Les récepteurs 5-HT2A de la sérotonine et mGlu2 du glutamate suscitent un grand intérêt vu la dérégulation des deux récepteurs observée dans la schizophrénie et leur statut de cibles des antipsychotiques dits atypiques et de nouvelle génération, respectivement. Même si les antipsychotiques atypiques ciblant le récepteur 5-HT2A ont montré une efficacité contre les symptômes positifs, leur effet reste très limité contre les symptômes négatifs et cognitifs, et leurs effets secondaires nombreux. Depuis les années 1990, une nouvelle classe d’antipsychotiques ciblant le système glutamatergique, en particulier le récepteur mGlu2, est en développement. Les tests cliniques n’ont montré leur efficacité que pour les patients n’ayant pas été traités auparavant par des antipsychotiques atypiques. Ceci suggère une interaction fonctionnelle forte entre les récepteurs 5-HT2A et mGlu2 dans le mode d’action de ces deux classes d’antipsychotiques. De plus, plusieurs études ont démontré l’existence d’un hétéromère des deux récepteurs dans le cortex préfrontal qui semble important pour la réponse aux hallucinogènes et aux antipsychotiques ciblant l’un ou l’autre récepteur. Ainsi, étant donné l’impact du profil de phosphorylation adopté par les récepteurs couplés aux protéines G (RCPG) sur leur fonction, j’ai caractérisé au cours de ma thèse l’impact de la co-expression du récepteur 5-HT2A sur le profil de phosphorylation du récepteur mGlu2 en réponse à différentes stimulations. Parmi les 5 sites de phosphorylation identifiés, la phosphorylation de la Ser843 est potentialisée en réponse à la stimulation par un agoniste du récepteur mGlu2 uniquement lorsque le récepteur 5-HT2A est co-exprimé. Ces résultats ont été validés grâce à la génération d’un nouvel anticorps dirigé spécifiquement contre la forme phosphorylée de la Ser843 sur culture cellulaire HEK-293 et in vivo dans le cortex préfrontal de souris, région où les deux récepteurs sont co-exprimés. Des études fonctionnelles ont démontré que la phosphorylation de la Ser843 est nécessaire à la potentialisation de l’activité Gi/o du récepteur mGlu2 en réponse à ses agonistes et constitue un cross-talk fonctionnel entre les deux récepteurs puisque les agonistes du récepteur 5-HT2A stimulent également la phosphorylation de la Ser843 du récepteur mGlu2. Ainsi, mes résultats de thèse ont permis d’identifier la phosphorylation du récepteur mGlu2 sur la Ser843 comme un événement moléculaire clé du cross-talk fonctionnel avec le récepteur 5-HT2A et apporte un élément important dans la compréhension du mode d’action des antipsychotiques atypiques et de nouvelle génération. / The serotonin 5-HT2A and glutamate mGlu2 receptors keep on attracting particular attention given their implication in psychosis associated with schizophrenia and in the mechanism of action of atypical antipsychotics and of a new class of antipsychotics, respectively. Though atypical antipsychotics, targeting 5-HT2A receptor, are efficient against positive symptoms, these drugs do not act against negative, cognitive symptoms and display many side effects. Since the 90’s, new classes of antipsychotics triggering glutamatergic system, in particular mGlu2 receptor, have been developed. Their clinical trials have shown efficacy only in patients who have not been previously treated with atypical antipsychotics. This suggests a strong interaction between 5-HT2A and mGlu2 receptors in the mechanism of action of both classes of antipsychotics. Moreover, a large body of evidence indicates the presence, in prefontal cortex, of 5-HT2A/mGlu2 heteromer that is important for the response to hallucinogens and antipsychotics targeting one receptor or the other. Thus, in view of the importance of the phosphorylation profile adopted by G-protein coupled receptor (GPCR) on their activity, I characterized the impact of 5-HT2A receptor co-expression on the phosphorylation profile of mGlu2 receptor in response to various stimulations. Among the five identified phosphorylated residues, the phosphorylation of Ser843 increases upon mGlu2 receptor stimulation only when the 5-HT2A receptor is co-expressed. A new antibody against the phosphorylated form of Ser843 confirmed these results in HEK-293 cells and in mouse prefrontal cortex, area where both receptors are co-expressed. Functional studies demonstrated that Ser843 phosphorylation is necessary to enhance Gi/o signaling of mGlu2 receptor and constitutes a functional crosstalk between 5-HT2A and mGlu2 receptor since 5-HT2A receptor agonists also stimulate Ser843 phosphorylation. Collectively, my thesis findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event of the functional crosstalk with 5-HT2A receptor that might be critical to understand the mechanism of action of atypical and potential future antipsychotics treatments.

A esquizofrenia é uma doença psiquiátrica caracterizada classicamente pela perda de contato com a realidade, onde os pacientes são incapazes de distinguir uma experiência real da imaginária. Pacientes esquizofrênicos apresentam importante transtorno psicossocial e emocional, prejudicando a vida de relações interpessoais e familiares. As características da doença incluem a presença de delírios, alucinações, alterações de comportamento e diminuição da capacidade mental. A etiologia da doença é complexa e multifatorial, estando envolvidos fatores genéticos, biológicos e ambientais. A utilização de medicamentos antipsicóticos é peça fundamental no tratamento. Os fármacos antipsicóticos são agrupados em “típicos” e “atípicos”, atuando sobre o sistema dopaminérgico e serotoninérgico. Neste estudo, foram selecionados 79 pacientes diagnosticados com esquizofrenia, atendidos no Programa de Atendimento do Ambulatório de Esquizofrenia e Demências do Hospital de Clínicas de Porto Alegre, cujo diagnóstico seguiu critérios do CID-10 e DSM-IV. O objetivo do presente estudo foi associar o tempo de exposição de drogas antipsicóticas e o estado nutricional destes pacientes. Para tanto, foram coletados, analisados e interpretados dados referentes a exames laboratoriais, medidas de pressão arterial, avaliação antropométrica e o tempo diagnóstico de início da doença e procura por auxílio clínico. Concluímos que pacientes esquizofrênicos deste estudo apresentam sobrepeso (34,2%), elevada circunferência da cintura (68,4%), elevado índice cintura-quadril (72,2%) e excesso de adiposidade (96,2%) com risco aumentado para alterações metabólicas. Entretanto, apenas o índice cintura-quadril mostrou associação e correlação positiva e significativa com o tempo de uso da medicação. / The schizophrenia is a psychotic illness classically marked by the lost of contact with reality, when the patients are unable to distinguish a real experience from an imaginary one. Schizophrenic patients present an important psychosocial and emotional disorder, affecting the life of interpersonal and family relations. The characteristics of this illness include the presence of delusions, hallucinations, behavior changes and lowering of mental capacity. The etiology of this condition is complex and multifactorial, being involved genetic, biological and environmental factors. The use of antipsychotic drugs is a fundamental part in the process of treatment. The antipsychotic medicines are grouped in typical and atypical, acting on the dopaminergic and serotoninergic systems. This study selected 79 schizofrenic patients who were treated in the Ambulatory Treatment Program for Schizophrenia and Dementia in the Hospital de Clínicas de Porto Alegre, which the diagnoses followed criteria from the CID-10 and DSM-IV. The objective of the present study was to associate the exposition time of antipsychotic drugs and the nutricional condition of these patients. In order to achieve that, rererent data and laboratorial exams, arterial pressure measurement, anthropometric avaluation and the diagnosis time between the beginning of the illness and the search for clinical help were collected, analysed and interpreted. We concluded that the schizophrenic patients in this study present overweight (34,2%), high waist circumference (68,4%), high waist-hip ratio (72,2%) and adipositivity excess (96,2%) with increased risk for metabolic alterations. However, just the waist-hip ratio shown positive and significant association and correlation with the time period of the medication use.

Submitted by Biblioteca do Instituto Biomédico BIB (uffbib@gmail.com) on 2017-06-05T19:29:21Z No. of bitstreams: 1 Débora Guerra e Silva.pdf: 888747 bytes, checksum: 6d26a3772f933c6b9b96451e0e5c6100 (MD5) / Made available in DSpace on 2017-06-05T19:29:21Z (GMT). No. of bitstreams: 1 Débora Guerra e Silva.pdf: 888747 bytes, checksum: 6d26a3772f933c6b9b96451e0e5c6100 (MD5) / Introdução: O uso de antipsicóticos (AP), especialmente atípicos (AA), em adultos pode levar a ganho de peso, obesidade e risco de doenças cardiovasculares. Ainda há poucos estudos relacionados ao uso destes medicamentos em crianças e adolescentes. Objetivo: Avaliar o estado nutricional de adolescentes conforme o tempo de uso de AP, em especial AA. Metodologia: Estudo aprovado pelo Comitê de Ética da UFF (Nº de licença: 047536/2015). Trata-se de amostra de conveniência e estudo transversal com 49 adolescentes de ambos os sexos com idade entre 10 a 19 anos em tratamento psiquiátrico no CAPSi Zé Garoto- São Gonçalo/RJ. Foram incluídos no estudo adolescentes com déficit intectual, autismo, transtorno de conduta e psicose. Excluídos os portadores de doença endócrino-metabólica (diabetes, hipo e hipertiroidismo). Com autorização, os participantes realizaram avaliação antropométrica de peso, estatura e perímetro da cintura (PC) e foram calculados o Índice de Massa Corporal (IMC), considerando a classificação de z-Score e percentil 75 da amostra como ponto de corte para PC (P75 – PC: 96,5 cm). Para análise da composição corporal, foi selecionada uma subamostra de pacientes em uso de risperidona (RP) como medicação principal (esquizofrênicos e déficit intelectual) e analisado percentual de gordura corporal (PGC) através de balança de bioimpedância e somatório de dobras cutâneas (SDC). Resultados: Participaram do estudo 41 meninos e 8 meninas, com idade média de 14,4 ± 2,7 anos. Destes, 8 não usavam medicação AP (SA), 32 a usavam há mais de 1ano (> 1 ano) e 9 a usavam há menos de 1 ano (< 1 ano). Houve diferença significativa quanto ao IMC em relação ao tempo de uso de medicação [Teste Kruswall Wallis (mediana): SA = 18,55 / <1 ano = 22,93 / >1ano = 24,56 kg/m²; p=0,003], sendo significativamente maior o IMC entre os que usaram AP em comparação aos sem uso e maior IMC após primeiro ano de uso [Teste Mann- Whitney, IMC x não há uso de AP x > 1ano, p= 0,028; IMC x não há uso de APx < 1ano, p=0,221; IMC x < 1 ano x > 1 ano, p= 0,757]. Também houve mais obesos entre os usuários de AP por mais de 1 ano (p=0,007 – Teste Qui quadrado; obesos= 40,6%). Pacientes em uso de RP apresentaram maior média de IMC, independente do tempo [IMC x com e sem risperidona / Teste Mann- Whitney, p= 0,034 (mediana): IMC SEM RP = 19,61/ IMC COM RP= 24,80]; [ IMC x tempo / Teste Kruskal-Wallis, p= 0,097]. Foram encontradas alterações no percentual de gordura corporal pelo SDC em relação ao tempo de uso da RP, sendo maior PGC entre os que usavam RP em comparação aos sem uso e maior no primeiro ano de uso. [Gordura Corporal X Tempo / Teste Kruskal-Wallis, p= 0,038, Gordura sem RP= 20,40, Gordura 1mês - 1ano = 28,95 , Gordura > 1ano = 26,12] ; [ Gordura x com x sem RP; Teste Mann-Whitney, p= 0,018/ Gordura (sem RP) = 20,40 e Gordura (com RP) = 26,99], [Teste de Mann Whitney; Gordura x não há RP x 1 mês - 1ano, p= 0,014 / Gordura x não há RP x > 1ano; p= 0,062]. Conclusão: A análise sugere que há associação temporal entre uso de AP, aumento de IMC e obesidade. A RP está associada com aumento de IMC e há relação temporal entre o uso de RP e aumento de gordura corporal. / Introduction: The use of antipsychotics (AP), especially atypical (AA) in adults can lead to weight gain, obesity and cardiovascular disease risk. There are few studies related to the use of these medications in children and adolescents. Objective: To evaluate the nutritional status of adolescents according to the AP use of time, especially AA. Methodology: This study was approved by the Ethics Committee of the UFF (license number: 047536/2015). This is a convenience sample and cross-sectional study with 49 adolescents of both sexes aged 10 to 19 years in psychiatric treatment in CAPSi Ze Garoto- São Gonçalo / RJ. The study included adolescents with borderline intellectual deficit, autism, conduct disorder and psychosis. Excluding patients with endocrine-metabolic disease (diabetes, hypo- and hyperthyroidism). With authorization, the participants underwent anthropometric measurements of weight, height and waist circumference (PC) and were calculated the body mass index (BMI), considering the classification of z-score and percentile 75 of the sample as a cutoff point for PC ( P75 - PC: 96.5 cm). For body composition analysis, we selected a subsample of patients on risperidone use (RP) as the primary medication (schizophrenics and intellectual deficit) and analyzed body fat percentage (PGC) by bioimpedance scale and sum of skinfolds (SDC). Results: The study included 41 boys and 8 girls, mean age 14.4 ± 2.7 years. Of these, 8 were not receiving medication AP (SA), 32 used it for more than 1 year (> 1 year) and 9 used for less than one year (<1 year). There was a significant difference in BMI over time use of medication [Test Kruswall Wallis (median): SA = 18.55 / <1 year = 22.93 /> 1 year = 24.56 kg / m²; p = 0.003], being significantly higher BMI among those who used AP compared to unused and higher BMI in the first year of use [Mann-Whitney test, BMI x no x > 1 year, p = 0.028; BMI x no x <1 year, p = 0.221; BMI x <1 year x> 1 year, p = 0.757]. There were also more obese between AP users for more than 1 year (p = 0.007 - Chi square test; obese = 40.6%). Patients in PR use had higher mean BMI, independent of time [BMI x with and without risperidone / Mann-Whitney test, p = 0.034 (median) BMI S / = 19.61 / BMI C / = 24.80]; [BMI x time / Kruskal-Wallis test, p = 0.097]. Changes were found in the percentage of body fat (SDC) in relation to the RP use time, higher PGC among those who used RP compared to unused and higher in the first year of use. [Fat X Time / Kruskal-Wallis test, p = 0.038 ]; [Fat x with and without risperidone; Test Mann- Whitney, p = 0.018 / Fat S / = 20,40 and fat C / = 26.99 / Fat x no x 1 month - 1 year; Mann-Whitney test, p = 0.014 / Fat x no x> 1 year; Mann-Whitney test, p = 0.062]. Conclusion: The analysis suggests that there is temporal association between use of AP, increased BMI and obesity. The RP is associated with increased BMI and no temporal relationship between the use of RP and increased body fat.

Only one third of depressed patients experience a beneficial therapeutic effect after using a first-line medication, leaving two-thirds of patients without effective treatment. It has been shown that a combination of two drugs with different modes of action result in an increase in the number of patients responding to treatment. One of the most effective strategies is the addition of low doses of an atypical antipsychotic. In depth evaluation of the neurobiological properties of atypical antipsychotics have revealed that these agents produce antidepressant effects and enhance the therapeutic response of first-line medications through antagonism of the 5-HT2A, 5-HT2C, 5-HT1B/D, 5-HT7 receptors and NET; agonism of the 5-HT1A receptor; and/or D2/3 partial agonism. The present experiments focused on determining the mode of action of this combination of drugs to help design better antidepressant treatment in the future. A series of electrophysiological experiments were proposed to assess 5-HT and NE neurotransmission in the rat hippocampus, as well as DA transmission in the rat forebrain.

Les antipsychotiques sont des agents psychoactifs utilisés pour traiter les symptômes de la schizophrénie. Si la mise sur le marché de la seconde génération de molécule a permis de diminuer l’apparition des troubles extrapyramidaux, elle reste néanmoins associée à des effets secondaires caractérisés principalement par une prise de poids assortie d’une dyslipidémie et d'un développement du diabète de type 2. Ces effets indésirables entraînent chez les patients une dégradation de leurs conditions de vie et constituent l'une des principales causes d'abandon de ce traitement, les exposant à un risque accru de rechute. L’objectif de ce travail était double : (i) caractériser les troubles métaboliques induits par un traitement à long terme à la rispéridone en utilisant des techniques non-invasives de résonance magnétique ; (ii) prévenir ces troubles par un régime alimentaire supplémenté en curcuminoïdes. Notre modèle a permis de montrer qu'un traitement hebdomadaire de 24 semaines entraînait des perturbations apparentées au syndrome métabolique. L’imagerie par résonance magnétique était suffisamment sensible pour caractériser ces conséquences métaboliques iatrogènes et permettait de définir des biomarqueurs prédictifs de sévérité comme le ratio hydro-lipidique, le degré d’insaturation des acides gras et le remodelage de la répartition des tissus adipeux. Sur le plan pharmacologique, la supplémentation en curcuminoïdes permettait de prévenir l’hépatomégalie et l’intolérance au glucose induite par la rispéridone. Ces bénéfices étaient associés à une modulation de l’expression de gènes hépatiques impliqués dans la lipogenèse (FAS, ACC1), dans la lipolyse (ACO) ou bien dans l’inflammation (NFκB). Le cadre expérimental défini dans ce travail met en avant la possibilité de transférer cette approche prédictive par résonance magnétique en clinique humaine. / Antipsychotics are widely used psychoactive drugs for the treatment of schizophrenia symptoms. The use of second-generation agents has reduced the onset of extrapyramidal disorders, but still causes side effects comprising weight gain, dyslipidemia, and type-2 diabetes. The ensuing deterioration of patients’ conditions is one of the main reasons for the abandonment of this treatment exposing patients to an increased risk of relapse. This PhD had two objectives: (i) to characterize the metabolic disorders generated by a long-term treatment with risperidone, through the use of non-invasive techniques of magnetic resonance (MR); (ii) to prevent these disorders by means of a curcuminoid-supplemented diet. Our murine model enabled us to show that a 24-week treatment including weekly given risperidone induced metabolic disturbances related to the Metabolic Syndrome. Magnetic resonance imaging was sensitive enough to highlight these disturbances and to allow the identification of predictive biomarkers for severity such as the hydrolipidic ratio, fatty acid unsaturation rate, and adipose tissues repartitioning. At the pharmacological level, curcuminoid supplementation prevented the risperidone-induced hepatomegaly and glucose intolerance. These benefits were associated with the modulation of gene expression related to lipogenesis (FAS, ACC1), lipolysis (ACO) or inflammation (NFκB). In a clinical perspective, the herein PhD underlines the diagnostic potential of this MR-based experimental framework for the monitoring of metabolic disturbances.

Abstract The focus of this study was to examine mortality, disability, psychiatric treatment and medication utilizing register-based five-year follow-up data on all first-onset schizophrenia patients between the years 1995 to 2003 in Finland. The data were obtained from the Finnish Hospital Discharge Register, the national Finnish Causes of Death Register, and registers of pensions and reimbursed medicines. People with first-onset schizophrenia had a 4.45-fold higher mortality rate than the general population. Mortality was significantly elevated in all age groups. The most prominent single unnatural cause of death was suicide and the most common natural cause of death was circulatory diseases. Half of all first-onset schizophrenia patients retired on disability pension within the five-year follow-up period. Men retired at an earlier age and more commonly than women. Regional differences in mortality and disability retirement were evident. Patients first identified as outpatients had better outcomes than patients first identified following hospitalization. In total, 40% of outpatient-treated patients and 74% of hospital-treated patients had experienced a relapse during follow-up period. The use of second generation antipsychotics (SGAs) was associated with reduced risk of all-cause mortality, while clozapine was associated with lower suicide risk. First generation antipsychotics (FGAs) were associated with increased all-cause mortality and, particularly chlorprothixene, with increased suicide mortality. An increased likelihood of cardiovascular death was found among users of levomepromazine. In antidepressants, use of mirtazapine was associated with increased risk of suicide. In this study, the results and outcomes of first-onset schizophrenia patient treatment were analysed using register-based data. The results indicate that the outcome of first-onset schizophrenia is not good enough. Regional differences were seen in mortality and treatment practices. In clinical work more attention should be paid to health promotion and somatic screening, but also treatment of depressive symptoms. The results indicate that more effective treatments and rehabilitation are needed along with improved equality of treatment practices between hospital districts. / Tiivistelmä Tavoitteena oli tutkia skitsofreniaan sairastuneiden kuolleisuutta, työkyvyttömyyttä ja sairaalahoitoa sekä selvittää lääkehoidon yhteyttä kuolleisuuteen. Tutkimusaineistona olivat hoitoilmoitus-, kuolinsyyrekisteri-, eläkerekisteri- ja lääkekorvattavuustiedot. Tutkimusjoukkona olivat vuosien 1995-2003 aikana skitsofreniaan sairastuneet henkilöt. Seuranta-aika oli 5 vuotta. Skitsofreniaa sairastavien kuolleisuus oli 4.4 -kertainen normaaliväestöön verrattuna. Kuolleisuus oli korkeaa kaikissa ikäryhmissä sairastumisiästä riippumatta. Yleisin kuolinsyy oli itsemurha. Yleisin luonnollinen kuolinsyy olivat sydän- ja verenkiertoelinten sairaudet. Skitsofreniaan sairastuneista puolet jäi työkyvyttömyyseläkkeelle viiden vuoden seurannan aikana. Miehet eläköityivät nuorempina ja useammin kuin naiset. Kuolleisuudessa ja eläkkeelle siirtymisessä oli havaittavissa alueellista vaihtelua. Avohoidossa hoidetuilla vasta skitsofreniaan sairastuneilla oli parempi ennuste kuin sairaalahoitoon joutuneilla. Heidän kuolleisuutensa sekä sairaalahoitopäivien, relapsien ja vastentahtoisen hoidon määrät olivat alhaisemmat kuin sairaalassa hoidetuilla. Toisen polven antipsykoottien käyttö oli yhteydessä alentuneeseen kuolleisuuteen ja ensimmäisen polven antipsykootit kohonneeseen kuolemanriskiin. Klotsapiinin käyttö oli yhteydessä alhaisempaan itsemurhariskiin, kun taas masennuslääkkeistä mirtatsepiinin käyttö liittyi kohonneeseen itsemurhariskiin. Skitsofrenian hoidon kehittymisestä huolimatta sairauden ennuste on edelleen huono. Skitsofreniaa sairastavilla on yhä korkeampi kuolleisuusriski kuin muulla väestöllä. Hoitomenetelmien kehittymisestä huolimatta puolet sairastuneista on työkyvyttömyyseläkkeellä viiden vuoden kuluessa sairastumisesta. Sairauden vakavuutta osoittaa myös se, että iso osa skitsofreniaan sairastuneista tarvitsee useamman sairaalahoitojakson ja tahdosta riippumatonta hoitoa. Lisäksi useat tarvitsevat tuettua asumispalvelua. Skitsofrenian somaattisten sairauksien ja masennusoireiden arviointi vaatii edelleen huomioita. Hoitoon ja kuntoutukseen pitää panostaa ja taata, että skitsofrenian hoito olisi yhtä laadukasta koko Suomessa. Potilaat ovat eriarvoisessa asemassa, mikäli hoitokäytännöt ja mahdollisuus saada kuntoutusta vaihtelevat asuinpaikasta riippuen.

L’utilisation des antipsychotiques (AP) pour une indication non approuvée autrement dite off-label, peut être associée avec des effets indésirables graves chez les ainés. Étant donné le peu d’études portant sur le sujet, cette étude vise à déterminer la prévalence et les facteurs associés à l’utilisation off-label des AP chez les ainés âgés ≥ 65 ans vivant dans la communauté au Québec. Des analyses secondaires des données provenant de 2 enquêtes «l’Étude sur la Santé des Aînés» (ESA) et ESA-Services, étaient effectuées sur un échantillon total de 4018 ainés. L’utilisation off-label d’AP était définie par l’absence d’une indication approuvée selon la liste d’approbation publiée par Santé Canada en juin 2016, durant la même année. Les diagnostics ont été repérés dans les registres administratifs des services médicaux et pharmaceutiques de la « Régie de l’Assurance médicale du Québec» (RAMQ) en utilisant les codes internationaux de maladies (CIM-9) validés par d’autres études, et les codes CIM-10 appropriés selon la formule de changement CIM-9/10 fournie par la RAMQ. Le cadre conceptuel d’Andersen & Newman conçu pour expliquer le comportement de l'utilisation des services de santé selon trois catégories de facteurs (prédisposant, facilitants et de besoin) a été utilisé pour étudier, avec des régressions multinomiales, l’utilisation off-label des AP comparée à la non-utilisation et à l’utilisation approuvée dite labeled. La prévalence d’utilisation d’AP dans cet échantillon d’ainés était estimée à 2.5%. Parmi les utilisateurs d’AP, 78% étaient considérés comme off-label. L’utilisation off-label des antipsychotiques comparée à la non-utilisation était associée à l’âge (RC : 0.46; 95%CI: 0.27-0.78) , le niveau de scolarité (RC: 2.68; 95%IC: 1.64- 4.40), le nombre de visites ambulatoires incluant les visites chez le médecin traitant (≥ 6) (RC: 2.39; 95%IC: 1.34- 4.25), l’utilisation d’antidépresseurs ou de benzodiazépines (RC: 5.81; 95%IC: 3.31- 10.21), et la présence d’un syndrome cérébral organique et de la maladie d’Alzheimer (RC: 5.73; 95%IC: 1.74- 18.89). L’utilisation off-label des AP comparée à l’utilisation labeled était associée avec l’insomnie (RC: 0.13; 95%IC: 0.02- 0.91) et la dépression majeure (RC: 0.02; 95%IC: <0.01-0.11). Cette étude a montré une prévalence élevée de l’utilisation off-label des AP chez les ainés vivant dans la communauté au Québec. En résumé, l’utilisation off-label des AP était associée à la présence de visites ambulatoires répétées, l’utilisation d’autres médicaments psychotropes et la présence d’un syndrome cérébral organique, reflétant potentiellement un profil des cas cliniques plus complexes. / Abstract: The risk of using antipsychotics (AP) for off-label indications may outweigh the benefits in older adults. Due to the scarcity of studies describing off-label use of AP in older adults, this study aimed to determine the prevalence of the off-label use of AP in Quebec, and to determine, using Andersen & Newman’s model of healthcare seeking behaviour, the predisposing, enabling and need factors associated with the off-label use of AP. We used data from a socio-demographically (age, sex, and postal code representing population density) weighted sample (n = 4018) of older adults living in the community and who participated in the «Enquête sur la Santé des Aînés» (ESA) and ESA-Services health studies. AP use was identified from the RAMQ pharmaceutical registry. The presence of off-label use of AP (yes/no) was identified from validated ICD-9/10 diagnoses codes found in the RAMQ and MED-ÉCHO medical services and hospitalisations databases. The off-label use of AP was defined by the absence, during the same one-year period, of an approved indication for a delivered AP, according to Health Canada’s approval database as of June 2016. Multinomial logistic regression was used to study the off-label use of AP as compared to both labeled use and non-use as a function of predisposing, enabling and need factors. In this study, the prevalence of AP use reached 2.5%, of which 78% was off-label. Compared to non-use, off-label AP use was associated with age (OR: 0.46; 95%CI: 0.27-0.78); education level (OR: 2.68; 95% CI: 1.64- 4.40), a higher number of outpatient visits including physicians visits (OR: 2.39; 95%CI: 1.34- 4.25), antidepressant or benzodiazepine use (OR: 5.81; 95%CI: 3.31- 10.21), and the presence of an organic brain syndrome & Alzheimer’s disease (OR: 5.73; 95%CI: 1.74- 18.89). Compared to labeled use, off-label use was less likely in those with major depression (OR: 0.02; 95%CI: <0.01-0.11) and insomnia (OR: 0.13; 95%CI: 0.02- 0.91). In summary, off-label use is highly prevalent among community living older adults using AP. Off-label use was associated with the presence of an organic brain syndrome & Alzheimer’s disease, other psychotropic drug use and with increased outpatient visits, suggesting the off-label use of AP in more complex and severe clinical cases. Future longitudinal studies should focus on health related changes among incident off-label users of AP.

Os transtornos do espectro autista (TEA) são distúrbios neuropsiquiátricos bastante comuns, graves, e que propiciam grande impacto social e financeiro. A identificação de vias moleculares e processos celulares alterados que são compartilhados pelos pacientes, mesmo que estes apresentem causas etiológicas distintas, pode contribuir de forma significativa para o entendimento de sua patofisiologia desses transtornos. Ainda, a identificação destas vias pode propiciar o desenvolvimento de abordagens terapêuticas mais eficientes, uma vez que o uso de medicamentos nos TEA ainda é inadequado, envolvendo baixa melhora funcional e diversos efeitos colaterais, como o ganho excessivo de peso e anormalidades metabólicas associadas. Neste trabalho, selecionamos como uma primeira abordagem o estudo da via de sinalização PI3K-mTOR em pacientes com TEA não-sindrômico, via esta envolvida com diversos aspectos do desenvolvimento e funcionamento neuronal, assim como com a patofisiologia de síndromes monogênicas que apresentam alta prevalência de TEA em seu quadro clínico. Foram utilizadas como modelo experimental in vitro células-tronco mesenquimais provenientes de polpa de dente decíduo (SHEDs) de pacientes e indivíduos controles. Os resultados aqui obtidos sugerem a importância da desregulação da via PI3K/mTOR na patofisiologia de uma parcela importante dos casos de TEA não-sindrômico. Ainda, observamos que as células dos pacientes com alterações nessa via de sinalização apresentam maior capacidade proliferativa, e que a modulação deste fenótipo alterado por meio do uso concomitante de inibidores de PI3K e mTOR nas células de um destes pacientes sugere esta via como um alvo promissor para o desenvolvimento de novas abordagens terapêuticas para estes pacientes. Em seguida, na tentativa de desvendar os mecanismos subjacentes aos efeitos metabólicos adversos associados com o uso de antipsicóticos prescritos para o tratamento de pacientes com TEA, investigamos os efeitos destes psicofármacos sobre a biologia do tecido adiposo humano. Foram utilizadas como modelos in vitro células-tronco (ADSCs) e adipócitos maduros derivados de tecido adiposo humano de indivíduos controles. Os resultados obtidos sugerem que a ação direta dos antipsicóticos com alta propensão ao ganho de peso (como a olanzapina e a clozapina) sobre a proliferação, diferenciação, e o metabolismo do tecido adiposo humano parece não constituir um mecanismo importante associado ao ganho de peso apresentado pelos pacientes, e que a ação desses medicamentos sobre os sistemas centrais que regulam o peso e o metabolismo deve ser o mecanismo principal levando aos efeitos metabólicos adversos. Juntos, os resultados gerados neste trabalho podem, de certa forma, contribuir para da farmacoterapia dos TEA / Autism spectrum disorders (ASD) are common neuropsypchiatric disorders, which has serious social and economic impacts. Identification of common molecular and cellular processes altered in patients, despite the underlying genetic heterogeneity, can contribute significantly to our understanding of the disease pathophysiology and can help to develop more effective treatments, since available pharmacotherapy for ASD is inefficient and frequently associated with adverse side effects, such as weight gain and metabolic disturbances. Here, we used patient-derived Stem cells from Human Exfoliated Deciduous teeth (SHEDs) as an intro model system to investigate whether non-syndromic ASD patients show altered regulation of PI3K/mTOR signaling pathway, which is involved in multiple aspects of neuronal development and physiology, and in the pathogenesis of monogenic syndromes that share features with ASD. Our results suggest that dysregulation of PI3K/mTOR-linked networks play an important role in the pathogenesis of a subgroup of non-syndromic ASD. In addition, we found enhanced proliferative capacity in cells with altered PI3K/mTOR activity, which was rescued in one of these patients through combined pharmacological inhibition of both PI3K and mTOR kinase activity, suggesting that PI3K-mTOR signaling is a promising target for the development of new therapeutic approaches for these individuals. Next, in an attempt to better understand the mechanisms underlying the metabolic side effects of the antipsychotics prescribed for ASD treatment, we investigated the effects of some of these drugs on the biology of human adipose tissue using as in vitro model systems human adipose-derived stem cells (ADSCs) and mature adipocytes. Our results suggest that a direct and potent effect of antipsychotics with high weight gain liability (such as clozapine and olanzapine) on cell proliferation, differentiation, and metabolism of human adipose tissue is not an important mechanism by which these drugs induce metabolic disturbances. Consequently, our results suggest that these side effects may mainly reflect the action of these drugs on central pathways involved in weight control and metabolism. Together, our results can, to some extent, contribute to improving pharmacotherapy of ASD

Breast cancer is the most prevalent form of cancer and the second leading cause of mortality, affecting 1 in 9 women in the United States. Recent studies have shown that antipsychotic drug use is associated with increased prolactin levels, which, in turn, is associated with increased risk of breast cancer. However, studies of the association between antipsychotic drug use and the risk of breast cancer are sparse and have largely been conducted in homogenous populations. Therefore, we evaluated this relationship in postmenopausal women (N = 119 524) in a diverse population of the Women’s Health Initiative (WHI) cohort. Antipsychotic drug use was self-reported and in situ and invasive breast cancer cases were confirmed by medical records for the WHI clinical trial (CT) and the WHI observational study (OS), from 1993 through 2018. We used Cox proportional hazards regression to model breast cancer risk against antipsychotic drug use while adjusting for dietary and lifestyle factors. Overall, antipsychotic users made up 0.41% of this population. There was no overall association between antipsychotic drug use and postmenopausal breast cancer risk (HR = 1.01, 95% CI = 0.73 – 1.40). Among typical antipsychotic drug users, there was a suggested two-fold increased risk in developing in situ breast cancer (HR = 2.02, 95% CI = 0.84, 4.86). Thus, antipsychotic drug use does not appear to increase breast cancer risk overall, but the potential association between antipsychotics and in situ breast cancer merits further study.

Oscillations in the brain’s electrical potential, recorded through the technique of electroencephalography (EEG), reflect the ensemble activity of a large population of neurons. Auditory steady-state response (ASSR) is the time-locked entrainment in EEG to an auditory stimulus such as a train of clicks. ASSR to a 40 Hz (gamma frequency) click train is especially reduced in schizophrenia patients, reflecting the sensory processing deficits that impact real-world functional outcomes. Since the 40 Hz ASSR is demonstrable across species and is responsive to pharmacological treatments, it can be a translational biomarker for drug development studies. Prototypical antipsychotic drugs (APDs) like haloperidol and clozapine are examples of typical and atypical classes used to treat schizophrenia patients. While both are D2 receptor blockers, they have additional pharmacological effects that may differentiate them. Here, we investigated the acute effect of clozapine (atypical) or haloperidol (typical) on the 40 Hz ASSR, in two independent studies. The doses for the two drugs were chosen to reflect comparable in vivo D2 receptor occupancy. We used female Sprague-Dawley rats implanted with epidural EEG recording electrodes. In the first experiment, vehicle or clozapine 2.5, 5, and 10 mg/kg were administered (sc) and the 40 Hz ASSR paradigm (65 dB, 40 clicks for 1 second, 2-sec inter-stimulus interval) was used to record responses at 30, 60, 90 and 120 minutes post-drug. Resting-state EEG was recorded at 60 minutes post-treatment. Treatment effects were evaluated on the evoked power and phase-locking factor (PLF), a measure of trial-to-trial consistency of the 40 Hz ASSR. Clozapine improved both measures in a dose and time-dependent manner. Clozapine also tended to reduce the resting-state gamma (30-100 Hz) power, a hallmark of cortical noise. However, the effect was not significant (P>0.05). Next, we tested the effect of haloperidol on the 40 Hz ASSR. Doses of 0.02 mg/kg -0.08 mg/kg (sc) were evaluated at 30, 60, 90 and 120-minutes post-injection. Haloperidol failed to improve the 40 Hz ASSR (evoked power and PLF). Moreover, it had no discernible effect on the resting-state gamma. These results show that despite the comparable blockade of D2 receptors, the putative target for these APDs, clozapine, and haloperidol have different effects on the 40 Hz ASSR. We conclude that the effects of clozapine on 40 Hz ASSR may be unrelated to its affinity to D2 receptors and may be mediated through other pharmacological mechanisms.