UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for developing breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for developing prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and the development of endometrial, prostate, and breast cancer. Available data indicate that the protective effect against breast cancer of a later age at menarche is limited to wild-type CYP 17 allele carriers. Among women with the polycystic ovary syndrome, carriage of mutant CYP 17 alleles is sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for developing breast cancer, advanced breast cancer stages, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to genes that encode estrogen-metabolizing enzymes as strong hereditary determinants of the susceptibility to benign as well as malignant conditions.
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PMID:Genetic modelling of the estrogen metabolism as a risk factor of hormone-dependent disorders. 1202 Sep 74

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

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.
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PMID:Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects. 1235 74

Antipsychotic drug-induced tardive dyskinesia (TD) is a serious problem during psychopharmacologic treatment of schizophrenic patients. In search of genetic factors contributing to TD, there is a lack of consensus regarding the role of the polymorphic isozyme cytochrome P450 CYP2D6, which is involved in the oxidative metabolism of antipsychotic drugs. In the present case-control study, we tested the putative influence of the CYP2D6 genotype on the development of TD. Out of 157 patients, 109 were retrospectively selected meeting DSM IV criteria for schizophrenia or schizoaffective disorder, and 50 of them persistently presenting with TD. Genotyping detected the functional allele CYP2D6 *1, the known major defective alleles CYP2D6 *3, *4, *5, *6, and gene duplication. According to their number of functional CYP2D6 alleles, subjects were divided into carriers of none, one, or at least two functional CYP2D6 alleles. The proportions of these categories did not differ between patients and an ethnically homogenous control population (n = 195, p = 0.99) or between patients with and without TD (p = 0.818). Schizophrenic patients were carriers of gene duplication more often than healthy probands, without revealing statistical significance (p = 0.10). Out of seven patients with gene duplication, three developed persistent TD. Furthermore, patients with and without TD were comparable according to age, age of onset, gender, and duration of illness, but subjects with TD had taken more lifetime chlorpromazine equivalents (CPZ) than had patients without TD (chi 2-test, Student's t-test). Forward as well as backward logistic regression analyses confirmed that the presence of TD was influenced by lifetime CPZ but not by age, age of onset, gender, duration of illness, or CYP2D6 genotype. In contrast to the relevance of lifetime CPZ, the lifetime dose of antipsychotic drugs known to be metabolized by CYP2D6 did not significantly influence the presence of TD. In conclusion, our results provide no evidence for the contribution of CYP2D6 genotype to the development of TD in schizophrenic patients receiving long-term antipsychotic medication.
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PMID:CYP2D6 polymorphism and tardive dyskinesia in schizophrenic patients. 1273 65

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).
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PMID:Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism. 1550 41

Since H3 receptor (H3R) antagonists/inverse agonists can improve cognitive function in animal models, they may have the potential to be used as add-on therapy in the treatment of schizophrenia, a disease with significant cognitive deficits. However, a recent study showed potentiation of haloperidol-induced catalepsy by ciproxifan, an imidazole-containing H3R antagonist/inverse agonist, suggesting there is a potential risk of exacerbating extrapyramidal symptoms (EPS) if H3R antagonists were used as adjunctive treatment [Pillot, C., Ortiz, J., Heron, A., Ridray, S., Schwartz, J.C. and Arrang, J.M., Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, potentiates neurochemical and behavioral effects of haloperidol in the rat, J Neurosci, 22 (2002) 7272-80]. In order to clarify the basis of this finding, we replicated this result and extended the work with another imidazole and two non-imidazole H3R antagonists. The results indicate that ciproxifan significantly augmented the effects of haloperidol and risperidone on catalepsy. Another imidazole H3R antagonist, thioperamide, also potentiated the effect of risperidone on catalepsy. In contrast, no catalepsy-enhancing effects were observed when selective non-imidazole H3R antagonists, ABT-239 and A-431404, were coadministered with haloperidol and/or risperidone. As ciproxifan and thioperamide are inhibitors of cytochrome P450 enzymes, responsible for metabolizing risperidone and haloperidol, the possibility that the augmentation of antipsychotics by imidazoles resulted from drug-drug interactions was tested. A drug metabolism study revealed that an imidazole, but not a non-imidazole, potently inhibited the metabolism of haloperidol and risperidone. Furthermore, ketoconazole, an imidazole-based CYP 3A4 inhibitor, significantly augmented risperidone-induced catalepsy. Together, these data suggest the potentiation of antipsychotic-induced catalepsy may result from pharmacokinetic drug-drug interactions and support the potential utility of non-imidazole H3R antagonists in treatment of cognitive impairment in schizophrenia without increased risk of increased EPS in patients.
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PMID:Lack of cataleptogenic potentiation with non-imidazole H3 receptor antagonists reveals potential drug-drug interactions between imidazole-based H3 receptor antagonists and antipsychotic drugs. 1591 Jul 72

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.
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PMID:Inhibitory effects of psychotropic drugs on mexiletine metabolism in human liver microsomes: prediction of in vivo drug interactions. 1619 7

(1) Neuroleptics are the standard treatment for schizophrenia. The first drugs of this class, such as haloperidol, were marketed nearly 50 years ago, and neuroleptics released over the past 15 last years have provided no major advance. (2) Aripiprazole is a new neuroleptic licensed for the treatment of schizophrenia. (3) Five double-blind placebo-controlled trials lasting 4 to 6 weeks showed that aripiprazole was a little more effective than placebo at daily doses of 10 mg to 30 mg, without a clear dose-response relationship. Based on the least demanding definition of "treatment response" (a 30% reduction in the PANSS global score), less than 50% of patients responded to aripiprazole. (4) In a double-blind trial lasting 6 months, aripiprazole 15 mg/day was more effective than placebo in preventing acute relapses of schizophrenia (34% versus 57%), but the clinical relevance of the combined endpoint used to define relapse is unclear. (5) The only double-blind comparison versus another neuroleptic (haloperidol) involved two trials that were pooled for analysis. Haloperidol was provided at a moderate dose (10 mg/day). These trials were designed to demonstrate the superiority of high-dose aripiprazole (30 mg/day), but failed to do so. The proportion of patients who "responded" during an acute episode, based on the least stringent definition, was about 70% in both groups. In both groups, response persisted in approximately three-quarters of patients. (6) Aripiprazole exhibits the adverse effects classically seen with neuroleptics. In clinical trials, daily doses of aripiprazole, ranging from 15 mg to 30 mg, provoked fewer extrapyramidal disorders than haloperidol 10 mg/day. In contrast, there was no difference in the frequency of extrapyramidal disorders with aripiprazole 20 or 30 mg/day and risperidone (6 mg). Aripiprazole has no proven advantage over haloperidol in terms of the risk of tardive dyskinesia. One trial showed no difference between aripiprazole and olanzapine in the risk of diabetes. Weight gain appears to be comparable with aripiprazole and haloperidol. Aripiprazole provoked postural hypotension and neuroleptic malignant syndrome, but the precise risk relative to other neuroleptics has not been documented. Supra-therapeutic doses of aripiprazole cause dose-dependent QT prolongation. (7) Increased mortality was seen in elderly patients treated with aripiprazole. (8) Animal studies have shown retinal degeneration in rats and biliary lithiasis in monkeys. These adverse effects have not been observed in clinical trials, but they have not been specifically assessed in humans. (9) Animal studies raised the possibility of fetal toxicity and teratogenicity. (10) The aripiprazole dose must be either halved or doubled during co-administration with inhibitors or inducers of cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6. (11) In practice, there are too many unanswered questions to recommend aripiprazole for patients with schizophrenia.
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PMID:Aripiprazole: new drug. Just another neuroleptic. 1628 69

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.
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PMID:Association study between functional polymorphisms in the cytochrome P450 1A2 and 2D6 genes and polydipsia in schizophrenia. 1677 89

We evaluated whether cytochrome P450 (CYP) poor metabolizer polymorphisms of CYP2D6 and CYP2C19 are relevant for the outcome (measured by length of hospitalization) during treatment with psychotropic medications in patients with depression or schizophrenia. 229 patients were genotyped by real-time PCR hybridization probe melting curve technique for CYP2C19*2, CYP2D6*3, *4, and *6, respectively. The gene deletion CYP2D6*5 was analyzed by a long PCR method. Detailed clinical information was obtained from 53 subjects. Patients genotyped homozygous or heterozygous for those CYP2D6 and CYP2C19 poor metabolizer alleles were treated for a longer time in hospital (median 57.5 vs. 40.0 days). Psychiatric patients might benefit from CYP genotyping, the duration of stay as inpatient might be reduced by a priori selection of the appropriate drug for the individual patient.
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PMID:Cytochrome P-450 2D6 and 2C19 polymorphisms and length of hospitalization in psychiatry. 1681 49

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