Exposure to psychotropics in the French older population living with dementia: a nationwide population-based study.

BACKGROUND: Little is known about the level of psychotropic chronic exposure in all patients living with dementia. The aim of the study was to quantify chronic psychotropic exposure in older adults with dementia compared with the general population of the same age. METHODS: This prospective cohort study was conducted in France between 2009 and 2011. Aged at least 65 years, 10,781,812 individuals (440,215 of them with dementia) either community based or nursing home residents were included. The numbers of single or combined prescriptions, per year for antipsychotics, antidepressants, anxiolytics, or hypnotics were measured. RESULTS: Of patients with dementia, 15.5% are exposed to antipsychotics compared with 2.2% of the age-matched population (relative risk [RR] = 6.44, 95% confidence interval [CI] [6.39-6.48]), 39.5% to antidepressants compared with 12.6% (RR = 4.10, 95% CI [.4.07-4.12]), and 39.6% to anxiolytics or hypnotics compared with 26.9% (RR = 1.74, 95% CI [1.72-1.75]). Among older adults with dementia, 13.8% simultaneously consumed at least three psychotropics. All class age of older patients with dementia is more exposed to all psychotropics except for long-acting benzodiazepines. During the study period, chronic anxiolytic/hypnotic and antipsychotic exposure slightly decreased in population with dementia while chronic exposure to antidepressant drugs tended to increase. CONCLUSION: This nationwide, population-based, drug-used study showed for the first time that older patients with dementia are chronically overexposed not only to antipsychotics but also to psychotropics.

Genomic data provide insights into the classification of extant termites.

The higher classification of termites requires substantial revision as the Neoisoptera, the most diverse termite lineage, comprise many paraphyletic and polyphyletic higher taxa. Here, we produce an updated termite classification using genomic-scale analyses. We reconstruct phylogenies under diverse substitution models with ultraconserved elements analyzed as concatenated matrices or within the multi-species coalescence framework. Our classification is further supported by analyses controlling for rogue loci and taxa, and topological tests. We show that the Neoisoptera are composed of seven family-level monophyletic lineages, including the Heterotermitidae Froggatt, Psammotermitidae Holmgren, and Termitogetonidae Holmgren, raised from subfamilial rank. The species-rich Termitidae are composed of 18 subfamily-level monophyletic lineages, including the new subfamilies Crepititermitinae, Cylindrotermitinae, Forficulitermitinae, Neocapritermitinae, Protohamitermitinae, and Promirotermitinae; and the revived Amitermitinae Kemner, Microcerotermitinae Holmgren, and Mirocapritermitinae Kemner. Building an updated taxonomic classification on the foundation of unambiguously supported monophyletic lineages makes it highly resilient to potential destabilization caused by the future availability of novel phylogenetic markers and methods. The taxonomic stability is further guaranteed by the modularity of the new termite classification, designed to accommodate as-yet undescribed species with uncertain affinities to the herein delimited monophyletic lineages in the form of new families or subfamilies.

Influence of the drug exposure definition on the assessment of the antipsychotic metabolic impact in patients initially treated with mood-stabilizers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: • Metabolic disturbances represent a well-known side effect of second generation antipsychotics. However, studies comparing second generation antipsychotic drugs (SGAPs) and first generation antipsychotic drugs (FGAPs) through administrative databases have shown contrasting findings, which may be attributable to methodological differences. WHAT THIS PAPER ADDS: • The definition of antipsychotic exposure impacts on the association between antipsychotics and metabolic risk in studies carried out through administrative databases. • Considering cumulative exposure to antipsychotics or including patients exposed to an antipsychotic drug for months or years is likely to over-represent patients who tolerate the drug well with a depletion of susceptible effects. • Antipsychotic drug exposure is a time-varying determinant and episodes of no use, past use and current use should be distinguished over the study period to avoid any misclassification bias that might lead to misleading findings. AIMS: To assess the influence of three definitions of antipsychotic exposure on the comparison between first generation (FGAP) and second generation (SGAP) antipsychotic drugs and 'conventional' mood stabilizers towards the risk of metabolic events using (i) a dichotomous measure (exposed/non-exposed over the follow-up), (ii) a categorical measure taking into account the chronology of exposure at the time of the metabolic event (current, recent and no use) and (iii) a continuous measure (cumulative duration). METHODS: A historical fixed cohort was identified from the 2004-2006 claims database of the French health insurance programme for self-employed workers, including 3172 patients aged 18 years and over who used conventional mood stabilizers over a 3 month period. A metabolic event was defined as an incident dispensing of an anti-diabetic or lipid-lowering drug. RESULTS: A metabolic event occurred in 367 patients (11.6%). At least one FGAP had been prescribed in 29% of patients who did not develop a metabolic event and in 22% of patients who developed a metabolic event. In addition, at least one SGAP had been prescribed in 12% of patients who did not develop a metabolic event and in 7% of patients who developed a metabolic event. Compared with conventional mood stabilizers, the risk of a metabolic event was negatively associated with exposure to SGAPs over the follow-up period (HR 0.53, 95% CI 0.34, 0.82, P= 0.004), positively associated with recent, but not current, exposure to SGAPs (HR 2.1, 95% CI 1.2, 3.7, P= 0.006) and not associated with cumulative duration of SGAPs (HR 1.001, 95% CI 0.999, 1.003, P= 0.20). CONCLUSIONS: The definition of exposure to antipsychotics in epidemiological studies exploring their metabolic impact is of paramount importance in understanding this association. Different definitions can lead to opposite and seemingly nonsensical results. Not taking into account past exposure, in order to minimize the depletion of susceptible effects, may lead to absurd results.

Psychotropic medication in the French child and adolescent population: prevalence estimation from health insurance data and national self-report survey data.

BACKGROUND: The aim of this work is to estimate the French frequencies of dispensed psychotropic prescriptions in children and adolescents. Prevalence estimations of dispensed prescriptions are compared to the frequencies of use of psychotropic reported by 17 year-old adolescents. METHODS: Prescription data is derived from national health insurance databases. Frequencies of dispensed prescriptions are extrapolated to estimate a range for the 2004 national rates. Self-report data is derived from the 2003 and 2005 ESCAPAD study, an epidemiological study based on a questionnaire focused on health and drug consumption. RESULTS: The prevalence estimation shows that the prevalence of prescription of a psychotropic medication to young persons between 3 and 18 years is about 2.2%.In 2005, the self-report study (ESCAPAD) shows that 14.9% of 17 year-old adolescents took medication for "nerves" or "to sleep" during the previous 12 months. The same study in 2003 also shows that 62.3% of adolescents aged 17 and 18 reporting psychotropic use, took the medication for anxiety and 56.8% to sleep. Only 49.7% of these medications are suggested by a doctor. CONCLUSION: This study underlines a similar range of prevalence of psychotropic prescriptions in France to that observed in other European countries. Nevertheless, the proportion of antipsychotics and benzodiazepines seems to be higher, whereas the proportion of methylphenidate is lower.Secondly, a disparity between the prevalence of dispensed prescriptions and the self-report of actual use of psychotropics has been highlighted by the ESCAPAD study which shows that these treatments are widely used as "self-medication".

Association Between Psychotropic and Cardiovascular Iatrogenic Alerts and Risk of Hospitalizations in Elderly People Treated for Dementia: A Self-Controlled Case Series Study Based on the Matching of 2 French Health Insurance Databases.

BACKGROUND: Elderly people are at risk of repeated hospitalizations, some of which may be drug related and preventable. In 2011, a group of French healthcare experts selected 5 iatrogenic alerts (IAs), based on criteria identified in a literature search and from their professional experience, to assess the appropriateness of medication in elderly patients. OBJECTIVES: Our objective was to examine the association between hospitalizations and IAs in elderly patients treated for Alzheimer disease who are particularly sensitive to adverse drug events. DESIGN: A 2-year (January 1, 2011, to December 31, 2012) longitudinal national database study, with a study design similar to self-controlled case series, was performed to analyze data on drug prescriptions and hospitalization. IAs were defined as (1) long half-life benzodiazepine; (2) antipsychotic drugs in patients with Alzheimer disease; (3) co-prescription of 3 or more psychotropic drugs; (4) co-prescription of 2 or more diuretics; and (5) co-prescription of 4 or more antihypertensive drugs. Data were obtained by matching of 2 French National Health Insurance Databases. SETTING: France. PARTICIPANTS: All affiliates, aged ≥75 years, receiving treatment for Alzheimer disease, alive on January 1, 2011 were included. MEASUREMENTS: We calculated the relative increase in the number of hospitalizations in patients with IAs. The analysis was performed over four 6-month periods. RESULTS: A total of 10,754 patients were included. During the periods with IAs, hospitalization rates increased by 0.36/year compared with 0.23/year in the periods without for the same patient, and the number of hospitalizations doubled [proportional fold change = 1.9, 95% confidence interval (1.8, 2.1)]. We estimated that 22% [95% confidence interval (20%, 23%)] of all hospitalizations were associated with IAs, 80% of which were due to psychotropic IAs. CONCLUSIONS: The IAs could be used as a simple and clinically relevant tool by prescribing physicians to assess the appropriateness of the prescription in elderly patients treated for Alzheimer disease.

[Selective cyclooxygenase-2 inhibitors. A population-based analysis of use in France over a three-year period and comparison with randomised clinical trials]. / Inhibiteurs sélectifs de la cyclo-oxygénase 2. Analyse des conditions réelles d'utilisation en France pendant 3 ans et étude comparative avec les essais cliniques randomisés.

OBJECTIVES: The use of selective cyclooxygenase-2 (COX-2) inhibitors is highly controversial today, mainly because of doubts about cardiovascular tolerance. Few studies have assessed the use of these drugs in daily clinical practice. This study aims to assess the changes in their use in daily practice in France and to compare it with their use in randomized clinical trials. METHODS: The French National Health Insurance Fund AMPI database of self-employed workers in non-agricultural occupations was used to obtain the following information: patients requesting reimbursement for celecoxib and rofecoxib between November 2000 and October 2003, morbidity assessed by enrollment on the lists of chronic diseases for which care is fully (100%) reimbursed, pregnancy (assessed by the payment of physicians' or hospital fees for delivery or by maternity benefits), and concomitant drugs (by claims for reimbursement). We compared these patients with those in randomized clinical trials (RCT) of celecoxib or rofecoxib published in either English or French before November 2003; we focused on their demographic characteristics, morbidity, pregnancy and concomitant drug use. RESULTS: Use of COX-2 inhibitors in France did not vary over the study period, except for patients' mean age (range: 64.2-62.9 years), proportion of women (56.7%-54.7%) and use of gastroprotective drugs (18.2%-28.4%). The mean age of patients in our study was 10 years older than that of RCT patients, and the proportion of women in our study was 15% lower. The percentage of women who took these drugs while pregnant was 0.02% in our study and 0.09% in the RCT. The percentage of patients with long-term chronic disorders overall was higher in our study than in the RCT, and the percentage for all specific long-term diseases except rheumatoid arthritis was also higher (for example, more patients had cardiovascular diseases or diabetes in our study [15%] than in the RCT [6%]). Patients in our study also used concomitant drugs from 9 of the 14 principal Anatomical Therapeutic Chemical classification groups more frequently than RCT patients: for cardiovascular drugs, for example, the figures were 55% and 5%, respectively. CONCLUSION: The demographic characteristics, prevalence of chronic morbidity and use of concomitant drugs among COX-2 inhibitor users in France varied little over the three years after marketing approval. Compared with RCT patients, these users were less often female, were older and more often had cardiovascular diseases. Cardiovascular events occurring among COX-2 inhibitor users in France should be evaluated.

Drug exposure during the periconceptional period: a study of 1793 women.

BACKGROUND: Many studies have described the prescribing of drugs to pregnant women, but only very few have data concerning the periconceptional period specifically. AIM: The aim of the study was to evaluate the incidence of exposure to teratogenic drugs during early pregnancy and to determine whether a safer drug exists. METHODS: In a French health insurances database, we analyzed drugs prescribed during the period starting 1 month before and ending 2 months after the beginning of pregnancy between 1 January 2006 and 31 December 2007. Based on the Summary of Product Characteristics (SPC), drugs we considered were those 'contraindicated', 'not recommended', 'to be avoided', and 'possible' for use during the first trimester of pregnancy. For drugs 'contraindicated', we established if there were alternatives with similar efficacy for the mother and lower risk for the fetus. RESULTS: Over a period of 2.25 years, 8754 drugs were prescribed to 1793 women starting 1 month prior to and ending 2 months after conception. Among these drugs, 20 (0.2%) were 'contraindicated', 195 (2.2%) were 'not recommended', and 1209 (13.8%) were 'to be avoided' during the first trimester of pregnancy. Twenty (1.1%) women received at least one drug that was 'contraindicated' during the first trimester, 171 (9.5%) received a drug that was 'not recommended' and 768 (42.8%) received a drug that was 'to be avoided'. At least one possible alternative was available for all except one 'contraindicated' drug. CONCLUSIONS: During the highest teratogenic risk period, 1.1% of women received a contraindicated drug, despite existence of a safer alternative drug. This may be partly accounted for by physicians not being aware of the pregnancy at the time the drug was administered and could be reduced by adding a section entitled 'women of child-bearing potential' to the SPC.

Prevalence and patterns of methylphenidate use in French children and adolescents.

OBJECTIVE: The aim of the study was to describe the prevalence and utilization patterns of methylphenidate (MPH) in children and adolescents in France. METHODS: This was a population-based retrospective study in which the cohort consisted of patients for whom data were extracted from the dispensation drug claims database of the national health insurance (NHI) fund for self-employed workers. Annual prevalence of MPH use was evaluated on patients aged 6-18 years who were reimbursed for at least one MPH prescription a year. Between January 2004 and June 2005, features of MPH medication and user profile were described for the "new starters" having a screening period of 1 year without receiving a MPH prescription and a follow-up >or=12 months. Time to interruption of MPH regular use was analysed by Kaplan-Meier survival analysis. Mean duration of exposure to MPH treatment was computed with the 95% confidence interval (CI). RESULTS: Annual prevalence of MPH per 1000 persons was 1.1 in 2003, 1.5 in 2004 and 1.8 in 2005 (relative increase of 63.5%). New starters (n = 447) received their first MPH prescription through the hospital (65.1%) or through private practitioners (34.9%). The user profiles were: short (16.6%), occasional (33.8%) and regular (49.6%). Among the new starters, the median time to interruption of MPH regular use was 10.2 months (95% CI: 7.9-12.4). The mean duration of exposure to MPH treatment was: occasional (4.9 months, 95% CI: 4.3-5.5) and regular (25.7 months, 95% CI: 24.6-26.8). CONCLUSION: Although there is a low prevalence of MPH use in France, this survey revealed a wide profile of users and heterogeneous use patterns.

Antipyretic drug use in children in French office based medical practice.

PURPOSE: To analyse antipyretics (APs) prescriptions profile in children, particularly the frequency of AP combinations. METHODS: APs (acetylsalicylic acid, paracetamol, ibuprofen or ketoprofen) prescribed to children below 12 years and refunded by a public health insurer in 2003, throughout France, were examined. RESULTS: A total of 513 034 prescriptions were refunded for 240 720 children. The mean number of AP prescriptions per child was the highest in children aged 6 months to 2 years. Paracetamol was the main AP prescribed, but its prescription declined with age, from 90.8% below 3 months old to 57.4% between 6 and 12 years old. Ibuprofen-only prescriptions were rare below 3 months and maximal between 2 and 6 years. The ibuprofen/paracetamol combination was prescribed from 6 months old, and its frequency was maximal between 2 and 6 years old (21.7%). CONCLUSIONS: The clear predominance of paracetamol prescriptions suggests that French prescribers are relatively aware of the relative risk-benefit ratio of the different APs. Studies are required to determine if the APs are prescribed to be used alternately or when a monotherapy fails. Guidelines to manage fever in children are needed in France to restrict APs combination to the case of paracetamol failure.

Morphology and ultrastructure of paired prototergal glands in the adult rove beetle Philonthus varians (Coleoptera, Staphylinidae).

Philonthus and other genera of Philonthina possess a pair of prototergal glands located in the first abdominal tergum and hidden at rest by hind wings and elytra. In Philonthus varians they occupy the whole length of the tergum and form a pouch-like invaginated reservoir with a scaly glandular zone and a smooth outlet. A grille of long setae covers the opening of each gland. The fine structure of these glands is given for the first time. Three types of cells are found in the glandular epithelium. Epidermal cells underlie the cuticular scales, numerous class 1 secretory cells open in the centre of calyces made of finger-like processes of the cuticle, and class 3 cells are connected to pored tubercles. A cytological comparison is made with the diverse class 1 cells described to date in Coleoptera. In these cells different evolutionary trends are shown in the structure of the cuticular apparatus, particularly in the number, size and position of the cuticular apertures as well as in the length and abundance of epicuticular filaments. A possible defensive function of the prototergal glands against pathogens and their interest for the phylogenetic study of Staphylininae are discussed.

Absolute contraindications in relation to potential drug interactions in outpatient prescriptions: analysis of the first five million prescriptions in 1999.

OBJECTIVES: Adverse drug interactions increase morbidity and mortality. To prevent these, situations leading to adverse prescriptions must be clarified. This study quantifies and analyses prescriptions with potential adverse drug interactions in primary health care in the North of France over a 3-month period. METHODS: All prescriptions administered between 1 January 1999 and 31 March 1999 were analysed to identify potential interactions amongst drugs appearing on the same prescription sheet. The regional French healthcare database was compiled to further classify contraindications. RESULTS: There were 5,358,374 prescriptions administered to 44% of the overall population of the Nord-Pas de Calais area (1,754,372 patients per 3,990,167 general population). There were 14,390 prescriptions classified as either absolute (26%) or relative contraindications (74%). Nine drug categories accounted for most of the absolute contraindications: dopaminergic antiparkinsonians, neuroleptic agents, migraine treatments (such as ergot alkaloids, sumatriptan and other triptan derivatives), prokinetic drugs (cisapride), antibacterial drugs (macrolides), antifungals (imidazoles), antiarrhythmics, beta-blockers and analgesics (opioids and floctafenine). In 54% of patients exposed, the incurred risk was either QT prolongation/Torsade de Pointes or antagonism of dopaminergic antiparkinson agents with dopamine receptor antagonists prescribed as antipsychotic agents. CONCLUSIONS: Among a non-selected population of ambulatory outpatients, the number of quarterly prescriptions with contraindications with potentially harmful drug interactions is 27 in 10,000 prescriptions. This would extrapolate to nearly 200,000 contraindications on same-prescription sheets in France in the first quarter of 1999.

Absolute contraindications in relation to potential drug interactions in outpatient prescriptions: analysis of the first five million prescriptions in 1999.

OBJECTIVES: Adverse drug interactions increase morbidity and mortality. To prevent these, situations leading to adverse prescriptions must be clarified. This study quantifies and analyses prescriptions with potential adverse drug interactions in primary health care in the north of France over a 3-month period. METHODS: All prescriptions administered between 1 January and 31 March 1999 were analysed to identify potential interactions amongst drugs appearing on the same prescription sheet. The regional French healthcare database was compiled to further classify contra-indications. RESULTS: There were 5,358,374 prescriptions administered to 44% of the overall population of the Nord-Pas de Calais area (1,754,372 patients/3,990,167 general population). There were 14,390 prescriptions classified as either absolute (26%) or relative contraindications (74%). Nine drug categories accounted for most of the absolute contraindications: dopaminergic antiparkinsonians, neuroleptic agents, migraine treatments (such as ergot alkaloids, sumatriptan and other triptan derivatives), prokinetic drugs (cisapride), antibacterial drugs (macrolides), antifungals (imidazoles), antiarrhythmics, betablockers and analgesics (opioids and floctafenine). In 54% of patients exposed, the incurred risk was either QT prolongation/Torsade de Pointes or antagonism of dopaminergic antiparkinson agents with dopamine receptor antagonists prescribed as antipsychotic agents. CONCLUSIONS: Among a non-selected population of ambulatory outpatients, the number of quarterly prescriptions with contra-indications with potentially harmful drug interaction was 27 in 10,000 prescriptions. This would extrapolate to nearly 200,000 contra-indications on the same-prescription sheets in France in the first quarter of 1999.