A depressão periparto (PPD) é subtipo altamente prevalente e subdiagnosticado do transtorno depressivo maior (MDD), e causa um importante sofrimento para a mulher, sua família e seu filho. Uma interação complexa entre hormônios, neurotransmissores e fatores genéticos e ambientais pode estar envolvida na etiologia da PPD. Contudo, estudos de neuroimagem na PPD ainda são escassos, particularmente os que identificam alterações neuroquímicas. Sabe-se que a região do córtex pré frontal dorsolateral (dlPFC) está relacionada à funções executivas no circuito pré frontal, e juntamente com o giro do cíngulo anterior (ACG) faz parte das vias neuronais envolvidas no processamento emocional, desde a geração, regulação e reavaliação do estado afetivo. Existem evidências de que ambas as áreas estejam disfuncionais na MDD. A avaliação neuroquímica obtida pela espectroscopia de próton por ressonância magnética (MRS) permite inferir o metabolismo, a neurotransmissão e a viabilidade do tecido neuronal de interesse destas áreas fronto-límbicas. Objetivo: comparar puérperas com depressão periparto (grupo PPD) com puérperas saudáveis (grupo HP) quanto à avaliação neuroquímica no dlPFC esquerdo e no ACG bilateral. Métodos: 36 puérperas do grupo PPD e 25 puérperas do grupo HP foram submetidas à duas entrevistas psiquiátricas estruturadas e à aplicação de questionários e escalas psicométricas, sendo a segunda avaliação realizada seccionalmente à MRS. A MRS foi adquirida pro MRI com campo de 3 Tesla, estando o volume de interesse (VOI) posicionado no dlPFC esquerdo e no ACG bilateral e processada pelo software LCModel. Os resultados neuroquímicos expressos em valores absolutos e normalizados pela creatina (razão metabólito/creatina) foram analisados por ANCOVA, incluindo a idade, o tempo de puerpério e o tipo de contraceptivo, enquanto covariáveis. Resultados: No dlPFC, o grupo PPD apresentou menores valores de Glu/Cr (-0,17; p=0,05), Glx (-0,95 mM; p=0,04), Glx/Cr (-0,22; p=0,03), NAA (-0,60 mM; p<0,01), e NAA/Cr (-0,13; p=0,02) em relação ao grupo HP. No ACG, o uso de hormônios contraceptivos somente com progestágenos resultou em um aumento dos valores de Glu (2,18 mM; p=0,03), Glx (1,84 mM; p=0,03), e redução de Cho/Cr (-0,08; p=0,03) quando comparados ao grupo que não utilizou somente progestágenos, independentemente dos grupos HP e PPD. Conclusão: Os níveis reduzidos de Glu e NAA no grupo PPD estão relacionados, respectivamente, à disfunção metabólica glutamatérgica e neuroglial no dlPFC, o que pode explicar sintomas cognitivos também relacionados à PPD, tal como já verificado no MDD. O uso de hormônios contraceptivos com progestágenos isoladamente interferiu com a neuroquímica do ACG, mas não se relacionou com a PPD. Embora o aumento do glutamato possa sugerir uma hiperfuncionalidade do ACG, e a redução da Cho/Cr representar diminuição de \"turnover\" da membrana lipídica ou da transdução sináptica, seu significado clínico e fisiopatológico ainda é incerto. Estes resultados contribuem com a compreensão dos substratos neuroquímicos de PPD / Peripartum depression (PPD) is a highly prevalent subtype of major depressive disorder (MDD) related to a significant loss for mother, family and baby. An Interaction between hormones, genetic, and environmental factors must be involved in its etiology. However, neuroimaging studies on PPD are still rare, particularly those that identify neurochemical changes. However, neuroimaging studies in PPD are still rare, particularly those that identify neurochemical changes. It is known that the region of the dorsolateral prefrontal cortex (dlPFC) is related to executive functions in the prefrontal circuit, and together with the anterior cingulate gyrus (ACG) is part of the neural pathways involved in emotional processing, including the generation, regulation, and reappraisal of affective state. And, there is evidence that both areas are dysfunctional in MDD. The neurochemical evaluation obtained by spectroscopy of proton magnetic resonance (MRS) allows to infer metabolism, neurotransmission and the viability of the neuronal tissue of interest these frontal-limbic areas. Objective: Compare postpartum women with peripartum depression (PPD group) with healthy postpartum women (HP group) regarding the neurochemical evaluation in the left dlPFC and bilateral ACG. Methods: 36 postpartum women of PPD group and 25 postpartum women of the HP group were subjected to two structured psychiatric interviews and questionnaires and psychometric scales, with the second evaluation performed sectionally at MRS. The MRS was obtained by 3-T MRI system with the volume of interest (VOI) positioned on the left dlPFC and bilateral ACG and processed by LC Model software. The neurochemical results expressed in absolute values and normalized by creatine (reason metabolite/creatine) were analyzed using ANCOVA, including age, postpartum time, the type of contraceptive as covariates. Results: In the dlPFC, PPD group presented significantly lower values of Glu/Cr (-0.17; p=0.05), Glx (-0.95mM; p=0.04), Glx/Cr (-0.22; p=0.03), NAA (-0.60mM; p<0.01), and NAA/Cr (-0.13; p=0.02) than HP. In ACG, progestogens isolated contraceptive hormones use resulted in significantly increased Glu (2.18mM; p=0.03), Glx (1.84mM; p=0.03), and reduced Cho/Cr (-0.08; p=0.03), compared to women without use them, regardless of diagnostic groups. Conclusions: The reduced levels of Glu and NAA in the PPD group are related respectively to the glutamatergic and neuroglial metabolic dysfunction in the dlPFC, which may explain cognitive symptoms also related to PPD as already verified in MDD. Progestogens isolated contraceptive hormones use interfered with neurochemistry of ACG, but not associated with PPD. Although the increase of glutamate may suggest an overactive ACG, and lower Cho/Cr represent decrease of the lipid membrane turnover or synaptic transduction its clinical and pathophysiological significance remains uncertain. These results contribute to the understanding of the neurochemical substrates of PPD

Introduction : Issus des données animales, les modèles neurotrophiniques du mécanisme d’action des médicaments antidépresseurs pourraient permettre d’identifier chez l’Homme des biomarqueurs prédictifs de la réponse et de la rémission sous antidépresseurs. Nous évaluons l’intérêt clinique, chez les patients souffrant de trouble dépressif caractérisé unipolaire, de 11 biomarqueurs : polymorphismes nucléotidiques simples (SNP) du Brain Derived Neurotrophic Factor (BDNF) et de son récepteur, le Récepteur Tyrosine-Kinase B (TRKB), taux plasmatiques de BDNF et volume hippocampique sur la réponse/rémission sous antidépresseurs. Méthode : Les données originales de ce travail sont issues de la cohorte METADAP. Il s’agit d’une cohorte, prospective, multicentrique incluant 624 patients présentant un épisode dépressif caractérisé dans le cadre d’un trouble dépressif caractérisé unipolaire et nécessitant l’introduction d’un traitement antidépresseur. Le traitement antidépresseur est prescrit de façon naturaliste (tous antidépresseurs commercialisés en France). Les patients sont évalués 1, 3 et 6 mois après l’introduction du traitement antidépresseur. Les biomarqueurs étudiés sont les polymorphismes Val66Met du BDNF et 8 SNP du TRKB et les dosages de BDNF plasmatiques. Une étude ancillaire est menée à partir de 63 patients ayant bénéficié d’Imagerie par Résonnance Magnétique cérébrale réalisée en pratique courante à l’inclusion de cette cohorte afin d’évaluer les volumes hippocampiques. Résultats : 1) Une revue de la littérature met en évidence une association entre la réponse aux antidépresseurs et 12 SNP du BDNF/TRKB sur 242 étudiés, ainsi qu’une association entre allèle Met du polymorphisme Val66Met du BDNF et meilleure réponse sous antidépresseurs chez les patients asiatiques. 2) Nos données ne mettent pas en évidence d’impact de 8 SNP du TRKB sur la réponse/rémission après traitement antidépresseur, mais un effet différentiel du Val66Met du BDNF selon la classe de traitement antidépresseur. 3) L’étude des dosages de BDNF plasmatiques n’est pas concluante. 4) Concernant les volumes hippocampiques, notre méta-analyse montre que des volumes hippocampiques moindres prédisent une moindre réponse/rémission après traitement antidépresseur. 5) Concernant les liens entre les biomarqueurs étudiés, nous ne mettons pas en évidence d’association. Conclusion : Sur les 11 biomarqueurs étudiés, seuls 2 pourraient présenter une utilité en pratique clinique. Si nos travaux étaient répliqués, le polymorphisme Val66Met du BDNF et le volume hippocampique pourraient conduire à orienter le choix des antidépresseurs dans le traitement des épisodes dépressifs caractérisés. Malgré une littérature cohérente chez l’Animal, nous n’avons pas mis en évidence, dans l’échantillon étudié, de lien entre les biomarqueurs génétiques étudiés et les volumes hippocampiques. Nous poursuivons ce travail d’évaluation des biomarqueurs neurotrophiniques et neurogéniques avec des méthodes d’évaluations nouvelles : séquençage nouvelle génération pour la génétique et imagerie multimodale (acquisition répétée d’IRM structurelle, fonctionnelle et de diffusion) de l’hippocampe. Nous évaluerons également de nouveaux biomarqueurs. / Introduction: developed with Animal preclinical approachs, neurtrophinic and neurogenic models of antidepressant mechanism of action lead to identify biomarkers in Human which could be predict antidepressant response and remission in depressed patients. We assess the clinical benefit of 11 biomarkers in depressed patients: Brain Derived Neurotrophic Factor (BDNF) and its receptor Tyrosine Receptor -Kinase B (TRKB), Plasma BDNF and Hippocampal volumes to predict antidepressant response/remission. Methods: The original research data of this work are from METADAP cohort. It is a prospective, multicentric cohort including 624 patients with a diagnosis of major depressive disorder and a current major depressive episode at the start of the index antidepressant treatment. Antidepressant treatment is prescribed in naturalistic conditions (all commercialized antidepressant in France). Patient are assessed 1, 3 and 6 months after the start of antidepressant treatment. Studied biomarkers are BDNF Val66Met polymorphism, 8 TRKB SNP and plasma BDNF. Ancillary study are done with 63 patients which benefit in clinical practice of Magnetic Resonnance (MRI) at the inclusion of the cohort. Results: 1) A review of literature reports associations between antidepressant efficacy and 12 BDNF/TRKB SNP on 242 studied SNP and an association with Met allele of Val66Met BDNF polymorphism and a best antidepressant efficacy in Asian patients. 2) Our original data show no impact of 8 TRKB SNP on antidepressant response remission but a differential effect of Val66Met BDNF polymorphism depending on antidepressant treatment class. 3) Plasma BDNF study is not conclusive. 4) Concerning hippocampal volumes, our meta-analysis show that smaller hippocampal volumes predict lower response/remission rate after antidepressant treatment. 5) No association is found between studied biomarkers. Conclusion: 2 of the 11 studied biomarkers could be useful in clinical practice. After replication of our results, Val66Met polymorphism could lead to personalized antidepressant prescription in major depressive disorder. Although the animal prelinical littérature appar strong, we dont report association between genetic biomarker and hippocampal volume in ours ample. We will assess neurotrophinic and neurogenic biomarkers with new methods: next generation sequencing for genetic, multimodal imaging (repeated structural, functional and diffusion MRI) of hippocampus. We also will assess new biomarkers.

Introdução: A ocorrência de episódios depressivos e abuso ou dependência de álcool após um evento agudo de insuficiência coronariana pode representar um marcador independente de mau prognóstico. Portanto, investigamos a presença de sintomas depressivos, transtorno depressivo maior (TDM) e abuso ou dependência de álcool em uma subamostra de uma coorte prospectiva de Síndrome Coronariana Aguda (SCA), Estratégia de Registro de Insuficiência Coronariana Aguda (ERICO) em andamento no pronto-socorro do Hospital Universitário. Métodos: Foi realizado um estudo observacional em 146 participantes do estudo ERICO. A gravidade dos sintomas depressivos foi avaliada em três momentos: 1ª) na admissão hospitalar pelo Patient Health Questionnaire (PHQ-9 itens); 2º) 30 dias pós-SCA pelo PHQ-9, Inventário de Depressão de Beck (BDI) e Escala de Depressão de Hamilton (HDRS-21 itens); e 3º) 180 dias pós-SCA pelo PHQ-9 e BDI. O abuso e uso nocivo de álcool foram avaliados pelo AUDIT e CAGE em 30 e 180 dias pós-SCA. Resultados: Ao longo do estudo as frequências de sintomas depressivos variaram entre 40% e 60% e de TDM entre 28% e 33%. Na admissão hospitalar houve maior predominância de sintomas depressivos entre os homens (58%; p=0,03) e sedentários (72,1%; p=0,02), entretanto, TDM foi mais frequente na população feminina (55,1%; p < 0,001) com uma razão de chances [(RC) 4,5; intervalo de confiança IC 95% 1,85-10,98]. Após 30 dias do evento agudo constatou-se um maior risco de sintomas depressivos entre os tabagistas (RC 5,8; IC 95% 1,81-18,72) e diabéticos (RC 3,6; IC 95% 1,40-9,60). Os diabéticos também apresentaram (RC 3,5; IC 95% 1,39-8,71) para desenvolver TDM. No seguimento de 180 dias verificou-se que indivíduos com angina instável (AI) (RC 4, 46; IC 95% 1,39-14,32) e infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCST) (RC 3,40; IC 95% 1,30-8,87) apresentaram maior probabilidade de desenvolverem sintomas depressivos em relação aos indivíduos que apresentaram IAMSST. Os únicos fatores de risco que se mantiveram associados a um maior risco de sintomas depressivos após 180 dias foi o sexo feminino (RC 3,9; IC 95% 1,54-9,73) e o tabagismo (RC 5,34; IC 95% 1,64-17,44). Em relação à TDM, encontramos uma RC de 14 (IC 95% 2,94-67,51) para associação com tabagismo. Quanto ao abuso e uso nocivo de álcool as frequências variaram ao longo do estudo pelo AUDIT e CAGE entre 18,3% e 33,6%. Verificamos na populacão masculina uma frequência de 88,2% (p=0,001) e entre os tabagistas de 55,9% (p=0,003) e foi encontrada uma RC de 51,64 para população mais jovem (35-44 anos) e uma RC de 42,95 para tabagistas. Finalmente, não foi encontrada nenhuma associação entre abuso de álcool e depressão de acordo com os subtipos de SCA nos períodos analisados. Conclusão: A frequência de depressão variou entre 40% e 60% da admissão até 180 dias pós-SCA. Indivíduos que desenvolveram AI ou IAMCST, além de mulheres e tabagistas apresentaram maiores chances de desenvolver depressão ao longo do seguimento de 180 dias e indivíduos entre 35 e 44 anos e tabagistas apresentaram maior possibilidade de abusar do álcool / Introduction: The occurrence of depression and alcohol abuse or dependence after an acute coronary insufficiency may represent an independent marker of poor prognosis. Therefore, we investigated the presence of depressive symptoms, major depressive disorder (MDD) and alcohol abuse or dependence in a subsample of a prospective cohort of Acute Coronary Syndrome (ACS), Strategy of Registry of Acute Coronary Syndrome Study (ERICO study), which is still ongoing in the emergency room of the Hospital Universitário. Methods: We conducted an observational study in 146 participants of the ERICO study. The severity of depressive symptoms was evaluated in 3 moments: 1st) at the hospital admission using The Patient Health Questionnaire (PHQ-9 items); 2nd) 30 days post-ACS using the PHQ-9, the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS -21 items), and 3rd) 180 days post -ACS through PHQ-9 and BDI. The abuse and harmful alcohol consumption were assessed by the AUDIT and the CAGE 30 and 180 days post-ACS. Results: Along the study, the frequencies of depressive symptoms ranged from 40% to 60% and MDD from 28% to 33%. At the hospital admission there was a higher prevalence of depressive symptoms among men (58%, p= 0.03) and sedentary patients (72.1%, p= 0.02), however, MDD was higher among women (55.1%, p < 0.001) with an increased risk of [odds ratio [(OR) 4.5; confidence interval CI 95% 1.85-10.98]. After 30 days of the acute event, we observed an increased risk of depressive symptoms among smokers (OR 5.8; CI 95%, 1.81-18.72) and among diabetics (OR 3.6; CI 95%, 1.40-9.60) the diabetics were also more likely to develop MDD (OR 3.5; IC 95% 1,39-8,71). At 180 days follow-up, individuals with unstable angina (UA) (OR 4.46; CI 95% 1.39-14.32) and ST elevation myocardial infarction (STEMI) (OR 3.40; CI 95% 1.30-8.87) were more likely to develop depressive symptoms compared with patients who had NSTEMI. The only two factors that remained associated with a higher risk of depressive symptoms after 180 days were female gender (OR 3.9; CI 95% 1.54-9.73) and smokers (OR 5.34; CI 95% 1.64-17.44). Regarding MDD we found an OR of 14 (CI 95% 2.9-67.51) for smokers. In relation to abuse and hazardous consumption of alcohol, the frequencies for CAGE and AUDIT ranged from 18.3% to 33.6% along the study. We found among the male population a frequency of 88.2% (p=0.001) and smokers 55.9% (p=0.003). We also found OR of 51.64 among younger (aged 35-44 years) and OR of 42.95 for smokers. Finally, no association between alcohol abuse and depression according to ACS subtypes was observed. Conclusion: The prevalence of depression post-ACS ranged from 40% to 60% during the follow-up (admission hospital to 180 days). Individuals who developed UA or STEMI, besides women and smokers were more likely to develop depression during follow-up of 180 days and individual aged between 35-44 years and smokers were more likely to abuse of alcohol

O acelerado processo de envelhecimento tem trazido não só mudanças no perfil demográfico, mas também no perfil epidemiológico da população. Entre os problemas de saúde encontrados em idosos, merecem destaque os transtornos mentais, visto que acometem cerca de um terço dessa população, sendo os transtornos depressivos e a demência os problemas de saúde mental mais prevalentes. O transtorno depressivo maior (TDM), bem como o comprometimento cognitivo leve (CCL), tem sido associado prejuízo das funções cognitivas, além de aumentar o risco de desenvolvimento de demência, principalmente doença de Alzheimer (DA). Sendo assim, é importante que haja identificação preventiva de pessoas com maior risco para o desenvolvimento de DA a fim de proporcionar um tratamento precoce. Dessa maneira este estudo objetivou comparar os marcadores biológicos envolvidos na cascata amiloide, expressos em leucócitos e líquor, nas condições clínicas TDM, CCL, DA e controles saudáveis. Para tanto, foi determinada a expressão proteica das secretases ADAM10, BACE1 e PSEN1 e do peptídeo A? em leucócitos e líquor pelos métodos de Western Blotting, ELISA e Luminex. Ao analisarmos a expressão das secretases e do peptídeo Abeta em leucócitos não observamos diferenças estatisticamente significantes entre os grupos, exceto pela expressão da proteína PSEN1, que apresentou menores níveis em DA em relação à TDM. Em relação ao líquor, observamos uma significativa diminuição do peptídeo A? no grupo DA quando comparado aos grupos CCL, TDM e também a controles saudáveis; porém não foram observadas diferenças de expressão desse peptídeo entre CCL, TDM e controles saudáveis. Esses resultados sugerem que a matriz leucocitária, apesar de expressar os componentes desta via, sugerindo dispor da maquinaria enzimática necessária para o processamento da proteína precursora do amiloide (APP), não é a ideal para estudos sobre a cascata amiloide. Além disso, os resultados obtidos em amostras de líquor, de acordo com a casuística analisada, reforçam os dados da literatura que estabelecem a redução da concentração do peptídio Abeta no líquor como um biomarcador da DA, sem termos detectado alterações nos demais grupos estudados. Nossos resultados (negativos) em relação à expressão das APP-secretases no líquor acrescentam dados a este domínio ainda controverso da literatura. Assim sendo, mais estudos devem ser realizados para que possamos compreender melhor as vias relacionadas ao desenvolvimento da DA / The accelerated aging process has brought not only changes in the demographic profile, but also in the epidemiological profile of the population. Among the health problems found in the elderly, mental disorders are worth mentioning, since they affect about a third of this population, being the depressive disorders and dementia the most prevalent mental health problems. Major depressive disorder (MDD), as well as mild cognitive impairment (MCI), have been associated with higher levels of cognitive symptoms and increased risk of developing dementia, especially Alzheimer\'s disease (AD). Therefore, it is important to identify individuals at greater risk for the development of AD in order to provide treatment at early stages of the disease process. In this way, this study aimed to compare the biological markers involved in the amyloid cascade under the clinical conditions TDM, CCL, DA and healthy controls expressed in leukocytes and CSF. We determined the protein expression of ADAM10, BACE1 and PSEN1 and A? peptides in leucocytes and CSF using the Western Blotting, ELISA and Luminex methods. When analyzing the expression of the secretases and the A? peptide in leukocytes, we did not observe statistically significant differences between the groups, except for the expression of the PSEN1 protein, which presented lower levels in AD in relation to MDD. In relation to CSF, we observed a significant reduction of the Abeta peptide in AD when compared to MCI, TDM and also to healthy controls, but no differences in expression of this peptide were observed between MCI, MDD and healthy controls. These results suggest that the leukocytes, although expressing the key components and the enzymatic machinery necessary for the proteolytic processing of the amyloid precursor protein (APP), may not represent an adequate biological matrix for studies addessing the amyloid cascade. In addition, results obtained in CSF samples, according to the analyzed series, reinforce the literature data that establish the reduction of A? peptide concentration in CSF as a biomarker of AD, without detecting alterations in the other groups studied. Our (negative) results in relation to the expression of APP-secretases in CDescriptors: MSF add data to this still controversial domain of the literature. Therefore, more studies should be done so that we can better understand the pathways related to the development of AD

Introduction: Coronary artery disease (CAD) has been associated with depressive symptoms and deficits in cognitive performance, both of which have been associated with poorer medical prognoses and poorer psychosocial outcomes. Physical activity can improve cognitive and depressive symptoms, and, for those with CAD, improve medical prognoses. It was hypothesized that depressive symptoms and poorer cognitive performance would be associated with poorer cardiopulmonary fitness in patients with CAD, and that these sequelae would be associated prospectively with noncompletion of cardiac rehabilitation (CR). The benefits of physical activity are thought to result, in part, from decreased inflammatory activity and increased adaptive neural plasticity, to which the ratio of kynurenine to tryptophan (K/T) and brain derived neurotrophic factor (BDNF), respectively, in peripheral blood may pertain. Methods and Results: In a cohort study of patients entering CR, depressive symptoms (Center for Epidemiological Studies Depression scale; CES-D scores) were associated with cardiopulmonary fitness (peak volume of oxygen uptake; VO2Peak) during an exercise stress test (B=-.404, p=.001, n=366). The VO2Peak was also associated with performance across multiple cognitive domains, but most strongly with performance on tests involving executive function, attention and psychomotor processing speed (β=.322, p=.002 for composite score, n=81) in a cohort of patients entering CR. In prospective cohort studies, Major Depressive Disorder (adjusted hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.3–4.7, n=195) and poorer performance on a verbal memory test (HR 0.86, 95% CI 0.77-0.96, p=.009, n=131) predicted non-completion of CR. In patients undertaking CR, higher serum K/T ratios were associated with CES-D scores (β=.322, p=.002, n=95) and with VO2Peak (β=-.391, p<.001, n=95), and in a cohort of patients entering CR (n=88), serum concentrations of BDNF were associated with psychomotor processing speed (F1,87=9.620, p=.003), overall cognitive status (Mini Mental Status Exam) scores (F1,87=15.406, p<.0005) and VO2Peak (β=.305, p=.013). Conclusions: Depressive symptoms and poorer cognitive performance are clinically important in patients with CAD entering CR and they are both associated with poorer cardiopulmonary fitness. Poorer cardiopulmonary fitness was also associated with higher K/T ratios and with lower BDNF concentrations in serum, which predicted depressive symptoms and poorer cognitive performance, respectively.

Introduction: Coronary artery disease (CAD) has been associated with depressive symptoms and deficits in cognitive performance, both of which have been associated with poorer medical prognoses and poorer psychosocial outcomes. Physical activity can improve cognitive and depressive symptoms, and, for those with CAD, improve medical prognoses. It was hypothesized that depressive symptoms and poorer cognitive performance would be associated with poorer cardiopulmonary fitness in patients with CAD, and that these sequelae would be associated prospectively with noncompletion of cardiac rehabilitation (CR). The benefits of physical activity are thought to result, in part, from decreased inflammatory activity and increased adaptive neural plasticity, to which the ratio of kynurenine to tryptophan (K/T) and brain derived neurotrophic factor (BDNF), respectively, in peripheral blood may pertain. Methods and Results: In a cohort study of patients entering CR, depressive symptoms (Center for Epidemiological Studies Depression scale; CES-D scores) were associated with cardiopulmonary fitness (peak volume of oxygen uptake; VO2Peak) during an exercise stress test (B=-.404, p=.001, n=366). The VO2Peak was also associated with performance across multiple cognitive domains, but most strongly with performance on tests involving executive function, attention and psychomotor processing speed (β=.322, p=.002 for composite score, n=81) in a cohort of patients entering CR. In prospective cohort studies, Major Depressive Disorder (adjusted hazard ratio [HR] 2.5, 95% confidence interval [CI] 1.3–4.7, n=195) and poorer performance on a verbal memory test (HR 0.86, 95% CI 0.77-0.96, p=.009, n=131) predicted non-completion of CR. In patients undertaking CR, higher serum K/T ratios were associated with CES-D scores (β=.322, p=.002, n=95) and with VO2Peak (β=-.391, p<.001, n=95), and in a cohort of patients entering CR (n=88), serum concentrations of BDNF were associated with psychomotor processing speed (F1,87=9.620, p=.003), overall cognitive status (Mini Mental Status Exam) scores (F1,87=15.406, p<.0005) and VO2Peak (β=.305, p=.013). Conclusions: Depressive symptoms and poorer cognitive performance are clinically important in patients with CAD entering CR and they are both associated with poorer cardiopulmonary fitness. Poorer cardiopulmonary fitness was also associated with higher K/T ratios and with lower BDNF concentrations in serum, which predicted depressive symptoms and poorer cognitive performance, respectively.

La prise en charge des patients souffrant d’un trouble mental justifie une meilleure compréhension des mécanismes influençant les comportements des patients et des cliniciens vis-à-vis des stratégies thérapeutiques. Le principal objectif de cette thèse est d’étudier et d’identifier le rôle des attitudes des patients et des cliniciens vis-à-vis du comportement d’usage d’une thérapeutique. Pour cela, nous avons réalisé plusieurs études permettant d’appréhender cette problématique dans différentes pathologies et envers différentes thérapeutiques.Concernant les attitudes des patients envers leur traitement, nous avons détaillé un travail visant à évaluer les croyances de patients souffrant de schizophrénie envers leur antipsychotique et une étude qualitative sur les attitudes des patients bipolaires envers leur prise en charge en phase d’euthymie. Nous avons montré l’impact des attitudes négatives sur le niveau d’observance ou d’adhésion des patients à leur prise en charge et l’intérêt de cibler des stratégies de prise en charge individualisées visant à améliorer ces attitudes. Concernant les psychiatres, nous avons présenté une étude évaluant les attitudes des cliniciens vis-à-vis des recommandations professionnelles ainsi qu’un travail concernant leurs attitudes envers les antipsychotiques d’action prolongée. Certaines attitudes des psychiatres apparaissaient associées à une plus faible utilisation des recommandations ou des formulations d’action prolongée. Nos résultats montrent ainsi que l’observance ou l’adhésion des patients à une prise en charge ou le choix thérapeutique des cliniciens sont sous-tendus par leurs attitudes. L’étude des attitudes dans le domaine de la santé mentale apparaît comme une étape indispensable dans la compréhension de certains comportements d’usage des thérapeutiques. Les données issues des travaux présentés mais aussi d’études récentes permettent d’envisager un changement de paradigme dans l’appréhension des comportements d’observance des patients et de décision médicale des cliniciens dans le choix d’une thérapeutique centré sur leurs attitudes. / The management of patients with severe mental illnesses needs a better understanding of thefactors affecting the behaviours of clinicians and patients toward therapeutic strategies.The main objective of this thesis was to assess and identify the role of the clinician’s attitudes and patients’ attitudes toward the medication use behaviour. We conducted several studies to address this point in different mental disorders and for different type of treatment. Concerning the patients ‘attitudes toward treatment, we reported data from a study assessing the beliefs toward antipsychotics of schizophrenic patients and from a qualitative study assessing the patient’s attitudes toward the management of bipolar disorder in euthymic periods. We showed that the negative attitudes had a marked impact on the level of adherence of patients and could determine individual targets of interventions to improve them. Concerning the psychiatrists, we reported two studies assessing the clinician’s attitudes toward guidelines and long-acting injectable antipsychotics. Some specific attitudes were associated with a lower use of guidelines or long-acting formulations. These findings showed that the adherence of patient to treatment and the medical decisions of clinicians were related to their attitudes. The assessment of attitudes or beliefs in the field of mental health appears to be an essential step to promote a better comprehension of some treatment use behaviours. Our results and from other recent studies support a new paradigm for the patient adherence to treatment and the medical decision of clinicians focused on their attitudes as predicting variables.

Introdução: A privação de sono (PdS) tem sido utilizada como um estratégia alternativa para o tratamento do Transtorno Depressivo Maior (TDM), contudo sua eficácia e efetividade carecem de estudos homogêneos e de bom delinemento para dar um grau de evidência científica para seu uso na prática diária. Assim sendo, desde a primeira publicação, em 1971, num relato de caso de um paciente com TDM grave tipo melancólico, por Plug e Tölle, o mesmo estava assintomático no dia seguinte à privação total de sono. Contudo, na noite seguinte de sono seus sintomas depressivos retornaram. Nestes quase 40 anos desde esta publicação houve dezenas de estudos em sua maioria relatos de caso, série de casos ou até estudos abertos só que misturando pacientes com TDM com Depressão Bipolar sem mesmo distinguir se tipo I ou II. A cafeína com seu efeito estimulador poderia ser uma alternativa para facilitar a privação de sono. No entanto, não há dados sobre o sua potencial influência no efeito antidepressivo da PdS. O objetivo deste estudo é avaliar o efeito da cafeína na PdS em pacientes deprimidos unipolares moderados a graves não psicóticos. Métodos: Ensaio Clínico randomizado, duplo cego, cruzado, comparando cafeína contra placebo em pacientes deprimidos moderados a graves submetidos à privação total de sono (PdS). Os pacientes foram avaliados por itens da escala de Lader, HAMD- 6 itens, CGI Severidade e Melhora Global. Resultados: Foram avaliados 20 pacientes. Os pacientes que usaram cafeína mantiveram o mesmo escore de energia pré e pós-privação de sono (item energético-letárgico da escala de Lader) enquanto os do grupo placebo diminuíram o escore de energia pós-privação de sono. (p = 0,0045). Não houve diferença entre o grupo cafeína e placebo nos demais itens da escala de Lader. Conclusão: O uso combinado de cafeína e PdS pode ser uma estratégia útil para manter os pacientes mais acordados sem o prejuízo do cansaço da PdS em pacientes ambulatoriais deprimidos. Contudo, mais estudos envolvendo pacientes que tenham 10 respondido à PdS são necessários para verificar se a cafeína também não interfere nos resultados deste grupo. / Introduction: Sleep deprivation (SD) has been used as an alternative approach to treat major depressive disorder (MDD), however the efficacy and the effectiveness needs studies with homogeneity and better delineament to strengthen the evidence based medicine to the use in the practical daily use. Besides, since the 1° puplication in 1971 of a case report, by Plug and Tölle, in that one patient with severe melancholic depressive disorder achieved remission in the next day after a total sleep deprivation. However his depressive sintomtology was back after the next night of sleep. Since this almost 40 years, a lot of papers were puplished, and the majority where case report, case reports and open trials with patients with MDD, bipolar depression without make difference between tipe I or II. Caffeine, due to its stimulating effect, could be an alternative to promote sleep deprivation. However, there are no data about its potential influence on the antidepressive effect of SD. The objective of this study is to assess the effect of caffeine on SD in non-psychotic patients with moderate to severe unipolar depression. Methods: Randomized, double-blind, crossover clinical trial comparing caffeine and placebo in moderate to severe depressed patients who underwent total sleep deprivation (SD). The patients were assessed with items of the Bond-Lader Scale, the 6-item Hamilton Depression Rating Scale (HAMD-6), and the Clinical Global Impression (CGI)-Severity/Improvement. Results: Twenty patients participated in this study. The patients who consumed caffeine presented the same score of energy before and after sleep deprivation (lethargicenergetic item of the Bond-Lader scale), while the patients in the placebo group had a reduced score of energy after sleep deprivation (p = 0.0045). There was no difference between the caffeine and placebo groups in the other items of the Bond-Lader scale. Conclusion: The combined use of caffeine and SD can be a useful strategy to keep the 12 patient awake without impairing the effect of SD on depressed outpatients. However, further studies involving patients who have responded to SD are needed in order to verify if caffeine also does not interfere with the results in this group.

Introdução: A privação de sono (PdS) tem sido utilizada como um estratégia alternativa para o tratamento do Transtorno Depressivo Maior (TDM), contudo sua eficácia e efetividade carecem de estudos homogêneos e de bom delinemento para dar um grau de evidência científica para seu uso na prática diária. Assim sendo, desde a primeira publicação, em 1971, num relato de caso de um paciente com TDM grave tipo melancólico, por Plug e Tölle, o mesmo estava assintomático no dia seguinte à privação total de sono. Contudo, na noite seguinte de sono seus sintomas depressivos retornaram. Nestes quase 40 anos desde esta publicação houve dezenas de estudos em sua maioria relatos de caso, série de casos ou até estudos abertos só que misturando pacientes com TDM com Depressão Bipolar sem mesmo distinguir se tipo I ou II. A cafeína com seu efeito estimulador poderia ser uma alternativa para facilitar a privação de sono. No entanto, não há dados sobre o sua potencial influência no efeito antidepressivo da PdS. O objetivo deste estudo é avaliar o efeito da cafeína na PdS em pacientes deprimidos unipolares moderados a graves não psicóticos. Métodos: Ensaio Clínico randomizado, duplo cego, cruzado, comparando cafeína contra placebo em pacientes deprimidos moderados a graves submetidos à privação total de sono (PdS). Os pacientes foram avaliados por itens da escala de Lader, HAMD- 6 itens, CGI Severidade e Melhora Global. Resultados: Foram avaliados 20 pacientes. Os pacientes que usaram cafeína mantiveram o mesmo escore de energia pré e pós-privação de sono (item energético-letárgico da escala de Lader) enquanto os do grupo placebo diminuíram o escore de energia pós-privação de sono. (p = 0,0045). Não houve diferença entre o grupo cafeína e placebo nos demais itens da escala de Lader. Conclusão: O uso combinado de cafeína e PdS pode ser uma estratégia útil para manter os pacientes mais acordados sem o prejuízo do cansaço da PdS em pacientes ambulatoriais deprimidos. Contudo, mais estudos envolvendo pacientes que tenham 10 respondido à PdS são necessários para verificar se a cafeína também não interfere nos resultados deste grupo. / Introduction: Sleep deprivation (SD) has been used as an alternative approach to treat major depressive disorder (MDD), however the efficacy and the effectiveness needs studies with homogeneity and better delineament to strengthen the evidence based medicine to the use in the practical daily use. Besides, since the 1° puplication in 1971 of a case report, by Plug and Tölle, in that one patient with severe melancholic depressive disorder achieved remission in the next day after a total sleep deprivation. However his depressive sintomtology was back after the next night of sleep. Since this almost 40 years, a lot of papers were puplished, and the majority where case report, case reports and open trials with patients with MDD, bipolar depression without make difference between tipe I or II. Caffeine, due to its stimulating effect, could be an alternative to promote sleep deprivation. However, there are no data about its potential influence on the antidepressive effect of SD. The objective of this study is to assess the effect of caffeine on SD in non-psychotic patients with moderate to severe unipolar depression. Methods: Randomized, double-blind, crossover clinical trial comparing caffeine and placebo in moderate to severe depressed patients who underwent total sleep deprivation (SD). The patients were assessed with items of the Bond-Lader Scale, the 6-item Hamilton Depression Rating Scale (HAMD-6), and the Clinical Global Impression (CGI)-Severity/Improvement. Results: Twenty patients participated in this study. The patients who consumed caffeine presented the same score of energy before and after sleep deprivation (lethargicenergetic item of the Bond-Lader scale), while the patients in the placebo group had a reduced score of energy after sleep deprivation (p = 0.0045). There was no difference between the caffeine and placebo groups in the other items of the Bond-Lader scale. Conclusion: The combined use of caffeine and SD can be a useful strategy to keep the 12 patient awake without impairing the effect of SD on depressed outpatients. However, further studies involving patients who have responded to SD are needed in order to verify if caffeine also does not interfere with the results in this group.

Introdução: A ocorrência de episódios depressivos e abuso ou dependência de álcool após um evento agudo de insuficiência coronariana pode representar um marcador independente de mau prognóstico. Portanto, investigamos a presença de sintomas depressivos, transtorno depressivo maior (TDM) e abuso ou dependência de álcool em uma subamostra de uma coorte prospectiva de Síndrome Coronariana Aguda (SCA), Estratégia de Registro de Insuficiência Coronariana Aguda (ERICO) em andamento no pronto-socorro do Hospital Universitário. Métodos: Foi realizado um estudo observacional em 146 participantes do estudo ERICO. A gravidade dos sintomas depressivos foi avaliada em três momentos: 1ª) na admissão hospitalar pelo Patient Health Questionnaire (PHQ-9 itens); 2º) 30 dias pós-SCA pelo PHQ-9, Inventário de Depressão de Beck (BDI) e Escala de Depressão de Hamilton (HDRS-21 itens); e 3º) 180 dias pós-SCA pelo PHQ-9 e BDI. O abuso e uso nocivo de álcool foram avaliados pelo AUDIT e CAGE em 30 e 180 dias pós-SCA. Resultados: Ao longo do estudo as frequências de sintomas depressivos variaram entre 40% e 60% e de TDM entre 28% e 33%. Na admissão hospitalar houve maior predominância de sintomas depressivos entre os homens (58%; p=0,03) e sedentários (72,1%; p=0,02), entretanto, TDM foi mais frequente na população feminina (55,1%; p < 0,001) com uma razão de chances [(RC) 4,5; intervalo de confiança IC 95% 1,85-10,98]. Após 30 dias do evento agudo constatou-se um maior risco de sintomas depressivos entre os tabagistas (RC 5,8; IC 95% 1,81-18,72) e diabéticos (RC 3,6; IC 95% 1,40-9,60). Os diabéticos também apresentaram (RC 3,5; IC 95% 1,39-8,71) para desenvolver TDM. No seguimento de 180 dias verificou-se que indivíduos com angina instável (AI) (RC 4, 46; IC 95% 1,39-14,32) e infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCST) (RC 3,40; IC 95% 1,30-8,87) apresentaram maior probabilidade de desenvolverem sintomas depressivos em relação aos indivíduos que apresentaram IAMSST. Os únicos fatores de risco que se mantiveram associados a um maior risco de sintomas depressivos após 180 dias foi o sexo feminino (RC 3,9; IC 95% 1,54-9,73) e o tabagismo (RC 5,34; IC 95% 1,64-17,44). Em relação à TDM, encontramos uma RC de 14 (IC 95% 2,94-67,51) para associação com tabagismo. Quanto ao abuso e uso nocivo de álcool as frequências variaram ao longo do estudo pelo AUDIT e CAGE entre 18,3% e 33,6%. Verificamos na populacão masculina uma frequência de 88,2% (p=0,001) e entre os tabagistas de 55,9% (p=0,003) e foi encontrada uma RC de 51,64 para população mais jovem (35-44 anos) e uma RC de 42,95 para tabagistas. Finalmente, não foi encontrada nenhuma associação entre abuso de álcool e depressão de acordo com os subtipos de SCA nos períodos analisados. Conclusão: A frequência de depressão variou entre 40% e 60% da admissão até 180 dias pós-SCA. Indivíduos que desenvolveram AI ou IAMCST, além de mulheres e tabagistas apresentaram maiores chances de desenvolver depressão ao longo do seguimento de 180 dias e indivíduos entre 35 e 44 anos e tabagistas apresentaram maior possibilidade de abusar do álcool / Introduction: The occurrence of depression and alcohol abuse or dependence after an acute coronary insufficiency may represent an independent marker of poor prognosis. Therefore, we investigated the presence of depressive symptoms, major depressive disorder (MDD) and alcohol abuse or dependence in a subsample of a prospective cohort of Acute Coronary Syndrome (ACS), Strategy of Registry of Acute Coronary Syndrome Study (ERICO study), which is still ongoing in the emergency room of the Hospital Universitário. Methods: We conducted an observational study in 146 participants of the ERICO study. The severity of depressive symptoms was evaluated in 3 moments: 1st) at the hospital admission using The Patient Health Questionnaire (PHQ-9 items); 2nd) 30 days post-ACS using the PHQ-9, the Beck Depression Inventory (BDI) and the Hamilton Depression Rating Scale (HDRS -21 items), and 3rd) 180 days post -ACS through PHQ-9 and BDI. The abuse and harmful alcohol consumption were assessed by the AUDIT and the CAGE 30 and 180 days post-ACS. Results: Along the study, the frequencies of depressive symptoms ranged from 40% to 60% and MDD from 28% to 33%. At the hospital admission there was a higher prevalence of depressive symptoms among men (58%, p= 0.03) and sedentary patients (72.1%, p= 0.02), however, MDD was higher among women (55.1%, p < 0.001) with an increased risk of [odds ratio [(OR) 4.5; confidence interval CI 95% 1.85-10.98]. After 30 days of the acute event, we observed an increased risk of depressive symptoms among smokers (OR 5.8; CI 95%, 1.81-18.72) and among diabetics (OR 3.6; CI 95%, 1.40-9.60) the diabetics were also more likely to develop MDD (OR 3.5; IC 95% 1,39-8,71). At 180 days follow-up, individuals with unstable angina (UA) (OR 4.46; CI 95% 1.39-14.32) and ST elevation myocardial infarction (STEMI) (OR 3.40; CI 95% 1.30-8.87) were more likely to develop depressive symptoms compared with patients who had NSTEMI. The only two factors that remained associated with a higher risk of depressive symptoms after 180 days were female gender (OR 3.9; CI 95% 1.54-9.73) and smokers (OR 5.34; CI 95% 1.64-17.44). Regarding MDD we found an OR of 14 (CI 95% 2.9-67.51) for smokers. In relation to abuse and hazardous consumption of alcohol, the frequencies for CAGE and AUDIT ranged from 18.3% to 33.6% along the study. We found among the male population a frequency of 88.2% (p=0.001) and smokers 55.9% (p=0.003). We also found OR of 51.64 among younger (aged 35-44 years) and OR of 42.95 for smokers. Finally, no association between alcohol abuse and depression according to ACS subtypes was observed. Conclusion: The prevalence of depression post-ACS ranged from 40% to 60% during the follow-up (admission hospital to 180 days). Individuals who developed UA or STEMI, besides women and smokers were more likely to develop depression during follow-up of 180 days and individual aged between 35-44 years and smokers were more likely to abuse of alcohol