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)

Advances in our understanding of schizophrenia have led to a new generation of antipsychotic agents. These medications not only demonstrate reduced extrapyramidal symptoms but also possess pharmacologic profiles that can be especially advantageous in treating the negative symptoms of schizophrenia. The pharmacokinetics of many of the newer agents are compared and contrasted with typical neuroleptics. Changes in the pharmacokinetics and dosage of the newer agents are also reviewed. A particular emphasis is placed on the metabolism of the newer agents and their potential for drug-drug pharmacokinetic interactions. Clozapine, the archetypal atypical agent, has a complex pharmacokinetic profile with extremely large interpatient variability and many well-documented drug-drug interactions. Thus, clozapine presents special challenges in dose optimization and requires vigilant clinical monitoring for cardiovascular, neurologic, and hematologic adverse effects. Olanzapine demonstrates a very low potential for drug-drug interactions; it requires extremely high inhibitory concentrations at cytrochrome P450 (CYP) systems, typically 30-fold above the usual concentrations observed at steady-state oral high-dose therapy. The metabolic pathways of olanzapine include N-glucuronidation, reducing its overall sensitivity to drugs that might induce or inhibit its own metabolism via CYP or flavin-containing monooxygenase (FMO) systems. Plasma olanzapine concentrations at steady state typically demonstrate only a fourfold to fivefold variability among patients at a standard dose of medications. Sertindole and risperidone demonstrate polymorphic metabolism characteristics mirroring the CYP 2D6 phenotype. The inhibitory potentials of sertindole at CYP 2D6 and CYP 3A are modest and not likely to be of clinical significance. However, in those patients taking CYP 2D6 inhibitors or in those who are genotypic poor metabolizers, concentrations achieved by sertindole and its metabolites might result in moderate inhibition of CYP 3A.
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PMID:Pharmacokinetics and drug interactions: update for new antipsychotics. 937 97

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

Members of the cytochrome P450 (P450) family of drug-metabolizing enzymes are present in the human brain, and they may have important roles in the oxidation of endogenous substrates. The polymorphic CYP2D6 is one of the major brain P450 isoforms and has been implicated in neurodegeneration, psychosis, schizophrenia, and personality traits. The objective of this study was to determine whether the endocannabinoid arachidonoylethanolamide (anandamide) is a substrate for CYP2D6. Anandamide is the endogenous ligand to the cannabinoid receptor CB1, which is also activated by the main psychoactive component in marijuana. Signaling via the CB1 receptor alters sensory and motor function, cognition, and emotion. Recombinant CYP2D6 converted anandamide to 20-hydroxyeicosatetraenoic acid ethanolamide and 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EET-EAs) with low micromolar K(m) values. CYP2D6 further metabolized the epoxides of anandamide to form novel dioxygenated derivatives. Human brain microsomal and mitochondrial preparations metabolized anandamide to form hydroxylated and epoxygenated products, respectively. An inhibitory antibody against CYP2D6 significantly decreased the mitochondrial formation of the EET-EAs. To our knowledge, anandamide and its epoxides are the first eicosanoid-like molecules to be identified as CYP2D6 substrates. Our study suggests that anandamide may be a physiological substrate for brain mitochondrial CYP2D6, implicating this polymorphic enzyme as a potential component of the endocannabinoid system in the brain. This study also offers support to the hypothesis that neuropsychiatric phenotype differences among individuals with genetic variations in CYP2D6 could be ascribable to interactions of this enzyme with endogenous substrates.
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PMID:The endocannabinoid anandamide is a substrate for the human polymorphic cytochrome P450 2D6. 1869

There is wide variability in the response of individuals to standard doses of antipsychotic drugs. It has been suggested that this may be partly explained by differences in the cytochrome P450 (CYP450) enzyme system responsible for metabolizing the drugs. We conducted a systematic review and meta-analyses to consider whether testing for CYP450 single nucleotide polymorphisms in adults starting antipsychotic treatment for schizophrenia predicts and leads to improvements in clinical outcomes. High analytic validity in terms of sensitivity and specificity was seen in studies reporting P450 testing. However, there was limited evidence of the role of CYP2D6 polymorphisms in antipsychotic efficacy, although there was an association between CYP2D6 genotype and extrapyramidal adverse effects. No studies reported on the prospective use of CYP2D6 genotyping tests in clinical practice. In conclusion, evidence of clinical validity and utility of CYP2D6 testing in patients being prescribed antipsychotics is lacking, and thus, routine pharmacogenetic testing prior to antipsychotic prescription cannot be supported at present. Further research is required to improve the evidence base and to generate data on clinical validity and clinical utility.
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PMID:Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses. 2087 99

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.
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PMID:Interaction of St John's wort (Hypericum perforatum) with clozapine. 2211 52

We are living in an era of implementing complete smoking cessation in all closed areas, following the example of the USA and other countries in the European Union. We appear more tolerant in our mentally ill in-patients, especially the ones suffering from long-term schizophrenia, where smoking is accepted and even encouraged. We tried to investigate the effect of smoking in these patients. We performed an in depth literature research of medical databases and web search engines containing relevant articles, opinions and arguments. It has been shown from a lot of different studies that the proportion of persons with mental health problems who smoke is considerably higher compared to the general population. 51% of individuals with diagnosis of schizophrenia and 50% of those with bipolar affective disorder smoke more than 20 cigarettes per day against 8% of the general population who smoke the same amount. In another study from the USA , it was calculated that 45% of all cigarettes smoked in one month, were consumed by individuals with diagnosis of mental disorder or substance abuse. Smokers that suffer from schizophrenia present more positive symptoms, although clinical observation and research confirmed data show a positive effect in extrapyramidal symptoms and other side effects of medication. For other parameters such as attention, cognitive function and impulsivity, research is non conclusive and with contradictory results. Rates of premature death are higher for persons with mental illnesses compared with the general population, even if we don't include suicides. Much of these deaths are attributed to cardiovascular and respiratory problems and smoking is considered to be a major contributor to these illnesses. Substances found in cigarette's tar act as enhancers of P450 liver enzymes, increasing the metabolism of certain of antipsychotic medication, including clozapine, fluphenazine, haloperidol and olanzapine. This leads to higher required doses of medication. Smoking adds a big economical burden upon the smoker, who, as an individual with mental illness, is likely to have low income and should be directed to cover other real life necessities that could improve the overall quality of life. People who are heavy smokers find difficult to participate in certain activities or attend places where smoking is not allowed. This contributes further to their social exclusion. This habit should be treated as an addiction. Currently a lot of different treatments both pharmacological and non-pharmacological are available, which can be combined with promising results.
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PMID:Smoking in patients with psychiatric disorders: Effects on their psychopathology and quality of life. 2221 78

Activation of metabotropic glutamate receptor subtype 5 (mGlu5) represents a novel strategy for therapeutic intervention into multiple central nervous system disorders, including schizophrenia. Recently, a number of positive allosteric modulators (PAMs) of mGlu5 were discovered to exhibit in vivo efficacy in rodent models of psychosis, including PAMs possessing varying degrees of agonist activity (ago-PAMs), as well as PAMs devoid of agonist activity. However, previous studies revealed that ago-PAMs can induce seizure activity and behavioral convulsions, whereas pure mGlu5 PAMs do not induce these adverse effects. We recently identified a potent and selective mGlu5 PAM, VU0403602, that was efficacious in reversing amphetamine-induced hyperlocomotion in rats. The compound also induced time-dependent seizure activity that was blocked by coadministration of the mGlu5 antagonist, 2-methyl-6-(phenylethynyl) pyridine. Consistent with potential adverse effects induced by ago-PAMs, we found that VU0403602 had significant allosteric agonist activity. Interestingly, inhibition of VU0403602 metabolism in vivo by a pan cytochrome P450 (P450) inactivator completely protected rats from induction of seizures. P450-mediated biotransformation of VU0403602 was discovered to produce another potent ago-PAM metabolite-ligand (M1) of mGlu5. Electrophysiological studies in rat hippocampal slices confirmed agonist activity of both M1 and VU0403602 and revealed that M1 can induce epileptiform activity in a manner consistent with its proconvulsant behavioral effects. Furthermore, unbound brain exposure of M1 was similar to that of the parent compound, VU0403602. These findings indicate that biotransformation of mGlu5 PAMs to active metabolite-ligands may contribute to the epileptogenesis observed after in vivo administration of this class of allosteric receptor modulators.
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PMID:Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism. 2382 Nov 85

Allosteric modulation of G protein-coupled receptors has gained considerable attention in the drug discovery arena because it opens avenues to achieve greater selectivity over orthosteric ligands. We recently identified a series of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu(5)) for the treatment of schizophrenia that exhibited robust heterotropic activation of CYP3A4 enzymatic activity. The prototypical compound from this series, 5-(4-fluorobenzyl)-2-((3-fluorophenoxy)methyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (VU0448187), was found to activate CYP3A4 to >100% of its baseline intrinsic midazolam (MDZ) hydroxylase activity in vitro; activation was CYP3A substrate specific and mGlu(5) PAM dependent. Additional studies revealed the concentration-dependence of CYP3A activation by VU0448187 in multispecies hepatic and intestinal microsomes and hepatocytes, as well as a diminished effect observed in the presence of ketoconazole. Kinetic analyses of the effect of VU0448187 on MDZ metabolism in recombinant P450 or human liver microsomes resulted in a significant increase in V(max) (minimal change in K(m)) and required the presence of cytochrome b5. The atypical kinetics translated in vivo, as rats receiving an intraperitoneal administration of VU0448187 prior to MDZ treatment demonstrated a significant increase in circulating 1- and 4-hydroxy- midazolam (1-OH-MDZ, 4-OH-MDZ) levels compared with rats administered MDZ alone. The discovery of a potent substrate-selective activator of rodent CYP3A with an in vitro to in vivo translation serves to illuminate the impact of increasing intrinsic enzymatic activity of hepatic and extrahepatic CYP3A in rodents, and presents the basis to build models capable of framing the clinical relevance of substrate-dependent heterotropic activation.
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PMID:Heterotropic activation of the midazolam hydroxylase activity of CYP3A by a positive allosteric modulator of mGlu5: in vitro to in vivo translation and potential impact on clinically relevant drug-drug interactions. 2400 50

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.
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PMID:In Vitro Characterization of the Human Liver Microsomal Kinetics and Reaction Phenotyping of Olanzapine Metabolism. 2632 89