Prediction of response to risperidone treatment with respect to plasma concentrations of risperidone, catecholamine metabolites, and polymorphism of cytochrome P450 2D6

ArticleinInternational Clinical Psychopharmacology 20(2):71-8 · April 2005with18 Reads
DOI: 10.1097/00004850-200503000-00002 · Source: PubMed
Abstract
In the present study, we examined the relationships between plasma concentrations of risperidone and clinical responses, extrapyramidal symptoms, plasma levels of cotinine and caffeine, or cytochrome (cyp)2D6 genotypes. In addition, we also investigated the relationships between plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) or homovanillic (HVA) acid and clinical responses to risperidone. One hundred and 36 patients (male/female: 58/78, age 37+/-13 years) who met DSM-IV criteria for schizophrenia, schizoaffective disorder, delusional disorder and brief psychotic disorder, and who were being treated with risperidone alone, were evaluated regarding their clinical improvement and extrapyramidal symptoms using the Positive and Negative Syndrome Scale (PANSS) and Simpson and Angus (SAS), respectively, and plasma levels of cotinine, caffeine, MHPG and HVA were analysed by high-performance liquid chromatography. The cyp2D6*5 and *10 alleles were identified using the polymerase chain reaction. There was a positive correlation between plasma levels of risperidone plus 9-hydroxyrisperidone (active moiety) and SAS scores, but not the PANSS. Pretreatment HVA levels in responders were higher than those in nonresponders. In addition, there was a negative correlation between changes in HVA levels and improvement in PANSS scores. There was no association between plasma levels of risperidone and plasma levels of cotinine or caffeine. Furthermore, there were no differences in the risperidone/9-hydroxyrisperidone ratio, clinical improvements and extrapyramidal symptoms among cyp2D6 genotypes. These results indicate that pretreatment HVA levels and plasma concentrations of active moiety might play a part in predicting the clinical response and occurrence of extrapyramidal symptoms, respectively, when treating patients with risperidone.
    • "Plasma homovanillic acid (HVA) was shown to reflect central or brain dopamine activity based on studies in animals and humans[7][8][9]. Several studies of schizophrenia have noted that the behavioral response to antipsychotic drugs, such as a decrease in psychosis, parallels a decrease in plasma HVA levels in schizophrenic patients over time[10][11][12][13][14][15][16][17][18][19][20]. Atypical antipsychotics increase the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels and are associated with negative symptoms and cognitive functions[19,21,22]. "
    [Show abstract] [Hide abstract] ABSTRACT: Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing aripiprazole treatment. We evaluated cognitive function in 51 patients with schizophrenia using Brief Assessment of Cognition in Schizophrenia (BACS), as well as background information, psychiatric symptoms, plasma catecholamine metabolites—homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG)—, and serum brain-derived neurotrophic factor (BDNF). Multivariate analyses were performed in order to identify factors independently associated with cognitive function. Brain-derived neurotrophic factor levels, number of hospitalizations, and MHPG levels were associated with verbal memory and learning. Total hospitalization period and MHPG levels were associated with working memory. Age at first hospitalization and education were associated with motor speed. The number of hospital admissions, Positive and Negative Syndrome Scale negative subscale scores (PANSS-N), MHPG levels, BDNF levels, and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were associated with verbal fluency. Homovanillic acid and MHPG levels, duration of illness, and PANSS-N scores were associated with attention and processing speed. Brain-derived neurotrophic factor and MHPG levels were associated with executive function. These results suggest that treatment of psychiatric symptoms and cognitive dysfunction may be improved in patients treated with aripiprazole by controlling for these contributing factors.
    Full-text · Article · Mar 2017
    • "Page 4 of 7@BULLET In Asian samples, the A allele or A/A genotype was associated with better improvement after risperidone treatment (Xing et al.[51], n=125; Ikeda et al.[30], n=120) but took a long time to respond to risperidone in the American sample (Lencz et al.[44], n=61)A: African, C: Caucasian and/or European, E: European, H: Hispanic, As: Asian, N/A: Not Available, n: sample size, FGA: First Generation Antipsychotic, PM: Poor Metabolizer, IM: Intermediate Metabolizer, UM: Ultrarapid Metabolizer, EM: Extensive Metabolizer, Del: Deletion, Ins: Insertion(PMs) typically cause Risperidone build up in the blood. Thus, there is a lower dose requirement to attain a therapeutic effect for PMs[21,22]. In contrast, ultra rapid metabolizers (UMs) are needed in higher doses to produce a therapeutic effect[23]. "
    Article · Jan 2017 · Polski merkuriusz lekarski: organ Polskiego Towarzystwa Lekarskiego
    • "1996; Sirvio and MacDonald, 1999). We have previously reported that atypical antipsychotic drug monotherapy increases plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine (Kakihara et al., 2005; Hori et al., 2007; Yoshimura et al., 2007 Yoshimura et al., , 2010 Yoshimura et al., , 2012). These results support that atypical antipsychotic drug enhances noradrenergic functions. "
    [Show abstract] [Hide abstract] ABSTRACT: This study sought to examine whether switching polypharmacy therapy to monotherapy would improve the cognitive function and social function of patients with schizophrenia. Thirty-nine patients with schizophrenia who were receiving therapy with two antipsychotics were randomly divided into a switch to monotherapy group (switching group) and a polypharmacy continued group (continuing group). For the patients allocated to the switching group, the dose level of one of the two antipsychotic drugs was gradually reduced to zero. Psychotic symptoms, cognitive function and social function scale scores were assessed immediately before and 24 weeks after switching, and the time courses of these scores were compared between the two groups. Compared with the continuing group, the switching group demonstrated significantly greater improvement in attention after switching (p = 0.02). Furthermore, the improvement in daily living (p = 0.038) and work skills (p = 0.04) was significantly greater in the switching group. In an analysis of the correlation among sub-items with respect to the degrees of improvement, a significant correlation was noted between improvement in executive function and improvement in daily living (r = -0.64, p = 0.005) and between improvement in work skills and improvement in attention (r = -0.51, p = 0.038). In patients with schizophrenia receiving polypharmacy, switching to monotherapy resulted in improvements in attention. Furthermore, improvements in executive function led to improvements in daily living, and improvements in attention led to improvements in work skills. Thus, switching to monotherapy is a useful option.
    Full-text · Article · Sep 2013
    • "Thus, if the metabolism of haloperidol is extremely reduced by PMs, then the therapeutic dosage should be reduced accordingly in these patients (Kirchheiner et al., 2004). It was recently observed that the CYP2D6 phenotype does not predict the effectiveness of risperidone, but rather predicts the metabolic rate and side effects of the drug (de Leon et al., 2005a; Kakihara et al., 2005; Riedel et al., 2005). Several associations between the CYP2D6 gene and TD have been reported, showing that genetic variants for reduced CYP2D6 metabolism are particularly associated with TD development. "
    [Show abstract] [Hide abstract] ABSTRACT: Tardive dyskinesia (TD) is one of the most serious adverse side effects of antipsychotic drugs and is an important topic of pharmacogenetic studies. Since there is a genetic susceptibility for developing this adverse reaction, and given that it is hard to predict its development prior to or during the early period of medication, the genetic study of TD is a promising research topic that has a direct clinical application. Moreover, such studies would improve our understanding of the genetic mechanism(s) underlying abnormal dyskinetic movement. A substantial number of case-control association studies of TD have been performed, with numbers of studies focusing on the genes involved in antipsychotic drug metabolism, such as those for cytochrome P450 (CYP) and oxidative stress related genes as well as various neurotransmitter related genes. These studies have produced relatively consistent though controversial findings for certain polymorphisms such as CYP2D6*10, DRD2 Taq1A, DRD3 Ser9Gly, HTR2A T102C, and MnSOD Ala9Val. Moreover, the application of the genome-wide association study (GWAS) to the susceptibility of TD has revealed certain associated genes that previously were never considered to be associated with TD, such as the rs7669317 on 4q24, GLI2 gene, GABA pathway genes, and HSPG2 gene. Although a substantial number of genetic studies have investigated TD, many of the positive findings have not been replicated or are inconsistent, which could be due to differences in study design, sample size, and/or subject ethnicity. We expect that more refined research will be performed in the future to resolve these issues, which will then enable the genetic prediction of TD and clinical application thereof.
    Article · Dec 2011
    • "Functional polymorphisms in CYP metabolic enzymes are obvious candidates for investigation in relation to toxic reactions and adverse effects. Several studies in different ethnic groups have suggested the presence of CYP2D6 poor metabolizervariants to be associated with increased risk of developing TD or EPS[103,173,176,178,[182][183][184]232]with some non-significant reports.[177,179,181,182]CYP2D6 poor metabolizer variants may contribute to EPS by causing toxic accumulations of drug metabolites and/or an increase in plasma drug concentrations leading to higher occupancy of brain receptors. "
    [Show abstract] [Hide abstract] ABSTRACT: This review presents the findings of pharmacogenetic studies exploring the influence of gene variants on antipsychotic treatment response, in terms of both symptom improvement and adverse effects, in patients with schizophrenia. Despite numerous studies in the field, replicating findings across different cohorts that include subjects of different ethnic groups has been challenging. It is clear that non-genetic factors have an important contribution to antipsychotic treatment response. Differing clinical, demographic and environmental characteristics of the cohorts studied have added substantial complexity to the interpretation of the positive and negative findings of many studies. Pharmacogenomic genome-wide investigations are beginning to yield interesting data although they have failed to replicate the most robust findings of candidate gene studies, and are limited by the sample size, especially given the need for studying homogeneous cohorts. Most of the studies conducted on cohorts treated with single antipsychotics have investigated clozapine, olanzapine or risperidone response. These studies have provided some of the most replicated associations with treatment efficacy. Serotonergic system gene variants are significantly associated with the efficacy of clozapine and risperidone, but may have less influence on the efficacy of olanzapine. Dopamine D3 receptor polymorphisms have been more strongly associated with the efficacy of clozapine and olanzapine, and D2 genetic variants with the efficacy of risperidone. Serotonin influences the control of feeding behaviour and has been hypothesized to have a role in the development of antipsychotic-induced weight gain. Numerous studies have linked the serotonin receptor 2C (5-HT2C) -759-C/T polymorphism with weight gain. The leptin gene variant, -2548-G/A, has also been associated with weight gain in several studies. Pharmacogenetic studies support the role of cytochrome P450 enzymes and dopamine receptor variants in the development of antipsychotic-induced movement disorders, with a contribution of serotonergic receptors and other gene variants implicated in the mechanism of action of antipsychotics. Clozapine-induced agranulocytosis has been associated with polymorphisms in the major histocompatibility complex gene (HLA).
    Full-text · Article · Nov 2011
    • "Osoby będące ultraszybkimi metabolizerami wykazywały bardzo małe stężenie risperidonu, co wiązało się z małą skutecznością terapeutyczną leku. Natomiast u chorych – wolnych metabolizerów częściej występowały działania niepożądane, głównie pod postacią objawów pozapiramidowych [12]. Suzuki i wsp. "
    [Show abstract] [Hide abstract] ABSTRACT: Polymorphism of drugs biotransformation is clinically significant from the point of view of the effectiveness and safety of pharmacotherapy and an increased risk of some illnesses. The paper presents molecular mechanisms and clinical implication of several genetic polymorphisms of cytochrome P-450 (CYP) xenobiotics metabolizing enzymes and genetic predisposition to the occurrence of some diseases.
    Full-text · Article · Aug 2009
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