Translational research on cognitive and behavioural disorders in neurological and psychiatric diseases.

The important medical and social burden of nervous system diseases contrasts with the currently limited therapeutic armamentarium and with the difficulty encountered in developing new therapeutic options. These failures can be explained by the conjunction of various phenomena related to the limitations of animal models, the narrow focus of research on precise pathophysiological mechanisms, and methodological issues in clinical trials. It is perhaps the paradigm itself of the way research is conducted that may be the real reason for our incapacity to find effective strategies. The purpose of this workshop was to define overall lines of research that could lead to the development of effective novel therapeutic solutions. Research has long focused on diseases per se rather than on cognitive and behavioural dimensions common to several diseases. Their expression is often partial and variable, but can today be well-characterised using neurophysiological or imaging methods. This dimensional or syndromic vision should enable a new insight to the question, taking a transnosographic approach to re-position research and to propose: translational models exploring the same functions in animal models and in humans; identification of homogeneous groups of patients defined according to the clinical, anatomico-functional and molecular characteristics; and preclinical and clinical developments enriched by the use of cognitive-behavioural, biological neurological, and imaging biomarkers. For this mutation to be successful, it must be accompanied by synchronised action from the public authorities and by ad hoc measures from the regulatory agencies.

Translational research: precision medicine, personalized medicine, targeted therapies: marketing or science?

Personalized medicine is based on: 1) improved clinical or non-clinical methods (including biomarkers) for a more discriminating and precise diagnosis of diseases; 2) targeted therapies of the choice or the best drug for each patient among those available; 3) dose adjustment methods to optimize the benefit-risk ratio of the drugs chosen; 4) biomarkers of efficacy, toxicity, treatment discontinuation, relapse, etc. Unfortunately, it is still too often a theoretical concept because of the lack of convenient diagnostic methods or treatments, particularly of drugs corresponding to each subtype of pathology, hence to each patient. Stratified medicine is a component of personalized medicine employing biomarkers and companion diagnostics to target the patients likely to present the best benefit-risk balance for a given active compound. The concept of targeted therapy, mostly used in cancer treatment, relies on the existence of a defined molecular target, involved or not in the pathological process, and/or on the existence of a biomarker able to identify the target population, which should logically be small as compared to the population presenting the disease considered. Targeted therapies and biomarkers represent important stakes for the pharmaceutical industry, in terms of market access, of return on investment and of image among the prescribers. At the same time, they probably represent only the first generation of products resulting from the combination of clinical, pathophysiological and molecular research, i.e. of translational research.

Information and communication on risks related to medications and proper use of medications for healthcare professionals and the general public: precautionary principle, risk management, communication during and in the absence of crisis situations.

Recent drug crises have highlighted the complexity, benefits and risks of medication communication. The difficulty of this communication is due to the diversity of the sources of information and the target audience, the credibility of spokespersons, the difficulty to communicate on scientific uncertainties and the precautionary principle, which is influenced by variable perceptions and tolerances of the risk. Globally, there is a lack of training in risk management with a tendency of modern society to refuse even the slightest risk. Communication on medications is subject to regulatory or legal requirements, often uses tools and messages that are not adapted to the target audience and is often based on a poor knowledge of communication techniques. In order to improve this situation, the available information must be coordinated by reinforcing the unique medication information website and by coordinating communication between authorities by means of a single spokesperson. A particular effort must be made in the field of training in the proper use and risk of medications for both the general population and patients but also for healthcare professionals, by setting up a unified academic on-line teaching platform for continuing medical education on medications and their proper use.

Off-label prescriptions: how to identify them, frame them, announce them and monitor them in practice?

Following the Mediator crisis and the passage of the Health and Safety Law of December 2011, off-label prescriptions are a real concern shared by all those involved in healthcare system. Off-label, in the strictest sense of the term, is defined as all prescriptions that do not correspond to the summary of product characteristics (SPC), particularly those that fail to comply with the indications and dosage regimens defined by the marketing authorization (MA) for clear safety reasons. There are various rasons for off-label prescriptions, both conscious and unconscious. They are intended to respond to unmet medical needs, the needs of poorly studied populations or not studied at all in trials, but in relation to whom it is reasonable to extrapolate that MA would be given (common-sense prescriptions) and, additionally, to urgent public health needs (such as baclofen, pregnant women, and HIV drugs). All these prescriptions would deserve to be studied for a potential MA. However, there are off-label prescriptions that need to be restricted or even penalized in the case of compassionate prescriptions or unjustified prescriptions or prescriptions not based on any scientific grounds. Off-label prescriptions are not easy to track down because if the prescriber has to write "off-label" on his prescription, then clearly, in practice, he will only do so in exceptional cases. Neither the pharmacists who dispense the drug nor the Social Security that reimburses it, have access to the diagnosis (or targeted indication). Thus, in order to identify the off-label prescription, we must be able to cross reference the available databases (such as pharmacovigilance database, medicalized information system program [programme de médicalisation des systèmes d'information, PMSI], hospital drug formularies, general sample of beneficiaries [échantillon généraliste de bénéficiaires, EGB] or national inter-regional Health Insurance Information System [système national d'informations inter-régions d'Assurance maladie, SNIIRAM], sales data, and data from market surveys). The shared computerized patient file may resolve this problem. The temporary use recommendation (TUR) proposed by the Drug Safety Law will only partially deal with this problem for recently marketed molecules. This temporary and exceptional mechanism will authorize a recognized off-label prescription, which may be reimbursed and monitored for 3 years. These TURs will only concern a small portion of "off-label" drugs having yet a positive risk/benefit ratio (conditional MA) but this is far from matching with majority of off-label prescriptions. As such, and in order to improve the use of drugs, it is important to propose a control system for all "off-label" prescriptions with a dedicated committee: the "off-label" committee which would determine the frame of the "off-label" prescriptions.

Roles and practices of general practitioners and psychiatrists in management of depression in the community.

BACKGROUND: Little is known about depressed patients' profiles and how they are managed. The aim of the study is to compare GPs and psychiatrists for 1 degrees) sociodemographic and clinical profile of their patients considered as depressed 2 degrees) patterns of care provision. METHODS: The study design is an observational cross-sectional study on a random sample of GPs and psychiatrists working in France. Consecutive inclusion of patients seen in consultation considered as depressed by the physician. GPs enrolled 6,104 and psychiatrists 1,433 patients. DATA COLLECTED: sociodemographics, psychiatric profile, environmental risk factors of depression and treatment. All clinical data were collected by participating physicians; there was no direct independent clinical assessment of patients to check the diagnosis of depressive disorder. RESULTS: Compared to patients identified as depressed by GPs, those identified by psychiatrists were younger, more often urban (10.5% v 5.4% - OR = 2.4), educated (42.4% v 25.4% - OR = 3.9), met DSM-IV criteria for depression (94.6% v 85.6% - OR = 2.9), had been hospitalized for depression (26.1% v 15.6% - OR = 2.0) and were younger at onset of depressive problems (all adjusted p < .001). No difference was found for psychiatric and somatic comorbidity, suicide attempt and severity of current depression. Compared to GPs, psychiatrists more often prescribed tricyclics and very novel antidepressants (7.8% v 2.3% OR = 5.0 and 6.8% v 3.0% OR = 3.8) with longer duration of antidepressant treatment. GPs' patients received more "non-conventional" treatment (8.8% v 2.4% OR = 0.3) and less psychotherapy (72.2% v 89.1% OR = 3.1) (all adjusted p < .001). CONCLUSION: Differences between patients mainly concerned educational level and area of residence with few differences regarding clinical profile. Differences between practices of GPs and psychiatrists appear to reflect more the organization of the French care system than the competence of providers.

Disability in patients consulting for anxiety or mood disorders in primary care: response to antidepressant treatment.

BACKGROUND: The primary objective of this prospective observational study was to evaluate changes in self-reported disability in patients with anxiety or mood disorders 3 months after initiating antidepressant treatment. METHODS: This study included 8396 patients consulting 2433 general practitioners in France for a major mood episode, generalized anxiety disorder, social anxiety disorder, panic disorder, or obsessive-compulsive disorder. Treatment was initiated with the antidepressant that the physician considered appropriate. Patients were evaluated with the Sheehan Disability Scale (SDS), Hospital Anxiety and Depression Scale, and Clinical Global Impression-Severity (CGI-S) at baseline and after 6 and 12 weeks. RESULTS: At 12 weeks, 6617 patients (78.8%) were evaluable. At inclusion, the mean SDS subscores were 6.5 ± 2.2 on the work/school activities dimension, 6.8 ± 1.9 on the social activities dimension, and 6.5 ± 2.0 on the family life dimension. At the 12-week follow-up visit, the mean change in score on these three dimensions was -3.9 ± 2.6, -4.2 ± 2.5, and -4.0 ± 2.5, respectively. At the 12-week follow-up visit, 90.0% of patients were responders (defined as patients whose SDS dimension scores decreased by at least one point) on the work/school SDS subscores; 92.8% were responders on the social life SDS subscores, and 91.1% were responders on family life/home responsibilities SDS subscores. Functional remission (defined as an SDS subscore of 0 at study end) rates were 18.0% for the work/school dimension, 16.8% for the social activities dimension, and 19.5% for the family life dimension. Using a cutoff of ≤2, remission rates were 56.8%, 55.0%, and 58.0%, respectively. Improvements in self-rated disability were correlated with improvements in symptoms measured with clinician-rated CGI-S. CONCLUSION: Patients consulting for anxiety or mood disorders report significant disability, which can be effectively reduced by antidepressant treatment.

Psychotropic drug consumption at admission and discharge of nursing home residents.

OBJECTIVES: To quantify transitions of residents into or out of nursing homes (NHs) and to describe psychotropic drug prescription at admission and discharge and with regard to dementia diagnosis. DESIGN: A descriptive, cross-sectional, noninterventional study. SETTING: The setting included 300 NH in France. PARTICIPANTS: Participants included 2231 NH residents. MEASUREMENTS: Participants reported the number, origin, and destination of residents transiting into or out of the NH in the previous 3 months and provided information on NH characteristics. For eight residents admitted or discharged by the NH, information was collected on medical characteristics, including psychotropic and antidementia drug prescription, and dementia status. RESULTS: The mean number of beds in participating NHs was 85.9 ± 33.2 (mean occupation rate = 96.6%). The mean number of admissions and discharges in the previous 3 months was 13.7 ± 8.5 and 11.2 ± 4.3, respectively. Most admissions (direct admission 3.2 ± 3.3 or readmission 6.4 ± 6.0) and discharges (4.4 ± 6.7) were from and to the hospital. Of the 2231 residents included, 1005 (45.0%) were diagnosed with dementia. At least one psychotropic drug (antidepressant, hypnotic, antipsychotic, or anxiolytic) was prescribed to 70.7% of residents and in particular an antipsychotic to 19.1% of residents. Psychotropic drugs, and in particular antipsychotic drugs, were significantly more prescribed to demented residents than to nondemented residents (76.2% vs 64.3% and 28.0% vs 11.8%, respectively). The extent of prescription (at least one psychotropic drug) was similar in residents admitted to (70.2%) and discharged from (67.5%) the NHs. Antidementia drugs (acetylcholinesterase inhibitors or NMDA receptor antagonists) were prescribed to 53.7% of demented residents. CONCLUSION: Movement of residents into and out of NHs and especially from and to the hospital is extensive and the prescription rate for psychotropic drugs is very high in this population, especially in residents with dementia. Multiple groups of health care providers should be targeted by educational measures to improve the quality of care for NH residents.

Screening for Alzheimer's disease with the short cognitive evaluation battery.

Because Alzheimer's disease (AD) tends to be underdiagnosed, there is an increasing need for accurate neuropsychological screening tools that are easy to administer by general practitioners or specialists. The aim of the present study was to validate, in French, a sensitive and specific screening battery designed to improve the discrimination between patients with AD, patients with depression and healthy elderly subjects. The Short Cognitive Evaluation Battery (SCEB) consists of 4 brief tests: temporal orientation, 5-word test, clock-drawing test and a semantic verbal fluency task. The SCEB was administered to 123 ambulatory subjects (mean age 76.4+/-2.3 years): 49 patients with mild AD, 27 patients with depressive symptoms and 47 healthy elderly subjects. The mean time for administration of the test was 11.2 min in the AD group, 8.2 min in the depressive group and 7.2 min in the control group (p < 0.001). Multivariate analysis showed that, compared with controls, patients with mild AD were significantly impaired for all four tests. Response operating characteristics analysis of the SCEB showed: 93.8% sensitivity and 85% specificity for discriminating AD from control patients, and 63% sensitivity and 96% specificity for discriminating AD from depressive patients. In summary, the SCEB appears to be a highly sensitive and specific tool for discriminating between patients with mild AD and healthy elderly individuals. Furthermore, in combination with clinical evaluation, the SCEB could improve the specificity of the difficult discrimination between mild AD and depression.