Project

Discipline

Genetic analysis; personnalized medicine; psychotropic drugs; pharmacogenetics; pharmacogenomics; metabolic syndrome; psychiatry; weight gain

Lead
La prise de poids et les complications métaboliques (augmentation du cholestérol et des triglycérides, hypertension, diabète, obésité abdominale) sont des effets indésirables majeurs de certains médicaments psychotropes, et augmentent la morbidité et la mortalité dans la population psychiatrique. Il existe une variabilité dans la susceptibilité aux effets indésirables expliquée par des facteurs cliniques, environnementaux et génétiques
Lay summary
Etude pharmacogénétique sur les effets secondaires induits par les médicaments psychotropes Pharmacogenetic study on the side-effects induced by psychotropic drugs Pharmakogenetische Studie über Nebenwirkungen, die von Psychopharmaka verursacht werden Contenu et objectif du travail de recherche Certains patients peuvent développer rapidement un surpoids voire une obésité sous médication psychotrope, alors que d’autres semblent être protégés. Notre groupe ainsi que d’autres groupes de recherche avons mis en évidence l’implication de plusieurs gènes dans la prise de poids et l’obésité induites par la médication psychotrope. Notre principal objectif est de faire une étude détaillée des facteurs génétiques contribuant à la variabilité de la réponse au traitement pharmacologique en psychiatrie, en particulier ceux concernant les effets indésirables métaboliques. Après obtention d’un consentement écrit, une analyse génétique est effectuée afin de déterminer les gènes susceptibles de modifier la réponse au traitement. Le but ultime de cette étude étant dans le futur de pouvoir déterminer, avant de prescrire le médicament, quels patients ont la plus forte probabilité de répondre au traitement et/ou courent le plus de risques de développer des effets indésirables. Contexte scientifique et social du projet de recherche La prévalence de surpoids et d’obésité est élevée chez les patients psychiatriques. Notre travail contribuera à une meilleure compréhension des mécanismes impliqués dans l’apparition d’un syndrome métabolique induit par les psychotropes. Il conduira aussi à une médecine personnalisée, avec une possibilité de pouvoir choisir, pour un nombre grandissant de médicaments, le meilleur traitement pour chaque patient, cela grâce à un test génétique adapté

Direct link to Lay Summary

Last update: 05.12.2012

Active participation

Number	Title	Start	Funding scheme

This SNF project constitutes the continuation of our previous SNF project (320030-120686). Weight gain and metabolic complications are major side effects induced by some psychotropic drugs, and increase the risk of cardiovascular events and long term morbidity and mortality in psychiatric populations. Our Department of Psychiatry has therefore implemented an internal guideline requiring that patients being prescribed atypical antipsychotics must be followed up for side-effects. For the purpose of the previous project, informed consents were obtained from 800 patients in routine clinical monitoring, with DNA available. A very important feature of this cohort is that plasma levels have been measured for all psychotropic drugs of interest, which allows to study the relationship between the clinical variables and the plasma levels, and to exclude false negatives, i.e. absence of side-effects due to poor or non-compliance. Very interesting clinical as well as genetic results (in particular influence of CRTC1 genetic polymorphism on weight have been obtained during the previous project). A very large data base has thus been collected (initial weight and weight gain during treatment; variables from the metabolic syndrome i.e waist measurement, triglycerides and cholesterol levels, blood pressure, fasting glucose; UKU rating scales for extra pyramidal symptoms; Clinical Global Impression (CGI) rating scales). The first major aim of the present project is to perform a thorough analysis of genetic factors possibly associated with all collected clinical variables, in a cohort of 1000 patients (800 already included plus 200 first future patients to be included in the present project). Associations will first be continued to be searched on between genetic factors and weight as well as weight gain during treatment. In addition, other abovementioned clinical variables, in particular those associated with metabolic syndrome, will also be examined. In genetic and pharmacogenetic studies, it is of major importance to obtain large cohorts of patients, to increase the power of the study as well as to validate the results. The majority of published studies were performed with small or moderate number of patients, which can also contribute to the fact that original positive results are not confirmed in subsequent studies. The second major aim of the present SNF project is therefore to continue the inclusions of patients during the next 3 years and to include 700 more patients (total number: 1500 patients) hence allowing to increase the power of the study. The last 500 patients included in the present project will be used in particular to confirm positive results found in the first group of 1000 patients. Weight gain during antipsychotic treatment, with drugs such as clozapine, olanzapine, risperidone or quetiapine is the rule rather than the exception. However, a small proportion of patients appear to be protected against this side-effect despite a good compliance. It would be extremely interesting to determine whether some genetic factors can be shown to be associated with a protection against weight gain during treatment and/or against other variables of the metabolic syndrome. The first minor aim of this project is to include 75 patients with such a phenotype. They will be age, gender, diagnostic, type and duration of treatment matched with 225 patients who presented a major weight gain during their treatment (> 15% of initial weight during the first 3 months of treatment). These 300 patients with be analyzed with the Illumina Cardiometabochip, which contains more than 200’000 SNPs in relation with cardio metabolic diseases identified through genome wide association studies. The second minor aim is to analyze drug levels using a population pharmacokinetic approach in order to quantify variability in drug levels, to identify genetic and non-genetic sources of variability and to explore concentration-effect and toxicity relationships. The third minor aim is to analyze the prevalence, intensity and evolution of side effects (weight gain, BMI change, abdominal fat, deterioration of lipid and glycemic profile, hypertension, hyperprolactinemia, extrapyramidal symptoms) in the whole cohort of 1500 psychiatric patients, with a follow-up of up to one year. During the previous project, this analysis has been performed in a group of 197 adult psychiatric patients and the present project is intended to obtain results in a much larger cohort, including children, adolescents and old aged patients. Because of the experience acquired during the previous project, thanks to the implications of the heads of our Department of Psychiatry, the feasibility of the present project seems excellent, as shown by the number of patients included in the previous project as planned. In addition, a collaboration was established with the main investigators from the CoLaus study which will be continued. CoLaus is a population-based sample with over 5300 subjects who have been extensively clinically characterized for variables of the metabolic syndrome, and with genome wide analysis data. Thus, if any gene is found to influence weight and/or other variables of the metabolic syndrome in psychiatric patients, it will be determined whether this is also the case in a general population, thus widening the implication of the findings.