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

A 35-year-old man with schizophrenia was successfully treated with clozapine at a daily oral dose of 700-725 mg for more than 7 consecutive years. Two weeks after abrupt cessation of chronic heavy cigarette smoking, he suddenly developed tonic clonic seizures followed by stupor and coma. After 2 days of intensive care, the patient recovered completely but could not recall the episode. Clozapine therapy was reinstituted and could be carried out successfully at 425 mg daily, i.e., at an approximately 40% reduction of the daily dose before he stopped smoking. The sudden cessation of smoking most likely caused a rise in plasma concentrations of clozapine and/or clozapine metabolites resulting in the seizure episode. A likely mechanism is that the heavy smoking had induced cytochrome P450-1A2, the main enzyme involved in the metabolism of clozapine.
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PMID:Could discontinuing smoking be hazardous for patients administered clozapine medication? A case report. 1051 59

Atypical antipsychotics such as clozapine represent a significant improvement over typical antipsychotics in the treatment of schizophrenia, particularly regarding extrapyramidal symptoms. Despite their benefits, use is limited by the occurrence of adverse reactions such as sedation and weight gain. This article provides a comprehensive review and discussion of obesity-related pathways and integrates these with the known mechanisms of atypical antipsychotic action to identify candidate molecules that may be disrupted during antipsychotic treatment. Novel preliminary data are presented to genetically dissect these obesity pathways and elucidate the genetic contribution of these candidate molecules to clozapine-induced weight gain. There is considerable variability among individuals with respect to the ability of clozapine to induce weight gain. Genetic predisposition to clozapine-induced weight gain has been suggested. Therefore, genetic variation in these candidate molecules may predict patient susceptibility to clozapine-induced weight gain. This hypothesis was tested for 10 genetic polymorphisms across 9 candidate genes, including the serotonin 2C, 2A, and 1A receptor genes (HTR2C/2A/1A); the histamine H1 and H2 receptor genes (H1R/H2R); the cytochrome P450 1A2 gene (CYPIA2); the beta3 and alpha,alpha-adrenergic receptor genes (ADRB3/ADRAIA); and tumor necrosis factor alpha (TNF-alpha). Prospective weight gain data were obtained for 80 patients with schizophrenia who completed a structured clozapine trial. Trends were observed for ADRB3, ADRA1A, TNF-alpha, and HTR2C; however, replication in larger, independent samples is required. Although in its infancy, psychiatric pharmacogenetics will in the future aid clinical practice in the prediction of response and side effects, such as antipsychotic-induced weight gain, and minimize the current "trial and error" approach to prescribing.
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PMID:Genetic dissection of atypical antipsychotic-induced weight gain: novel preliminary data on the pharmacogenetic puzzle. 1160 85

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

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.
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PMID:Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. 1520 69

According to the literature, there is an association between schizophrenia and caffeine consumption, but it is not clear whether schizophrenia is associated with either higher prevalence of daily caffeine intake or the amount consumed. In this study we compared our previously published schizophrenia patients (n=250) with a control sample (n=290) after controlling for demographic variables and tobacco and alcohol consumption. Current caffeine intake was less frequent in schizophrenia patients (59%, 147/250) than in controls (70%, 204/290). In the multivariate analyses, caffeine intake was less frequent at an older age and in schizophrenia patients, and more frequent in smokers and alcohol users. Among caffeine consumers, heavy caffeine intake (> or =200 mg/day) was significantly associated with schizophrenia (64%, 94/147 in schizophrenia versus 36%, 73/204 in controls), as well as older age and smoking. Daily amount of caffeine intake and smoked cigarettes correlated significantly in the schizophrenia group but not in the control group; the correlation of caffeine intake with nicotine dependence was low and non-significant in both groups. The association between current smoking and heavy caffeine intake may be partly explained by a pharmacokinetic effect: tobacco smoke compounds induce caffeine metabolism by the cytochrome P450 1A2. Although schizophrenia by itself may be associated with heavy caffeine intake in caffeine users, part of this association was explained by the association between schizophrenia and smoking. The relationship between caffeine and alcohol intake appeared to be more complex; alcohol and caffeine use were significantly associated, but within caffeine users alcohol was associated with less frequent heavy caffeine consumption among smokers. In future studies, the measurement of plasma caffeine levels will help both to better define heavy caffeine intake and to control for smoking pharmacokinetic effects.
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PMID:Fewer but heavier caffeine consumers in schizophrenia: a case-control study. 1678 37

Although patients with have low motivations to quit smoking, smoking cessation treatment can be effective for these patients. Patients schizophrenia who achieve significant smoking reduction during a treatment intervention can at least maintain that level of reduction at 2 years. Cigarette smoking by patients with frequently goes unaddressed, contributing to excess mortality in this population. Behavioural interventions improve smoking cessation in schizophrenia patients. Nicotine replacement can substantially reduce withdrawal symptoms. Bupropion enhances smoking abstinence rates. Bupropion is well-tolerated and safe for use in schizophrenia patients: bupropion does not worsen clinical symptoms of schizophrenia. Atypical antipsychotics may reduce smoking consumption in schizophrenia patients, in particular clozapine. Atypical antipsychotic medication, in combination with the nicotine transdermal patch, significantly enhance the rate of smoking cessation. Interactions between smoking and antipsychotic medication - Smoking increases the metabolism of the antipsychotic medications by inducing the cytochrome P450 1A2 isoform. Smoking lowers the blood levels of typical or atypical antipsychotic medication, in particular haloperidol, chlorpromazine, olanzapine and clozapine. -Abstinence can increase many psychotropics' blood levels. Accordingly, smoking appears to reduce neuroleptic-induced parkinsonism. In contrast, smoking is a risk factor for tardive dyskinesia, independent of neuroleptic exposure.
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PMID:[Tobacco and schizophrenia: therapeutic aspects]. 1803 54

Schizophrenia is a chronic illness with a progressive course that can be marked by resistance to antipsychotic treatment. This can make therapeutic support challenging for the practitioner, with results that are partial and unsatisfactory. In the literature, treatment with high-dose olanzapine (>20mg/day) appears to be a good alternative to clozapine, the gold standard for treatment-resistant schizophrenia. In the present observational prospective study, we studied the clinical and biological profiles of patients treated with olanzapine doses up to 100mg/day. In total, 50 patients were clinically and biologically assessed. We found a linear relationship between oral dose and serum concentration (Pearson's r=0.83, p<0.001) with effects of tobacco (p<0.05) and of coffee and tea consumption (p<0.01). Tolerance seemed to be good regardless of dose. No link was found between concentration and efficiency. Despite a nonexhaustive assessment of pharmacokinetic parameters, not least pharmacogenetic data (e.g., genotyping of cytochrome P450-1A2 or glycoprotein P Abcb1a), pharmacokinetic aspects alone cannot account for why the disease may sometimes be resistant to 20mg of olanzapine but respond to higher doses. A nuclear imaging study exploring brain occupancy by high-dose olanzapine, coupled with the abovementioned pharmacokinetic assessment, may prove a relevant experimental paradigm for studying the pathophysiological mechanisms of resistant schizophrenia.
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PMID:Use of very-high-dose olanzapine in treatment-resistant schizophrenia. 2527 3