Arne Risselada

Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics : a replication study

In two previous studies we found an association between HTR2C polymorphisms and the prevalence of the metabolic syndrome in patients using antipsychotics. In this study, we set out to replicate our findings in a third separate sample of patients. Data for this cross-sectional study came from the ongoing Pharmacotherapy Monitoring and Outcome survey study, investigating the association between schizophrenia and metabolic or cardiovascular risk factors. Primary end point was the prevalence of the metabolic syndrome. Primary determinants were two polymorphisms in the HTR2C gene: rs3813929 (−759 C/T) and rs1414334:C>G. Carriership of the variant rs1414334 C-allele was significantly associated with an increase prevalence of the metabolic syndrome (odds ratio (OR) 3.73; 95% confidence interval (CI) 1.29–10.79, P=0.015). No association was found between the HTR2C −759 C/T polymorphism and the metabolic syndrome. This study confirms previous findings that the variant C-allele of the rs1414334 polymorphism is associated with the metabolic syndrome.

Pharmacogenetic testing to predict antipsychotic-induced weight gain: a systematic review

Weight gain is an important side effect of antipsychotic drugs. Since the high interindividual difference in weight gain suggests that genetic factors play a role in this weight gain, studies have tried to identify these factors. Most of these studies were carried out in the past few years and focussed largely on receptor polymorphisms, although some tried to explain the variation in weight gain by differences in pharmacokinetics. Unfortunately, the results of these association studies are often conflicting, which makes it hard to apply this genetic knowledge in daily clinical practice. This article summarizes the findings of these association studies and focuses on differences in study methodology in an attempt to explain why study results could have been conflicting. Furthermore, the feasibility of genetic testing in todays clinical practice is discussed, using a model that consists of four components; analytical validity, clinical validity, clinical utility and ethical, legal and social issues.

Association Between the 1291-C/G Polymorphism in the Adrenergic α-2a Receptor and the Metabolic Syndrome

The prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle can possibly be explained by variations in the gene coding for the adrenergic &agr;-2a receptor (ADRA2A) because this receptor plays an important role in lipolysis. Three studies have found an association between the &agr;-2a 1291-C/G polymorphism and antipsychotic induced weight gain, with conflicting results between whites and Asians. No studies have been published investigating the association between the 1291-C/G polymorphism and the metabolic syndrome. The primary objective of this cross-sectional study was to investigate the association between the ADRA2A 1291-C/G polymorphism and the metabolic syndrome in 470 patients using antipsychotic drugs. There was no significant association between carriership of the variant 1291-G allele and prevalence of the metabolic syndrome (odds ratio, 0.73; 95% confidence interval, 0.49-1.15). Exploratory analysis showed an association between carriership of the variant 1291-G allele and a reduced prevalence of the metabolic syndrome in patients not currently using antipsychotics (odds ratio, 0.05; 95% confidence interval, 0.003-0.97; P = 0.048). In conclusion, this study shows that the ADRA2A 1291-C/G polymorphism does not seem to be a strong predictor for long-term occurrence of the metabolic syndrome in antipsychotic using patients. Studies investigating this association using a prospective, or retrospective, design, as well as studies investigating this association in a nonpsychiatric population, are warranted.

Association between the ROBO1 gene and body mass index in patients using antipsychotics

Background Weight gain is one of the major problems in patients using antipsychotic medication, leading to relevant morbidities and reduced compliance to pharmacotherapy. Recently, an association has been reported between a single nucleotide polymorphism (rs1455832) of the roundabout axon guidance receptor, homolog 1 (ROBO1) gene and body mass index (BMI) in persons younger than 30 years. The aim of this study is to investigate the association between BMI and rs1455832 in patients with a psychotic disorder using antipsychotics. Methods A cross-sectional design was used in a pooled sample of Caucasian psychiatric patients obtained from three comparable Dutch psychiatric populations. Patients were eligible for inclusion in this study if they met the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for a nonaffective psychotic disorder, were 18 years or older, and used one or more antipsychotics. Genotyping was performed according to standard protocols. Linear (for BMI) and logistic (for obesity, defined as BMI>30) regression analyses, corrected for age and sex, were applied in the statistical analyses. Results A total of 435 patients were included in this association analyses. The rs1455832 polymorphism studied was significantly associated with BMI and obesity in female patients. Female patients had a statistically significant (P=0.025) decrease of 1.76 kg/m2 in BMI values per C allele. In contrast to female patients, this association was not exhibited in male patients. Conclusion The rs1455832 polymorphism may play a role in inducing obesity in female patients using antipsychotics.

Medication Discrepancies at Outpatient Departments for Mood and Anxiety Disorders in the Netherlands: Risks and Clinical Relevance

OBJECTIVE To identify discrepancies between actual drug use by outpatients with mood and anxiety disorders and medication overviews from health care providers as well as to investigate the clinical relevance of those discrepancies. METHODS A cross-sectional study in adults visiting 1 of 4 participating outpatient departments for mood and anxiety disorders was conducted between March and November 2014. DSM-5 criteria were used to assign the psychiatric diagnosis. The primary outcome was the number of discrepancies between the actual medication use, as determined by medication reconciliation with the patient, and the medication overview from the outpatient department, general practitioner, and community pharmacy. Our secondary outcome was the clinical relevance of discrepancies, as assessed by an expert panel that reviewed all discrepancies for their potential to cause patient harm. RESULTS Of 367 patients included, 94.8% had at least 1 discrepancy in the medication overview from the outpatient department. A mean of 3.9 discrepancies existed per patient. Most discrepancies (74.5%) related to omitted drugs (drugs taken regularly by patients but absent from the medication overview). Of all discrepancies at the outpatient departments, 22.7% had the potential to cause moderate to severe discomfort or clinical deterioration, affecting 49.3% of the patients. Both total number and number of clinically relevant discrepancies were lower in medication overviews from general practitioners and pharmacies. CONCLUSION Patients from outpatient departments for mood and anxiety disorders may be at substantial risk for medication discrepancies that are often clinically relevant. Medication reconciliation at mental health care outpatient departments is in need of improvement.

Combined HTR2C-LEP and HTR2C-LEPR genotypes as a determinant for obesity in patients without antipsychotic drugs.

To the Editors: Obesity is an important problem in the modern society because of its association with cardiovascular disease, type 2 diabetes mellitus, and hypertension among others, resulting in an increase in overall mortality. Eleven different genes have already been associated with mendelian forms of human obesity, and more than 52 genes have been shown to cause obesity in knockout or transgenic mice. Among these genes are the genes coding for leptin (LEP), the LEP receptor (LEPR), and the 5HT2C receptor (HTR2C). Apart from genetic determinants, there are also other factors (eg, environmental factors) that explain an increased prevalence of obesity in some populations. One of these populations is formed by patients with schizophrenia, because of antipsychotic-induced weight gain. The LEP, LEPR, and HTR2C genes that have been associated with obesity also seem to be relevant for these patients because polymorphisms within these genes have been associated with antipsychoticinduced weight gain and obesity. The HTR2C 759 C/T polymorphism (rs3813929) in particular has repeatedly been associated with antipsychotic-induced weight gain, which was summarized in 2 metaanalyses that showed a protective effect of the variant 759T allele. However, because weight gain and obesity have a multifactorial origin, it is likely that various gene-gene interactions play a role in their etiology and have to be taken into account. This was shown in 2 studies where an interaction between the HTR2C 759 C/T and LEP 2548 A/G polymorphisms and body weight in patients with schizophrenia was found. Patients without the variant 759T allele carrying the 2548G allele had a higher body mass index (BMI) than patients without the 2548G allele carrying the 759Tallele in the study by Yevtushenko et al (29.89 vs 26.09 kg/m, respectively; P = 0.021) and an increased risk for obesity in the study by Gregoor et al (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.05Y7.95). The study by Gregoor et al5 also included the HTR2C rs1414334 and LEPR Q223R polymorphisms, but no other interactions were found. The question arose as to whether this interaction between the LEP and serotonergic system would also be present in patients without antipsychotic drugs. Furthermore, comparing the results between studies in patients with and without antipsychotic drugs could uncover the extent to which antipsychotic drugs modify the effects of this interaction. A design similar to the study by Gregoor et al was therefore chosen for the current study with the primary objective to investigate whether the prevalence of combined HTR2C-LEP and HTR2C-LEPR genotypes differs between obese and nonobese patients without antipsychotic drugs and to investigate if the interaction found by Yevtushenko et al and Gregoor et al is also present in these patients. Patients without antipsychotic drugs were recruited in the Wilhelmina Hospital Assen in the northern part of the Netherlands between July 2008 and January 2011 in accordance with the Declaration of Helsinki. In this study population, we have previously investigated the association between the HTR2C polymorphisms and obesity. We used a crosssectional, case-control design to assess the association between HTR2C-LEP and HTR2C-LEPR genotype combinations and obesity. Obese patients without antipsychotic drugs (cases) were recruited from the obesity clinic located within the hospital. Patients were eligible for inclusion if they had a BMI greater than or equal to 30 kg/m, were 18 years or older, and white. Obese patients using weight-increasing drugs or drugs with 5HT2C agonistic or antagonistic properties were excluded. Normalweight patients without antipsychotic drugs (controls) were primarily recruited in the orthopedic ward and among employees of the hospital pharmacy. Controls were eligible for inclusion in this study if they had a BMI less than or equal to 25 kg/m, were 18 years or older, and white. Smoking, cancer, following a diet, use of weightreducing drugs or drugs with 5HT2C agonistic or antagonistic properties, and excessive drug or alcohol use were considered as exclusion criteria for the controls. After complete description of the study to the patients, informed consent was obtained and blood sample was drawn for genotyping. Our primary determinants were combined HTR2C-LEP and HTR2C-LEPR genotypes as investigated in the study by Gregoor et al. The following polymorphisms were investigated: rs1137101 (Q223R, Gln223Arg, or 668A/G) in the LEPR gene on chromosome 1p31; rs7799039 (2548G/A) in the promoter region of the LEP gene on chromosome 7q31.3; rs3813929 (759C/T) in the promoter region of the X-linked HTR2C gene; and rs1414334, a polymorphism in intron 5 close to the ¶3 UTR of the HTR2C gene. We considered the rs1414334 C-allele to be the variant allele based on our previous studies. Genomic DNA was isolated from EDTAanticoagulated peripheral blood using standard methods. The HTR2C, LEP, and LEPR genotypes were determined using the StepOnePlus Real Time Polymerase Chain Reaction system from Applied Biosystems, Nieuwerkerk a/d IJssel, the Netherlands (genotypingwith allelic discrimination using TaqMan single nucleotide polymorphism also from Applied Biosystems). Detailed information on genotyping procedures is available upon request. Differences between cases and controls regarding frequencies of HTR2C-LEP and HTR2C-LEPR genotype combinations were investigated using logistic regression and expressed as ORs with 95% CIs. Data were investigated for potential confounding effects of age and sex. We included these variables in the multivariate model if they were univariately associated with prevalence of obesity at a significance level of P G 0.20. Data were also investigated for interaction between genotype and sex. A P value of 0.05 or less was regarded as significant. Data were analyzed using SPSS 17.0 (SPSS Inc, Chicago, IL). In total, 216 patients were included in this study, consisting of 116 cases (BMI, Q30 kg/m) and 100 controls (BMI, e25 kg/m). Mean age in the case group was significantly lower compared with the control group (mean [SD], 45.7 [12.5] vs 65.1 [15.0] years, respectively; P G 0.0001). Two thirds of the patients in both groups were females. Prevalence of diabetes was 20% (n = 23) in the case group. No patients with diabetes were present in the control group mostly because of being overweight or using insulin or metformin, which were regarded as weight-reducing agents. Smoking was reported by 3% (n = 3) of the case group. Genotype distribution of the polymorphisms did not deviate significantly from Hardy-Weinberg equilibrium (calculated in females) (rs3813929 [j759 C/T], P = 0.95 and rs1414334: C 9 G, P = 0.83). No significant linkage disequilibrium was LETTERS TO THE EDITORS

Association between the alpha-2a-adrenergic receptor 1291 C/G polymorphism and the metabolic syndrome

A. Risselada1 °, J. Vehof2, R. Bruggeman3, B. Wilffert4, D. Cohen5, A.F. Al Hadithy6, J. Arends7, H. Mulder8. 1Wilhelmina Hospital Assen, Department of Clinical Pharmacy, Assen, The Netherlands; 2University Medical Centre Groningen, Department of Epidemiology, Groningen, The Netherlands; 3University Medical Centre Groningen, Department of Psychiatry, Groningen, The Netherlands; 4University Medical Centre Groningen, Department of Pharmacotherapy and Pharmaceutical Care, Groningen, The Netherlands; 5Mental Health Services NHN, Department of Chronic Care, Heerhugowaard, The Netherlands; 6Erasmus University Medical Centre, Department of Hospital Pharmacy, Rotterdam, The Netherlands; 7Mental Health Services Drenthe, Department of psychosis, Assen, The Netherlands; 8Utrecht University, Department of Pharmacoepidemiology and pharmacotherapy, Utrecht, The Netherlands