Avec une prévalence de 1% dans la population générale, le trouble bipolaire (TB) est une maladie psychiatrique commune, chronique et sévère. Les études familiales réalisées pour cette affection ont montré une contribution génétique forte dans la prédisposition au TB, plus particulièrement pour les formes à début précoce de la maladie (TBDP). Malgré tout, les mécanismes moléculaires à l'origine de la maladie restent mal connus. Ainsi, suivant une étude de liaison génétique, nous avons pu identifier des variations rares dans un gène codant la protéine activatrice de l'exocytose dépendante du calcium (CADPS for Calcium- dependant activator protein for secretion) chez des patients avec un TBDP. CADPS est une protéine essentielle pour la régulation de l'exocytose et du chargement vésiculaire des monoamines dans les cellules neuronales et neuroendocrines. Nous avons étudié l'impact de ces mutations sur la fonction de ce gène, et montré que plusieurs d'entre elles altéraient son expression ainsi que ses fonctions. D'autre part, nous nous sommes intéressés au modèle murin privé d'un allèle de Caps (Caps1+/-) et montré que celles-ci décrivaient des comportements hyperactifs ainsi qu'une réponse au stress variable comparée aux souris sauvages.L'ensemble de nos résultats suggèrent pour la première fois que ce gène pourrait jouer un rôle dans les formes à début précoce de trouble bipolaire et ouvrent de nouvelles voies de recherche pour comprendre les mécanismes moléculaires qui sont altérés chez les sujets atteints. / Summary not transmitted

Syftet med denna studie var att undersöka hur personer med bipolär sjukdom upplever att diagnosen har påverkat deras liv, samt hur de hanterar sjukdomen i det vardagliga livet. Studien har genomförts med en kvalitativ ansats med narrativa intervjuer med fem kvinnor som alla fått diagnosen bipolär sjukdom. Resultatet visar att diagnosen har hjälp de diagnostiserade individerna till att acceptera och lära känna sin sjukdom, och därefter kunnat göra nödvändiga förändringar anpassade för att må så bra som möjligt. Informanterna beskriver olika strategier som de använder för att hantera sin sjukdom på ett vardagligt plan. Exempel på strategier som lyfts fram är sömn, rutiner, mediciner, inte företa sig för många göromål samma dag, lyssna på kroppen, mindfulness, terapisamtal och motion. Resultatet av intervjuerna har analyserats med begreppen stigma och identitet samt i relation till tidigare forskning. / The aim of this study was to investigate how people with bipolar disorder experience that the diagnosis has affected their lives, and how they handle the disease in everyday life. The study has been conducted with a qualitative approach with narrative interviews with five women who have all been diagnosed with bipolar disorder. The result has shown that the diagnosis has helped the diagnosed individuals to accept and gotten to know their illness, and then how to make the necessary changes adapted to feel as good as possible. The informants describe the different strategies they use to manage their illness on a daily basis. Examples of strategies presented are sleep, routines, medication, do not undertake for many purposes the same day, listen to the body, mindfulness, therapy and exercise. The results of the interviews have been analyzed with the terms stigma and identity as well as in relation to previous research.

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Orientadores: Cláudio Eduardo Muller Banzato , Clarissa de Rosalmeida Dantas / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T15:11:19Z (GMT). No. of bitstreams: 1 Silva_LuizFernandodeAlmeidaLimae_M.pdf: 4787027 bytes, checksum: 41b58615628a8ce9c086589e9db94ca8 (MD5) Previous issue date: 2015 / Resumo: O transtorno afetivo bipolar (TAB) é uma morbidade mental crônica e grave, que habitualmente se manifesta na adolescência ou início da vida adulta. Sua forma mais prevalente de apresentação é a de episódios maníacos ou hipomaníacos, intercalados por episódios depressivos ou períodos de eutimia. Modernamente, uma miríade de medicações possuem aprovação para o tratamento do TAB, porém o lítio ainda é considerado um dos fármacos de primeira linha no tratamento de manutenção do transtorno. Como a resposta ao lítio não é uniforme, a tentativa de identificar possíveis preditores de resposta terapêutica vem sendo alvo de diversos estudos. Neste contexto, um grande desafio é avaliação da melhora clínica de pacientes tratados fora de um protocolo estrito de pesquisa. Para contornar este problema, a escala ALDA vem se mostrando como um valioso instrumento nos trabalhos publicados na literatura. OBJETIVOS: estudar a confiabilidade da escala ALDA, avaliar de forma padronizada a resposta terapêutica ao lítio no tratamento de manutenção do TAB e identificar possíveis preditores clínicos e epidemiológicos de resposta. MÉTODOS: quarenta pacientes em tratamento ambulatorial com diagnostico confirmado de TAB e história de uso de lítio foram avaliados, com revisão minuciosa dos prontuários médicos. Um instrumento padronizado (a escala ALDA), que se baseia em informações clínicas obtidas de forma retrospectiva, foi usado para avaliar a melhora clínica global e possíveis fatores confundidores. Foram também coletados dados acerca de variáveis clínicas e sociodemográficas, para avaliar possíveis fatores preditores de resposta ao tratamento. Também aferimos a confiabilidade interavaliadores para o escore total e para cada um dos itens da escala ALDA, por meio do Coeficiente de Correlação Intraclasse (ICC), entre dois pesquisadores que realizaram suas avaliações de modo independente. RESULTADOS: nosso estudo encontrou uma relação inversa entre o número de episódios de humor com sintomas psicóticos e melhor desfecho no tratamento com lítio (PE -1,24241). Também constatamos a relação direta entre uso atual ou prévio de tabaco e melhora clínica com lítio (PE 7,66608). Com relação ao estudo de ICC nos diferentes itens da escala ALDA, encontramos valores que variaram de 0,610 a 0,833. CONCLUSÃO: nossos achados apontam que a escala ALDA pode ser uma ferramenta útil e confiável para a avaliação padronizada da resposta terapêutica em pacientes com TAB. Os resultados obtidos reforçam a hipótese que o lítio parece ser menos eficaz em pacientes que manifestam sintomas psicóticos, além de nos levarem a questionar o papel do tabaco no prognóstico de pacientes com transtorno bipolar / Abstract: Bipolar disorder (BD) is a chronic and severe mental illness, that usually manifest its first symptoms in early adulthood. The most prevalent clinical form of the disorder is the occurrence of episodes of mania or hypomania, interspersed with episodes of depression and periods of euthymia. Currently, a myriad of drugs have approval for treating BD, nevertheless lithium still stands as a gold standard in the prophylactic treatment of the disorder. Since lithium response is not uniform between patients, different studies have been trying to identify possible predictors of response to the treatment. In this scenario, accessing clinical improvement in patients not treated following a strict research protocol is a great challenge. To solve this issue, the ALDA scale appeared as a valuable tool in different published studies. OBJECTIVES: to study the reliability of the ALDA scale, to systematically access the response of prophylactic lithium treatment in BD and to identify possible clinical and epidemiological predictors of lithium response. METHODS: forty outpatients in treatment for confirmed clinical diagnose of BD, and with history of lithium use, were accessed with a thorough review of their medical charts. A standardized instrument (the ALDA scale), which is based on clinical information obtained retrospectively, was used to evaluate clinical improvement and possible confounding factors. In this process, we have obtained other clinical and sociodemographic data, to investigate possible predictive variables to treatment response. We have also used the Interclass Correlation Coefficient (ICC) to determine the inter-rater reliability between two independent researchers, for the ALDA scale total score and each of its sub items. RESULTS: our study found an inverse relation between the number of mood episodes with psychotic symptoms and improvement with lithium therapy (PE -1,24241). We have also found a direct relation between current or previous tobacco use and clinical improvement with lithium (PE 7,66608). Concerning the ICC for each of the ALDA scale sub items, we found values ranging between 0,610 and 0,833. CONCLUSION: our findings suggest that the ALDA scale can be a useful and trustworthy instrument in the standardized evaluation of clinical response in patients with BD. Our results also reinforce the hypothesis that lithium treatment seems to be less efficacious in patients with psychosis, and lead us to speculate the role of tobacco use in the outcome of patients with bipolar disorder / Mestrado / Saude Mental / Mestre em Ciências Médicas

O Transtorno Bipolar (TB) é uma das doenças mais incapacitantes no mundo. É frequentemente acompanhado de comorbidades, tanto clínicas quanto psiquiátricas. Ansiedade é uma das comorbidades mais prevalente em TB, e o tratamento é difícil, pois as medicações podem induzir mania. Portanto, os métodos alternativos com potencial para melhorar sintomas ansiosos são muito importantes. Respiração profunda (RP) é uma técnica simples, que não necessita de grandes investimentos, não precisa de espaço específico. A respiração profunda tem grande potencial para o tratamento de transtornos psicológicos, porém a literatura ainda carece de avaliações dos benefícios e um protocolo definido de RP, com tempo de duração e frequência dos exercícios respiratórios. Essa dissertação tem como objetivo geral avaliar os efeitos de um protocolo de exercícios de respiração profunda em pacientes com Transtorno Bipolar. Os pacientes realizaram sete encontros, sendo três destes para avaliação (antes e após aplicação do protocolo e um mês após protocolo) e quatro para intervenção. Foi utilizado o programa estatístico R para compilação e análise dos dados. Vinte pacientes aceitaram participar do estudo e realizaram a avaliação pré-intervenção, porém quatorze pacientes completaram o protocolo, sendo que 3 desistiram devido a questões de logística e 3 foram excluídos do estudo por não atenderem todos os critérios de inclusão. As escalas HAM-A, BECK-A, HAM-D e YMRS tiveram diferenças significativas pré, pós-intervenção e follow-up. Os resultados indicam que o protocolo de Respiração Profunda é efetivo na redução dos níveis de ansiedade em pacientes com Transtorno Bipolar. O protocolo de Respiração Profunda não tem efeitos colaterais e pode ser aplicado para aliviar os sintomas de ansiedade em pacientes com Transtorno Bipolar. / Bipolar Disorder (BD) is one of the most disabling diseases in the world. It is often accompanied by comorbidities, both clinical and psychiatric. Anxiety is one of the most prevalent comorbidities in BD, and treatment is difficult as medications can induce mania. Therefore, alternative methods with potential for improving anxiety symptoms are very important. Deep breathing (DB) is a simple technique that does not require large investments, does not need specific space. Deep breathing has great potential for the treatment of psychological disorders, but the literature still lacks benefits assessments and a defined DB protocol, with duration and frequency of breathing exercises. This project aims to evaluate the effects of a protocol of deep breathing exercises in patients with Bipolar Disorder. The patients performed seven meetings, three of which were for evaluation (before and after the application of the protocol and one day after the protocol) and four for the intervention. The statistical program R was used for data compilation and analysis. Twenty patients accepted to participate in the study and carried out the pre-intervention evaluation, but fourteen patients completed the protocol, three of whom gave up due to logistics issues and three were excluded from the study because they did not meet all the inclusion criteria. The HAM-A, BECK-A, HAM-D and YMRS scales had significant pre, post-intervention, and follow-up differences. The results indicate that the Deep Breathing protocol is effective in reducing anxiety levels in patients with Bipolar Disorder. The Deep Breathing protocol has no negative side effects and can be applied to alleviate anxiety symptoms in patients with Bipolar Disorder.

O Transtorno Bipolar é uma doença crônica e grave que apresenta curso episódico e alto impacto sobre a funcionalidade do paciente. Possui potencial para alto grau de severidade, recorrência e intensidade e estima-se que sua prevalência ao longo da vida seja de 2,4% da população mundial. A fisiopatologia deste transtorno ainda não é bem compreendida e ainda o fármaco de primeira escolha é o lítio, embora tampouco seja claro seu mecanismo de ação. O sistema purinérgico principalmente devido a suas ações sobre neuroproteção, inflamação e ativação microglial se destaca como uma via promissora de novos alvos terapêuticos, especialmente o receptor purinérgico P2X7 (P2X7R). Dessa maneira, o objetivo desta tese é caracterizar o envolvimento do sistema purinérgico na fisiopatologia do transtorno bipolar. De maneira geral, avaliamos metabólitos do sistema purinérgico em soro de pacientes e controles, correlacionando com dados clínicos. Avaliamos a frequência do polimorfismo do P2RX7 1513A>C em pacientes e controles. Realizamos um modelo animal farmacológico de mania e investigamos o envolvimento do P2X7R neste modelo e por último buscamos melhor compreender a ação neuroprotetora do lítio verificando a participação purinérgica. Nossos resultados primeiramente nos mostraram uma diminuição nos níveis de adenosina em pacientes em comparação a controles e uma importante correlação inversa entre os níveis de adenosina e a piora dos sintomas. Demonstramos ainda que pacientes com transtorno bipolar apresentam diminuição na frequência do alelo 1513C e o potencial aumento na frequência do genótipo 1513AA e 1513AA/AC em relação aos controles configurando um pior prognóstico de aumento da forma mais ativa do receptor. Também mostramos que o P2X7R possui um papel importante no estabelecimento do modelo de mania, modulando principalmente a via dopaminérgica que é refletida na mudança comportamental observada pelo modelo e por último, o lítio foi capaz de prevenir a resposta de insulto nas células neuronais (linhagem PC-12) e não foi capaz de prevenir a ativação mediada pelo P2X7R em células microgliais (linhagem N9), indicando uma resposta celular diferenciada. Podemos concluir que de maneira translacional conseguimos demonstrar a participação do sistema purinérgico na fisiopatologia do transtorno bipolar, sugerindo ainda um possível biomarcador tanto para diagnóstico como para progressão da doença, os níveis séricos de adenosina, e ainda um potencial biomarcador genético de predição e diagnóstico da doença, o polimorfismo do P2X7R 1513A>C, assim como contribuímos para o entendimento do mecanismo de ação do lítio e definimos um potencial novo alvo terapêutico para o transtorno, o receptor P2X7. / Bipolar Disorder is a severe and chronic psychiatric disorder that presents an episodic course and high impact on the patient's functionality. It has potential for a high degree of severity, recurrence and intensity. The prevalence throughout life of bipolar disorder is 2.4% of the world population. The pathophysiology of this disorder is still not well understood and the drug of first choice is lithium, although its mechanism of action is not clear. The purinergic system mainly due to its actions on neuroprotection, inflammation and microglial activation stands out as a promising pathway for new therapeutic targets, especially the purinergic receptor P2X7 (P2X7R). Thus, the purpose of this thesis is to characterize the involvement of the purinergic system in the pathophysiology of bipolar disorder. In general, we evaluated purinergic system metabolites in serum from bipolar disorder patients and healthy controls, correlating with clinical data. We evaluated the frequency of P2RX7 1513A>C polymorphism in bipolar disorder patients and in healthy subjects. We performed a pharmacological animal model of mania and investigated the involvement of the P2X7 purinergic receptor in this model and finally we sought to better understand the neuroprotective action of lithium by verifying the purinergic participation. Our results primarily showed a decrease in adenosine levels in patients compared to controls and a significant inverse correlation between adenosine levels and worsening of symptoms. We also demonstrated that patients with bipolar disorder present a decrease in the frequency of the 1513C allele and the potential increase in the frequency of genotype 1513AA and 1513AA/AC in relation to controls, setting a worse prognosis of the most active form of the receptor. We also showed that P2X7R plays an important role in the establishment of the mania model, modulating mainly the dopaminergic pathway that is reflected in the behavioral change observed by the model. Finally, lithium was able to prevent the insult response in neuronal cells (PC-12 lineage) and was not capable of preventing P2X7R-mediated activation in microglial cells (N9 lineage), indicating a differentiated cellular response. We can conclude that in a translational way we could demonstrate the participation of the purinergic system in the pathophysiology of bipolar disorder. We also suggested a possible biomarker for both diagnosis and progression of the disorder, the serum adenosine levels, and a potential genetic marker for prediction and diagnosis, the polymorphism of P2X7R 1513A>C. Lastly we contributed to the understanding of lithium action mechanism and defined a potential new therapeutic target for the disorder, the P2X7 receptor.

Mental and behavioural disorders such as bipolar disorder and depression are critical healthcare issues that affected approximately 45 and 264 million people around the world, respectively in 2020. Early detection and intervention are crucial for limiting the negative effects that these illnesses can have on people’s lives. Although the symptoms for different mental disorders vary, they generally are characterized by a combination of abnormal behaviours, thoughts, and emotions. Mental disorders can affect one’s ability to relate to others and function every day. To assess symptoms, clinicians often use structured clinical interviews and standard questioners. However, there is a scarcity of automated or technology-assisted tools that can simplify the diagnostic process. The main objective of this thesis is to investigate, develop, and propose automated methods for mental disorder detection. We focus in our research on bipolar disorder and depression as they are two of the most common and debilitating mental illnesses. Bipolar disorder is one of the most prevalent mental illnesses in the world. Its principal indicator is the extreme swings in the mood ranging from the manic to depressive states. We propose automatic ternary classification models for the bipolar disorder manic states. We employ a dataset that uses the Young Mania Recall Scale to distinguish the manic states of patients as: Mania, Hypo- Mania, and Remission. The dataset comprises audio-visual recordings of bipolar disorder patients undergoing a structured interview. We propose three bipolar disorder classification solutions. The first approach uses a hybrid LSTM-CNN model. We apply a CNN model to extract facial features from video signals. We supply the features’ sequence to an LSTM model to resolve the bipolar disorder state. Our solution achieved promising results on the development and test set of the Turkish Audio-Visual Bipolar Disorder Corpus with the Unweighted Average Recall of 60.67% and 57.4%, respectively. The second solution employs additional features from the structured interview recordings. We acquire visual representations along with audio and textual cues. We capture Mel-Frequency Cepstral Coefficients and Geneva Minimalistic Acoustic Parameter Set as audio features. We compute linguistic and sentiment features for each subject’s transcript. We present a stacked ensemble classifier to classify all fused features after feature selection. A set of three homogeneous CNNs and an MLP constitute the first and second levels of the stacked ensemble classifier respectively. Moreover, we use reinforcement learning to optimize the networks and their hyperparameters. We show that our stacked ensemble solution outperforms existing models on the Turkish Audio-Visual Bipolar Disorder corpus with a 59.3% unweighted average unit on the test set. To the best of our knowledge, this is the highest performance achieved on this dataset. The Turkish Audio-Visual Bipolar Disorder dataset comprises a relatively small number of videos. Moreover, the labels for the testing set are kept confidential by the dataset provider. Hence, this motivated us to train a classifier using a semi-supervised ladder network for the third solution. This network benefits from unlabeled data during training. Our goal was to investigate whether a bipolar disorder states classifier can be trained using a mix of labelled and unlabelled data. This would alleviate the burden of labelling all the videos in the training set. We collect informative audio, visual, and textual features from the recordings to realize a multi-model classifier of the manic states. The third proposed model achieved a 53.7% and 60.0% unweighted average unit on the test and development sets, respectively. There is a growing demand for automated depression detection system to control the subjective bias in diagnosis. We propose an automated depression severity detection model that uses multi- modal fusion of audio and textual information. We train the model on the E-DAIC corpus, which labels the individual’s depression level with patient health questionnaire score. We use MFCCs and eGeMAPs as audio representations and Word2Vec embeddings for the textual modality. Then, we implement a stacked ensemble regressor to detect depression severity. The proposed model achieves a concordance correlation coefficient 0.49 on the test set. To the best of our knowledge, this is the highest performing model on this dataset.

Bipolär sjukdom är en kronisk och allvarlig sjukdom och risken för återinsjuknande är livslång. Risken för suicid och olycksfall är förhöjd under både maniska och depressiva episoder. Farmakologisk långtidsbehandling är den primära behandlingen för att behandla och förebygga maniska och depressiva skov vid bipolär sjukdom. Bristande läkemedelsföljsamhet är den vanligaste orsaken till återinsjuknande och ett stort hälsoproblem. Syftet med studien var att utforska aspekter som kan påverka följsamheten till underhållsbehandling hos personer med bipolär sjukdom. En integrativ litteraturstudie genomfördes inspirerad av Whittemore och Knafls metod. Totalt 15 studier med kvalitativ, kvantitativ och mixad ansats inkluderades. Som teoretisk utgångspunkt i resultatdiskussionen användes Orlandos teori om en reflektiv omvårdnadsprocess. Ur dataanalysen framkom fyra teman vilka innehöll totalt åtta underteman. De fyra identifierade teman var: Patient/sjukdom; Familj och samhälle; Läkemedel samt Behandlingsallians och undervisning. Att ha kunskap om avgörande faktorer för läkemedelsföljsamhet kan fungera som ett viktigt verktyg i specialistsjuksköterskans hälsoarbete med patienter med bipolär sjukdom. Behandlingsalliansens betydelse för följsamheten framkom i studien. Samlad kunskap om faktorer som påverkar följsamheten till långtidsmedicinering kan ge ökad förståelse och verktyg för sjuksköterskan i mötet med patientgruppen.

Bakgrund: Bipolär sjukdom är en psykisk sjukdom som påverkar sinnesläget hos individen och drabbar ca 1–2,4 % av den svenska befolkningen. Sjukdomen debuterar kring 15–35 årsåldern och diagnostiseringen sker ofta sent. Sjukdomen medför stora konsekvenser för såväl individen som för samhället. Syfte: Att beskriva individens erfarenheter av att leva med en bipolär sjukdom. Metod: Litteraturstudie med deskriptiv design. Artikelsökning utfördes i PubMed och psycINFO, vilket resulterade i 11 involverade artiklar, av både kvalitativ och kvantitativ ansats, vilka analyserades med en tematisk metod. Huvudresultat: Fem teman identifierades i resultatet, upplevelse av bipolär sjukdom, upplevelse av stigma samt dess påverkan, upplevelse av medicinsk behandling och självmedicinering, viljan att fly samt copingresurser och copingstrategier. Att leva med en bipolär sjukdom upplevdes för många individer som en utmaning, ofta förekom ett substansmissbruk till följd av ett missnöje till ordinerad behandling. En problematik relaterat till ett stigma över sjukdomen uttrycktes frekvent. Stigmat var något som riskerade att individerna applicerade på sig själva. Slutsats: Individer uppfattar den bipolära sjukdomen som påfrestande relaterat till; ett fluktuerande känsloliv, stigma och medicinering. För att hantera sjukdomen beskrevs ett socialt stöd vara viktigt, då känsla av tillhörighet ingav en motiverande kraft, även sjuksköterskan beskrivs ha en viktig motiverande roll. Att vårdrelationen baserades på respekt och frånvaro av stigma beskrevs vara en förutsättning för sjuksköterskans arbete till att främja individens hälsa. / Background: Bipolar disorder is a mental illness that affects the state of mind of the individual and affects about 1–2,4% of the swedish population. The disease debuts around the age of 15–35 and the diagnosis is often set late. The disease has major consequences for the individual as well as for society. Aim: To describe individuals experiences of living with a bipolar disorder. Method: Literature study with descriptive design. Search for involved articles where performed in PubMed and psycINFO, which resulted in a total of 11 articles, of both qualitative and quantitative approach, which were analyzed using a thematic method Main result: Five themes were identified in the result, experience of bipolar disorder, experience of stigma and its work, experience of medical treatment and self-medication, the will to escape and coping resources and coping strategies. Living with a bipolar disorder was seen as a challenge for many individuals. Substance abuse were often described, related to a series of dissatisfaction with prescribed treatment. A problem related to a stigma over the disease were frequently expressed. The stigma were something that risked the individuals themselves, started to apply the prejudices to their own identity. Conclusion: Individuals perceive the bipolar disorder as strenuous related to; fluctuating emotions, stigma and medication. To deal with the disease, social support describes being important, as a sense of belonging served as a motivating power. The nurse where also described as having an important motivating role. The fact that the nursing relationship were based on respect and absence of stigma were described as a prerequisite for the nurse's work to promote the individual's health.