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 case of a folate-responsive psychosis that was associated with a defect in N5-10-methylenetetrahydrofolate reductase (methylene reductase) suggested the need to examine whether abnormally low activity of this enzyme might be of etiological importance in schizophrenia. We now report that there were no statistically significant differences in the platelet methylene reductase activity of chronic schizophrenics, compared with either hospitalized or nonhospitalized age-matched control subjects. Although it is possible that a larger survey might reveal a subpopulation of schizophrenics who are characterized by abnormal methylene reductase activity, this study suggests that chronic schizophrenia is not generally associated with such changes.
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PMID:Platelet methylene reductase activity in schizophrenia. 87 76

In patients taking haloperidol (HP), circulating concentrations of reduced haloperidol (RHP increase disproportionately to the dose or concentration of the parent drug. In the current study, we tested the hypothesis that the nonlinearity is due to preferential saturation of the reoxidation of RHP to HP, and two factors that could amplify the nonlinearity-concentration-dependent binding of RHP by plasma proteins, or by red blood cells. In 25 patients with schizophrenia who were taking HP, the unbound fraction of HP (0.085 +/- 0.016) and RHP (0.244 +/- 0.026) in plasma, and the blood:plasma ratio for each compound were independent of their concentration. Thus, saturable binding of RHP to plasma proteins or red blood cells can be excluded. HP reductase and RHP oxidase activity were measured in human liver cytosol and microsomal fractions, respectively. Because ketone reductase-catalysed formation of RHP is stereospecific, we examined each enantiomer of RHP separately. The Vmax for the oxidation of the S(-) and R(+) RHP enantiomers in four livers was 0.23 +/- 0.15 and 0.60 +/- 0.32 mumol/g protein per min (mean +/- SD), respectively. The Km was 110 +/- 40 and 70 +/- 10 microM, respectively. In contrast, HP reductase activity displayed greater capacity and was not saturable. The rate of production of RHP at a HP concentration of 122 microM (the limit of HP solubility) in the same livers was 2.6 +/- 0.7 mumol/g protein per min. Despite the observed nonlinearity between the enzymatic pathways in vitro, RHP concentrations in vivo are 2-3 orders of magnitude lower than the Km for oxidation of each enantiomer of RHP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nonlinear relationship between circulating concentrations of reduced haloperidol and haloperidol: evaluation of possible mechanisms. 786 45

Haloperidol (HAL) is a widely used and clinically effective neuroleptic. Its metabolism differs in various animal species. In humans, reduced haloperidol (RHAL), a hydroxy metabolite of HAL, is produced by a cytosolic ketone reductase. Interconversion is known to occur whereby HAL is found in the plasma after administration of RHAL in vivo. Interconversion of HAL and RHAL has been observed in man. However, the capacity for reductive HAL is greater than its oxidation back from RHAL. RHAL, the resulting metabolite of HAL, is reported to be about 10-25% as active as HAL in an animal model. Large intersubject variation has been observed in the pharmacokinetics of HAL and RHAL. A wide variation in reductive drug-metabolizing has been observed in schizophrenic patients treated with HAL. Both high and low RHAL/HAL ratios or RHAL levels were reported to be linked to poor response in HAL-treated patients and might be correlated with the therapeutic window effect of HAL treatment. It is conceivable, therefore, that subjects with high reductive capacity relative to oxidative capacity may have less therapeutic response from the same dose of HAL than those with a low reductive capacity relative to oxidative capacity. This aim of this study was to investigate the HAL reduction among a sample of HAL-treated schizophrenic patients. Because ketone reductases are generally not tissue specific, we investigate the reductase activity in Red blood cells (as described by Inaba), before and during the treatment. Steady-state plasma drug levels during 2 weeks of treatment were quantified. We examined the relationships between fixed doses of HAL treatment, Red blood cells ketone reductase activity, plasma HAL and RHAL levels and the percentage of change of the Positive and Negative Syndrome Scale for Schizophrenia. The participants in this study were 15 inpatients consecutively being treated in the adult psychiatric wards of the University of Lille. All subjects met DSM III-R criteria for schizophrenia (paranoid form). Upon induction subjects were evaluated clinically by trained raters using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). Subjects were required to score 40 or higher on the general psychopathology subscale of the PANSS to continue participation. All subjects were drug free. Haloperidol was administered orally at three times daily dose. Patients were randomized to treatment at three orally fixed doses: 6 mg per day, 10 mg per day and 15 mg per day. Patients were treated for 2 periods of one week. At the end of each period, dosages could be modified according to the clinic evolution of the patient. PANSS was repeated by the same raters blinded to the haloperidol dosage, plasma concentration and Rbc haloperidol ketone reductase activity, at the beginning and at the end of each period. Blood samples were collected on the same day that clinical assessment were made. Multiple regression analysis (forward stepwise) revealed that Red blood cells reductase activity at D0 is an important variable predicting haloperidol plasma levels at week 2. Similarly Red blood cells reductase activity at D0 and D7 predicted Reduced haloperidol plasma concentrations at week 2. In this sample, no parameter was found to be consistency predicted the percentage change in the PANSS positive subscale from baseline, at week 2. Nevertheless, Red blood cells reductase activity at D0, Reduced haloperidol/haloperidol ratio at week 2, haloperidol plasma levels at week 2 and the dose of haloperidol at week 1 were important variables predicting the percentage change in the PANSS general subscale from baseline at week 2. These results suggest that the knowledge of reductase activity could predict the treatment response in acute schizophrenic patients.
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PMID:[Erythrocyte ketone reductase activity, total plasma haloperidol and acute psychoses]. 867 66

Gene expression has been studied in post-mortem frontal cortex samples from patients who had suffered from schizophrenia and depressive illness. mRNA was extracted and characterised by translation and separation of the products by 2D gel electrophoresis. Post-mortem artefacts and the agonal experience did not affect the size distribution or amount of specific translation products. Four expression products were specifically reduced in samples from schizophrenics compared with normals. The expression of six products was altered in affective disorder, one in common with schizophrenia, two the same as in schizophrenia but increased. cDNA libraries were produced from the mRNA samples and 5 clones present at abnormal levels in schizophrenia identified by differential screening, isolated and sequenced. All the sequences encode mitochondrial transcripts; four encode mitochondrial rRNA and one the amino acid sequence of cytochrome oxidase sub-unit II. Increased cytochrome oxidase transcripts were found in a further set of mRNA extracts from schizophrenic patients including two who had not received neuroleptic medication. The effects of neuroleptic administration as exemplified by alpha-flupenthixol compared with the ineffective beta-flupenthixol were studied in experimental animals. It was found that 13 out of 28 clones whose levels were altered were mitochondrial in origin including rRNA, COX I & II and the NADH-Q reductase. Those encoding respiratory enzymes were at abnormally low levels as a result of alpha-flupenthixol administration. Measurements of the enzymic activity of cytochrome c oxidase in post-mortem frontal cortex of schizophrenics did not indicate any differences in overall activity but there was a decreased sensitivity to azide that was abolished by neuroleptics. Studies on NADH-cytochrome c reductase showed that schizophrenics whether medicated or not had a reduced rotenone sensitive activity that was compensated for by increased rotenone insensitive activity. We conclude that changes in mitochondrial gene expression are involved in schizophrenia and probably other functional psychoses.
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PMID:Mitochondrial involvement in schizophrenia and other functional psychoses. 889 62

Plasma concentrations of bromperidol (BRP) and reduced bromperidol (RBRP) were determined in 31 patients with schizophrenia who were administered BRP for their psychiatric symptoms. Activities of carbonyl reductase in red blood cells were assayed using BRP as a substrate. Plasma concentrations of BRP and RBRP ranged from 2.2 to 23.5 ng/mL and from 0.2 to 8.2 ng/mL, respectively. RBRP-to-BRP ratios in plasma ranged from 0.01 to 0.94 (mean +/- SD: 0.31 +/- 0.20), values notably lower than the previously reported values of reduced haloperidol to haloperidol (HAL) in the plasma from patients on HAL. The activity of BRP reductase in red blood cells was determined as 6.8-12.3 pmol/hr/10(6) red blood cells, which was at approximately the same level as that of HAL reductase. Patients with positive responses to BRP treatment were evaluated using the Brief Psychiatric Rating Scale. We found that the number of patients who had a positive response to BRP did not increase after BRP plasma levels had reached the level of 12 ng/mL. This finding suggests that a therapeutic plateau in BRP pharmacotherapy of schizophrenia occurs, and there is no advantage to raising the dose once this plateau is reached.
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PMID:Interindividual variation in bromperidol metabolism and relationship to therapeutic effects. 1077 Apr 55

Homozygous mutation of the thermolabile variant of methylene tetrahydrofolate reductase (MTHFR) may result in hyperhomocystinemia, leading to an increased risk for early cardiovascular disease, neural tube defects, and possibly major depression, schizophrenia. According to recent studies heterozygosity for the thermolabile variant of the MTHFR gene mutation is also more frequent in patients with thrombotic disease compared to that in the average population. We report on a family with different types of early vascular disease. In four consecutive generations MTHFR heterozygosity was detected: in the proband and in her mother, grandfather and daughter. Further conditions of the family members, possibly due to carrying the mutation, came to light by the pedigree analysis and examinations. The patient had pulmonary emboli at young age, her aunt died of spina bifida shortly after birth. The patient's mother suffers from schizophrenia and depression. The grandfather had pulmonary emboli, her sister with spina bifida occulta also carries the same mutation, as does her daughter who is sofar asymptomatic. In other asymptomatic members of the family no mutations were found. Unexpectedly, hyperhomocystinemia was detected in all heterozygote individuals. Our study demonstrates the necessity for folic acid therapy in mutation carriers to prevent early vascular events, depression and schizophrenia, and also to reduce the risk for neural tube defects in a preconception setting.
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PMID:[Vascular diseases, spina bifida and schizophrenia in a single family associated with the heterozygote mutation of the heat-sensitive variant of methylenetetrahydrofolate reductase]. 1148 7

Alteration in the isoprenoid metabolites--digoxin, ubiquinone, and dolichol--have been reported in neuronal degeneration (Parkinson's disease), oncogenesis (central nervous system glioma), functional neuropsychiatric disorders (schizophrenia and epilepsy), and immune-mediated disorders (multiple sclerosis). The coexistence of these disorders has been documented in literature and a central dysfunction related to digoxin and the isoprenoid pathway may underlie all these disorders. A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome X, rheumatoid arthritis, and epilepsy has been described. The psychological behavioral patterns of the family were: creativity and high IQ, hypersexual behavior, reduced appetite and eating behavior, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less bonding and affectionate behavior, and left handedness/right hemispheric dominance. Digoxin, an endogenous Na(+)-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and red blood cell (RBC) membrane Na(+)-K+ ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine, resulting in increased levels of depolarizng tryptophan catabolites, serotonin, quinolinic acid, strychnine, and nicotine, and decreased levels of hyperpolarizing tyrosine catabolites, dopamine, noradrenaline, and morphine, contributing to membrane Na(+)-K+ ATPase inhibition in all the above disorders and the indexed family. Digoxin-induced membrane Na(+)-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced Mg2+ levels, leading on to glutamate excitotoxicity, oncogene activation, and immune activation. Digoxin-induced altered Ca2+/Mg2+ ratios, reduced ubiquinone, and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure, and mitochondrial function, leading to the diverse disorders described above, including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/LH dominant and left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated hydroxymethylglutarylcoenzyme A reductase activity, with increased serum digoxin and dolichol levels. The serum ubiquinone, serum Mg2+ and RBC Na(+)-K+ ATPase activity were reduced in left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated levels of serum tryptophan, quinolinic acid, serotonin, nicotine, and strychnine. The levels of tyrosine, dopamine, noradrenaline, and morphine were low in left-handed/RH dominant compared to right-handed/LH dominant individuals. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and coordinate the functions of various cellular organelles.
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PMID:Central role of hypothalamic digoxin in conscious perception, neuroimmunoendocrine integration, and coordination of cellular function: relation to hemispheric dominance. 1232 12

NAD(P)H: quinone oxidoreductase (NQO1), an obligate two-electron reductase of quinones, prevents their participation in redox cycling and subsequent generation of reactive oxygen species (ROS). Reduced or negative activity of NQO1 would lead to an excess of neurotoxic compounds of cathecolamine o-quinones and ROS. Recently, there has been increasing evidence that catecholamine o-quinones and ROS might contribute to the development of schizophrenia. We investigated the genetic association between a functional polymorphism (Pro 187Ser) in the human NQO1 gene and schizophrenia (244 Japanese schizophrenic patients and 204 healthy controls). No significant differences in the allelic and genotypic distribution between patients and controls were observed. In addition, our results revealed no association between the genotypes of the polymorphism and any characteristics of patients such as gender, age at onset, family history or current neuroleptic dosage. Our results suggest that the NQO1 gene polymorphism does not confer increased susceptibility for schizophrenia in the present sample.
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PMID:NAD(P)H: quinone oxidoreductase (NQO1) gene polymorphism and schizophrenia. 1283 17

gamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABA is converted from glutamic acid by the action of glutamic acid decarboxylase (GAD) of which two isoforms exist GAD65 and GAD67. GABA then is broken down, both within the cell and in the synaptic cleft by GABA transaminase to form succinic semialdehyde. In turn, succinic semialdehyde is converted either to succinic acid by succinic semialdehyde dehydrogenase or into gamma-hydroxybutyric acid (GHB) by succinic semialdehyde reductase. Because GABA modulates the majority of inhibition that is ongoing in the brain, perturbations in GABAergic inhibition have the potential to result in seizures. Therefore, the most common disorder in which GABA is targeted as a treatment is epilepsy. However, other disorders such as psychiatric disease, spasticity, and stiff-person syndrome all have been related to disorders of GABAergic function in the brain. This review covers the roles of GABAergic neurotransmission in epilepsy, anxiety disorders, schizophrenia, stiff-person syndrome, and premenstrual dysphoric disorder. In the final section of this review, the GABA metabolite GHB is discussed in terms of its physiological significance and its role in epilepsy, sleep disorders, drug and alcohol addiction, and an inborn error of GABA metabolism, succinic semialdehyde dehydrogenase deficiency.
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PMID:GABA, gamma-hydroxybutyric acid, and neurological disease. 1289 48

We have previously reported a changed mitochondrial (mt) gene expression in brain from patients with schizophrenia [Schizophr. Res. 14 (1995) 203]; now, we describe the distribution in the mtDNA from lymphocytes of a heteroplasmic sequence variation that was originally found in the mtDNA from the postmortem brain of a patient with schizophrenia. The variant is m.12027T>C and results in the change from isoleucine to threonine at position 423 of the ND4 subunit of NADH-ubiquinone reductase. Using a PCR-RFLP method, we have determined the heteroplasmy as the ratio of variant to total (variant ratio) at m.12027 in 184 controls and 181 patients with schizophrenia as well as 24 postmortem brain samples. The distribution of variants is bimodal having peaks at variant ratios of 0.262 and 0.732. The variant-rich fraction is very significantly associated with schizophrenia in males (47%), while there is only 18% in control males. There are significantly more variant-rich control females (36%) than control males (18%), suggesting that the female population is less sensitive to the presence of a variant in terms of liability to schizophrenia. In variant-rich samples from postmortem brain originating from both sexes, there is an increased superoxide production, suggesting that the variation contributes to oxidative stress. Antioxidant glycosides, such as quercetin rutoside, quench the superoxide production without (in contrast to neuroleptic drugs) interfering with the electron transfer activity of the reductase.
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PMID:A mitochondrial DNA sequence variant associated with schizophrenia and oxidative stress. 1462 72


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