Tools in pharmacovigilance in psychiatry: therapeutic drug monitoring, pharmacogenetic tests and drug-drug interactions databases

SUMMARYIn order to increase drug safety we must better understand how medication interacts with the body of our patients and this knowledge should be made easily available for the clinicians prescribing the medication. This thesis contributes to how the knowledge of some drug properties can increase and how to make information readily accessible for the medical professionals. Furthermore it investigates the use of Therapeutic drug monitoring, drug interaction databases and pharmacogenetic tests in pharmacovigilance.Two pharmacogenetic studies in the naturalistic setting of psychiatric in-patients clinics have been performed; one with the antidepressant mirtazapine, the other with the antipsychotic clozapine. Forty-five depressed patients have been treated with mirtazapine and were followed for 8 weeks. The therapeutic effect was as seen in other previous studies. Enantioselective analyses could confirm an influence of age, gender and smoking in the pharmacokinetics of mirtazapine; it showed a significant influence of the CYP2D6 genotype on the antidepressant effective S-enantiomer, and for the first time an influence of the CYP2B6 genotype on the plasma concentrations of the 8-OH metabolite was found. The CYP2B6*/*6 genotype was associated to better treatment response. A detailed hypothesis of the metabolic pathways of mirtazapine is proposed. In the second pharmacogenetic study, analyses of 75 schizophrenic patients treated with clozapine showed the influence of CYP450 and ABCB1 genotypes on its pharmacokinetics. For the first time we could demonstrate an in vivo effect of the CYP2C19 genotype and an influence of P-glycoprotein on the plasma concentrations of clozapine. Further we confirmed in vivo the prominent role of CYP1A2 in the metabolism of clozapine.Identifying risk factors for the occurrence of serious adverse drug reactions (SADR) would allow a more individualized and safer drug therapy. SADR are rare events and therefore difficult to study. We tested the feasibility of a nested matched case-control study to examine the influence of high drug plasma levels and CYP2D6 genotypes on the risk to experience an SADR. In our sample we compared 62 SADR cases with 82 controls; both groups were psychiatric patients from the in-patient clinic Königsfelden. Drug plasma levels of >120% of the upper recommended references could be identified as a risk factor with a statistically significant odds ratio of 3.5, a similar trend could be seen for CYP2D6 poor metaboliser. Although a matched case-control design seems a valid method, 100% matching is not easy to perform in a relative small cohort of one in-patient clinic. However, a nested case-control study is feasible.On the base of the experience gained in the AMSP+ study and the fact that we have today only sparse data indicating that routine drug plasma concentration monitoring and/or pharmacogenetic testing in psychiatry are justified to minimize the risk for ADR, we developed a test algorithm named "TDM plus" (TDM plus interaction checks plus pharmacogenetic testing).Pharmacovigilance programs such as the AMSP project (AMSP = Arzneimittelsicherheit in der Psychiatrie) survey psychiatric in-patients in order to collect SADR and to detect new safety signals. Case reports of such SADR are, although anecdotal, valuable to illustrate rare clinical events and sometimes confirm theoretical assumptions of e.g. drug interactions. Seven pharmacovigilance case reports are summarized in this thesis.To provide clinicians with meaningful information on the risk of drug combinations, during the course of this thesis the internet based drug interaction program mediQ.ch (in German) has been developed. Risk estimation is based on published clinical and pharmacological information of single drugs and alimentary products, including adverse drug reaction profiles. Information on risk factors such as renal and hepatic insufficiency and specific genotypes are given. More than 20'000 drug pairs have been described in detail. Over 2000 substances with their metabolic and transport pathways are included and all information is referenced with links to the published scientific literature or other information sources. Medical professionals of more than 100 hospitals and 300 individual practitioners do consult mediQ.ch regularly. Validations with comparisons to other drug interaction programs show good results.Finally, therapeutic drug monitoring, drug interaction programs and pharmacogenetic tests are helpful tools in pharmacovigilance and should, in absence of sufficient routine tests supporting data, be used as proposed in our TDM plus algorithm.RESUMEPour améliorer la sécurité d'emploi des médicaments il est important de mieux comprendre leurs interactions dans le corps des patients. Ensuite le clinicien qui prescrit une pharmacothérapie doit avoir un accès simple à ces informations. Entre autres, cette thèse contribue à mieux connaître les caractéristiques pharmacocinétiques de deux médicaments. Elle examine aussi l'utilisation de trois outils en pharmacovigilance : le monitorage thérapeutique des taux plasmatiques des médicaments (« therapeutic drug monitoring »), un programme informatisé d'estimation du risque de combinaisons médicamenteuses, et enfin des tests pharmacogénétiques.Deux études cliniques pharmacogénétiques ont été conduites dans le cadre habituel de clinique psychiatrique : l'une avec la mirtazapine (antidépresseur), l'autre avec la clozapine (antipsychotique). On a traité 45 patients dépressifs avec de la mirtazapine pendant 8 semaines. L'effet thérapeutique était semblable à celui des études précédentes. Nous avons confirmé l'influence de l'âge et du sexe sur la pharmacocinétique de la mirtazapine et la différence dans les concentrations plasmatiques entre fumeurs et non-fumeurs. Au moyen d'analyses énantiomères sélectives, nous avons pu montrer une influence significative du génotype CYP2D6 sur l'énantiomère S+, principalement responsable de l'effet antidépresseur. Pour la première fois, nous avons trouvé une influence du génotype CYP2B6 sur les taux plasmatiques de la 8-OH-mirtazapine. Par ailleurs, le génotype CYP2B6*6/*6 était associé à une meilleure réponse thérapeutique. Une hypothèse sur les voies métaboliques détaillées de la mirtazapine est proposée. Dans la deuxième étude, 75 patients schizophrènes traités avec de la clozapine ont été examinés pour étudier l'influence des génotypes des iso-enzymes CYP450 et de la protéine de transport ABCB1 sur la pharmacocinétique de cet antipsychotique. Pour la première fois, on a montré in vivo un effet des génotypes CYP2C19 et ABCB1 sur les taux plasmatiques de la clozapine. L'importance du CYP1A2 dans le métabolisme de la clozapine a été confirmée.L'identification de facteurs de risques dans la survenue d'effets secondaire graves permettrait une thérapie plus individualisée et plus sûre. Les effets secondaires graves sont rares. Dans une étude de faisabilité (« nested matched case-control design » = étude avec appariement) nous avons comparé des patients avec effets secondaires graves à des patients-contrôles prenant le même type de médicaments mais sans effets secondaires graves. Des taux plasmatiques supérieurs à 120% de la valeur de référence haute sont associés à un risque avec « odds ratio » significatif de 3.5. Une tendance similaire est apparue pour le génotype du CYP2D6. Le « nested matched case-control design » semble une méthode valide qui présente cependant une difficulté : trouver des patients-contrôles dans le cadre d'une seule clinique psychiatrique. Par contre la conduite d'une « nested case-control study » sans appariement est recommandable.Sur la base de notre expérience de l'étude AMSP+ et le fait que nous disposons que de peux de données justifiant des monitorings de taux plasmatiques et/ou de tests pharmacogénétiques de routine, nous avons développé un test algorithme nommé « TDMplus » (TDM + vérification d'interactions médicamenteuses + tests pharmacogénétique).Des programmes de pharmacovigilances comme celui de l'AMSP (Arzneimittelsicherheit in der Psychiatrie = pharmacovigilance en psychiatrie) collectent les effets secondaires graves chez les patients psychiatriques hospitalisés pour identifier des signaux d'alertes. La publication de certains de ces cas même anecdotiques est précieuse. Elle décrit des événements rares et quelques fois une hypothèse sur le potentiel d'une interaction médicamenteuse peut ainsi être confirmée. Sept publications de cas sont résumées ici.Dans le cadre de cette thèse, on a développé un programme informatisé sur internet (en allemand) - mediQ.ch - pour estimer le potentiel de risques d'une interaction médicamenteuse afin d'offrir en ligne ces informations utiles aux cliniciens. Les estimations de risques sont fondées sur des informations cliniques (y compris les profils d'effets secondaires) et pharmacologiques pour chaque médicament ou substance combinés. Le programme donne aussi des informations sur les facteurs de risques comme l'insuffisance rénale et hépatique et certains génotypes. Actuellement il décrit en détail les interactions potentielles de plus de 20'000 paires de médicaments, et celles de 2000 substances actives avec leurs voies de métabolisation et de transport. Chaque information mentionne sa source d'origine; un lien hypertexte permet d'y accéder. Le programme mediQ.ch est régulièrement consulté par les cliniciens de 100 hôpitaux et par 300 praticiens indépendants. Les premières validations et comparaisons avec d'autres programmes sur les interactions médicamenteuses montrent de bons résultats.En conclusion : le monitorage thérapeutique des médicaments, les programmes informatisés contenant l'information sur le potentiel d'interaction médicamenteuse et les tests pharmacogénétiques sont de précieux outils en pharmacovigilance. Nous proposons de les utiliser en respectant l'algorithme « TDM plus » que nous avons développé.

Usefulness of intra-articular bupivacain and lidocain adjunction in MR or CT arthrography: a prospective study in 148 patients.

PURPOSE: To evaluate the influence of shorter- and longer-acting intra-articular anaesthetics on post-arthrographic pain. MATERIALS AND METHODS: 154 consecutive patients investigated by MR or CT arthrographies were randomly assigned to one of the following groups: 1--intra-articular contrast injection only; 2--lidocain 1% adjunction; or 3--bupivacain 0.25% adjunction. Pain was assessed before injection, at 15 min, 4 h, 1 day and 1 week after injection by visual analogue scale (VAS). RESULTS: At 15 min, early mean pain score increased by 0.96, 0.24 and 0 in groups 1, 2 and 3, respectively. Differences between groups 1 & 3 and 1 & 2 were statistically significant (p=0.003 and 0.03, respectively), but not between groups 2 & 3 (p=0.54). Delayed mean pain score increase was maximal at 4 h, reaching 1.60, 1.22 and 0.29 in groups 1, 2 and 3, respectively. Differences between groups 1 & 2 and 2 & 3 were statistically significant (p=0.002 and 0.02, respectively), but not between groups 1 & 2 (p=0.46). At 24 h and 1 week, the interaction of local anaesthetics with increase in pain score was no longer significant. Results were independent of age, gender and baseline VAS. CONCLUSION: Intra-articular anaesthesia may significantly reduce post-arthrographic pain. Bupivacain seems to be more effective than lidocain to reduce both early and delayed pain.

Personality traits and virtual reality performance.

BACKGROUND: Surgeons' personalities have been described as different from those of the general population, but this was based on small descriptive studies limited by the choice of evaluation instrument. Furthermore, although the importance of the human factor in team performance has been recognized, the effect of personality traits on technical performance is unknown. This study aimed to compare surgical residents' personality traits with those of the general population and to evaluate whether an association exists between their personality traits and technical performance using a virtual reality (VR) laparoscopy simulator. METHODS: In this study, 95 participants (54 residents with basic, 29 with intermediate laparoscopic experience, and 12 students) underwent personality assessment using the NEO-Five Factor Inventory and performed five VR tasks of the Lap Mentor? basic tasks module. The residents' personality traits were compared with those of the general population, and the association between VR performance and personality traits was investigated. RESULTS: Surgical residents showed personality traits different from those of the general population, demonstrating lower neuroticism, higher extraversion and conscientiousness, and male residents showed greater openness. In the multivariable analysis, adjusted for gender and surgical experience, none of the personality traits was found to be an independent predictor of technical performance. CONCLUSIONS: Surgical residents present distinct personality traits that differ from those of the general population. These traits were not found to be associated with technical performance in a virtual environment. The traits may, however, play an important role in team performance, which in turn is highly relevant for optimal surgical performance.

Health inequalities among the elderly in western Europe

Background: This paper analyses gender inequalities in health status and in social determinants of health among the elderly in Western Europe. Methods: Data came from the first wave of the “Survey of Health, Ageing and Retirement in Europe” (SHARE, 2004). For the purposes of this study a subsample of community-residing people aged 65-85 years with no paid work was selected (4218 men and 5007 women). Multiple logistic regression models separated by sex and adjusted for age and country were fitted. Results: Women were more likely to report poor health status, limitations in mobility and poor mental health. Whereas in both sexes educational attainment was associated with the three health indicators, household income was only related to poor self-rated health among women. The relationship between living arrangements and health differed by gender and was primarily associated with poor mental health. In both sexes, not living with the partner but living with other people and being the household head was related to poor mental health status (aOR=2.14; 95% CI=1.11-4.14 for men and aOR=1.75; 95% CI=1.12-2.72 for women). Additionally, women living with their partner and other(s) and those living alone were more likely to report poor mental health status (aOR=1.67; 95% CI=1.17-2.41 and aOR=1.58; 95% CI=1.26-1.97, respectively). Conclusions: Health inequalities persist among the elderly. Women have poorer health status than men and in both sexes the risk of poor health status increases among those with low educational attainment. Living arrangements are primarily associated with poor mental health status with patterns that differ by gender.

An olfactory receptor for food-derived odours promotes male courtship in Drosophila.

Many animals attract mating partners through the release of volatile sex pheromones, which can convey information on the species, gender and receptivity of the sender to induce innate courtship and mating behaviours by the receiver. Male Drosophila melanogaster fruitflies display stereotyped reproductive behaviours towards females, and these behaviours are controlled by the neural circuitry expressing male-specific isoforms of the transcription factor Fruitless (FRU(M)). However, the volatile pheromone ligands, receptors and olfactory sensory neurons (OSNs) that promote male courtship have not been identified in this important model organism. Here we describe a novel courtship function of Ionotropic receptor 84a (IR84a), which is a member of the chemosensory ionotropic glutamate receptor family, in a previously uncharacterized population of FRU(M)-positive OSNs. IR84a-expressing neurons are activated not by fly-derived chemicals but by the aromatic odours phenylacetic acid and phenylacetaldehyde, which are widely found in fruit and other plant tissues that serve as food sources and oviposition sites for drosophilid flies. Mutation of Ir84a abolishes both odour-evoked and spontaneous electrophysiological activity in these neurons and markedly reduces male courtship behaviour. Conversely, male courtship is increased--in an IR84a-dependent manner--in the presence of phenylacetic acid but not in the presence of another fruit odour that does not activate IR84a. Interneurons downstream of IR84a-expressing OSNs innervate a pheromone-processing centre in the brain. Whereas IR84a orthologues and phenylacetic-acid-responsive neurons are present in diverse drosophilid species, IR84a is absent from insects that rely on long-range sex pheromones. Our results suggest a model in which IR84a couples food presence to the activation of the fru(M) courtship circuitry in fruitflies. These findings reveal an unusual but effective evolutionary solution to coordinate feeding and oviposition site selection with reproductive behaviours through a specific sensory pathway.

A qualitative study about immigrant workers’ perceptions of their working conditions in Spain

Background: Spain has recently become an inward migration country. Little is known about the occupational health of immigrant workers. This study aimed to explore the perceptions that immigrant workers in Spain had of their working conditions.Methods: Qualitative, exploratory, descriptive study. Criterion sampling. Data collected between September 2006 and May 2007 through semi-structured focus groups and individual interviews, with a topic guide. One hundred and fifty-eight immigrant workers (90 men/68 women) from Colombia (n = 21), Morocco (n = 39), sub-Saharan Africa (n = 29), Romania (n = 44) and Ecuador (n = 25), who were authorised (documented) or unauthorised (undocumented) residents in five medium to large cities in Spain.Results: Participants described poor working conditions, low pay and health hazards. Perception of hazards appeared to be related to gender and job sector. Informants were highly segregated into jobs by sex, however, so this issue will need further exploration. Undocumented workers described poorer conditions than documented workers, which they attributed to their documentation status. Documented participants also felt vulnerable because of their immigrant status. Informants believed that deficient language skills, non-transferability of their education and training and, most of all, their immigrant status and economic need left them with little choice but to work under poor conditions.Conclusions: The occupational health needs of immigrant workers must be addressed at the job level, while improving the enforcement of existing health and safety regulations. The roles that documentation status and economic need played in these informants' work experiences should be considered and how these may influence health outcomes.

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Doing Intersectionality: Repertoires of Feminist Practices in France and Canada

Intersectionality has been adopted as the preferred term to refer to and to analyze multiple axes of oppression in feminist theory. However, less research examines if this term, and the political analyses it carries, has been adopted by women's rights organizations in various contexts and to what effect. Drawing on interviews with activists working in a variety of women's rights organizations in France and Canada, I show that intersectionality is only one of the repertoires that a women's rights organization might use to analyze the social experience and the political interests of women situated at the intersection of several axes of domination. I propose a typology of four repertoires that activists use to reflect on intersectionality and inclusiveness. Drawing on a quantitative and qualitative analysis of the interview data, I show that hegemonic repertoires about racial or religious identity in one national context shape the way activists and organizations understand intersectionality and its challenges. The identity of organizations, as well as their main function (advocacy or providing service), also shape their understanding of intersectional issues.

Epidemiology of incident heart failure in a contemporary elderly cohort: the health, aging, and body composition study.

BACKGROUND: The race- and sex-specific epidemiology of incident heart failure (HF) among a contemporary elderly cohort are not well described. METHODS: We studied 2934 participants without HF enrolled in the Health, Aging, and Body Composition Study (mean [SD] age, 73.6 [2.9] years; 47.9% men; 58.6% white; and 41.4% black) and assessed the incidence of HF, population-attributable risk (PAR) of independent risk factors for HF, and outcomes of incident HF. RESULTS: During a median follow-up of 7.1 years, 258 participants (8.8%) developed HF (13.6 cases per 1000 person-years; 95% confidence interval, 12.1-15.4). Men and black participants were more likely to develop HF. No significant sex-based differences were observed in risk factors. Coronary heart disease (PAR, 23.9% for white participants and 29.5% for black participants) and uncontrolled blood pressure (PAR, 21.3% for white participants and 30.1% for black participants) carried the highest PAR in both races. Among black participants, 6 of 8 risk factors assessed (smoking, increased heart rate, coronary heart disease, left ventricular hypertrophy, uncontrolled blood pressure, and reduced glomerular filtration rate) had more than 5% higher PAR compared with that among white participants, leading to a higher overall proportion of HF attributable to modifiable risk factors in black participants vs white participants (67.8% vs 48.9%). Participants who developed HF had higher annual mortality (18.0% vs 2.7%). No racial difference in survival after HF was noted; however, rehospitalization rates were higher among black participants (62.1 vs 30.3 hospitalizations per 100 person-years, P < .001). CONCLUSIONS: Incident HF is common in older persons; a large proportion of HF risk is attributed to modifiable risk factors. Racial differences in risk factors for HF and in hospitalization rates after HF need to be considered in prevention and treatment efforts.