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)

It has been suggested that the cytochrome P450 mono-oxygenase, debrisoquine 4-hydroxylase, is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells. It is also thought to be related to the dopamine transporter that acts to take released dopamine back up into presynaptic terminals. The present study used the association approach to test the hypothesis that mutations in the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT) confer susceptibility to schizophrenia. There were no differences in allele or genotype frequencies between patients and controls in the mutations causing the poor metaboliser phenotype in CYP2D6. In addition there was no association found between schizophrenia and a 48bp repeat within the 3' untranslated region of DAT.
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PMID:No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT). 748 41

1. The atypical antipsychotic drug clozapine, used in the treatment of resistant schizophrenia, is metabolized partly by the hepatic cytochrome P450 enzyme CYP2D6. Two phenotypes with respect to the activity of the enzyme are recognized (extensive metabolisers (EM) and poor metabolisers (PM)), resulting from allelic variation in the gene, CYP2D6. 2. Genotype was determined in 123 schizophrenic patients currently being treated with clozapine, in order to determine if EM or PM status influences response to this drug. Patients were divided into responders and non-responders using the Global Assessment Scale, and genotyped for the A and B poor metaboliser mutations by digesting PCR products with HpaII or BstNI. 3. Fifty-nine patients were heterozygous for allele B and for allele A. Eight patients were determined as poor metabolisers since they were homozygous either for A and B. Poor metabolisers were equally distributed between responders and nonresponders and no correlation between CYP2D6 alleles and response to clozapine was found. 4. The results are consistent with recent findings showing that CYP1A2, rather than CYP2D6, is the major enzyme responsible for the metabolism of clozapine.
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PMID:Cytochrome P4502D6 genotype does not determine response to clozapine. 764 Jan 49

The cytochrome P450 mono-oxygenases are a group of enzymes that metabolize a variety of exogenous and endogenous compounds, some of which are potentially toxic. Individual variations in the metabolism of potential toxins could influence susceptibility to disorders having genetic and environmental components, such as schizophrenia. The frequency of two common mutant alleles of the gene for the cytochrome P450 enzyme debrisoquine-4-hydroxylase (CYP2D6) was determined in 264 Caucasian schizophrenic patients and 217 controls, using the polymerase chain reaction and restriction enzyme digestions. The patient and control samples showed no significant deviation from Hardy-Weinberg equilibrium and the frequency of each mutant allele (CYP2D6A and CYP2D6B) did not differ between patients and controls.
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PMID:An association study of debrisoquine hydroxylase (CYP2D6) polymorphisms in schizophrenia. 771 18

The use of classic anti-psychotic drugs in the long-term treatment of schizophrenia is associated with risk for extrapyramidal side-effects, such as akathisia, parkinsonism and tardive dyskinesia (TD). Approximately 5-10% of European Caucasians lack the cytochrome P450 enzyme CYP2D6 (so-called poor metabolizers; PM), which normally metabolizes several drugs including many neuroleptics. PM subjects may achieve high or toxic plasma levels upon standard drug therapy. In this study we have examined 100 subjects from the Nithsdale cohort of schizophrenic patients in South-west Scotland receiving long-term neuroleptic medication, which enabled us to perform both a cross-sectional and longitudinal evaluation of extrapyramidal side-effects in relation to the genetically impaired CYP2D6 metabolism. We identified ten (10%) schizophrenic subjects with the PM genotype. In the cross-sectional study, the prevalence of TD, parkinsonism and akathisia was 51%, 38% and 15%, respectively. Patients with TD or parkinsonism were significantly older than patients without these side-effects. In contrast, patients with akathisia were significantly younger than patients without akathisia. There was a non-significant tendency for PM subjects to have more severe ratings for TD and parkinsonism. In the long-term evaluation based on repeated ratings since 1981, there was a non-significant 3-fold higher frequency of PM subjects among schizophrenic patients with longitudinal TD, as compared with the group of patients with fluctuating or no TD. These results indicate that genetically impaired CYP2D6 metabolism may be a contributing factor for the development of persistent TD.
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PMID:Non-functional CYP2D6 alleles and risk for neuroleptic-induced movement disorders in schizophrenic patients. 920 6

Debrisoquine 4-hydroxylase (CYP2D6) is a cytochrome P450 enzyme involved in the metabolism of most neuroleptics, which are the drugs of choice for the treatment of psychotic symptoms. CYP2D6 in the brain was suggested to be functionally similar to the dopamine transporter, thus possibly influencing a neurotransmitter system involved in schizophrenia. Swedish schizophrenic patients (n = 124) and control individuals (n = 85) were investigated for two CYP2D6 polymorphisms, responsible for approximately 90% of mutations leading to poor debrisoquine metabolism. No significant CYP2D6 allele or genotype difference was found between schizophrenic patients and control individuals. Taken together with previous results, no major effect appears to be caused by the CYP2D6 gene on schizophrenia.
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PMID:Lack of association between debrisoquine 4-hydroxylase (CYP2D6) gene polymorphisms and schizophrenia. 956 84

In the present study, the occurrence of tardive dyskinesia (TD) in chronic schizophrenia patients was investigated in relation to pharmacogenetic polymorphisms. It is known that the metabolism of important neuroleptic drugs is influenced by polymorphisms of the CYP2D6 gene, which encodes the cytochrome P450 enzyme debrisoquine/spartein hydroxylase. Forty-five patients meeting the DSM IV criteria for schizophrenia, chronic course, were recruited. The patients were examined for the mutations CYP2D6*3, CYP2D6*4 and CYP2D6*5. The CYP2D6 genotype distribution in the patient group did not differ from that in healthy Caucasian populations. Tardive dyskinesia was found in 26 patients (57.8%). When comparing patients without CYP2D6 mutations with patients heterozygous for one mutation, we found a higher incidence of TD in the latter (81.3% vs. 46.4%, p = 0.031, multiple regression analysis), which demonstrates a significant influence of the CYP2D6 genotype of the manifestation of TD. As slight differences in the metabolism of drugs in patients heterozygous for CYP2D6 mutations and patients without such mutations are known, we conclude that heterozygous carriers of 2D6 mutated alleles may show an increased susceptibility to developing TD.
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PMID:Genetic polymorphisms for drug metabolism (CYP2D6) and tardive dyskinesia in schizophrenia. 971 5

Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism of risperidone (100 microM) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8, CYP2C9-arg144, CYP2C9-cys144, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol(-1) CYP min(-1), respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore, inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat.
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PMID:Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. 1004

1. The cytochrome P450 monooxygenases, CYP2D6, CYP2C19, and CYP2C9, display polymorphism. CYP2D6 and CYP2C19 have been studied extensively, and despite their low abundance in the liver, they catalyze the metabolism of many drugs. 2. CYP2D6 has numerous allelic variants, whereas CYP2C19 has only two. Most variants are translated into inactive, truncated protein or fail to express protein. 3. CYP2C9 is expressed as the wild-type enzyme and has two variants, in each of which one amino acid residue has been replaced. 4. The nucleotide base sequences of the cDNAs of the three polymorphic genes and their variants have been determined, and the proteins derived from these genes have been characterized. 5. An absence of CYP2D6 and/or CYP2C19 in an individual produces a poor metabolizer (PM) of drugs that are substrates of these enzymes. 6. When two drugs that are substrates for a polymorphic CYP enzyme are administered concomitantly, each will compete for that enzyme and competitively inhibit the metabolism of the other substrate. This can result in toxicity. 7. Patients can be readily phenotyped or genotyped to determine their CYP2D6 or CYP2C19 enzymatic status. Poor metabolizers (PMs), extensive metabolizers (EMs), and ultrarapid metabolizers (URMs) can be identified. 8. Numerous substrates and inhibitors of CYP2D6, CYP2C19, and CYP2C9 are identified. 9. An individual's diet and age can influence CYP enzyme activity. 10. CYP2D6 polymorphism has been associated with the risk of onset of various illnesses, including cancer, schizophrenia, Parkinson's disease, Alzheimer's disease, and epilepsy.
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PMID:Polymorphic cytochromes P450 and drugs used in psychiatry. 1031 91

Recent advances in our understanding of schizophrenia along with neuroscience insights into antipsychotic medication mechanisms of action have led to a renaissance in new drug development, including an expanded therapeutic spectrum encompassing more of the symptoms encountered in schizophrenia. Atypical antipsychotics, or new generation therapies, also demonstrate greater selectivity for therapeutic actions than for extrapyramidal symptoms (EPS). Our modern armamentarium of drugs spans a wide range of pharmacologies, and it is more accurate to envision shades of gray rather than a black-and-white description for typical versus atypical properties of medications. As our paradigms for antipsychotic efficacy have shifted, a reexploration of the "older" neuroleptics is warranted to determine if they possess pharmacologic attributes that might have been overlooked during the era of high-dose neuroleptic therapy. Loxapine appears to be in the center of this spectrum, somewhere between haloperidol and risperidone. Dosing implications for drugs with a more even serotonin-2A (5-HT2A) receptor and dopamine-2 (D2) receptor blocking effect are discussed. Loxapine might have a window of partial atypicality at doses < or = 50 mg/day. These lower doses might have potential as both monotherapy in responsive patients with persistent psychotic disorders and as an adjunctive treatment in partially responding patients on concurrent atypical antipsychotic treatments. The pharmacologic properties of loxapine within its usable dosage range are quite complex and are the net sum of the parent's plus metabolites' contributions (demethylation and hydroxylation by cytochrome P450 enzymes). These pharmacologic effects include alpha-adrenergic blockade, inhibition of the noradrenergic transporter protein (reuptake inhibition), and antimuscarinic effects. Drug interactions and cigarette smoking might alter the parent-to-metabolite concentration ratios, affecting the relative atypicality of this antipsychotic therapy. Moreover, with the intramuscular formulation, which does not undergo first-pass metabolism, the parent compound of loxapine, i.e., not its metabolites, is predominantly detected in the plasma of patients, reducing the likelihood for EPS during emergency interventions in patients with positive symptoms. Further study is warranted to determine loxapine's place in our treatment of schizophrenia.
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PMID:Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic. 1034 Jun 84

Psychoactive medication is frequently used in methadone maintenance treatment programs (MMP) to treat comorbid mental disorders (depression, anxiety, schizophrenia) in opiate-addicts. Thus, several pharmacological interactions are possible. This problem becomes more relevant with the introduction of new CNS-drugs like SSRI, atypical antipsychotics or new anticonvulsants. The most common interactions seen in practice are pharmacodynamic in nature, most often due to the cumulative effects of different drugs on the central nervous system (e.g. neuroleptics or benzodiazepine interactions). However important pharmacokinetic interactions may occur particularly between methadone and antidepressant drugs: Desipramine plasma levels are increased by methadone; further fluvoxamine (and fluoxetine to a less extent) may cause an important increase in serum methadone concentrations. The inhibition of different clusters of the cytochrome P450 system are involved in these interactions. Several lines of evidence suggest that benzodiazepines and methadone may have synergistic interactions and that opiate sedation or respiratory depression could be increased. This is a serious problem, given the widespread use of benzodiazepines among MMP patients. Experimental but not clinical data support methadone and lithium interactions. Finally, classic anticonvulsant drugs, such as phenytoin, carbamazepine and phenobarbital, produce dramatic decreases in methadone levels, which may precipitate a withdrawal syndrome; valproic acid and the new anticonvulsant drugs do not have these effects. Accordingly, caution is advised in the clinical use of methadone when other CNS-drugs are administered.
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PMID:[Drug interactions of methadone with CNS-active agents]. 1038 Jan 52


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