Macarena C. Cáceres

The Role of Cytochrome P450 Enzymes in the Metabolism of Risperidone and Its Clinical Relevance for Drug Interactions

In the recent years it has been increasingly recognized that pharmacogenetical factors play an important role in the drug treatment. These factors may influence the appearance of side-effects and drug interactions due to interindividual differences in the activity of metabolizing enzymes. Risperidone in humans is mainly metabolized to 9-hydroxyrisperidone by the polymorphic cytochrome enzyme P450 2D6 (CYP2D6). Plasma concentrations of risperidone and 9-hydroxyrisperidone show large interindividual variability, which may be partly related to the activity of the CYP2D6 enzyme. Around seven percent of Caucasians have a genetically inherited impaired activity of the CYP2D6 enzyme. Debrisoquine metabolic ratio (a marker of CYP2D6 activity) and the number of CYP2D6 active genes have been related to risperidone plasma concentrations among patients during steady-state conditions. A large number drugs have been described to be metabolized by CYP2D6, and it is therefore important to evaluate the clinical significance of the impaired metabolism and possible drug interactions on the enzyme. Since risperidone/9-hydroxyrisperidone ratio strongly correlates with CYP2D6 enzyme activity and the number of CYP2D6 active genes, thus it might be a useful tool in clinical practice to estimate the possible risk of drug interactions due to impaired CYP2D6 enzyme activity. CYP3A4 is the most abundant drug metabolizing enzyme in humans, and in vitro and in vivo results suggest also a role for the enzyme in risperidone metabolism. The consideration of the implication of cytochrome P450 enzymes in risperidone metabolism may help to individualize dose schemes in order to avoid interactions and potentially dangerous side-effects, such us QTc interval lengthening among patients with cardiac risk factors.

Determination of risperidone and 9-hydroxyrisperidone in human plasma by liquid chromatography: application to the evaluation of CYP2D6 drug interactions.

A high-pressure liquid chromatography with ultra-violet detection method for the simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma after liquid-liquid extraction has been developed. The limit of quantitation was 5 nmol/L, and the inter-day coefficient of variation was less than 8% for both compounds. The mean recoveries of risperidone and 9-hydroxyrisperidone added to plasma were 96.8 and 99.4%, with an intra-day coefficient of variation of under 5 and 6%, respectively. Studies of analytical interference showed that the most commonly co-administered antidepressants and benzodiazepines did not interfere. The method was used for the determination of the plasma concentrations of a schizophrenic patient treated daily with an oral dose of 4.5 mg risperidone. The patient suffered severe extrapyramidal side-effects after adding risperidone to his previous medication of haloperidol and levomepromazine. The risperidone plasma concentration was well above the average (182 nmol/L), which suggests that a pharmacokinetic interaction occurred, presumably due to inhibition of the enzyme CYP2D6.

Schizophrenia stigma among medical and nursing undergraduates

Negative attitudes toward schizophrenia are associated with difficulty of integration of those suffering from this mental illness into the community. The program “Open the doors” (World Psychiatric Association, http//www.openthedoors.com) has detected in Spain that stigma was experienced by those who have contact with the illness (patients, family and professionals), while the general population showed little rejection. Other studies have found in the UK that the general population commonly perceived people with schizophrenia as dangerous [1], while in Canada [2], it was those of the general population with a greater knowledge of schizophrenia who tended to have lessdistancing attitudes. To our knowledge, there are no data about schizophrenia stigma in health care undergraduates. Therefore, the present study was aimed at exploring the knowledge and perceptions toward schizophrenia in this population with a potential influence on schizophrenia stigma. A total of 274 students of medicine and 70 students of nursing (18–24 years old) from the University of Extremadura (Spain) were surveyed during 2000 about their general knowledge of schizophrenia. They reported to have high awareness of the mental illness, its onset, associated risk factors, manifestations and treatment, with no significant differences between the both groups, medical and nursing undergraduates. However, they thought that people with schizophrenia never recover (50%), considered that they were or could be dangerous or violent (78%), and rejected or were ambivalent about whether to accept them in a social situation (40%). In addition, they did not feel they had enough information about schizophrenia (95%) and they did not know someone with this disorder (75%). The present findings suggest that medical and nursing undergraduates have ambivalent or discriminatory attitudes toward the recovery, level of violence or dangerousness, and social management of people with schizophrenia. Paradoxically, these results contrast with the fact that the students seem to be knowledgeable about the nature of schizophrenia, even so they do not perceive themselves to have enough information. This could be explained by the evidence that knowledge of the symptoms associated with the acute phase of schizophrenia creates more stigma than the label of schizophrenia alone; on the contrary, knowledge about the aftercare settings may reduce it [3]. A second explanation for the present findings might lie in the absence of social contact with people suffering the disorder. In this sense, it has been reported that those people with previous contact with individuals with a mental illness were more likely to perceive them as less dangerous than people without previous contact [4].

Low frequency of CYP2D6 poor metabolizers among schizophrenia patients

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.

Increased risk for major depression associated with the short allele of the serotonin transporter promoter region (5-HTTLPR-S) and the CYP2C9*3 allele.

In the present study, we aimed to analyze the potential relevance of the polymorphism in the promoter region of the serotonin transporter (SERT or 5‐HTT) gene (5‐HTTLPR) and the risk of suffering major depression (MDD) in a population of patients previously genotyped for CYP2C9. Seventy white European psychiatric outpatients suffering from MDD and a group of 142 healthy volunteers (HVs) were studied. The frequency of subjects carrying the 5‐HTTLPR‐S allele was higher (P < 0.05) among MDD than in HV. The odds ratio associated with 5‐HTTLPR‐S allele was 2.03 for the MDD patients in comparison with the HV group. Previously, we found in this population that the CYP2C9*3 allele frequency was higher among this population of MDD patients than in HV. The frequency of subjects with the combination 5‐HTTLPR‐S and CYP2C9*3 alleles was higher (P < 0.01, odds ratio 3.47) in MDD than in HV. The present findings provide preliminary evidence about the greater risk of suffering MDD for individuals carrying both 5‐HTTLPR‐S and CYP2C9*3 alleles.

Association between T102C and A-1438G polymorphisms in the serotonin receptor 2A (5-HT2A) gene and schizophrenia: relevance for treatment with antipsychotic drugs.

Abstract Background: An involvement of serotonin receptor 2A (5-HT2A) in the aetiology of schizophrenia has been hypothesised. The 5-HT2A receptor also appears to be an important site of action of atypical antipsychotic drugs. Indeed, association between schizophrenia and the T102C silent polymorphism of the 5-HTR2A gene has been reported. Another polymorphism in the promoter region of 5-HTR2A (A–1438G) in linkage disequilibrium with the T102C polymorphism has also been reported. It has been suggested that the A–1438G polymorphism alters promoter activity and expression of 5-HT2A receptors and might be responsible for the associations with schizophrenia and the efficacy of atypical antipsychotics such as risperidone. Methods: We analysed the 5-HTR2A T102C and A–1438G polymorphisms in clinically stable schizophrenia patients (SPs) and healthy volunteers (HVs). We developed an allele-specific PCR-based restriction fragment length polymorphism (PCR-RFLP) method. In SPs, we also described differences across both diagnosis subtypes (paranoid vs. non-paranoid) and antipsychotic drug treatment (risperidone vs. other classical antipsychotic drugs). Results: Two groups of 114 SPs and 142 HVs were studied. The frequency of the 5-HTR2A –1438A allele was higher in SPs than in HVs (0.54 vs. 0.44; p<0.05). The frequency of the 102T allele was also higher among SPs than HVs (0.56 vs. 0.46; p<0.05). These two polymorphisms were in linkage disequilibrium. The percentage of carriers of the 1438A/A and 102T/T alleles was 26% and 15% for SPs and HVs, respectively (p<0.05; odds ratio 1.9). No differences in genotype or allele frequencies were found between paranoid and non-paranoid SPs or between SPs on risperidone and those on classical antipsychotic treatment. Conclusions: The present study demonstrates a higher frequency of 5-HTR2A –1438A and 102T alleles in SPs compared to HVs. Clin Chem Lab Med 2007;45:835–8.

Clinical implications of CYP2D6 genetic polymorphism during treatment with antipsychotic drugs

CYP2D6 is described as the most relevant enzyme in the metabolism of many antipsychotic drugs. Its contribution to the interindividual differences in drug response is reviewed here highlighting its role in the kinetics of antipsychotic drugs and the occurrence of drug interactions. The activity of CYP2D6 is inherited as a monogenetic trait and the CYP2D6 gene appears highly polymorphic in humans. The polymorphic alleles may lead to altered activity of the CYP enzymes causing absent, decreased (poor), or increased (ultrarapid) metabolism that in turn influence the disposition of the antipsychotic drugs. Antipsychotic drug biotransformation is mainly determined by genetic factors mediating CYP2D6 gene polymorphism, however the importance of environmental factors (dietary, smoking, diseases, etc.) is also recognized. Additionally, the potential interaction between CYP2D6 and the endogenous metabolism must be taken into consideration. The present review summarizes the relevance of physiological and environmental factors in CYP2D6 hydroxylation capacity, the inhibition of CYP2D6 activity during treatment, the use of drug/metabolite ratio as a tool to evaluate CYP2D6 hydroxylation capacity in a patient, and the relevance of CYP2D6 for drug plasma concentration and for QTc interval lengthening during treatment with antipsychotic drugs.

Increased use of second generation antipsychotic drugs in primary care: potential relevance for hospitalizations in schizophrenia patients

AimTo analyze the changes in the prescribing pattern of antipsychotic drugs in primary care in Extremadura (Spain) from 1990 to 2005, and the potential association with schizophrenia hospitalization rate.MethodsData from 1990–2005 about the prescribing of antipsychotic drugs was drawn from all community pharmacy sales figures reimbursed by the Health System of Extremadura. Drug consumption figures were expressed as the number of defined daily doses per 1,000 inhabitants and per day of treatment (DDD/1,000/day). The total number of annual hospital discharges with the diagnosis of schizophrenia according to DSM-IV criteria from all hospitals in Extremadura from 1 January 1995 to 31 December 2000 was also determined.ResultsThe use of second-generation antipsychotic drugs (SGAs) increased from 0% in 1990–1993 to 78% in 2005. Olanzapine was the most used SGA from 1999–2005. During 1995–2000 the sales of SGAs increased to 50% from 10%. In the same period, the hospitalization rate in schizophrenia patients fell by an average of 12%, which was significantly associated with SGA use (R = −0.88; P = 0.02).DiscussionThe increase in SGAs paralleled the decreased rate of hospitalization in schizophrenia patients. However, the influence of other factors such as SGA use for disorders other than schizophrenia can not be ruled out. Moreover changes in the health-care system, such as the increase in primary mental health care and social rehabilitation programs, may also have a relevant influence.

Determination of debrisoquine and 4-hydroxydebrisoquine by high-performance liquid chromatography: application to the evaluation of CYP2D6 genotype and debrisoquine metabolic ratio relationship

Abstract The drug-metabolizing cytochrome P450 (CYP) enzyme CYP2D6 is involved in the metabolism of several clinically important drugs. So far more than 50 different CYP2D6 allelic variants have been described, and thus there is an increased need for routine high-performance liquid chromatography (HPLC) methods for the evaluation of the functional implication of CYP2D6 polymorphism. Debrisoquine is metabolized to 4-hydroxydebrisoquine by CYP2D6, and therefore it has been used widely to determine the hydroxylation capacity of the enzyme. The aim of the present study was to develop a simple, accurate HPLC method with ultraviolet detection for the measurement of debrisoquine and 4-hydroxydebrisoquine in urine for evaluation of the relationship between CYP2D6 enzyme activity and genotypes. For the HPLC determination, a C18 extraction column was used with a flow rate of 0.8mL/min and detection at 210nm. The compounds were eluted from the column in less than 10min. Coefficients of variation at all concentrations were less than 4% for both compounds. The debrisoquine/4-hydroxydebrisoquine ratio (debrisoquine metabolic ratio) was determined in a panel of 16 Caucasian healthy volunteers with zero (poor metabolizers), one, two or more than two (ultrarapid metabolizers) CYP2D6 active genes. Significant correlation (p<0.05) between the number of CYP2D6 active genes and the hydroxylation capacity of the enzyme was found. The present HPLC method was simple, fast and accurate, and thus will be useful for the evaluation of CYP2D6 hydroxylation capacity in pharmacogenetic studies.

Impact factor evolution of nursing research journals: 2009 to 2014

BACKGROUND The use of bibliometric indicators (impact factor [IF], impact index, h-index, etc.) is now believed to be a fundamental measure of the quality of scientific research output. In this context, the presence of scientific nursing journals in international databases and the factors influencing their impact ratings is being widely analyzed. PURPOSE The aim of this study was to analyze the presence of scientific nursing journals in international databases and track the changes in their IF. METHODS A secondary analysis was carried out on data for the years 2009 to 2014 held in the JCR database (subject category: nursing). Additionally, the presence of scientific nursing journals in Medline, CINAHL, Scopus, and SJR was analyzed. DISCUSSION During the period studied, the number of journals indexed in the JCR under the nursing subject category increased from 70 in 2009 (mean IF: 0.99, standard deviation: 0.53) to 115 in 2014 (mean IF: 1.04, standard deviation: 0.42), of which only 70 were listed for the full six years. Although mean IF showed an upward trend throughout this time, no statistically significant differences were found in the variations to this figure. CONCLUSION Although IF and other bibliometric indicators have their limitations, it is nonetheless true that bibliometry is now the most widely used tool for evaluating scientific output in all disciplines, including nursing, highlighting the importance of being familiar with how they are calculated and their significance when deciding the journal or journals in which to publish the results of our research. That said, it is also necessary to consider other possible alternative ways of assessing the quality and impact of scientific contributions.