Stroke is the major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression. Recently, small trials have demonstrated that SSRIs might improve recovery after stroke, even in people who are not depressed. Systematic reviews and meta-analyses are the least biased way to bring together data from several trials. Given the promising effect of SSRIs on stroke recovery seen in small trials, a systematic review and meta-analysis is needed. To determine whether SSRIs improve recovery after stroke, and whether treatment with SSRIs was associated with adverse effects. We searched the Cochrane Stroke Group Trials Register (August 2011), Cochrane Depression Anxiety and Neurosis Group Trials Register (November 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8), MEDLINE (from 1948 to August 2011), EMBASE (from 1980 to August 2011), CINAHL (from 1982 to August 2011), AMED (Allied and Complementary Medicine) (from 1985 to August 2011), PsycINFO (from 1967 to August 2011) and PsycBITE (Pyschological Database for Brain Impairment Treatment Efficacy) (March 2012). To identify further published, unpublished and ongoing trials we searched trials registers, pharmaceutical websites, reference lists, contacted experts and performed citation tracking of included studies. We included randomised controlled trials that recruited stroke survivors (ischaemic or haemorrhagic) at any time within the first year. The intervention was any SSRI, given at any dose, for any period. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. In order to be included, trials had to collect data on at least one of our primary (dependence and disability) or secondary (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early) outcomes. We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. For trials in English, two review authors independently extracted data. For Chinese papers, one review author extracted data. We used standardised mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous effects, with their 95% confidence intervals (CIs). We identified 56 completed trials of SSRI versus control, of which 52 trials (4060 participants) provided data for meta-analysis. There were statistically significant benefits of SSRI on both of the primary outcomes: RR for reducing dependency at the end of treatment was 0.81 (95% CI 0.68 to 0.97) based on one trial, and for disability score, the SMD was 0.92 (95% CI 0.62 to 1.23) (22 trials involving 1310 participants) with high heterogeneity between trials (I² = 85%; P < 0.0001). For neurological deficit, depression and anxiety, there were statistically significant benefits of SSRIs. For neurological deficit score, the SMD was -1.00 (95% CI -1.26 to -0.75) (29 trials involving 2011 participants) with high heterogeneity between trials (I² = 86%; P < 0.00001). For dichotomous depression scores, the RR was 0.43 (95% CI 0.24 to 0.77) (eight trials involving 771 participants) with high heterogeneity between trials (I² = 77%; P < 0.0001). For continuous depression scores, the SMD was -1.91 (95% CI -2.34 to -1.48) (39 trials involving 2728 participants) with high heterogeneity between trials (I² = 95%; P < 0.00001). For anxiety, the SMD was -0.77 (95% CI -1.52 to -0.02) (eight trials involving 413 participants) with high heterogeneity between trials (I² = 92%; P < 0.00001). There was no statistically significant benefit of SSRI on cognition, death, motor deficits and leaving the trial early. For cognition, the SMD was 0.32 (95% CI -0.23 to 0.86), (seven trials involving 425 participants) with high heterogeneity between trials (I² = 86%; P < 0.00001). The RR for death was 0.76 (95% CI 0.34 to 1.70) (46 trials involving 3344 participants) with no heterogeneity between trials (I² = 0%; P = 0.85). For motor deficits, the SMD was -0.33 (95% CI -1.22 to 0.56) (two trials involving 145 participants). The RR for leaving the trial early was 1.02 (95% CI 0.86 to 1.21) in favour of control, with no heterogeneity between trials. There was a non-significant excess of seizures (RR 2.67; 95% CI 0.61 to 11.63) (seven trials involving 444 participants), a non-significant excess of gastrointestinal side effects (RR 1.90; 95% CI 0.94 to 3.85) (14 trials involving 902 participants) and a non-significant excess of bleeding (RR 1.63; 95% CI 0.20 to 13.05) (two trials involving 249 participants) in those allocated SSRIs. Data were not available on quality of life, fatigue or healthcare costs. There was no clear evidence from subgroup analyses that one SSRI was consistently superior to another, or that time since stroke or depression at baseline had a major influence on effect sizes. Sensitivity analyses suggested that effect sizes were smaller when we excluded trials at high or unclear risk of bias. Only eight trials provided data on outcomes after treatment had been completed; the effect sizes were generally in favour of SSRIs but CIs were wide. SSRIs appeared to improve dependence, disability, neurological impairment, anxiety and depression after stroke, but there was heterogeneity between trials and methodological limitations in a substantial proportion of the trials. Large, well-designed trials are now needed to determine whether SSRIs should be given routinely to patients with stroke. Inhibiteurs sélectifs de la capture de la sérotonine (ISRS) après un AVC L'accident vasculaire cérébral est une cause majeure d'invalidité chez l'adulte. Les inhibiteurs sélectifs de la capture de la sérotonine (ISRS) sont utilisés depuis de nombreuses années pour la prise en charge de la dépression. Récemment, de petits essais ont démontré que les ISRS pourraient améliorer la récupération après un AVC, même chez les personnes qui ne sont dépressives. Les revues systématiques et les méta-analyses sont l'approche qui présente le moins de risque de biais pour regrouper des données issues de plusieurs essais. Étant donné l'effet prometteur observé des ISRS sur la récupération après un AVC dans le cadre de petits essais, une revue systématique et une méta-analyse sont nécessaires. Déterminer si les ISRS améliorent la récupération après un AVC et si le traitement par ISRS a été associé à des effets indésirables. Nous avons effectué une recherche dans le registre des essais cliniques du groupe Cochrane sur les accidents vasculaires cérébraux (août 2011), le registre du groupe Cochrane sur la dépression, l’anxiété et la névrose (novembre 2011), le registre Cochrane des essais contrôlés (CENTRAL) (The Cochrane Library 2011, numéro 8), MEDLINE (de 1948 à août 2011), EMBASE (de1980 à août 2011), CINAHL (de 1982 à août 2011), AMED (Allied and Complementary Medicine) (de 1985 à août 2011), PsycINFO (de 1967 à août 2011) et PsycBITE (Pyschological Database for Brain Impairment Treatment Efficacy) (mars 2012). Pour identifier d'autres essais publiés, non-publiés et en cours, nous avons effectué une recherche dans les registres d'essais cliniques, les sites web pharmaceutiques, les bibliographies, avons contactés des experts et consulté les références citées dans les études incluses. Nous avons inclus des essais contrôlés randomisés qui ont recrutés des survivants à un AVC (ischémique ou hémorragique) au cours de l'année précédente. L'intervention était n'importe quel ISRS, administré à n'importe quelle dose, pendant n'importe quelle durée. Nous avons exclu les médicaments avec des effets pharmacologiques mixtes. L'agent comparateur était le soin de référence ou un placebo. Pour être inclus, les essais devaient recueillir des données sur au moins nos critères d'évaluation principaux (dépendance et invalidité) ou secondaires (déficits, dépression, anxiété, qualité de vie, fatigue, coût des soins de santé, décès, événements indésirables et abandon prématuré de l'essai). Nous avons extrait des données sur les caractéristiques démographiques, le type d'AVC, la durée écoulée depuis l'AVC, nos critères d'évaluation principaux et secondaires et les sources de biais. Pour les essais en anglais deux auteurs de la revue ont extrait les données de façon indépendante. Pour les articles chinois, un auteur de la revue a extrait les données. Nous avons utilisé la différence moyenne standardisée (DMS) pour estimer les effets des traitements pour des variables continues, et le risque relatif (RR) pour les effets dichotomiques, avec leurs intervalles de confiance (IC). Nous avons identifié 56 essais achevés sur des ISRS comparés à un agent de contrôle, dont 52 (4060 participants) ont fourni des données pour une méta-analyse. Les ISRS ont montré des bénéfices statistiquement significatifs sur les deux critères d'évaluation principaux : Le RR pour la diminution de la dépendance à la fin du traitement était de 0,81 (IC à 95 % de 0,68 à 0,97) d'après un essai, et pour le score d'incapacité, la DMS était de 0,92 (IC à 95 % de 0,62 à 1,23) (22 essais impliquant 1310 participants) avec une forte hétérogénéité entre les essais (I² = 85 % ; P < 0,0001). Pour le déficit neurologique, la dépression et l'anxiété, les ISRS ont montré des bénéfices statistiquement significatifs. Pour le score de déficit neurologique, la DMS était de -1,00 (IC à 95 % de -1,26 à -0,75) (29 essais impliquant 2011 participants) avec une forte hétérogénéité entre les essais (I² = 86 % ; P < 0,00001). Pour les scores de dépression dichotomiques, le RR était de 0,43 (IC à 95 % de 0,24 à 0,77) (huit essais impliquant 771 participants) avec une forte hétérogénéité entre les essais (I² = 77 % ; P < 0,0001). Pour les scores de dépression continus, la DMS était de -1,91 (IC à 95 % de -2,34 à -1,48) (39 essais impliquant 2728 participants) avec une forte hétérogénéité entre les essais (I² = 95 % ; P < 0,00001). Pour l'anxiété, la DMS était de -0,77 (IC à 95 % de -1,52 à -0,02) (huit essais impliquant 413 participants) avec une forte hétérogénéité entre les essais (I² = 92 % ; P < 0,00001). Les ISRS n'ont pas montré de bénéfice statistiquement significatif sur la fonction cognitive, les décès, les déficits moteurs et l'abandon prématuré de l'essai. Pour la fonction cognitive, la DMS était de 0,32 (IC à 95 % de -0,23 à 0,86), (sept essais impliquant 425 participants) avec une forte hétérogénéité entre les essais (I² = 86 % ; P < 0,00001). Le RR pour les décès était de 0,76 (IC à 95 % de 0,34 à 1,70) (46 essais impliquant 3344 participants) sans avec hétérogénéité entre les essais (I² = 0 % ; P = 0,85). Pour les déficits moteurs, la DMS était de -0,33 (IC à 95 % de -1,22 à 0,56) (deux essais impliquant 145 participants). Le RR pour l'abandon prématuré de l'essai était de 1,02 (IC à 95 % de 0,86 à 1,21) en faveur du groupe de contrôle, sans hétérogénéité entre les essais. Il y a eu une augmentation non significative des crises convulsives (RR 2,67 ; IC à 95 % de 0,61 à 11,63) (sept essais impliquant 444 participants), une augmentation non significative d'effets secondaires gastro-intestinaux (RR 1,90 ; IC à 95 % de 0,94 à 3,85) (14 essais impliquant 902 participants) et une augmentation non significative des saignements (RR 1,63 ; IC à 95 % de 0,20 à 13,05) (deux essais impliquant 249 participants) chez les patients recevant les ISRS. Aucune donnée n'était disponible sur la qualité de vie, la fatigue ou les coûts des soins médicaux. Les analyses des sous-groupes n'ont pas démontré de façon claire qu'un ISRS était systématiquement supérieur à un autre, ni que le temps écoulé entre l'AVC ou la dépression et la visite de référence avait une influence majeure sur l'importance des effets. Les analyses de sensibilité ont suggéré que l'importance des effets était moindre lorsque nous avons exclus les essais présentant un risque de biais élevé ou indéterminé. Seuls huit essais ont fourni des données sur les résultats cliniques après l'achèvement du traitement ; l'importance des effets étaient, dans l'ensemble, en faveur des ISRS, mais les IC étaient importants. Les ISRS ont semblé améliorer la dépendance, l'incapacité, le déficit neurologique, l'anxiété et la dépression après un AVC, mais les essais étaient hétérogènes et présentaient des limites substantielles en termes de méthodologie. Des essais bien conçus, à grande échelle sont désormais nécessaires pour déterminer si les ISRS doivent être administrés de façon standard aux patients après un AVC. Inibidores seletivos da recaptação da serotonina (ISRSs) na recuperação de pacientes com acidente vascular cerebral O acidente vascular cerebral (AVC) é uma causa importante de incapacidade em adultos. Os inibidores seletivos da recaptação da serotonina (ISRSs) têm sido usados por muitos anos para o tratamento da depressão. Recentemente alguns ensaios clínicos com poucos participantes mostraram que os ISRSs pode melhorar a recuperação de pacientes que sofreram um AVC, mesmo que eles não estejam deprimidos. As revisões sistemáticas e metanálises são a maneira de reunir dados de vários estudos que têm o menor risco de viés. Tendo em vista os resultados promissores de estudos pequenos sobre os ISRSs nos pacientes com AVC, é necessária uma revisão sistemática e metanálise. Avaliar se os ISRSs melhoram a recuperação de pacientes com AVC, e se esse tratamento provoca efeitos adversos. As buscas foram realizadas nas seguintes bases de dados eletrônicas: Cochrane Stroke Group Trials Register (agosto de 2011), Cochrane Depression Anxiety and Neurosis Group Trials Register (novembro de 2011), Cochrane Central Register of Controled Trials (CENTRAL)The Cochrane Library 2011, edição 8), MEDLINE (desde 1948 a agosto de 2011), Embase (desde 1980 a agosto de 2011), CINAHL (desde 1982 a agosto de 2011), AMED (Allied and Complementary Medicine) (desde 1985 a agosto de 2011), PsycINFO (desde 1967 a agosto de 2011) e PsycBITE (Psychological Database for Brain Impairment Treatment Efficacy) (março de 2012). Para identificar mais estudos publicados, não publicados e em andamento, fizemos buscas nas plataformas de registros de ensaios clínicos, nas páginas web da indústria farmacêutica e nas listas de referência dos estudos incluídos. Também entramos em contato com especialistas e realizamos o rastreamento das citações dos estudos incluídos. Foram incluídos ensaios clínicos randomizados que recrutaram sobreviventes de AVC (isquêmico ou hemorrágico) durante o primeiro ano do evento, que receberam qualquer ISRS, administrado em qualquer dose, por qualquer período de tempo. Excluímos os estudos que usaram drogas com efeitos farmacológicos mistos. Os comparadores foram cuidados habituais ou placebo. Para serem incluídos, os estudos tinham que coletar dados sobre pelo menos um dos nossos desfechos primários (dependência e incapacidade) ou secundários (deficiências, depressão, ansiedade, qualidade de vida, fadiga, custos com cuidados da saúde, morte, eventos adversos e abandono precoce do estudo). Colhemos dados sóciodemográficos, tipo de AVC, tempo decorrido desde o AVC, nossos desfechos primários e secundários e fontes de viés. Para os estudos em inglês, dois revisores extraíram independentemente os dados. Para os artigos chineses, um revisor extraiu os dados. Os efeitos das variáveis contínuas foram avaliados através da diferenças de médias padronizadas (inglês: SMD); para as variáveis dicotômicas, usamos o risco relativo (RR). Em ambos os casos, calculamos os respectivos intervalos de confiança de 95% (95% CI). Encontramos 56 estudos publicados que testaram 2 ISRS versus um controle, dos quais 52 estudos (4.060 participantes) forneceram dados para as metanálises. O uso de ISRs produziu benefícios estatisticamente significativos em ambos os desfechos primários. Baseado em 1 estudo, o RR para redução da dependência no final do tratamento foi de 0,81 (95% CI 0,68 a 0,97). A SMD para o escore de incapacidade foi 0,92 (95% CI 0,62 a 1,23; 22 estudos envolvendo 1.310 participantes), com elevada heterogeneidade entre estudos (I² = 85%; P < 0,0001). A intervenção também produziu diferenças significativas sobre o déficit neurológico, a depressão e a ansiedade. A SMD para o escore de déficit neurológico foi -1,00 (95% CI-12,6 a -0,75), 29 estudos envolvendo 2.011 participantes, com elevada heterogeneidade entre estudos (I² = 86%; P < 0,00001). O RR para depressão, avaliada como desfecho dicotômico, foi 0,43 (95% CI 0,24 a 0,77), 8 estudos envolvendo 771 participantes, com elevada heterogeneidade entre estudos (I² = 77%; P < 0,0001). A SMD para depressão como variável contínua, foi -1,91 (95% CI -2,34 a -1,48), 39 estudos envolvendo 2728 participantes, com elevada heterogeneidade entre estudos (I² = 95%; P < 0,00001). A SMD para ansiedade foi -0,77 (95% CI -1,52 a -0,02), 8 estudos envolvendo 413 participantes, com elevada heterogeneidade entre os estudos (I² = 92%; P < 0,00001). Não houve nenhum benefício estatisticamente significativo de uso de ISRS na cognição, na mortalidade ou nos déficits motores ou sobre a taxa de abandono precoce. Para a cognição, o SMD foi 0,32 (95% CI -0,23 a 0,86), 7 estudos envolvendo 425 participantes, com elevada heterogeneidade (I² = 86%; P < 0,00001). O RR para mortalidade foi 0,76 (CI 95% 0,34 a1,70), 46 estudos envolvendo 3.344...

Diabetes mellitus is associated with an increased risk of Alzheimer’s dementia and cognitive decline. The cause of neurodegeneration in chronic diabetic patients remains unclear. Changes in brain microglial activity due to glycemic fluctuations may be an etiological factor. Here, we examined the impact of acute ambient glucose fluctuations on BV-2 microglial activity. Biochemical parameters were assayed and showed that the shift from normal glucose (NG; 5.5 mM) to high glucose (HG; 25 mM) promoted cell growth and induced oxidative/inflammatory stress and microglial activation, as evidenced by increased MTT reduction, elevated pro-inflammatory factor secretion (i.e., TNF-α and oxygen free radicals), and upregulated expression of stress/inflammatory proteins (i.e., HSP70, HO-1, iNOS, and COX-2). Also, LPS-induced inflammation was enlarged by an NG-to-HG shift. In contrast, the HG-to-NG shift trapped microglia in a state of metabolic stress, which led to apoptosis and autophagy, as evidenced by decreased Bcl-2 and increased cleaved caspase-3, TUNEL staining, and LC3B-II expression. These stress episodes were primarily mediated through MAPKs, PI3K/Akt, and NF-κB cascades. Our study demonstrates that acute glucose fluctuation forms the stress that alters microglial activity (e.g., inflammatory activation or self-degradation), representing a novel pathogenic mechanism for the continued deterioration of neurological function in diabetic patients.

Background Stroke is a major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression and other mood disorders after stroke. The 2012 Cochrane Review of SSRIs for stroke recovery demonstrated positive effects on recovery, even in people who were not depressed at randomisation. A large trial of fluoxetine for stroke recovery (fluoxetine versus placebo under supervision) has recently been published, and it is now appropriate to update the evidence. Objectives To determine if SSRIs are more effective than placebo or usual care at improving outcomes in people less than 12 months post‐stroke, and to determine whether treatment with SSRIs is associated with adverse effects. Search methods For this update, we searched the Cochrane Stroke Group Trials Register (last searched 16 July 2018), the Cochrane Controlled Trials Register (CENTRAL, Issue 7 of 12, July 2018), MEDLINE (1946 to July 2018), Embase (1974 to July 2018), CINAHL (1982 July 2018), PsycINFO (1985 to July 2018), AMED (1985 to July 2018), and PsycBITE March 2012 to July 2018). We also searched grey literature and clinical trials registers. Selection criteria We included randomised controlled trials (RCTs) that recruited ischaemic or haemorrhagic stroke survivors at any time within the first year. The intervention was any SSRI, given at any dose, for any period, and for any indication. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. To be included, trials had to collect data on at least one of our primary (disability score or independence) or secondary outcomes (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early). Data collection and analysis We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. Two review authors independently extracted data from each trial. We used standardised mean differences (SMDs) to estimate treatment effects for continuous variables, and risk ratios (RRs) for dichotomous effects, with their 95% confidence intervals (CIs). We assessed risks of bias and applied GRADE criteria. Main results We identified a total of 63 eligible trials recruiting 9168 participants, most of which provided data only at end of treatment and not at follow‐up. There was a wide age range. About half the trials required participants to have depression to enter the trial. The duration, drug, and dose varied between trials. Only three of the included trials were at low risk of bias across the key 'Risk of bias' domains. A meta‐analysis of these three trials found little or no effect of SSRI on either disability score: SMD −0.01 (95% CI −0.09 to 0.06; P = 0.75; 2 studies, 2829 participants; moderate‐quality evidence) or independence: RR 1.00 (95% CI 0.91 to 1.09; P = 0.99; 3 studies, 3249 participants; moderate‐quality evidence). We downgraded both these outcomes for imprecision. SSRIs reduced the average depression score (SMD 0.11 lower, 0.19 lower to 0.04 lower; 2 trials, 2861 participants; moderate‐quality evidence), but there was a higher observed number of gastrointestinal side effects among participants treated with SSRIs compared to placebo (RR 2.19, 95% CI 1.00 to 4.76; P = 0.05; 2 studies, 148 participants; moderate‐quality evidence), with no evidence of heterogeneity (I² = 0%). For seizures there was no evidence of a substantial difference. When we included all trials in a sensitivity analysis, irrespective of risk of bias, SSRIs appeared to reduce disability scores but not dependence. One large trial (FOCUS) dominated the results. We identified several ongoing trials, including two large trials that together will recruit more than 3000 participants. Authors' conclusions We found no reliable evidence that SSRIs should be used routinely to promote recovery after stroke. Meta‐analysis of the trials at low risk of bias indicate that SSRIs do not improve recovery from stroke. We identified potential improvements in disability only in the analyses which included trials at high risk of bias. A further meta‐analysis of large ongoing trials will be required to determine the generalisability of these findings.