O Transtorno de Déficit de Atenção/Hiperatividade (TDAH) em adultos é comum e clinicamente relevante. É tratado principalmente através de estimulantes como o metilfenidato. Embora eficaz, há muita heterogeneidade na resposta ao metilfenidato. O objetivo deste estudo foi avaliar preditores da resposta e da remissão do transtorno após o uso de metilfenidato de liberação imediata por um curto período em uma amostra de adultos com TDAH (n=250). Os desfechos foram analisados através da variação na gravidade avaliada a partir dos escores de desatenção, hiperatividade/impulsividade e totais na escala SNAP-IV adaptada para adultos. Em um primeiro estudo, tendo como desfecho a variação quantitativa da gravidade destes sintomas, observou-se que o único fator associado a uma melhor resposta foram escores basais mais elevados nas subescalas e nos escores totais da SNAP-IV. Análises adicionais em uma subamostra (n=62) revelaram que a estabilização prévia das comorbidades não modificou o desfecho. Esta análise adicional também sugeriu que o fenômeno da regressão à média não parece ser relevante na explicação dos achados. No segundo estudo, que avaliou a remissão do TDAH de maneira categórica, três fatores mostraram-se significativamente associados a uma maior frequência de remissão: uma menor gravidade basal do transtorno, a condição de casado e a ausência do uso de outros psicofármacos no início do tratamento com metilfenidato. O conjunto de resultados sugere que, embora pacientes com elevados escores de gravidade apresentem boa resposta ao metilfenidato, eles também tem maior dificuldade em atingir a remissão propriamente dita, a qual é o objetivo maior do tratamento. / Attention Deficit/Hyperactivity Disorder (ADHD) in adults is common and clinically relevant. It is treated with stimulants such as methylphenidate. Although effective, there is high heterogeneity in the response to methylphenidate in these patients. The objective of this study was to evaluate, in a sample of adults with ADHD (n=250), predictors of response and remission after using immediate-release methylphenidate for a short period of time. Outcomes were analysed through the variation in severity scores of the SNAP-IV scale that was adapted to adults. Inattention and hyperactivity/impulsivity subscales and the total ADHD scores were evaluated. In a first study, the response to methylphenidate was analysed as a quantitative trait. We found that the only factors associated with a better response were higher baseline scores on the SNAP-IV subscales and total scores. Secondary analyses on a subsample of these patients (n=62) revealed that prior stabilization for other comorbidities did not change the results These additional analyses also suggested that the phenomenon of regression to the mean does not seem to be relevant in explaining the findings. In the second study, where ADHD remission was evaluated categorically, three factors were shown to significantly improve outcome: a lower baseline severity of the disorder, marital status, and the lack of use of other psychotropic drugs at initiation of treatment with methylphenidate. These sets of results suggests that although patients with high severity scores show better response to methylphenidate, they also have greater difficulty achieving remission itself, which is the primary goal of treatment. / El Trastorno de Déficit de Atención/Hiperactividad (TDAH) en adultos es común y clínicamente relevante. Se trata principalmente con los estimulantes como el metilfenidato, el medicamento más estudiado en adultos con TDAH. Aunque es muy eficaz, hay mucha heterogeneidad en la respuesta al metilfenidato en el TDAH en adultos. El objetivo principal de este estudio fue evaluar los predictores de respuesta y remisión de metilfenidato de liberación inmediata después de su uso durante un corto período en una muestra de adultos con TDAH (n=250). Los resultados se analizaron mediante la variación de la gravedad evaluada por marcadores de déficit de atención, hiperactividad/ impulsividad y la escala total de SNAP- IV adaptada para adultos. En un primer estudio, como fin de la variación cuantitativa se encontró que el único factor asociado con una mejor respuesta fueron las puntuaciones de referencia más altas en las subescalas de la SNAP- IV. Análisis adicionales revelaron que la estabilización previa para otras comorbilidades (n=62) no cambió el resultado. Este análisis adicional también sugirió que el fenómeno de regresión a la media no parece ser relevante para explicar los hallazgos. En el segundo estudio, que evaluó la remisión de TDAH categóricamente, tres factores fueron significativos: la menor severidad basal de la enfermedad, la condición del casado y la ausencia de uso de otras drogas psicotrópicas en el inicio del tratamiento con metilfenidato. El conjunto de los resultados sugiere que aunque los pacientes con puntuaciones de alta severidad muestran buena respuesta al metilfenidato, también tienen mayor dificultad para lograr remisión completa, que es el objetivo principal del tratamiento

O câncer de mama é uma das doenças mais temidas pelas mulheres, por não afetar apenas o corpo anatômico, mas também os aspectos psicossociais da paciente. Na atualidade, é considerada uma enfermidade crônica. Existe um grande número de pessoas que convivem com o câncer, seja em tratamento, seja em remissão ou com controle de sintomas. Esse panorama exige da Psicologia uma atuação mais eficiente, específica, interessada em compreender o que leva os pacientes a maiores dificuldades diante das diferentes etapas do tratamento. Considerada a inexistência de uma teoria própria para a Psico-Oncologia, na análise desta pesquisa, é utilizada a proposta teórica de Donald Woods Winnicott, para auxiliar na compreensão e interpretação dos relatos de mulheres que convivem com a doença oncológica. Esta pesquisa propõe-se a investigar as repercussões psicológicas de pacientes em primeira remissão de câncer de mama. O interesse por este estudo surge a partir da prática como psicóloga, na especialidade de Mastologia. Diversas pacientes são encaminhadas para o ambulatório de Psicologia, com impactos psicológicos que perduram além da presença da doença. O estudo é do tipo transversal descritivo, com método misto. A amostra é composta por oito pacientes que realizam tratamento oncológico na Irmandade da Santa Casa de Misericórdia de São Paulo. O procedimento para a coleta de dados consistiu na aplicação de uma ficha sociodemográfica e na realização de uma entrevista semidirigida, na Escala Hospitalar de Ansiedade e Depressão (HAD) e na Escala de Desesperança Beck (BHS). Este trabalho conclui que o término de um período de tratamento não coincide com o fim das preocupações com a doença. E, ainda que pese a relevância da Psico-Oncologia para o bem-estar dos pacientes com câncer, esta pesquisa considera necessária uma fundamentação teórica, que permita contextualizar o indivíduo e promova o conhecimento de sua totalidade, além das repercussões esperadas no adoecimento oncológico. Observa-se a importância da avaliação psicológica para compreender como essa paciente vivencia o câncer de mama, a partir de sua experiência e vida anterior. Este estudo pretende avançar nos temas da Psico-Oncologia e fornecer subsídios para profissionais da área da Saúde que tratam pacientes com câncer de mama / Breast cancer is one of the most feared diseases by women, because it affects not only the body anatomy but also the psychosocial aspects of the patient. At present, it is considered a chronic illness. There are a large number of people living with cancer, either in treatment, either in remission or in symptoms control. This scenario requires from Psychology a more efficient and specific approach, more interested in understanding what leads patients to greater difficulties on the different stages of treatment. Given the lack of a specific theory for Psycho-Oncology, the analysis of this research uses the theoretical proposal of Donald Woods Winnicott to assist in the understanding and interpretation of reports of women living with cancer. This research intends to investigate the psychological repercussions of patients in first remission of breast cancer. The interest behind this study arises from the practice as psychologist in the Mastology specialty. Several patients are sent to the Psychology clinic, with psychological impacts that endure beyond the presence of the disease. This is a cross-sectional descriptive study, with mixed methods approach. The sample consists of eight patients undergoing cancer treatment in Irmandade da Santa Casa de Misericórdia of São Paulo. The procedure for data collection consisted of the application of a socio-demographic form and the conduction of a semi-directed interview, following the Hospital Anxiety and Depression (HAD) Scale and the Beck Hopelessness Scale (BDS). This paper concludes that the end of a treatment period does not coincide with the end of the concerns with the disease. And, despite the relevance of Psycho-Oncology for the well-being of cancer patients, this research considers necessary a theoretical foundation that contextualizes the individual and promotes the understanding of her entirety, in addition to the expected consequences of the oncologic illness. It is noted the importance of a psychological assessment to understand how this patient experiences breast cancer, based on her past experience. This study aims to advance Psycho-Oncology themes and provide valuable input to Health professionals who treat patients with breast cancer

Type 2 diabetes mellitus (T2D) is a highly prevalent metabolic disorder linked with the development of specific complications and comorbidities that negatively affect life quality and greatly increase the risk of an early death. The main goal of T2D treatment, which in common clinical practice comprises lifestyle changes and pharmacotherapy, is to delay onset of these complications. Evidence from many recent studies shows the ability of some interventional methods to induce remission of T2D, meaning a major improvement or complete disappearance of T2D symptoms. Besides bariatric surgery procedures, some dietary regimens such as low-energy diet, low-carbohydrate diet and intermittent fasting, can also lead to T2D remission. Attributes of these dietary regimens, especially their effect in T2D treatment, is summarized in the theoretical part of this theses. The aim of the practical part of this thesis was to assess the effect of the dietary regimens mentioned above on morphometric and biochemical parameters associated with T2D by clinical and survey research. In most of the subjects with T2D, the individual dietary regimens, more precisely low-energy diet and low-carbohydrate diet, decreased body weight, where the weight loss induced by low-carbohydrate diet was caused by major decrease in the amount...

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第25159号 / 医博第5045号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 森田 智視, 教授 永井 洋士 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Insomni är ett vanligt problem och det finns behov av ökad tillgänglighet till kostnadseffektiva behandlingar. Syftet var att undersöka om en enkomponentsbehandling (EK), bestående av sömnrestriktion/sömnkomprimering, var non-inferior till en multikomponent (MK) KBT- behandling vid insomni och om det fanns en skillnad i symtomreduktion. Gränsvärden för non- inferiority var d = 0.8, utifrån tidigare forskning, respektive en strängare gräns d = 0.4. Data från en forskningsstudie där deltagarna erhöll EK (n = 193) jämfördes mot en riktlinje i form av en KBT-behandling i reguljärvården, MK (n = 289). Båda grupper erhöll behandling via samma internetplattform, och Insomnia Severity Index (ISI) användes som utfallsmått. Resultaten visade att EK inte kunde bekräftas som non-inferior till MK direkt efter behandling eller vid 1-årsuppföljning när en sträng gräns användes. När en liberal gräns användes kunde EK bekräftas som non-inferior direkt efter behandling men inte ett år senare. Direkt efter behandling och vid 1-årsuppföljningen visade båda grupperna en signifikant minskning av insomnisymtom, men vid 1-årsuppföljningen visade MK en större minskning. Ett stort bortfall vid 1-årsuppföljning och mer terapeutstöd för MK kan ha påverkat resultaten. Fler RCT-studier med långtidsuppföljningar behövs inom området, och även studier på andra populationer. MK är att föredra, men vid begränsade resurser kan EK erbjudas med god effekt på både kort och lång sikt. / Insomnia is a common problem and there is a need for increased accessibility to cost-effective treatments. The purpose was to examine if an one-component treatment (EK), consisting of sleep-restriction/sleep-compression, were non-inferior to a multi-component (MK) CBT treatment for insomnia and if there was a difference in symptom reduction. The prestated margins for non-inferiority were d = 0.8, based on previous research, and a stricter margin of d = 0.4. Data from a research study where participants received EK (n = 193) was compared to a benchmark consisting of a CBT treatment in regular health care (MK) (n = 289). Both groups received treatment at the same Internet platform, and Insomnia Severity Index (ISI) was used as outcome measurement. The results showed that EK could not be confirmed as non-inferior to MK directly after treatment or at the one-year follow up when using a strict limit. When a liberal limit was used, EK could be confirmed as non-inferior directly after treatment but not one year later. Directly after treatment and at the one-year follow up both groups showed a significant symptom reduction, but at the one-year follow up MK showed a greater reduction. A large number of missing data at the one-year follow up and more therapeutic support in MK may have affected the results. More RCT-studies with longterm follow ups are needed in the area, and also studies of other populations. MK is preferable, but with limited resources EK can be offered with good effect both short term and long term.

The additional tax ("penalties") imposable in terms of section 76(1) of the Income Tax Act (No 58 of 1962) when a taxpayer is in default, can be very harsh (up to 200% of the tax properly chargeable). The Commissioner may, in terms of section 76(2)(a), remit any penalty imposed, as he sees fit. However, when there was intent on the part of the taxpayer to evade the payment of tax, the Commissioner may not remit any portion of the 200% penalty imposable, unless he is of the opinion that "extenuating circumstances" exist. This dissertation examines the meaning of "extenuating circumstances", as interpreted by the judiciary, and lists the factors and defences that a taxpayer may plead to justify a remission of penalties, both in the case of an intention by the taxpayer to evade tax and in cases where the taxpayer is merely in default of section 76(1). / Accounting / MCOM (Accounting)

A leucemia linfóide aguda nos adultos apresenta prognóstico reservado. Os objetivos deste estudo são descrição e análise de parâmetros clínicos, laboratoriais e fatores prognósticos em 102 pacientes tratados com diferentes protocolos de quimioterapia no período de 1990 a 2005, no Serviço de Hematologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Em estudo de coorte retrospectivo, com exclusão de LLA subtipo L3 (FAB) ou B-IV (EGIL), foram analisadas a taxa de remissão completa (RC), sobrevida global (SG) e sobrevida livre de doença (SLD) para a população geral e para os dois principais protocolos de tratamento. A análise estatística foi feita pelo programa SPSS 10.0. Associação entre variáveis, fatores prognósticos e resposta foram observados através do teste ?2 de Person. Curvas de SG e SLD foram construídas pelo método de Kaplan-Meier e as diferenças analisadas pelo teste de log-rank. A idade média foi de 30,6 anos (12 a 82 anos) e predominou o sexo masculino (55,9%). Ao diagnóstico, os achados clínicos foram: fadiga (58,2%), esplenomegalia (59,7%), hepatomegalia (54,6%), linfadenopatia (52,6), febre (38,8%), dor óssea(28,6%), sangramento (27,5%) e cefaléia (15,3%). Envolvimento do sistema nervoso central (SNC) foi detectado em 11 (11,8%) pacientes, enquanto envolvimento testicular acometeu um paciente. O valor médio de hemoglobina, leucócitos e plaquetas foram 8,5g/dl, 84.341/mm3 e 76.275/mm3, respectivamente. 98,7% dos pacientes apresentaram linfoblastos no sangue periférico. A classificação FAB foi igualmente observada entre os tipos L1 e L2. As LLA B e T foram observadas em 69,7% e 30,2%, respectivamente. O cariótipo foi realizado em 40 pacientes, e t (9;22) foi identificada em 20% (8/40) dos casos. Os pacientes foram tratados com quatro diferentes protocolos: BFM 86 modificado (BFM 86M) em 47,15% (48/102), Linker et al em 39,2% (40/102), Lister et al em 5,9% (6/102) e CHOP em 7,8% (8/102). Na análise para a população geral, na fase de indução, 70,6% (65/92) dos pacientes entraram em RC. Idade inferior a 18 anos e ausência de infiltração de SNC foram fatores preditores positivos de resposta em análise multivariada (p=0,03). Com mediana de seguimento de 49 meses, observamos taxa de 30,5% e 27% para SG e SLD em 4 anos. Ausência de sangramento e hepatomegalia, ao diagnóstico, e idade < 35 anos estiveram associados à maior SG através de análise multivariada (p=0,01). Os dois protocolos com maior número de pacientes, apresentaram distribuição semelhante de parâmetros clínicos e laboratoriais, a exceção da variável FAB. RC foi obtida em 76,7% e 63,9% dos pacientes tratados respectivamente com os protocolos BFM 86M e Linker (p=0,21). A SG foi de 49,5% com o BFM 86M em 4 anos Vs 16% com o protocolo Linker (p=0,004). Observou-se que o protocolo BFM86M teve melhor SG para pacientes com idade <35 anos (p=0,01), sem sangramento e hepatomegalia ao diagnóstico (p=0,03 e p=0,01) e sem leucocitose (B <30.000mm3 e T <100.000mm) (p=0,04); enquanto que pacientes com LLA T tratados com o protocolo Linker apresentaram SG inferior (p=0,05). A diferença de SLD entre os dois protocolos não foi significativa (p=0,58), entretanto na faixa etária entre 21-35 anos, o protocolo BFM se mostrou superior (p=0,03). Verificamos que o BFM 86M é superior ao Linker et al, sendo um bom protocolo para tratamento de LLA em pacientes adolescentes e adultos jovens sem fatores de risco. / Acute lymphoblastic leukemia in adults has a poor outcome. The aim of this study is to describe and evaluate clinical, laboratory and prognostic factors in 102 patients reated with different protocols of chemotherapy from 1990 to 2005. Adult ALLsubtype L3 (FAB) or B-IV (EGIL) was excluded. We evaluated complete remission (CR), overall survival (OS) and disease free survival (DFS) rates for the whole population and for the two principal treatment protocols. This retrospective cohort was done in hematology department of the FMUSP. Statistical analysis was done by SPSS 10.0. The association of features and prognosis was assessed by Person\'s chi-square. OS and DFS curves were constructed by Kaplan-Meier method and the differences were calculated by the log-rank test. Mean age was 30,6 (12 to 82) years and 55,9% was male. Clinical findings, at diagnosis, were fatigue (58,2%), splenomegaly (59,7%), hepatomegaly (54,6%), ymphadenopathy (52,6%), fever (38,8%), bone pain (28,6%), bleeding (27,5%) and headache (15,3%). Involvement of central nervous system (CNS) was detected in 11 (11,8%) patients and testicular involvement was observed in one patient. Mean blood values were 8,5g/dl, 84.341/mm3 and 76.275/mm3 for hemoglobin, leucocytes and platelets respectively. 98,7% of the patients presented with lymphoblasts in peripheral blood. FAB classification was equally observed between L1 and L2. B and T ALL was noted in 69,7% and 30,2% respectively. Karyotype analysis was performed in 40 cases, where Philadelphia chromosome (ph) was identified in 20% (8/40) of them. Patients were treated with four different protocols: BFM 86 modified (BFM 86M) in 47,1% (48/102), Linker et al in 39,2% (40/102), Lister et al in 5,9% (6/102) and CHOP in 7,8% (8/102) of the patients. In the judgment for the entire population, in induction treatment, 70,6% (65/92) of the patients had CR. Age below 18 years and no infiltration in CNS were positive factors for CR in multivariate analyses (p=0,03). In a median follow up of 49 months, we have observed a 4 years OS and DFS of 30,5% and 27% respectively. No bleeding and hepatomegaly, at diagnosis, and age less than 35 years were factors associated a better OS in multivariate analyses (p=0, 01). Protocols with highest number of patients (BFM and Linker) showed the same distribution of clinical and laboratory factors; exception FAB classification. CR were seen in 76,7% and 63,9% of the patients treated with BFM 86M and Linker respectively. (p=0,21). OS was 49,5% with BFM protocol in 4 years Vs 16% with Linker (p=0,004). We observed a better OS for patients with age below 35 years (p=0,01), no bleeding and no hepatomegaly at diagnosis (p=0,03 ; p=0,01) and no leucocytosis ( B < 30000/mm3 and T < 100000/mm3) treated with BFM 86M; however ALL - T treated with Linker protocols had inferior OS (p=0,05). DFS between protocols wasn\'t significant (p=0,58), but with age between 21 and 35 years BFM was better (p=0,03). We conclude that BFM 86M is superior than Linker et al and it is a good treatment for childhood / young adults without risk factors

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.