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

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.

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

“…In recent studies, it was observed that CYP2D6 did not predict response to risperidone, but predicted metabolic ratios and side effects. [62][63][64] No association was found between CYP2D6 PM variants and clozapine response. 65 However, small adjustments of therapeutic doses of clozapine are recommended according to CYP2D6 genotypes, suggesting that these enzymes are only minor pathways for clozapine metabolism.…”

Cytochrome P450 testing for prescribing antipsychotics in adults with schizophrenia: systematic review and meta-analyses

“…Nine studies 58,60,70,76,78,88,89,96,97 clearly specified the number of missing genotypes and six of these provided reasons for the missing data. 58,60,70,76,78,96 In the remaining 42/51 studies, it was unclear whether the number contributing to each analysis was equal to the sample size.…”

“…Ten studies were interested in the relationship between efficacy and CYP2D6 [90][91][92][93][95][96][97][98][99] or CYP1A2. 94 A wide variety of outcomes were considered across the studies but no two studies measured outcomes in exactly the same way.…”

“…Clinical validity CYP2D6 is arguably the most important CYP450 gene with regard to the metabolism of antipsychotics, with six typical 78 Cross-sectional 99 Japanese CYP2D6 Any typical antipsychotic Scordo et al 80 Cross-sectional 119 Caucasian CYP2D6 Any antipsychotic Culav-Sumic et al 62 Cross 67 Cross-sectional 214 Japanese CYP2D6 Any antipsychotic Lohmann et al 73 Cross-sectional 109 Caucasian (assumed) CYP2D6 Any antipsychotic Liou et al 72 Retrospective 216 Chinese CYP2D6 Any typical antipsychotic Kakihara et al 97 Prospective 41 Japanese (assumed) CYP2D6 Risperidone Tiwari et al 87 Cross antipsychotics (thioridazine, perphenazine, fluphenazine, zuclopenthixol, haloperidol and chlorpromazine) and two atypical antipsychotics (risperidone and, to some extent, olanzapine) metabolized by the enzyme encoded by it. 108 Thus, it is not surprising that most of the clinical validity studies also focused on CYP2D6 where some significant associations between TD and parkinsonism and PM genotype.…”

A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms

“…First, the sample size (n ¼ 270), though limited, was higher than the mean sample size used in pharmacogenetic studies of acute AP-induced EPS (n ¼ 150). [7][8][9][10]32,33,[35][36][37][38][39][40][41][42][43][44][45] In fact, to our knowledge, only one study of Caucasians had a larger sample (n ¼ 665). 36 Second, although Bonferroni correction seems the most appropriate way to correct for multiple testing, it may be overly conservative.…”