La récupération fonctionnelle des patients victimes d’un accident vasculaire cérébral (AVC) ischémique est largement sous-tendue par les propriétés plastiques du cerveau et plus précisément par sa capacité à remodeler les réseaux de neurones épargnés par l’infarctus. Les études réalisées sur différents modèles animaux d’infarctus cérébral s’accordent à montrer que ces changements plastiques sont induits par le BDNF (Brain-Derived Neurotrophic Factor). Aussi, augmenter les taux cérébraux de BDNF est considéré comme une stratégie thérapeutique prometteuse de réduction des déficiences post-AVC. Dans ce contexte, notre travail avait 2 objectifs : 1) chez le rat, identifier les cellules impliquées dans la surproduction de BDNF et évaluer la pertinence de la mesure des taux circulants de BDNF pour estimer les taux de BDNF présents dans le cerveau, 2) chez le patient victime d’un infarctus cérébral, étudier l’efficacité de la fluoxétine sur la récupération motrice à 3 mois, la fluoxétine étant un inhibiteur spécifique de la recapture de la sérotonine commercialisé comme antidépresseur et capable non seulement d’augmenter la production cérébrale de BDNF mais aussi de stimuler la plasticité post-lésionnelle.Les études précliniques ont été réalisées chez le rat soumis à l’embolisation unilatérale du cerveau par un nombre variable de microsphères (en carbone et calibrées à 50 µm) afin de reproduire le large panel de souffrance cérébrale rencontré en clinique. Le BDNF a été mesuré dans le cerveau et dans le sang (plasma et sérum par technique ELISA) avant et après (4, 24h et 8j) embolisation. Nos résultats montrent :- que la production de BDNF est plus intense et plus durable dans l’hémisphère embolisé que dans l’hémisphère non embolisé et que cette production est indépendante du degré d’embolisation, marqueur indirect de la souffrance cérébrale. - que les cellules non-neuronales deviennent une source non négligeable de BDNF en cas d’ischémie, notamment les cellules endothéliales et microgliales avant 24h et les astrocytes au temps 8j.- que les taux circulants et cérébraux de BDNF ne sont pas corrélés mais qu’il existe une corrélation entre le BDNF plasmatique mesuré au temps 4h et le degré d’embolisation.L’étude clinique correspond à un essai randomisé contrôlé en double aveugle comparant la fluoxétine (20mg/j, voie orale, pendant 3 mois et débutée entre 5 et 10j après les premiers symptômes) au placebo chez des patients présentant un déficit moteur modéré à sévère sur l’échelle motrice de Fugl-Meyer (n=59 dans chaque groupe). Nos résultats montrent que l’amélioration de la fonction motrice est meilleure sous fluoxétine que placebo. En conclusion, notre travail montre l’intérêt des médicaments capables d’augmenter le BDNF et la plasticité post-lésionnelle pour améliorer le pronostic clinique de l’AVC et identifie pour la première fois les cellules endothéliales cérébrales comme une cible potentielle de ces médicaments. Il remet également en cause l’idée largement répandue selon laquelle les taux circulants de BDNF varient dans le même sens que les taux cérébraux. / Functional recovery after ischemic stroke largely involves brain plasticity and more accurately its ability to reorganize the neuronal networks spared by the infarct. Studies conducted on animals using different ischemic stroke models have demonstrated that plastic changes are induced by BDNF (Brain-Derived Neurotrophic Factor). Hence, increasing levels of BDNF in the brain is considered a promising therapeutic strategy to reduce post-stroke impairments. In this context, our work had 2 aims: 1) In a rat model, to identify cells involved in the over-production of BDNF and to evaluate the pertinence of the measurement of circulating BDNF levels to estimate brain BDNF levels; 2) In ischemic stroke patients, to study the effectiveness of fluoxetin on 3-month motor recovery. This drug is a selective serotonin-reuptake inhibitor commercialized as an antidepressant treatment that is not only able to increase brain production of BDNF, but also to stimulate post-lesion plasticity. Animal studies were performed on rats that underwent unilateral embolization of the brain with various amounts of carbonized calibrated (50 µm) micropsheres in order to mimick the large panel of brain injury observed in humans. BDNF levels were measured in the brain and the blood (plasma and serum, ELISA method) before and after (4, 24h, and 8d) embolization. Our results show that:- The production of BDNF was more intense and longer lasting in the embolized than in the non-embolized hemisphere, and this production was independent of the degree of embolization, an indirect marker of brain injury.- Several non-neuronal cells become a non-negligible source of BDNF after ischemia, particularly endothelial cells and microglia before 24h, and astrocytes at 8d.- Brain and circulating levels of BDNF did not correlate, but a correlation between plasma BDNF at 4h and the degree of embolization was noted.Our clinical study was a randomized placebo-controlled trial that evaluated the efficacy of fluoxetine (20mg/d, oral route, over 3 months, and starting between 5 and 10d after stroke onset) in patients with moderate to severe motor impairment measured by the Fugl-Meyer motor scale (n=59 in each group). Our results showed a greater improvement in motor recovery under fluoxetin than placebo.To conclude, our work underlines the fact that treatments able to increase BDNF levels and post-lesion brain plasticity are of interest to improve the prognosis after stroke. We have shown, for the first time, that endothelial cells are a potential target for these treatments. Our study also calls into question the widespread idea according to which circulating levels of BDNF vary in the same way as levels of BDNF in the brain.

O objetivo deste estudo foi verificar a elaboração e a recontagem de histórias de crianças com o diagnóstico de depressão maior unipolar (DSM-IV, 1997), bem como a influência da terapia medicamentosa com fluoxetina em um estudo duplo-cego longitudinal controlado com placebo. Fizeram parte do estudo trinta sujeitos com idades entre 10 e 14 anos e diagnosticados com depressão, randomizados para o uso de fluoxetina ou placebo. Ambos os grupos foram avaliados quanto à elaboração livre de textos orais e escritos e à recontagem de textos (fábulas de Êsopo ou La Fontaine) na etapa 0 (sem o uso de medicação) e na etapa 3 (três meses após a introdução de medicação ou placebo). Os textos foram analisados de acordo com o modelo de Kintsch e Van Dijk (1978), baseado no número de macro e microestruturas produzidas e/ou recordadas e nos componentes relativos à superestrutura textual. A este modelo foi acrescida a análise do conteúdo proposicional (positivo, negativo ou neutro), com o intuito de observar o fenômeno da “memória condizente com o humor". Não foram observadas diferenças significativas com relação a esses critérios entre os grupos ou períodos analisados, nem quanto à produção e/ou recontagem de textos orais ou escritos, mesmo com a melhora da sintomatologia clínica observada por meio da escala CDRS (Poznanski & Mokros, 1996). / The aim of this study was to evaluate the textual production and recontagem of children with unipolar major depression (DSM-IV, 1997), and the influence of drug therapy with fluoxetine in a longitudinal, double-blinded, placebo-controlled study. Thirty subjects with depression, aged between 10 and 14 years, were selected and randomized for the use of fluoxetine or placebo. Both groups were analyzed regarding to spontaneous oral and written production and to the recontagem of the texts (Esopo’s or La Fontaine’s fables) in the period zero (without medication) and period 3 (three months after starting placebo or fluoxetine). The texts were analyzed according to Kintsch and Van Dijk’s model (1978), taking in account the number of macro and microstructures elaborated and/or recalled and the textual superstructure. We added to this model the proposition-content analysis (positive, negative or neutral), in order to observe the “mood-congruent memory" phenomenon. Regarding these criteria, no differences were found amongst the groups or periods analyzed, neither amongst the oral and written elaborated or recontados texts, even after the improvement of clinical symptoms evaluated by CDRS scale (Poznanski and Mokros, 1996).

O objetivo deste estudo foi verificar a elaboração e a recontagem de histórias de crianças com o diagnóstico de depressão maior unipolar (DSM-IV, 1997), bem como a influência da terapia medicamentosa com fluoxetina em um estudo duplo-cego longitudinal controlado com placebo. Fizeram parte do estudo trinta sujeitos com idades entre 10 e 14 anos e diagnosticados com depressão, randomizados para o uso de fluoxetina ou placebo. Ambos os grupos foram avaliados quanto à elaboração livre de textos orais e escritos e à recontagem de textos (fábulas de Êsopo ou La Fontaine) na etapa 0 (sem o uso de medicação) e na etapa 3 (três meses após a introdução de medicação ou placebo). Os textos foram analisados de acordo com o modelo de Kintsch e Van Dijk (1978), baseado no número de macro e microestruturas produzidas e/ou recordadas e nos componentes relativos à superestrutura textual. A este modelo foi acrescida a análise do conteúdo proposicional (positivo, negativo ou neutro), com o intuito de observar o fenômeno da “memória condizente com o humor”. Não foram observadas diferenças significativas com relação a esses critérios entre os grupos ou períodos analisados, nem quanto à produção e/ou recontagem de textos orais ou escritos, mesmo com a melhora da sintomatologia clínica observada por meio da escala CDRS (Poznanski & Mokros, 1996). / The aim of this study was to evaluate the textual production and recontagem of children with unipolar major depression (DSM-IV, 1997), and the influence of drug therapy with fluoxetine in a longitudinal, double-blinded, placebo-controlled study. Thirty subjects with depression, aged between 10 and 14 years, were selected and randomized for the use of fluoxetine or placebo. Both groups were analyzed regarding to spontaneous oral and written production and to the recontagem of the texts (Esopo’s or La Fontaine’s fables) in the period zero (without medication) and period 3 (three months after starting placebo or fluoxetine). The texts were analyzed according to Kintsch and Van Dijk’s model (1978), taking in account the number of macro and microstructures elaborated and/or recalled and the textual superstructure. We added to this model the proposition-content analysis (positive, negative or neutral), in order to observe the “mood-congruent memory” phenomenon. Regarding these criteria, no differences were found amongst the groups or periods analyzed, neither amongst the oral and written elaborated or recontados texts, even after the improvement of clinical symptoms evaluated by CDRS scale (Poznanski and Mokros, 1996).

Background: Antidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain. Methods: Systematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis. results: Out of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects. conclusion: Our synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients’ comorbidities and co-medication.

Fluoxetin är den aktiva substansen i många serotoninreglerande läkemedel som förs in i vattendrag. Substansen har visats påverka beteende av vattenlevande organismer som fiskar, mollusker och kräftdjur genom att öka deras djärvhet. I denna studie undersöktes fluoxetins akuta (på vildfångade individer) och kroniska (på labbuppfödda individer) effekter av koncentrationerna 0, 3 och 30 ng L-1 på Asellus aquaticus (sötvattengråsugga) antipredatorbeteende. Detta gjordes genom tre beteendetest: (1) tid att lämna refug, (2) spontan aktivitet samt (3) flyktbeteende under predationsrisk. Överlag hittades få eller inga effekter på A. aquaticus från fluoxetin. De effekter som dock påverkade individer signifikant visade att exponerade individer flydde en signifikant kortare (30 %) tidsperiod från en simulerad predatorattack. Utöver denna huvudeffekt av fluoxetin hittades även signifikanta skillnader i fluoxetins påverkan på de två grupperna, när individer blev utsatta för den högsta koncentrationen ökade vildfångade individer sin aktivitet (38 % fler stopp och 49 % mer rörelse) medan labbuppfödda individer sänkte sin aktivitet (43 % färre stopp och 37 % mindre rörelse). Individer som inte var exponerade visade signifikanta skillnader i alla beteendetest för de två grupperna. Det är troligt att beteendeskillnader är en följd av olika uppfödningsmiljöer, dock går det inte att utesluta att ändrade genfrekvenser uppkommit. Studien lyser sken på behovet av fler studier av långtidsexponering av läkemedelsrester, de är sällan akut giftiga men har däremot subletal påverkan i låga doser. / Fluoxetine is the active substance in many selective serotonin reuptake inhibitive pharmaceuticals that currently enters surface waters. The substance has been shown to affect behaviors of water living organism such as fish, molluscs and crustaceans by making them less cautious. This study investigated the acute (on wild caught individuals) and chronic (on lab reared individuals) effects of fluoxetine on the antipredator behavior of Asellus aquaticus for three concentrations; 0,3 and 30 ng L-1. Three tests were used to determine the effects: (1) time to leave a shelter, (2) spontaneous activity and (3) escape behavior under predation risk. Few statistically significant effects of fluoxetine on A. aquaticus were found. However, individuals exposed to fluoxetine had a significantly shorter (30 %) escape period. Besides this main effect of fluoxetine, significant interactions between the two groups and fluoxetine were also found. When exposed to the highest concentration wild caught individuals increased their spontaneous activity (38 % more stops and 49 % more movement), while lab reared individuals reduced their activity (43 % fewer stop and 37 % less movement). Furthermore, non-exposed individuals from the two groups behaved significantly different in all the tests. It is likely that the differences in behavior occurred due to environmental effects of laboratory rearing, although altered gene frequencies cannot be excluded. This study emphasizes the need for development of methods for more chronic testing of pharmaceuticals, especially considering that pharmaceuticals are seldom acutely toxic but often has sub lethal effects in low doses.

Background: Antidepressants are widely used in the treatment of chronic pain. Applied doses are lower than those needed to unfold an antidepressive effect. While efficacy of antidepressants for chronic pain has been reported in large randomized-controlled trials (RCT), there is inconsistent data on adverse effects and tolerability. We aimed at synthesizing data from RCT to explore adverse effect profiles and tolerability of antidepressants for treatment of chronic pain. Methods: Systematic literature research and meta-analyses were performed regarding side effects and safety of different antidepressants in the treatment of chronic pain according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The National Center for Biotechnology Information library and MEDLINE were searched. Randomized placebo-controlled trials were included in quantitative data synthesis. results: Out of 1,975 screened articles, 33 papers published between 1995 and 2015 were included in our review and 23 studies were included in the meta-analyses. A higher risk for adverse effects compared to placebo was observed in all antidepressants included in our analyses, except nortriptyline. The most prevalent adverse effects were dry mouth, dizziness, nausea, headache, and constipation. Amitriptyline, mirtazapine, desipramine, venlafaxine, fluoxetine, and nortriptyline showed the highest placebo effect-adjusted risk of adverse effects. Risk for withdrawal due to adverse effects was highest in desipramine (risk ratio: 4.09, 95%-confidence interval [1.31; 12.82]) followed by milnacipran, venlafaxine, and duloxetine. The most common adverse effects under treatment with antidepressants were dry mouth, dizziness, nausea, headache, and constipation followed by palpitations, sweating, and drowsiness. However, overall tolerability was high. Each antidepressant showed distinct risk profiles of adverse effects. conclusion: Our synthesized data analysis confirmed overall tolerability of low-dose antidepressants for the treatment of chronic pain and revealed drug specific risk profiles. This encompassing characterization of adverse effect profiles might be useful in defining multimodal treatment regimens for chronic pain which also consider patients’ comorbidities and co-medication.