Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.
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PMID:CYP1A2 activity as measured by a caffeine test predicts clozapine and active metabolite steady-state concentrationin patients with schizophrenia. 1147 24

Several authors have suggested that psychological stress induces the production of reactive oxygen species (ROS). Several studies have supported the idea that bilirubin exerts antioxidative effects in vivo, and it was reported psychological stress provokes bilirubin oxidation in vivo [Yamaguchi T., Shioji I., Sugimoto A., Yamaoka M., 2002. Psychological stress increases bilirubin metabolites in human urine. Biochem. and Biophys. Res. Commun. 293, 517-520]. We investigated whether the concentration of bilirubin oxidative metabolites (biopyrrins) is increased in urine from patients with psychiatric disorders. The concentration of biopyrrins in urine of 25 patients with psychiatric disorders (schizophrenia, 15; depression, 10) was compared with 96 healthy volunteers. The concentrations of biopyrrins, as measured by enzyme-linked immunosorbent assay, were normalized to the urinary concentration of creatinine. The concentration of biopyrrins in patients with psychiatric disorders (schizophrenia and depression) was significantly higher than that of healthy volunteers. In schizophrenia, biopyrrins levels correlated with scores of the Brief Psychiatric Rating Scale (BPRS), and in depression, biopyrrins levels correlated with scores of the Hamilton Depression Rating Scale (HAM-D). These finding suggest that psychotic states are associated with an increase in the oxidative metabolites of bilirubin in human urine.
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PMID:Urinary excretion of biopyrrins, oxidative metabolites of bilirubin, increases in patients with psychiatric disorders. 1582 Apr 12

A 54-year-old woman with schizophrenia presented to hospital with unconsciousness, fever and marked muscle rigidity. She had been given fluphenazine decanoete 20 mg intramuscularly 15 days before the admission and she had continued taking haloperidol 20 mg daily and oral biperiden 2-4 mg. She was extremely rigid and unresponsive. On laboratory investigations revealed: serum sodium 120 mEq/l, creatinine phosphokinase 12,980 IU/l (normal up to 170), lactate dehydrogenase 1544 IU/l (150-500), free trioidothyronine < 1.00 pg/ml (1.5-4.5), free throxyine 0.76 ng/dl (0.8-1.9), thyroid stimulating hormone 1.14 microU/ml (0.4-4), cortisol (at 8.00 a.m.) 9 microg/dl (5-25). Antipsychotic drugs were withdrawn after admission. A diagnosis of secondary adrenal insufficiency and secondary hypothyroidism was made. Hormonal substitution with hydrocortisone and levothyroxine and correction of hyponatremia with intravenous hypertonic saline solution resulted in rapid improvement of symptoms and signs. It seems that the symptoms and signs of hypothyroidism and hyponatremia were attributed to acute psychosis in this patient. As a conclusion failure to recognize the endocrinopathy may not only produce recovery difficulties but also psychiatric and endocrine repercussions if psychotropic medications are given in such masked cases.
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PMID:Possible malignant neuroleptic syndrome that associated with hypothyroidism. 1592 37

Neuroleptic malignant syndrome is a rare but potentially lethal, rare reaction to neuroleptics which is characterized by altered levels of consciousness, extrapyramidal effects, autonomic instability, hyperthermia, and elevated serum creatine phosphokinase levels. The most serious complication of neuroleptic malignant syndrome is acute renal failure. We investigated six cases of neuroleptic malignant syndrome associated with myoglobulinemic acute renal failure due to rhabdomyolysis and effect of hemodialysis or hemodiafiltration. The patients were five males and one female with a mean age of 43.5 yr. All of the patients, who developed acute renal failure induced from rhabdomyolysis, had previously received butyrophenone (haloperidol), phenothiazine, benzamide, iminomide, benzisoxazole, antidepressants, and hypnotics (benzodiazepine and barbiturate) for the treatment of schizophrenia. The clinical manifestations of neuroleptic malignant syndrome were characterized by altered consciousness, muscle rigidity and weakness, fever, and excessive perspiration. The peak laboratory data were blood urea nitrogen 102 +/- 26 (mean +/- SD) mg/dL, serum creatinine 9.1 +/- 2.1 mg/dL, serum creatine phosphokinase 229,720 +/- 289,940 IU/L, and all of them developed oliguric acute renal failure. Dantrolene sodium administration was given to five cases and hemodialysis or hemodiafiltration was performed in all of them. The serum creatinine level after hemodialysis or hemodiafiltration was 1.4 +/- 1.0 mg/dL. All patients were successfully cured of acute renal failure by hemodialysis or hemodiafiltration. As a result, myoglobulinemic acute renal failure associated with neuroleptic malignant syndrome was successfully treated by hemodialysis or hemodiafiltration.
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PMID:Successful treatment of six patients with neuroleptic malignant syndrome associated with myoglobulinemic acute renal failure. 1652 19

Neuroleptic malignant syndrome (NMS) is a rare idiosyncratic reaction to antipsychotic drugs that is potentially fatal. Characteristic features of NMS are hyperthermia, muscular rigidity, severe autonomic dysregulation and disturbed consciousness. Signs and symptoms of serotonin syndrome (SS) can be grouped into four inclusive categories that are almost identical to those of NMS. Clinically, NMS and SS share many features, suggesting different spectrums of a similar disorder. To make a distinction between the two is often difficult because of a large clinical overlap. We present a case of a 42-year-old male with a history of schizophrenia that developed signs and symptoms inconsistent with either NMS or SS after intramuscular administration of 2 typical antipsychotics along with 1 dose of a selective serotonin reuptake inhibitor (SSRI). The patient abruptly developed the clinical features in just 24 h. The patient presented with altered mental status and increased levels of creatinine phosphokinase. Twelve days of intensive care unit treatment was chiefly supportive and included bromocriptine. The final outcome was positive with complete disappearance of the symptoms. The treatment for both NMS and SS is similar. The therapeutic interventions primarily consist of removing the suspected agent and providing supportive care. We present this case to highlight some controversial issues concerning the life threatening adverse effects of psychotropic drugs, which illustrate the spectrum concept.
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PMID:[The life threatening adverse effects of psychotropic drugs: a case report]. 1675 15

Neuroleptic malignant syndrome (NMS) is a rare clinical condition and potentially life-threatening complication of antipsychotic medications. We report a patient with an atypical presentation of NMS. A 60-year-old man with schizophrenia was admitted to our hospital with disturbed consciousness, fever and marked extrapyramidal rigidity both in the upper and lower extremities. He had been given i.m. zuclopenthixol 200 mg/month but had not taken the last dose. Laboratory investigations showed that creatinine phosphokinase 428 IU/l (normal up to 130), lactate dehydrogenase 772 IU/l (normal up to 450), blood glucose 256 mg/dl (65-110). Urine analyses revealed ketonuria. White blood cell (WBC) count was 6100 cells/mm(3). Therefore, the patient was diagnosed as having NMS and antipsychotic medications were stopped. Adequate hydration was provided and bromocryptine 5 mg was started three times a day. Despite treatment, the patient died due to acute myocardial infarction after 3 days of hospitalization.
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PMID:Zuclopenthixol-induced neuroleptic malignant syndrome presenting as fever of unknown origin, hyperglycaemia and acute myocardial infarction in a 60-year-old man. 1796 86

Obesity is a serious health issue for many patients with schizophrenia. There is a lack of predictors for and understanding of the development of obesity in the early phase of the illness. Therefore we investigated a set of routine biochemistry variables in blood as predictors of the development of obesity and weight gain over 5 years in an observational cohort study of patients with first-episode schizophrenia (n=59). Twelve percent of the patients were obese at baseline and 37% were obese at the 5-year follow-up. The mean body mass index (BMI) change over 5 years was a 4.1 kg/m(2) increase (4.5 SD). Obesity was predicted by baseline hemoglobin levels (odds ratio per standard deviation [OR/SD] 3.3, 95% confidence interval [CI] 1.4 to 7.5), red blood cell count (OR/SD 2.6, 95% CI 1.2 to 5.5), hematocrit (OR/SD 2.8, 95% CI 1.3 to 5.9), gamma-glutamyltransferase (OR/SD 2.8, 95% CI 1.2-6.3) and creatinine (OR/SD 3.1, 95% CI 1.2 to 8.0). After adjustment for baseline BMI, the associations were attenuated for gamma-glutamyltransferase and creatinine. Low baseline BMI was associated with a greater BMI increase. The major conclusion is that easily available routine biochemistry markers can be useful in predicting the development of obesity in first-episode schizophrenia. The mechanisms underlying the observed associations are unknown, but the predictors identified in this study could signify dehydration or insulin resistance. These observations open a new window to future research on the mechanisms underlying the development of obesity in schizophrenia.
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PMID:Biochemical risk factors for development of obesity in first-episode schizophrenia. 1984 78

A compound identified as 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA) was found in higher concentrations in urine samples of children with autism compared to age and sex appropriate controls and in an adult with recurrent diarrhea due to Clostridium difficile infections. The highest value measured in urine samples was 7500 mmol/mol creatinine, a value 300 times the median normal adult value, in a patient with acute schizophrenia during an acute psychotic episode. The psychosis remitted after treatment with oral vancomycin with a concomitant marked decrease in HPHPA. The source of this compound appears to be multiple species of anaerobic bacteria of the Clostridium genus. The significance of this compound is that it is a probable metabolite of m-tyrosine (3-hydroxyphenylalanine), a tyrosine analog which depletes brain catecholamines and causes symptoms of autism (stereotypical behavior, hyperactivity, and hyper-reactivity) in experimental animals.
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PMID:Increased urinary excretion of a 3-(3-hydroxyphenyl)-3-hydroxypropionic acid (HPHPA), an abnormal phenylalanine metabolite of Clostridia spp. in the gastrointestinal tract, in urine samples from patients with autism and schizophrenia. 2042 63

The objective of this prospective study was to characterize the metabolism of risperidone to (+)- and (-)-9-hydroxyrisperidone in vivo and to evaluate the influence of CYP2D6 genotype. A population pharmacokinetic modeling approach was used to estimate the interindividual variability of the pharmacokinetic parameters in 50 hospitalized patients with acute episode of schizophrenia. CYP2D6 genotype remarkably influenced the formation clearances of the risperidone metabolites, while creatinine clearance was related to the plasma clearance of 9-hydroxyrisperidone. CYP2D6 genotype was also associated with the average plasma concentration of risperidone active moiety (a sum of all three active compounds). In comparison to the patients with CYP2D6*1/*1 genotype, average steady-state plasma concentration of risperidone active moiety was 3.3- and 1.6-fold higher in poor metabolizers (both alleles nonfunctional; CYP2D6*3 or *4) and intermediate metabolizers (one nonfunctional allele and one allele for diminished enzyme activity; CYP2D6*10 or *41), respectively. Additionally, average plasma concentration of risperidone active moiety was higher in the patients with dystonia (p=0.0066) and parkinsonism (p=0.046). The results of this study imply the potential role of CYP2D6 genotyping in personalizing risperidone therapy in patients with schizophrenia to reduce the incidence of adverse extrapyramidal symptoms.
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PMID:A population pharmacokinetic evaluation of the influence of CYP2D6 genotype on risperidone metabolism in patients with acute episode of schizophrenia. 2144 70

During treatment of acute-phase schizophrenia, attention needs to be given to physical as well as psychological symptoms. It is often difficult, however, to obtain information on physical symptoms from patients with psychomotor excitation, and only laboratory examinations can provide objective data. The results of laboratory parameters measured in 68 patients with schizophrenia during psychomotor excitation and approximately 1 month later during the medicated recovery phase have been analyzed retrospectively. Abnormal laboratory values during psychomotor excitation were frequent. The most frequent (>/=35% of patients) were increased white blood cell count, low serum potassium levels, high levels of fasting blood sugar, lactate dehydrogenase and uric acid. There were fewer abnormal values during the medicated recovery phase. The most frequent (>/=25% of patients) were high serum levels of triglycerides, amylase, creatinine kinase, and low-density lipoprotein cholesterol. Abnormal triglyceride levels were found significantly more frequently in patients receiving olanzapine than those receiving risperidone. Abnormal values during the acute phase may be the result of excitation such as increased sympathetic tone and dehydration. Abnormal values during the recovery phase appeared to be related to the adverse metabolic effects of antipsychotic drugs. The frequency of these abnormal values was particularly high in patients receiving olanzapine alone or in combination with other medications.
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PMID:Abnormal laboratory values during the acute and recovery phases in schizophrenic patients: a retrospective study. 2063 80


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