Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glycoprotein (PGP) is a polymorphic efflux transporter located on the blood brain barrier that potentially affects the penetration of atypical antipsychotics into the central nervous system. Increased antipsychotic penetration to the primary site of activity may result in greater symptom improvement or the occurrence of side effects. This investigation examined the relationship between three common PGP polymorphisms (C1236T, G2677TA, and C3435T) and response to 6 weeks of open-label olanzapine treatment in patients with schizophrenia. Individuals with a PGP T allele at any of these polymorphisms would be expected to have greater antipsychotic penetration through the blood brain barrier, due to lower PGP activity. Forty-one patients were included in this reanalysis. For subjects in the 3435T allele carrier group, the plasma olanzapine level alone was positively associated with percent change in Brief Psychiatric Rating Scale score (p = 0.02). This relationship was not seen for the 3435CC group (p = 0.583). A similar trend was observed for negative symptom reduction, olanzapine plasma concentration, and the 3435T allele (p = 0.06), but this relationship did not meet statistical significance. There was no relationship between the PGP genotypes and changes in weight over the course of this 6 week study. The analysis using C1236T or G2677AT genotypes gave similar results, due to linkage of these polymorphisms.PGP polymorphisms may affect the penetration of olanzapine into the central nervous system as seen by a relationship between the 3435T allele, olanzapine plasma levels, and reduction in the positive symptoms of schizophrenia. This may stem from greater olanzapine central nervous system latency due to the presence of the 3435T allele and reduced PGP activity. The PGP C3435T genotype may help to determine positive symptom reduction from olanzapine clinically, but these findings should be replicated in a larger sample of subjects.
Ther Drug Monit 2006 Oct
PMID:The relationship between P-glycoprotein (PGP) polymorphisms and response to olanzapine treatment in schizophrenia. 1703 83

The aim of this study was to assess dose-related steady-state serum concentrations of olanzapine (OLZ) and its metabolites N-desmethyl OLZ (DMO) and 2-hydroxymethyl OLZ (2-OH-OLZ) (assessed by high-performance liquid chromatography) in 122 child and adolescent psychiatric patients (age 16.9 +/- 2.2, range, 10-21 years; 74 males, 48 females) with a variety of diagnoses: schizophrenia group (n = 80); nonschizophrenia group (n = 29); anorexia nervosa (AN) group (n = 13). Median OLZ serum concentrations were 32.7 (range, 1-118; all patients), 37.7 (2-115; schizophrenia group), and 18.7 (1-63, AN group) ng/mL. The median OLZ concentration-to-dose (C/D) ratio (n = 122) was 2.6, with 90% of the distribution between 0.8 and 5.5 (ng/mL)/(mg/d). OLZ concentration was significantly correlated with DMO (r = 0.567; P < 0.0005) but not with 2-OH-OLZ (r = 0.122; P = 0.188). Daily OLZ dose was correlated with OLZ concentration in all (r = 0.684; P < 0.0005), schizophrenic (r = 0.542; P < 0.0005), and AN (r = 0.805; P = 0.001) patients, respectively. Patients aged less than 16 years displayed similar C/D for OLZ (P = 0.58) but higher C/D for DMO (P = 0.003) than those 16 years or older. AN patients received lower median OLZ doses (7.5; 5-15 mg) than schizophrenic patients (12.5; 2.5-40 mg), even after correcting for body mass index (P = 0.02). OLZ dose did not differ (P = 0.088) between smokers and nonsmokers, but smokers showed lower C/D for OLZ than nonsmokers (P = 0.008). C/D for OLZ was 38% higher (P = 0.041) under comedication with selective serotonin reuptake inhibitors when compared with OLZ monotherapy. Multiple linear regression analysis revealed that 46% of the variation of OLZ concentration can be explained by dose, diagnosis, age, sex, smoking, and comedication. The data are compared with the literature, and the relevance of therapeutic antipsychotic drug monitoring in previously sparsely investigated subgroups, such as children and adolescents or patients with AN, is emphasized.
Ther Drug Monit 2006 Dec
PMID:Serum levels of olanzapine and its N-desmethyl and 2-hydroxymethyl metabolites in child and adolescent psychiatric disorders: effects of dose, diagnosis, age, sex, smoking, and comedication. 1716 90

Haloperidol and several other antipsychotic drugs are at least partially metabolized by the polymorphic cytochrome P450 2D6 (CYP2D6). The interindividual variation in metabolic capacity of CYP2D6 might be of importance when dosing. In this study, 26 outpatients with schizophrenia and depot haloperidol as monotherapy were genotyped. The authors found 1 patient with no functional alleles, 8 with one functional allele, 16 with two functional alleles, and 1 with three functional alleles. The daily dose of haloperidol ranged from 0.45 to 14.29 mg. Steady state plasma concentrations were measured at peak (range, 1.6-67 nmol/L) and at trough (range, 1.0-49 nmol/L). The Positive and Negative Syndrome scale for Schizophrenia and the Extrapyramidal Symptom Rating Scale were used to evaluate the clinical effect. The authors found a clear correlation between haloperidol plasma concentration and number of active CYP2D6 alleles. No correlation was found between plasma concentration of haloperidol or number of CYP2D6 alleles and treatment outcome or side effects. A model to predict plasma concentration from dose and number of active CYP2D6 alleles was formed from the obtained data by means of multiple linear regression.
Ther Drug Monit 2007 Aug
PMID:Depot haloperidol treatment in outpatients with schizophrenia on monotherapy: impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome. 1766 95

The neurodevelopmental hypothesis of schizophrenia proposes that a portion of schizophrenia is the result of an early brain insult which affects brain development and in which several types of virus might play an etiological role. The main arguments in favor of the neurodevelopmental hypothesis and the involvement of prenatal exposure to virus infection as a risk factor for adult schizophrenia are reviewed. Schizophrenia is associated with an increased incidence of craniofacial asymmetries and dermatoglyphic irregularities which might reflect an abnormal development of the ectoderm and the neural crest as a result of a viral infection between the first and second trimester of pregnancy. The brain histology of deceased schizophrenic patients shows disturbed neuronal migration and formations such as disorganized lamina strata or ectopic pyramidal cells, abnormal expression of the neural cell adhesion molecule, and absence of gliosis. The main epidemiological arguments are derived from studies of obstetrical complications and influenza virus infection during pregnancy, both considered to be early risk factors of schizophrenia. Because no virus has been consistently linked with the pathogenesis of schizophrenia, the most plausible hypothesis is that an endemic virus could initiate schizophrenia by direct brain lesion or by triggering an autoimmune response during the neurodevelopmental period on a genetically susceptible brain. In a neurodevelopmental model, the viral hypothesis is a step toward the goal of building a comprehensive theory that integrates the environmental, genetic, immune, and neuropsychological features of schizophrenia.
Med Sci Monit 2008 Jun
PMID:Schizophrenia and viral infection during neurodevelopment: a pathogenesis model? 1850 85

Suicidal behavior and substance abuse are frequent phenomena among patients with schizophrenia and may be attributable in part to antipsychotic treatment failure. Individuals who carry functional variants of the CYP2D6 and CYP2C19 genes, shown to cause altered drug metabolism of psychoactive drugs, are at risk of toxic accumulation or rapid elimination of these drugs, leading to treatment failure. We tested whether substance abuse disorder and suicidal behavior were associated with the CYP2D6 and CYP2C19 genotypes among patients with schizophrenia. Three hundred sixty-two patients with schizophrenia spectrum disorders (International Classification of Diseases, 10th Revision) were genotyped for functional CYP2D6 and CYP2C19 polymorphisms. Based on available medical records and clinical interviews, their suicidal behavior and substance abuse disorder were evaluated. No significant associations between the CYP2D6 and CYP2C19 genotypes and suicidal behavior or substance abuse disorder were noted, and we conclude that cytochrome P450 genotyping in its present form is clinically irrelevant with respect to these phenomena.
Ther Drug Monit 2008 Jun
PMID:The impact of CYP2D6 and CYP2C19 polymorphisms on suicidal behavior and substance abuse disorder among patients with schizophrenia: a retrospective study. 1852 May 96

Schizophrenia is a devastating psychiatric disorder that affects approximately one percent of the world's adult population. Despite substantial investigative efforts over the last decades, the exact mechanisms and pathogenesis of this condition are not yet fully understood. Published data support certain infectious agents as potential risk factors for schizophrenia. Since its discovery, Helicobacter pylori has been implicated in a variety of extra-digestive diseases, but its potential role in the pathogenesis of psychiatric disorders has thus far been neglected. It is hypothesized here that infection with H. pylori occurring in early childhood may induce persisting systemic biochemical aberrations, including dopaminergic dysfunction, decreased levels of essential polyunsaturated fatty acids, subtle inflammation, and homocysteine alterations, that may play a crucial role in the development of schizophrenia in genetically predisposed individuals. Evidence in favor of this hypothesis is provided and possible therapeutic implications are discussed.
Med Sci Monit 2008 Jul
PMID:Helicobacter pylori: a role in schizophrenia? 1859 25

Risperidone is metabolized to its active metabolite, 9-hydroxyrisperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisms in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype on the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisms have a moderate effect on those of 9-hydroxyrisperidone and the active moiety.
Ther Drug Monit 2008 Oct
PMID:ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety. 1870 91

A case of a 46-year-old woman with schizophrenia who was treated with risperidone and followed up for 1 year is reported. She was genotyped as a CYP2D6 poor metabolizer (PM): CYP2D6-4*/*6, which was confirmed by a dextromethorphan (DM) test (metabolic ratio = 5.8). Genotypes of ABCB1 (MDR1) were 2677TT and 3435TT. Because risperidone is CYP2D6 and P-glycoprotein substrate, the patient might have been expected to accumulate risperidone and suffer from significant side effects. However, the patient tolerated the drug extremely well. Plasma concentration of risperidone was 73.2 nmol/L and of 9-OH-risperidone was below the limit of quantitation (6.1 nmol/L). Target range of risperidone plus 9-hydroxyrisperidone is 50-150 nmol/L. During the follow-up, patient was continuously taking 3 mg/day of risperidone. Plasma levels of risperidone and 9-OH-risperidone were 70.2 and 18.1 nmol/L, respectively. We repeated a DM test, metabolic ratio was 3.6, thus confirming that the patient remained a PM. Psychopathology was assessed with Positive and Negative Syndrome Scale, and stable remission of illness was achieved over the stated period. No adverse effects were observed or reported by the patient. We conclude that PM phenotype for CYP2D6 does not necessarily have clinical significance in regard to risperidone treatment. DM and risperidone are both CYP2D6 and P-glycoprotein substrates and significant interactions might occur with both drugs, in parallel with the possible impact of ABCB1 and CYP2D6 polymorphic gene variants.
Ther Drug Monit 2008 Dec
PMID:Clinical significance of a CYP2D6 poor metabolizer--a patient with schizophrenia on risperidone treatment. 1880 96

Schizophrenia is a mental disorder in which the patient manifests with auditory hallucinations, paranoid or bizarre delusions, and disorganized speech and thinking. It is associated with significant social dysfunction. There are many hypotheses regarding schizophrenia. Most of these focus on schizophrenia as a manifestation of abnormalities from genetic [Mulle JG. Genomic structural variation and schizophrenia. Curr Psychiatry Rep 2008;10(2):171-7], viral [Fruntes V, Limosin F. Schizophrenia and viral infection during neurodevelopment: a pathogenesis model? Med Sci Monit 2008;14(6):RA71-7], neurochemical [e.g. dopamine (Lewis DA, Akil M. Cortical dopamine in schizophrenia: strategies for postmortem studies. J Psychiatr Res 1997;31(2):175-95) or interactions between neurotransmitters (Duncan GE, Sheitman BB, Lieberman JA. An integrated view of pathophysiological models of schizophrenia. Brain Res Brain Res Rev 1999;29(2):250-64)] or brain structural [Kotrla KJ, Weinberger DR. Brain imaging in schizophrenia. Annu Rev Med 1995;46:113-22] origins. Most of these hypotheses do not account for how or why these presumed causes lead to the manifestations of schizophrenia. We argue that brain structure and function is compatible with a hierarchical processing structure that forms the basis for perception and thought in healthy humans. We propose that perturbations of the types listed above lead to disruption of higher levels of perception and hierarchical temporal processing by the brain and that this constitutes the core deficit in schizophrenia. We present evidence that this model explains many of the features of schizophrenia and we make a series of predictions about schizophrenia.
 ...
PMID:Schizophrenia is a disorder of higher order hierarchical processing. 1923 Oct 93

The phenotyping cocktail is a practical approach for phenotyping of cytochrome P450 (CYP) enzymes in vivo. In this study, a liquid chromatography-tandem mass spectrometry method using a dual-extraction approach was developed and validated to quantify 5 selective substrates and their metabolites for the simultaneous phenotyping CYPs 1A2, 2C19, 2C9, 2D6, and 3A4 in patient blood samples. The assay was applied in a pilot study of 11 patients with schizophrenia. Five blood samples were collected before and at 1, 2, 4, and 6 hours after administration of a phenotyping cocktail consisting of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam. The method successfully quantitated the CYP enzyme activities without serious side effects in patients. The ratios of metabolite to parent area under the concentration-time curve values were calculated over the 6-hour postdosage to reflect CYP2D6, CYP3A4, and CYP2C9 activities. The ratios of metabolite to parent plasma concentrations were calculated at 4-hour postdosage for CYP1A2 and at 4- or 6-hour postdose for CYP2C19, respectively. The plasma concentration of midazolam at 4 hours was also estimated as another phenotyping index for CYP3A4 activity. The simultaneous assay of all these analytes in a single matrix (plasma) will increase the feasibility of CYP phenotyping in patients.
Ther Drug Monit 2009 Apr
PMID:A high-throughput assay using liquid chromatography-tandem mass spectrometry for simultaneous in vivo phenotyping of 5 major cytochrome p450 enzymes in patients. 1930 38


<< Previous 1 2 3 4 5 Next >>