CERIMP – Sud Est

Conseil en recherche médicale prospective [email protected] Dr Guy Ardiet, [email protected]

Revue de presse, février 2016 La revue de presse CERIMP de février 2016 est toujours passée aux personnes référentes du CH de St Cyr, car plusieurs abonnements nous ont été acquis en référence aux recherches menées dans cet établissement. Encore une fois, beaucoup en anglais. Mais c'est un anglais pour débutants … SOMMAIRE Dépression, genre et immunité ABILIFY, génériques (aripiprazole) : mise en garde utilisation hors AMM et risque de suicide Suicides en France : état des lieux, facteurs de risque et programmes de prévention La quetiapine XL n'est pas pour les obèses … Assessing the Risk Factors for Difficult-to-Treat Depression and Treatment-Resistant Depression Dealing with Racist Patients Exploratory study of once-daily transcranial direct current stimulation (tDCS) as a treatment for auditory hallucinations in schizophrenia Antidepressant Treatment and Risk of Dementia: A Population-Based, Retrospective CaseControl Study Poverty in Preschoolers Alters Mood and Brain Connectivity in Later Childhood

Dépression, genre et immunité ZDANOWICZ N.(1), REYNAERT C.(1), LEPIECE B.(1), JACQUES D.(1) Université Catholique de Louvain CHU Mont-Godinne, Yvoir BELGIQUE

Introduction: L’exposition à un stimulus stressant entraîne l’activation l’axe hypothalamohypophysaire-surrénalien avec une sécrétion de catécholamines.

Celles-ci modifient l’immunité humorale et cellulaire. D’une part, cette théorie psycho-immunologique permet de tisser des liens entre immunité et dépression. D’autre part, on sait qu’il existe des différences dans les réactions immunitaires des hommes et des femmes mais aussi dans l’expression clinique des épisodes dépressifs majeurs. Notre étude vise à pondérer l’intensité de la dépression et le genre dans la réaction immunitaire cellulaire liée à la dépression. Méthode : 549 patients atteints d’un épisode dépressif majeur sont enrôlés dans une étude ouverte. Outre un questionnaire socio-démographique, ils ont complété l’échelle de dépression de Beck. En cytométrie de flux, nous avons dosé les différents sous-types de lymphocytes. Résultats : En moyenne l’intensité de la réaction dépressive chez les femmes est plus élevée que chez les hommes de 2.9 points (p = 0.018, t = 2.379). Cette intensité est corrélée avec les valeurs absolues de CD3 (p = 0.003 ; r = -0.127), CD4 (p < 0.000 ; r = -0.189), CD8 (p = 0.05 ; r = 0.089), et CD16 & 56 (p = 0.05 ; r = 0.129). Du point de vue genre, il existe des différences significatives entre hommes et femmes pour le pourcentage des lymphocytes (h= 37.84, f=35.59 ; p = 0.008, t = 2.646), CD3 (h= 2.08, f=1.9 ; p = 0.014, t = 2.676), CD4 (h= 1.44, f=1.3 ; p = 0.012, t = 2.522), CD8 (h= 0.62, f=0.57 ; p = 0.03, t = 2.182). Un modèle de régression incluant les deux variables soutient l’existence de ces différences pour le pourcentage de lymphocytes (p = 0.001, R2 ajusté 0.025) et les CD8 (p = 0.021 ; R2 ajusté 0.012). Conclusions : S’il existe un lien bien documenté entre dépression et réaction immunitaire cellulaire, notre étude met en évidence que les hommes ont une réaction immunitaire plus forte que les femmes en terme de pourcentage de lymphocytes mobilisés et de lymphocytes cytotoxiques. Les lymphocytes tueurs naturels sont, eux, indépendants du genre mais bien de l’intensité de la dépression. La théorie psycho-immunologique devrait sans doute être repensée avec une immunité au moins partiellement dépendante du genre.

ABILIFY, génériques (aripiprazole) : mise en garde utilisation hors AMM et risque de suicide Par David PAITRAUD - Date de publication : 15 Février 2016 l'ANSM rappelle que le risque de suicide et de comportements suicidaires est connu et déjà

mentionné dans le résumé des caractéristiques du produit (RCP) et la notice d'ABILIFY et de ses génériques. Une surveillance rapprochée des patients à risque est en conséquence recommandée.

Suicides en France : état des lieux, facteurs de risque et programmes de prévention Par Stéphane KORSIA-MEFFRE - Date de publication : 18 Février 2016

L’Observatoire national du suicide vient de publier son deuxième rapport sur les statistiques des suicides en France. Si le nombre de suicides annuel tend à diminuer, certaines populations sont encore trop souvent concernées : personnes âgées, agriculteurs, jeunes cinquantenaires masculins, détenus, etc. De plus, la répartition géographique des suicides n’est pas homogène sur le territoire, avec un arc nord-ouest beaucoup plus touché. Ce rapport propose également une analyse de la littérature sur les facteurs de risques et un état des lieux des actions de prévention, du grand public aux professionnels de santé, prévues par plusieurs progammes nationaux et régionaux. La suite :

https://www.vidal.fr/actualites/19165/suicides_en_france_etat_des_lieux_facteurs_de_ris que_et_programmes_de_prevention

La quetiapine XL n'est pas pour les obèses ... Utilisation of extended release quetiapine (Seroquel XL™): Results from an observational cohort study in England - 24/02/16 Doi : 10.1016/j.eurpsy.2015.12.004 V. Osborne ⁎ , M. Davies, D. Layton, S.A.W. Shakir Background A post-authorisation safety study was carried out as part of the EU Risk Management Plan to examine the long-term (up to 12 months) use of quetiapine XL as prescribed in general practice in England. Aim To present a description of the drug utilisation characteristics of quetiapine XL.

Methods An observational, population-based cohort design using the technique of Modified Prescription-Event Monitoring (M-PEM). Patients were identified from dispensed prescriptions issued by general practitioners (GPs) for quetiapine XL between September 2008 and February 2013. Questionnaires were sent to GPs 12 months following the 1st prescription for each individual patient, requesting drug utilisation information. Cohort

accrual was extended to recruit additional elderly patients (special population of interest). Summary descriptive statistics were calculated. Results The final M-PEM cohort consisted of 13,276 patients; median age 43 years (IQR: 33, 55) and 59.0% females. Indications for prescribing included bipolar disorder (n=3820), MDD (n=2844), schizophrenia (n=2373) and other (non-licensed) indications (n=3750). Where specified, 59.3% (7869/13,276) were reported to have used quetiapine IR (immediate release formulation) previously at any time. The median start dose was highest for patients with schizophrenia (300mg/day [IQR 150, 450]). The final elderly cohort consisted of 3127 patients and 28.5% had indications associated with dementia. The median start dose for elderly patients was highest for patients with schizophrenia or BD (both 100mg/day [IQR 50, 300]). Conclusions The prevalence of off-label prescribing in terms of indication and high doses was common, as was use in special populations such as the very elderly. Whilst off-label use may be unavoidable in certain situations, GPs may need to re-evaluate prescribing in circumstances where there may be safety concerns. This study demonstrates the ongoing importance of observational studies such as M-PEM to gather real-world clinical data to support the postmarketing benefit:risk management of new medications, or existing medications for which license extensions have been approved.

Keywords : Mania and bipolar disorder, Schizophrenia and psychosis, Epidemiology, Psychopharmacology

Assessing the Risk Factors for Difficult-to-Treat Depression and Treatment-Resistant Depression Article complet pdf sur demande Bradley Gaynes, MD, MPH

Depression is the leading cause of disability among people across the globe, according to the World Health Organization. Among those who have been diagnosed, many fail to achieve remission after following recommended antidepressant medication and psychosocial therapies. In particular, difficult-to-treat and treatment-resistant depression may cause severe impairments for patients, including diminished cognitive functioning, increased medical bills, and decreased workplace performance, as well as an increased risk of developing comorbid illnesses. However, many tools are available to clinicians for identifying treatmentresistant depression, including rating scales such as the 9-question Patient Health Questionnaire (PHQ-9) and the Quick Inventory of Depressive Symptomatology (QIDSSR16), as well as clinical evidence related to risk factors for difficult-to-treat or treatmentresistant depression. Accurately identifying treatment-resistant depression is the first step toward changing treatment regimens to help patients achieve remission.

(J Clin Psychiatry 2016;77[suppl 1]:4–8)

Dealing with Racist Patients Article complet pdf sur demande Kimani Paul-Emile, J.D., Ph.D., Alexander K. Smith, M.D., M.P.H., Bernard Lo, M.D., and Alicia Fernández, M.D.

N Engl J Med 2016; 374:708-711February 25, 2016DOI: 10.1056/NEJMp1514939

A 77-year-old white man with heart failure arrives in the emergency department of an urban hospital at 3 a.m. with shortness of breath and a fever. When a black physician enters, the man immediately announces, “I don’t want to be cared for by a %$#!{& doctor!” Taken aback, the physician retreats from the room. She’s offended by the man’s rejection and demeaning language — but knows that he may have a serious medical condition and that she cannot treat him against his will. How should the physician proceed?

A patient’s refusal of care based on the treating physician’s race or ethnic background1 can raise thorny ethical, legal, and clinical issues — and can be painful, confusing, and scarring for the physicians involved. And we fear that race-based reassignment demands will only increase as the U.S. physician population becomes more racially and ethnically diverse. So we’ve created a framework for considering and addressing such demands.

Competent patients have the right to refuse medical care, including treatment provided by an unwanted physician. This right is granted by informed-consent rules and common law that protects patients from battery. Patients presenting with an emergency medical condition are also protected by the Emergency Medical Treatment and Active Labor Act (EMTALA),2 which requires hospitals to screen and stabilize patients and provide medical treatment, if necessary, or arrange for a transfer, with patient consent, to a facility able to provide appropriate treatment.

Physicians and other health care workers have employment rights that must be balanced with patients’ rights. Employees of health care institutions have the right to a workplace free from discrimination based on race, color, religion, sex, and national origin, according to Title VII of the 1964 Civil Rights Act.3 Organizations that make race-based staffing decisions or compel employees to accede to a patient’s request for reassignment on the basis of a worker’s race or ethnic background may violate Title VII. Nurses and nursing assistants have successfully sued employers who require employees to accommodate such demands by patients.4

Physicians, however, have not brought such lawsuits, perhaps for two reasons. First, unlike nurses, many physicians are not hospital employees but rather “independent contractors,” who are not covered by Title VII unless the hospital exercises a substantial amount of control over how they perform their jobs. Second, physicians commonly decide among themselves how to address reassignment requests and thus probably are not often forced by a hospital employer to accommodate such requests.

Beyond these general legal rules, when patients reject physicians on the basis of their race or ethnic background, there is little guidance for hospitals and physicians regarding ways of effectively balancing patients’ interests, medical personnel’s employment rights, and the duty to treat. We believe that sound decision making in this context will turn on five ethical and practical factors: the patient’s medical condition, his or her decision-making capacity, options for responding to the request, reasons for the request, and effect on the physician (see flow chartConsidering a Patient’s Request for Physician Reassignment Based on Race or Ethnic Background in an Emergency Setting.). It’s helpful for physicians to consider these factors as they engage in negotiation, persuasion, and (in some cases) accommodation within the practical realities of providing effective care for all patients.

The patient’s medical condition and the clinical setting should drive decision making. In an emergency situation with a patient whose condition is unstable, the physician should first treat and stabilize the patient. Reassignment requests based on bigotry may be attributable to delirium, dementia, or psychosis, and patients’ preferences may change if reversible disorders are identified and treated. Patients with significantly impaired cognition are generally not held to be ethically responsible.

The assigned physician’s options for responding include establishing mutually acceptable expectations and conditions for providing the patient with the care he or she needs and is seeking. Family members may be able to persuade the patient to accept necessary medical treatment. If other emergency physicians are available, it is reasonable for physicians to decide among themselves to assign the patient to another physician, within the practical constraints of providing appropriate care for other patients. If only one physician is available, or if the physician does not wish to reallocate patients, she may negotiate with the patient to allow her to provide care until another physician comes on duty. Another option is to allow a nurse or medical resident to conduct the patient’s evaluation, although the patient should know that the assigned physician is still responsible and that having someone else perform the physical evaluation is not the standard of care. Regardless of the approach taken, patients should be informed that hateful or racist speech is not allowed.

The reasoning behind a patient’s request for reassignment may be clinically and ethically important. Requests for an ethnically or a racially concordant physician may be ethically appropriate in certain cases — for instance, for reasons of religion or culture (e.g., Muslim women requesting female clinicians) or of language.4 Patients who are members of racial or ethnic minority groups may request concordant physicians because of a history of

discrimination or other negative experiences with the health care system that have resulted in mistrust. In such cases, physician–patient concordance is associated with greater trust, comprehension, and satisfaction.5 Practically speaking, distinguishing such requests from those in which an assigned physician is rejected on the basis of race or ethnic background is usually straightforward. Accommodation in these cases is justifiable, and many institutions facilitate linguistic and ethnic concordance for their patients.

In contrast, rejection of a clinician that is motivated by bigotry is less deserving of accommodation. Such refusals are generally directed at physicians who are members of racial or ethnic minority groups that have historically suffered discrimination. Still, in some rare cases, refusal of a physician may be reasonable or worth accommodating — if, for example, the patient has had a very negative personal experience with people of a particular race or ethnic group (e.g., a veteran with post-traumatic stress disorder who refuses treatment from a clinician of the same ethnic background as former enemy combatants).

The final consideration is the effect on the physician. For many minority health care workers, expressions of patients’ racial preferences are painful and degrading indignities, which cumulatively contribute to moral distress and burnout. Physicians must balance several ethical obligations. They should respect patients’ informed refusals of medical interventions. They should also subordinate their self-interest to a patient’s best interests and overcome any aversions they may have toward patients. Still, no ethical duty is absolute, and reasonable limits may be placed on unacceptable patient conduct. Institutions can track and collect data on these physician–patient encounters, including their effects on physicians and their ultimate resolution, with the goal of supporting staff and improving the handling of these situations.

Hospitals and other institutional providers have their own factors to consider when responding to race-based requests. Hospitals must meet EMTALA requirements while respecting physicians’ employment rights; their ability to remove physicians from cases in response to patients’ race-based requests is thus circumscribed. An on-call administrator can inform patients of their right to seek care elsewhere and their responsibility to refrain from hateful speech. We believe that institutions should not accommodate patients in stable condition who persist with reassignment requests based on bigotry. Outpatients may be informed that they are free to seek treatment elsewhere if they object on racial grounds to their assigned physician, and inpatients in stable condition can also be assisted in transferring to another hospital.

Patients who demand accommodation for racial biases present health care providers with a difficult conflict involving their professional obligation to provide nondiscriminatory care, their sense of social justice and personal integrity, and their ethical obligations to respect patients’ autonomy and medical best interests. Although institutions should not accommodate, for individual physicians the decision to accommodate may be sound when the accommodating physician is comfortable with the decision, employment rights are protected, and the decision

does not compromise good medical care.

Exploratory study of once-daily transcranial direct current stimulation (tDCS) as a treatment for auditory hallucinations in schizophrenia - 24/02/16 Doi : 10.1016/j.eurpsy.2015.11.005

F. Fröhlich a b c d e ⁎ , T.N. Burrello a, J.M. Mellin a, A.L. Cordle a, C.M. Lustenberger a, J.H. Gilmore a, L.F. Jarskog a

Background Auditory hallucinations are resistant to pharmacotherapy in about 25% of adults with schizophrenia. Treatment with noninvasive brain stimulation would provide a welcomed additional tool for the clinical management of auditory hallucinations. A recent study found a significant reduction in auditory hallucinations in people with schizophrenia after five days of twice-daily transcranial direct current stimulation (tDCS) that simultaneously targeted left dorsolateral prefrontal cortex and left temporo-parietal cortex. Hypothesis We hypothesized that once-daily tDCS with stimulation electrodes over left frontal and temporo-parietal areas reduces auditory hallucinations in patients with schizophrenia.

Methods We performed a randomized, double-blind, sham-controlled study that evaluated five days of daily tDCS of the same cortical targets in 26 outpatients with schizophrenia and schizoaffective disorder with auditory hallucinations. Results

We found a significant reduction in auditory hallucinations measured by the Auditory Hallucination Rating Scale (F2,50=12.22, P