing. Regarding treatment response, significant associations were exhibited in rs7787082 and rs10248420 of ABCB1 (P = 0.0005 and P = 0.0013, respectively) even after correction, and the rs7787082 G and rs10248420 A alleles in ABCB1 were more frequently observed in nonresponders. We also observed a trend in the associations of rs13064530 in HRH1 and rs4938013 in DRD2/ANKK1 with treatment response. We could not convincingly replicate most of the previous studies, a result that is possibly due to modest association between the suggested genes. Rather, we found a new candidate gene, ABCB1, for treatment response, which may provide a hypothesis on the relationship between the blood-brain distribution of CLZ and its clinical efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 61 | Tijdschr Psychiatr 2013 -1 55: 955-9 |
| PMID | 24366834 |
| Title | [A patient on clozapine in the general hospital: the need for discussion between specialists from different disciplines and for close monitoring of the patient's plasma level]. |
| Abstract | A 49-year-old man being treated with clozapine for schizophrenia was prescribed ciprofloxacin because of bile spill following cholecystectomy. Four days after surgery he showed symptoms of clozapine intoxication, probably because the ciprofloxacin had inhibited CYP1A2. Over the next few days the patient's plasma level was measured frequently but without any real sense of urgency. As a result, the patient's plasma level remained too high for a long period, then decreased, the decrease being accompanied by the recurrence of psychotic symptoms. Our advice, therefore, is that if a patient on clozapine is in a general hospital there needs to be pro-active discussion of the case between a psychiatrist and other medical specialists and the patient's clozapine plasma level should be measured whenever the patient's condition appears to be deteriorating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 62 | Bioorg. Med. Chem. 2013 Dec 21: 7612-23 |
| PMID | 24238902 |
| Title | Design and synthesis of novel benzimidazole derivatives as phosphodiesterase 10A inhibitors with reduced CYP1A2 inhibition. |
| Abstract | A novel class of phosphodiesterase 10A (PDE10A) inhibitors with reduced CYP1A2 inhibition were designed and synthesized starting from 2-{[(1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (1). Introduction of an isopropyl group at the 2-position and a methoxy group at the 5-position of the benzimidazole ring of lead compound 1 resulted in the identification of 2-{[(2-isopropyl-5-methoxy-1-phenyl-1H-benzimidazol-6-yl)oxy]methyl}quinoline (25b), which exhibited potent PDE10A inhibitory activity with reduced CYP1A2 inhibitory activity compared to compound 1. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 63 | CNS Drugs 2013 Dec 27: 1021-48 |
| PMID | 24170642 |
| Title | Clinically significant drug interactions with atypical antipsychotics. |
| Abstract | Atypical antipsychotics [also known as second-generation antipsychotics (SGAs)] have become a mainstay therapeutic treatment intervention for patients with schizophrenia, bipolar disorders and other psychotic conditions. These agents are commonly used with other medications--most notably, antidepressants and antiepileptic drugs. Drug interactions can take place by various pharmacokinetic, pharmacodynamic and pharmaceutical mechanisms. The pharmacokinetic profile of each SGA, especially with phase I and phase II metabolism, can allow for potentially significant drug interactions. Pharmacodynamic interactions arise when agents have comparable receptor site activity, which can lead to additive or competitive effects without alterations in measured plasma drug concentrations. Additionally, the role of drug transporters in drug interactions continues to evolve and may effect both pharmacokinetic and pharmacodynamic interactions. Pharmaceutical interactions occur when physical incompatibilities take place between agents prior to drug absorption. Approximate therapeutic plasma concentration ranges have been suggested for a number of SGAs. Drug interactions that markedly increase or decrease the concentrations of these agents beyond their ranges can lead to adverse events or diminished clinical efficacy. Most clinically significant drug interactions with SGAs occur via the cytochrome P450 (CYP) system. Many but not all drug interactions with SGAs are identified during drug discovery and pre-clinical development by employing a series of standardized in vitro and in vivo studies with known CYP inducers and inhibitors. Later therapeutic drug monitoring programmes, clinical studies and case reports offer methods to identify additional clinically significant drug interactions. Some commonly co-administered drugs with a significant potential for drug-drug interactions with selected SGAs include some SSRIs. Antiepileptic mood stabilizers such as carbamazepine and valproate, as well as other antiepileptic drugs such as phenobarbital and phenytoin, may decrease plasma SGA concentrations. Some anti-infective agents such as protease inhibitors and fluoroquinolones are of concern as well. Two additional important factors that influence drug interactions with SGAs are dose and time dependence. Smoking is very common among psychiatric patients and can induce CYP1A2 enzymes, thereby lowering expected plasma levels of certain SGAs. It is recommended that ziprasidone and lurasidone are taken with food to promote drug absorption, otherwise their bioavailability can be reduced. Clinicians must be aware of the variety of factors that can increase the likelihood of clinically significant drug interactions with SGAs, and must carefully monitor patients to maximize treatment efficacy while minimizing adverse events. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 64 | Int Rev Psychiatry 2013 Oct 25: 509-33 |
| PMID | 24151799 |
| Title | Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy. |
| Abstract | Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 65 | Psychiatry Res 2013 Sep 209: 242-5 |
| PMID | 23601795 |
| Title | The CYP1A2 -163C>A polymorphism is associated with clozapine-induced generalized tonic-clonic seizures in Brazilian schizophrenia patients. |
| Abstract | We evaluated two polymorphisms at CYP1A2 (*1C and *1F) in a sample of 108 European-derived patients with schizophrenia and their influence on the pro-convulsive effect of clozapine. We found the *1F/*1F genotype to be significantly associated with seizures, and no relationship was observed with combinations of *1F and *1C alleles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 66 | Schizophr. Res. 2013 Sep 149: 1-14 |
| PMID | 23870808 |
| Title | CYP450 pharmacogenetic treatment strategies for antipsychotics: a review of the evidence. |
| Abstract | Although a number of first- and second-generation antipsychotics are available, achieving optimal therapeutic response for patients with schizophrenia can be challenging. The presence of polymorphic alleles for cytochrome P (CYP) 450 may result in lack of expression, altered levels of expression, or altered function of CYP450 enzymes. CYP2D6, CYP1A2, and CYP3A4/5 are major enzymes in the metabolism of antipsychotics and polymorphisms of alleles for these proteins are associated with altered plasma levels. Consequently, standard dosing may result in drug plasma concentrations that are subtherapeutic or toxic in some patients. Patient CYP450 genotype testing can predict altered pharmacokinetics, and is currently available and relatively inexpensive. Evidence-based guidelines provide dose recommendations for some antipsychotics. To date few studies have demonstrated a significant association with genotype-guided antipsychotic use and clinical efficacy. However, many studies have been small, retrospective or cohort designs, and many have not been adequately powered. Numerous studies have shown a significant association between genotype and adverse effects, such as CYP2D6 polymorphisms and tardive dyskinesia. This review summarizes evidence for the role of CYP450 genetic variants in the response to antipsychotic medications and the clinical implications of pharmacogenetics in the management of patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 67 | Expert Opin Drug Metab Toxicol 2013 Sep 9: 1115-37 |
| PMID | 23641727 |
| Title | Considering CYP1A2 phenotype and genotype for optimizing the dose of olanzapine in the management of schizophrenia. |
| Abstract | schizophrenia, a mental disorder, is a debilitating condition which typically strikes young people in their early 20's. Antipsychotic medications are widely prescribed for the treatment of schizophrenia however a balancing act is necessary to provide the correct dose to each patient. It is suggested that a large number of patients discontinue antipsychotic pharmacotherapy because the treatments provided do not always reduce the positive symptoms of the disease, while many have adverse effects on the patients. This implies that neither the incorrect drug nor the optimal dosage for that patient is achieved. The current review investigates variability in response to olanzapine with a specific focus on the common intrinsic and extrinsic factors that influence both olanzapine and CYP1A2 activity. Furthermore, the authors discuss the utilization of phenotyping and genotyping of CYP1A2 and their potential utility in clinical practice for olanzapine dosing regimens. The authors also consider the potential of pharmacometrics compared to pharmacogenomics as a tool to personalize medicine. Careful consideration must be given to the impact of a genetic variant on the disposition of a drug prior to implementing genetic 'tests' to determine response. CYP1A2 phenotypic assessment can yield important information regarding the disposition of olanzapine; however, it relies on the accuracy of the metric and the minimal impact of other metabolic pathways. The application of pharmacometrics provides an effective method to establish covariates that significantly influence olanzapine disposition which can incorporate phenotype and/or genotype. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 68 | Front Med 2013 Jun 7: 180-90 |
| PMID | 23606027 |
| Title | Pharmacogenomics can improve antipsychotic treatment in schizophrenia. |
| Abstract | schizophrenia is a widespread mental disease with a prevalence of about 1% in the world population, and heritability of up to 80%. Drug therapy is an important approach to treating the disease. However, the curative effect of antipsychotic is far from satisfactory in terms of tolerability and side effects. Many studies have indicated that about 30% of the patients exhibit little or no improvements associated with antipsychotics. The response of individual patients who are given the same dose of the same drug varies considerably. In addition, antipsychotic drugs are often accompanied by adverse drug reactions (ADRs), which can cause considerable financial loss in addition to the obvious societal harm. So, it is strongly recommended that personalized medicine should be implemented both to improve drug efficacy and to minimize adverse events and toxicity. There is therefore a need for pharmacogenomic studies into the factors affecting response of schizophrenia patients to antipsychotic drugs to provide informed guidance for clinicians. Individual differences in drug response is due to a combination of many complex factors including ADEM (absorption, distribution, metabolism, excretion) process, transporting, binding with receptor and intracellular signal transduction. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this interindividual variability in antipsychotics response. In addition, epigenetic factors such as methylation of DNA and regulation by miRNA have also been reported to play an important role in the complex interactions between the multiple genes and environmental factors which influence individual drug response phenotypes in patients. In this review, we will focus on the latest research on polymorphisms of candidate genes that code for drug metabolic enzymes (CYP2D6, CYP1A2, CYP3A4, etc.), drug transporters (mainly ABCB1) and neurotransmitter receptors (dopamine receptors and serotonin receptors, etc.). We also discuss the genome-wide pharmacogenomic study of schizophrenia and review the current state of knowledge on epigenetics and potential clinical applications. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 69 | Acta Neuropsychiatr 2013 Feb 25: 2-11 |
| PMID | 26953068 |
| Title | Association between CYP1A2 gene single nucleotide polymorphisms and clinical responses to clozapine in patients with treatment-resistant schizophrenia. |
| Abstract | Despite clozapine's superior clinical efficacy in treatment-resistant schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes mandate a clinical need to predict its treatment response. Although cytochrome P450 1A2 (CYP1A2) is the principal determinant of metabolism of clozapine, the role of CYP1A2 gene in the clinical response to clozapine is uncertain. Hence, we investigated its association with treatment responses and adverse events of clozapine in TRS. We evaluated four single nucleotide polymorphisms (SNP) in the CYP1A2 gene, clinical responses and serum clozapine levels in 101 consecutive patients with TRS on stable doses of clozapine. We defined clozapine response a priori and investigated allelic and genotypic associations. We assessed the socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition and disability of the participants, using standard assessment schedules for appropriate multivariate analyses. Our results revealed that CYP1A2 gene SNP (*1C, *1D, *1E and *1F) were not associated with clozapine treatment response, adverse effects, serum clozapine levels or with disability (p values > 0.10). As CYP1A2 gene SNP do not help to predict the clinical response to clozapine, routine screening for them prior to start clozapine is currently unwarranted. We suggest future longitudinal genome-wide association studies investigating clinical and pharmacogenetic variables together. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 70 | PLoS ONE 2013 -1 8: e65719 |
| PMID | 23741510 |
| Title | Determination of olanzapine and N-desmethyl-olanzapine in plasma using a reversed-phase HPLC coupled with coulochemical detection: correlation of olanzapine or N-desmethyl-olanzapine concentration with metabolic parameters. |
| Abstract | Olanzapine (OLZ) is one of the most prescribed atypical antipsychotic drugs but its use is associated with unfavorable metabolic abnormalities. N-desmethyl-olanzapine (DMO), one of the OLZ metabolites by CYP1A2, has been reported to have a normalizing action on metabolic abnormalities, but this remains unclear. Our aim was to explore the correlation between the concentrations of OLZ or DMO with various metabolic parameters in schizophrenic patients. The chromatographic analysis was carried out with a solvent delivery system coupled to a Coulochem III coulometric detector to determine OLZ and DMO simultaneously in OLZ-treated patients. The correlation between the concentration of OLZ or DMO and the metabolic parameters was analyzed by the Spearman rank order correlation method (r s). The established analytical method met proper standards for accuracy and reliability and the lower limitation of quantification for each injection of DMO or OLZ was 0.02 ng. The method was successfully used for the analysis of samples from nonsmoking patients (n?=?48) treated with OLZ in the dosage range of 5-20 mg per day. There was no correlation between OLZ concentrations and tested metabolic parameters. DMO concentrations were negatively correlated with glucose (r s?=?-0.45) and DMO concentrations normalized by doses were also negatively correlated with insulin levels (r s?=?-0.39); however, there was a marginally positive correlation between DMO and homocysteine levels (r s?=?+0.38). The observed negative correlations between levels of DMO and glucose or insulin suggest a metabolic normalization role for DMO regardless of its positive correlation with a known cardiovascular risk factor, homocysteine. Additional studies of the mechanisms underlying DMO's metabolic effects are warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 71 | Australas Psychiatry 2014 Dec 22: 543-5 |
| PMID | 25388804 |
| Title | A clozapine conundrum: clozapine toxicity in an acute medical illness. |
| Abstract | The following report presents a case in which significant clozapine toxicity was demonstrated in a patient on established therapy, in the absence of identifiable risk factors. Through this case report, the authors aim to highlight the potential for clozapine toxicity to occur unexpectedly in times of acute medical illness, and the need to remain vigilant in such situations. Case report and review of the relevant literature. We describe a case of a 62 year old man whom developed life-threatening clozapine toxicity in the context of a severe lower respiratory infection. Following investigation to exclude the usual causes of toxicity, it was surmised that impaired CYP1A2 function, secondary to the acute inflammatory process, had led to a toxic level of the drug. Given the possibility that serum clozapine levels may significantly rise in acute illness, the team recommends measurement of clozapine levels in these situations, in combination with the usual full blood count investigation. Such a practice should be considered in the local monitoring protocol, to avoid incidence of potentially toxic outcomes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 72 | Expert Opin Drug Metab Toxicol 2014 Jun 10: 893-903 |
| PMID | 24793403 |
| Title | Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. |
| Abstract | Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes. The purpose of this review is to describe the chemistry, pharmacodynamics, and pharmacokinetics of asenapine. Asenapine has a complex pharmacodynamic profile with affinities at multiple dopamine, serotonin, histamine, and ?-adrenergic receptors, all at which asenapine functions as an antagonist. Sublingual asenapine tablets are absorbed in the oral mucosa, with a Tmax occurring between 30 and 90 min. Terminal half-life is approximately 24 h. Asenapine has multiple inactive metabolites, produced via direct glucuronidation (primarily via UGT1A4), demethylation, and oxidative metabolism (primarily via CYP1A2). Hepatic and renal routes contribute approximately equally to the elimination of asenapine and its metabolites. Two notable drug-drug interactions are evident: asenapine (an inhibitor of CYP2D6) can increase plasma levels of paroxetine, and fluvoxamine (a CYP1A2 inhibitor) can increase plasma levels of asenapine. Caution is required when coadministering asenapine with drugs that are both substrates and inhibitors of CYP2D6. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 73 | Int. J. Antimicrob. Agents 2014 Aug 44: 173-7 |
| PMID | 24929949 |
| Title | Effect of fosamprenavir/ritonavir on the pharmacokinetics of single-dose olanzapine in healthy volunteers. |
| Abstract | Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 74 | Int Clin Psychopharmacol 2015 Mar 30: 82-8 |
| PMID | 25025989 |
| Title | Pharmacogenetics of quetiapine in healthy volunteers: association with pharmacokinetics, pharmacodynamics, and adverse effects. |
| Abstract | Quetiapine is an atypical antipsychotic used for treatment of schizophrenia. Variability in response to this drug may be associated with pharmacogenetics. The aim of this study was to identify genetic markers related to the pharmacokinetics, pharmacodynamics, and adverse effects of quetiapine. The study population comprised 79 healthy volunteers from two bioequivalence trials who were genotyped to identify polymorphisms in genes encoding enzymes, receptors, and transporters. Quetiapine plasma levels were quantified using high-performance liquid chromatography/mass spectrometry. Prolactin plasma levels were detected by indirect chemiluminescence. Possible adverse effects were recorded throughout the study. Factors with P value of 0.1 or less in the univariate analysis were included in a multiple regression analysis (logistic regression for adverse reactions). The area under the curve and clearance of quetiapine were affected by polymorphisms in CYP1A2 and DRD3, respectively. Men had a lower quetiapine area under the curve compared with women. Prolactin iC(max) was higher in volunteers harboring polymorphisms in CYP2C19 and AGT. An association was detected between polymorphisms in CYP1A1 and CYP2C9 and somnolence. Several polymorphisms are responsible for differences in the pharmacokinetics, pharmacodynamics, and safety of quetiapine in healthy individuals. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 75 | Schizophr. Res. 2015 Dec 169: 502-3 |
| PMID | 26530626 |
| Title | The CYP1A2 -163C > A polymorphism is associated with super-refractory schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 76 | Therapie 2015 Jul -1: -1 |
| PMID | 26220922 |
| Title | [Therapeutic Drug Monitoring of Clozapine]. |
| Abstract | Clozapine is a prototypical atypical antipsychotic used to treat severe schizophrenia and for which a therapeutic drug monitoring (TDM) is quite commonly proposed. Clozapine is rapidly absorbed (maximum concentration reached within 1 to 4 hours), and is extensively metabolized in the liver by CYP1A2 to an active metabolite (and to a lesser extent, to inactive metabolites via other enzymes). Its half-life is 8 to 16 h. A therapeutic range has been proposed for clozapine as some studies have reported both a relationship between low plasmatic concentrations and resistance to treatment (threshold level is likely between 250 and 400 µg/L), and a relationship between high plasmatic concentrations and an increase in the occurrence of toxicity (alert level=1 000µg/L). Given the data obtained in different studies, the TDM was evaluated for this molecule, to: recommended. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 77 | Therapie 2015 Jul -1: -1 |
| PMID | 26220921 |
| Title | [Therapeutic Drug Monitoring of Olanzapine]. |
| Abstract | Olanzapine, atypical antipsychotic, is used to treat schizophrenia and bipolar disorder. Its therapeutic drug monitoring (TDM) is quite commonly done. Olanzapine is well absorbed orally (bioavailability 85%), with peak plasma occurring between 4 and 6 hours after oral administration. It is extensively metabolized by different hepatic enzymes (including CYP1A2 and CYP2D6 isoforms) to a large number of inactive metabolites, and its half-life is between 30 and 60 hours. No specific therapeutic range, or threshold concentration could not be a consensus, but the higher intra-and interindividual variability, as well as the existence of studies suggesting a correlation between circulating concentrations of olanzapine and occurrence of therapeutic relapse or toxic phenomena appear to justify the STP for this molecule. Given these data, the interest of the STP was evaluated for this molecule to: recommended with therapeutic window of 20 µg/L to 80 µg/L. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 78 | Expert Opin Drug Metab Toxicol 2015 -1 11: 1709-31 |
| PMID | 26364648 |
| Title | Pharmacogenetics of clozapine treatment response and side-effects in schizophrenia: an update. |
| Abstract | Clozapine (CLZ) is the most effective treatment for treatment-resistant schizophrenia (SCZ) patients, with potential added benefits of reduction in suicide risk and aggression. However, CLZ is also mainly underused due to its high risk for the potentially lethal side-effect of agranulocytosis as well as weight gain and related metabolic dysregulation. Pharmacogenetics promises to enable the prediction of patient treatment response and risk of adverse effects based on patients' genetics, paving the way toward individualized treatment. This article reviews pharmacogenetics studies of CLZ response and side-effects with a focus on articles from January 2012 to February 2015, as an update to the previous reviews. Pharmacokinetic genes explored primarily include CYP1A2, while pharmacodynamic genes consisted of traditional pharmacogenetic targets such as brain-derived neurotrophic factor as well novel mitochondrial genes, NDUFS-1 and translocator protein. Pharmacogenetics is a promising avenue for individualized medication of CLZ in SCZ, with several consistently replicated gene variants predicting CLZ response and side-effects. However, a large proportion of studies have yielded mixed results. Large-scale Genome-wide association studies (e.g., CRESTAR) and targeted gene studies with standardized designs (response measurements, treatment durations, plasma level monitoring) are required for further progress toward clinical translation. Additionally, in order to improve study quality, we recommend accounting for important confounders, including polypharmacy, baseline measurements, treatment duration, gender, and age at onset. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 79 | Drug Metab. Dispos. 2015 Nov 43: 1806-14 |
| PMID | 26329789 |
| Title | In Vitro Characterization of the Human Liver Microsomal Kinetics and Reaction Phenotyping of Olanzapine Metabolism. |
| Abstract | Olanzapine (OLZ) is an atypical antipsychotic used in the treatment of schizophrenia and related psychoses. The metabolism of OLZ is complex and incompletely characterized. This study aimed to elucidate the enzymes and pathways involved in the metabolism of OLZ and to determine the kinetics of OLZ oxidation and glucuronidation by human liver microsomes, recombinant cytochrome P450 (rP450) enzymes, and recombinant UDP-glucuronosyltransferase (rUGT) enzymes. An ultra-performance liquid chromatography-mass spectrometry method was developed and validated to quantify OLZ, its four oxidative metabolites (N-desmethyl-OLZ, 2-hydroxymethyl-OLZ, 7-hydroxy-OLZ, and OLZ-N-oxide), and two N-glucuronides (OLZ-10-N-glucuronide and OLZ-4'-N-glucuronide). Consistent with previous reports, UGT1A4, CYP1A2, and flavin-containing monooxygenase 3 play major roles in catalyzing the formation of OLZ-10-N-glucuronide, 7-hydroxy-OLZ, and OLZ-N-oxide, respectively. In addition, a previously uncharacterized major contribution of CYP2C8 to OLZ-N-demethylation was demonstrated. The kinetics of OLZ metabolite formation (Km and Vmax) by human liver microsomes, rP450 enzymes, and rUGT enzymes were characterized in the presence of bovine serum albumin [2% (w/v)]. Consistent with the known effect of bovine serum albumin on CYP1A2, CYP2C8, and UGT1A4 activities, Km values reported here are lower than previously reported values for OLZ metabolic pathways. In addition to CYP1A2-mediated OLZ-N-demethylation, these results suggest that other P450 enzymes, particularly CYP2C8, contribute significantly to oxidative OLZ metabolism through catalysis of OLZ-N-demethylation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 80 | World J. Biol. Psychiatry 2015 Apr 16: 200-5 |
| PMID | 25602162 |
| Title | Cytochrome P450 1A2 co-determines neuroleptic load and may diminish tardive dyskinesia by increased inducibility. |
| Abstract | The aim of this study was to investigate a possible association between tardive dyskinesia (TD) and CYP1A2 (*1F, -163C>?, rs762551) polymorphism in Russian psychiatric inpatients. TD was assessed cross-sectionally using the Abnormal Involuntary Movement Scale (AIMS). Orofacial and limb-truncal dyskinesia were assessed with AIMS 1-4 and 5-7, respectively. Standard protocols were applied for genotyping. Analysis of covariance (ANCOVA) was used to compare the mean AIMS scores for each of the genotypic classes. A total of 319 Caucasian patients from West Siberia with schizophrenia and 117 healthy volunteers were investigated. No significant differences between the patients and the controls in genotype frequencies were found. Analysis of covariance (ANCOVA) with age, sex, duration of disease, chlorpromazine equivalent (CPZEQ) incorporated as covariates showed that limb-truncal, but not orofacial TD, is associated with CYP1A2 (-163C>, rs762551) polymorphism (F = 3.27, P = 0.039). Patients with the C/C genotype had a higher mean AIMS 5-7 score than those with the A/C or the A/A genotype. Our results support the hypothesis that not only with clozapine, but also with other classical and atypical antipsychotics, smoking may decrease plasma levels; this is most extensively expressed in carriers of the CYP1A2*1F (-163C> A) polymorphism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 81 | Ther Drug Monit 2015 Apr 37: 152-60 |
| PMID | 25090458 |
| Title | CYP1A2*1D and *1F polymorphisms have a significant impact on olanzapine serum concentrations. |
| Abstract | Although several polymorphisms in olanzapine-metabolizing enzymes have been identified, the clear role and benefit for pharmacotherapy remain uncertain. The aim of the study was to investigate the potential influence of polymorphisms in the CYP1A2 gene (*1D,*1F), in the UGT1A4 gene (*3), and in the POR gene (rs2302429) on olanzapine serum concentrations and the clinical outcome. Ninety-eight white inpatients who received olanzapine as part of their treatment for at least 4 weeks were included in the retrospective investigation. Moreover, a sample of 209 inpatients receiving olanzapine or clozapine was built to investigate the influence of the relevant polymorphisms CYP1A2*1F, *1D, and CYP1A2 inducers on the clinical outcome. Carriers of the delT-allele (*1D) developed significantly higher dose-corrected olanzapine serum concentrations (analysis of covariance; P < 0.001, delT + delTdelT: 3.1, TT: 1.6 ng·mL·mg, adjusted model including the confounding factors age, sex, baseline weight, CYP1A2*1F genotype, and concomitant CYP1A2 inducers). Moreover, the CYP1A2*1F (AA) genotype also revealed a significant impact on olanzapine serum concentrations according to the analysis of covariance model (P = 0.028; CC + CA: 2.05, AA: 1.44 ng·mL·mg). The other polymorphisms studied revealed no significant influence. Regarding response and adverse effects, a higher increase of weight could be observed in schizophrenic Paranoid Depressive Scale (responder: +5.7 vs nonresponder: +1.8 kg; P = 0.007) and Clinical Global Impression responders (4.6 vs 1.8 kg; P = 0.017). No direct correlation between olanzapine serum concentrations and response or weight gain could be detected. Patients with at least 2 factors promoting higher serum concentrations (no CYP1A2 inducer, *1D deltT-allele, or *1F C-allele) showed a better response according to the Paranoid Depressive Scale (P = 0.002) and a significant correlation with the Clinical Global Impression Scale-2 after 4 weeks (n = 193, r = -0.177; P = 0.005). We, for the first time, identified a significant influence of polymorphisms in CYP1A2 in combination with CYP1A2 inducer status on the clinical outcome. Therefore, genotyping for CYP1A2*1D and *1F may be a useful tool for dose optimization and identification of high-risk patients. Further and larger studies are needed before genotype-based dosage recommendations can help patients treated with CYP1A2 metabolized drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 82 | Bull. Exp. Biol. Med. 2016 Mar 160: 687-90 |
| PMID | 27021090 |
| Title | CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects. |
| Abstract | Polymorphic variants of CYP1A2 and CYP2D6 genes of the cytochrome P450 system were studied in patients with schizophrenia with drug-induced motor disorders and hyperprolactinemia against the background of long-term neuroleptic therapy. We revealed an association of polymorphic variant C-163A CYP1A2*1F of CYP1A2 gene with tardive dyskinesia and association of polymorphic variant 1846G>A CY2D6*4 and genotype A/A of CYP2D6 gene (responsible for debrisoquin-4-hydroxylase synthesis) with limbotruncal tardive dyskinesia in patients with schizophrenia receiving neuroleptics for a long time. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 83 | Bull. Exp. Biol. Med. 2016 Mar 160: 687-90 |
| PMID | 27021090 |
| Title | CYP1A2 and CYP2D6 Gene Polymorphisms in Schizophrenic Patients with Neuroleptic Drug-Induced Side Effects. |
| Abstract | Polymorphic variants of CYP1A2 and CYP2D6 genes of the cytochrome P450 system were studied in patients with schizophrenia with drug-induced motor disorders and hyperprolactinemia against the background of long-term neuroleptic therapy. We revealed an association of polymorphic variant C-163A CYP1A2*1F of CYP1A2 gene with tardive dyskinesia and association of polymorphic variant 1846G>A CY2D6*4 and genotype A/A of CYP2D6 gene (responsible for debrisoquin-4-hydroxylase synthesis) with limbotruncal tardive dyskinesia in patients with schizophrenia receiving neuroleptics for a long time. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 84 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Mar 171: 181-202 |
| PMID | 26462458 |
| Title | Currently recognized genes for schizophrenia: High-resolution chromosome ideogram representation. |
| Abstract | A large body of genetic data from schizophrenia-related research has identified an assortment of genes and disturbed pathways supporting involvement of complex genetic components for schizophrenia spectrum and other psychotic disorders. Advances in genetic technology and expanding studies with searchable genomic databases have led to multiple published reports, allowing us to compile a master list of known, clinically relevant, or susceptibility genes contributing to schizophrenia. We searched key words related to schizophrenia and genetics from peer-reviewed medical literature sources, authoritative public access psychiatric websites and genomic databases dedicated to gene discovery and characterization of schizophrenia. Our list of 560 genes were arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms. Genome wide pathway analysis using GeneAnalytics was carried out on the resulting list of genes to assess the underlying genetic architecture for schizophrenia. Recognized genes of clinical relevance, susceptibility or causation impact a broad range of biological pathways and mechanisms including ion channels (e.g., CACNA1B, CACNA1C, CACNA1H), metabolism (e.g., CYP1A2, CYP2C19, CYP2D6), multiple targets of neurotransmitter pathways impacting dopamine, GABA, glutamate, and serotonin function, brain development (e.g., NRG1, RELN), signaling peptides (e.g., PIK3CA, PIK4CA) and immune function (e.g., HLA-DRB1, HLA-DQA1) and interleukins (e.g., IL1A, IL10, IL6). This summary will enable clinical and laboratory geneticists, genetic counselors, and other clinicians to access convenient pictorial images of the distribution and location of contributing genes to inform diagnosis and gene-based treatment as well as provide risk estimates for genetic counseling of families with affected relatives. © 2015 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 85 | Psychiatr. Genet. 2016 May -1: -1 |
| PMID | 27203225 |
| Title | Cigarette smoking has a differential effect on the plasma level of clozapine in Taiwanese schizophrenic patients associated with the CYP1A2 gene -163A/C single nucleotide polymorphism. |
| Abstract | The efficacy of clozapine clearance has been shown to be associated with smoking and genetic polymorphism of CYP1A2. This study aims to investigate the effect of smoking on the plasma level of clozapine in Taiwanese schizophrenic patients and its relevance to the CYP1A2 gene -163A/C single nucleotide polymorphism. A total of 143 hospitalized schizophrenic patients who had received clozapine therapy for at least 14 days were enrolled in this study. The trough plasma concentration of clozapine was measured with LC/MS/MS. The -163A/C variant in the CYP1A2 gene was identified by DNA sequencing and restriction fragment length polymorphism analysis. The effect of smoking on the clozapine level was examined by multiple linear regression analysis and its relation to the -163A/C variant of the CYP1A2 gene was analyzed using a general linear model with Bonferroni correction. Patients with smoking habits showed a significantly lower plasma level of clozapine than those without smoking habits (P=0.022) and the difference in clozapine levels between smokers and nonsmokers appeared to be significant in the individuals carrying the homozygous -163A allele (P=0.02). It was also found that nonsmokers carrying the -163A allele tended to have higher plasma levels of clozapine. This tendency was not found in the individuals with smoking habits. Cigarette smoking has a significant impact on the plasma level of clozapine in Taiwanese schizophrenic patients carrying the homozygous -163A allele in the CYP1A2 gene. Cigarette smoking may increase the clearance of clozapine in these patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |