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)

CYP2D6 has been suggested to be functionally similar to the dopamine transporter. The present study was aimed at analysing the frequency of CYP2D6 alleles and genotype among schizophrenic patients compared to healthy volunteers. CYP2D6 *3, *4, *5, *6, *10 and duplicated alleles were analysed in 128 unselected schizophrenia inpatients (SP) and 142 unrelated white European Spanish healthy volunteers (HV). SP and HV with >2, 2, 1 or 0 CYP2D6 active genes were 4.7, 64.8, 28.1 and 2.3%, and 6.3, 52.1, 33.1 and 8.5%, respectively. The frequency of homozygous for CYP2D6 inactive alleles or poor metabolizers (PMs) was lower (P<0.05) in SP than in HV. Furthermore, the frequency of CYP2D6 inactive alleles was also lower in SP than in HV (16.8 vs 25.7; P<0.05), specifically the CYP2D6*6 allele was not found among patients. The present study shows a lower frequency of PMs in schizophrenic patients than in healthy volunteers supporting the hypothesis of a potential role of CYP2D6 in the vulnerability to schizophrenia.
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PMID:Low frequency of CYP2D6 poor metabolizers among schizophrenia patients. 1732 35

The object of this study is to assess 1) the relationship between plasma antipsychotic drug concentration, serum prolactin levels and the clinical efficacy of risperidone, 2) the relationship between the CYP2D6 polymorphisms and metabolizing of risperidone and 3) the role of 9-hydroxyrisperidone in elevating prolactin levels. One-hundred and eighteen Chinese schizophrenia patients (40 males, 78 females, age 15-60 years) were given risperidone at dosages ranging from 2-8 mg/day for 8 weeks. Clinical efficacy was determined using the Brief Psychiatric Rating Scores (BPRS). Serum prolactin levels were assayed before and after the 8 week treatment and plasma risperidone and 9-hydroxyrisperidone levels were also measured at the end of the 8-week treatment. The results showed there was no significant correlation between the concentration of active moiety and clinical response. Risperidone treatment significantly increased serum prolactin levels. Furthermore, changes of prolactin levels were not correlated with the clinical response. For the risperidone/ 9-hydroxyrisperidone ratio, there was a statistically significant difference among the CYP2D6*1/*1, *1/*10, *10/*10 genotypes (Kruskal-Wallis test, p = 0.012). No significant differences were found in the concentration of 9-hydroxyrisperidone and active moiety among the genotypes. In addition, the concentration of 9-hydroxyrisperidone was not significantly correlated with the increase of serum prolactin. In conclusion, our study has, for the first time, produced evidence that in Chinese schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6. Neither changes in serum prolactin levels nor plasma concentration of active moiety were significantly correlated with clinical efficacy of risperidone. 9-hydroxyrisperidone may not play a predominant role in elevating serum prolactin level.
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PMID:Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia. 1771 6

The CYP2D6 gene is highly polymorphic, causing absent (poor metabolizers), decreased, normal or increased enzyme activity (extensive and ultrarapid metabolizers). The genetic polymorphism of the CYP2D6 influences plasma concentration of a wide variety of drugs metabolized in the liver by the cytochrome P450 (CYP) 2D6 enzyme, including antipsychotic drugs used for schizophrenia treatment. Additionally, CYP2D6 is involved in the metabolism of endogenous substrates in the brain, and reported to be located in regions such as the cortex, hippocampus and cerebellum, which are impaired in schizophrenia. Moreover, recently we have found that CYP2D6 poor metabolizers are under-represented in a case-control association study of schizophrenia. Furthermore, null CYP2D6 activity in healthy volunteers is associated with personality characteristics of social cognitive anxiety, which may bear some resemblance to milder forms of psychotic-like symptoms. In keeping with this, CYP2D6 may influence, not only variability to drug response, but also vulnerability to disease in schizophrenia patients.
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PMID:CYP2D6 polymorphism: implications for antipsychotic drug response, schizophrenia and personality traits. 1803 24

The authors describe the case of a female patient with the diagnosis of schizophrenia and the CYP2D6 poor metaboliser phenotype (PM phenotype), who experienced severe extrapyramidal side effects, including acute dystonia, while being treated with chloropromazine at 100 mg per day (in the third day of therapy). The CYP2D6 phenotype was determined using the sparteine test before and after 3 days of treatment. Metabolic ratio increased 12 times during treatment, from initial 30 to 355. The authors conclude that CYP2D6 poor phenotype leading to slow chloropromazine metabolism, which was further inhibited by chloropromazine during treatment (as chlorpromazine is a strong CYP2D6 enzyme inhibitor) had significant importance on the occurrence of acute extrapyramidal side effects. Most likely the antidopaminergic influence of the drug on the CNS was much more marked due to an inhibition of chlorpromazine metabolism leading probably to an increase of the chlorpromazine blood level.
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PMID:[Acute dyskinetic syndrome during chloropromazine treatment of a female patient with CYP2D6 poor metabolism phenotype]. 1804 80

We identified the null variants *3,*4,*5,*6,*7 and *8 of the CYP2D6 gene [encoding for cytochrome P450 (debrisoquine hydroxylase)] in a group of 84 chronic-stay psychiatric inpatients with severe schizophrenia or related disorders and receiving treatment with one or more CYP2D6 substrates for years. We also studied a group of 100 healthy controls of similar ethnic origin (Spanish Caucasians). Three patients were poor metabolizers (PMs) for antipsychotic drugs according to their CYP2D6 genotype (i.e. homozygous for the *4 allele) but they exhibited no adverse drug reaction over the years despite chronic treatment with CYP2D6 substrates. We suggest that CYP2D6 genetic screening is more useful in other type of psychiatric patients, particularly in younger ones starting treatment protocols.
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PMID:Identification of CYP2D6 null variants among long-stay, chronic psychiatric inpatients: is it strictly necessary? 1842 96

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.
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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

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

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.
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PMID:ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety. 1870 91

Manifestation of tardive dyskinesia (TD) among schizophrenia subjects on long-term antipsychotic treatment with typical drugs has been a clinical concern. Despite its association with extrapyramidal symptoms, typical drugs are still routinely prescribed globally though marginally superior atypical drugs have long been available. The genetic component in the etiology of TD is well documented. Search for these determinants has led to a few consensus associations of CYP2D6 *10, CYP1A2*1F, DRD2 Taq1A (rs1800497), DRD3 Ser9Gly (rs6280) and MnSOD Ala9Val (rs4880) variants with TD. However, translation of these observations into the clinic has not been achieved so far. This review discusses the salient features of TD etiopathology, current status of TD genetics, interactions between genetic and nongenetic factors, some major drawbacks, challenges and expected focus in TD research over the next decade, with emphasis on pharmacogenetics.
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PMID:Genetic underpinnings of tardive dyskinesia: passing the baton to pharmacogenetics. 1878 56

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.
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PMID:Clinical significance of a CYP2D6 poor metabolizer--a patient with schizophrenia on risperidone treatment. 1880 96


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