Os cuidadores são elementos essenciais na prestação dos cuidados de saúde, especialmente em situações de doenças crônicas e incapacitantes. Sobrecarga experimentada por cuidadores de pacientes com transtorno bipolar (TB) é pouco estudada em comparação a outras doenças, como a doença de Alzheimer (DA). O objetivo desse estudo é comparar a sobrecarga, desgaste emocional e os fatores associados em cuidadores de idosos com TB e DA. Trata-se de um estudo transversal, do tipo quanti-qualitativo, que avaliou 75 cuidadores e seus respectivos pacientes (36 com TB e 39 com DA). Para avaliação dos cuidadores foi utilizado o Inventário de Sobrecarga de Zarit (ZBI), o Inventário Neuropsiquiátrico de Desgaste do Cuidador (NPI-D) e uma entrevista semiestruturada interpretada pelo Discurso do Sujeito Coletivo. As questões norteadoras da entrevista foram: Como você se sente cuidando do seu familiar? Quais são as suas maiores dificuldades em relação ao cuidado prestado ao paciente? Os cuidadores também foram avaliados em relação aos sintomas depressivos e ansiosos, saúde global e qualidade de vida. Os pacientes foram avaliados nos aspectos cognitivos, funcionalidade, saúde global, qualidade de vida e sintomas depressivos, ansiosos e neuropsiquiátricos. Os resultados indicaram que os cuidadores de pacientes com TB apresentaram níveis semelhantes em relação aos cuidadores de DA na ZBI (p=0,097) e níveis mais altos no NPI-D (p=0,019). Em ambos os grupos, o ZBI foi correlacionado com o declínio funcional do paciente, maior número de tarefas do cuidador para o paciente, a presença de sintomas depressivos e ansiosos do próprio cuidador, consequentemente, uma pior qualidade de vida (r > 0,3; p < 0,05). O NPI-D relacionou-se com os sintomas neuropsiquiátricos dos pacientes em ambos os grupos (p < 0,001). A percepção dos cuidadores TB em relação ao cuidado esteve associada aos sentimentos positivos de gratidão, bem-estar e orgulho; sentimentos negativos como cansaço, obrigação e insegurança; e ao sentimento de conformismo. Quanto às dificuldades no cuidado com o paciente, os cuidadores TB referiram alterações do humor; tarefas de higiene corporal; falta de apoio familiar; falta de tempo, paciência e dinheiro. Conclui-se que a avaliação da funcionalidade e dos sintomas neuropsiquiátricos do paciente idoso com TB podem trazer benefícios para os profissionais, assim como a inclusão da avaliação da sobrecarga e do desgaste emocional dos cuidadores. Nossos resultados apontam para a necessidade de cuidar da saúde do cuidador, por meio de intervenções psicossociais, assistência médica e psicológica e o estabelecimento de redes de apoio a cuidadores na comunidade / Caregivers are essential elements in the health care, especially in situations of chronic diseases. Burden experienced by caregivers of patients with bipolar disorder (BD) is little studied compared to other diseases, such as Alzheimer\'s disease (AD). The objective of this study is to compare the caregiver burden, distress and associated factors in caregivers of the elderly with BD and AD. This is a cross-sectional study, quantitative-qualitative research that evaluated 75 caregivers and their respective patients (36 with BD and 39 with AD). The Zarit Burden Inventory (ZBI), Neuropsychiatric Inventory - Distress (NPI-D) and a semi-structured interview interpreted by the Collective Subject Discourse were used to assess the burden of the caregivers .The guiding questions of the interview were: How do you feel about taking care of your family member? What are your greatest difficulties in relation to the care given to the patient? Caregivers were also evaluated for depressive and anxious symptoms, global health, and quality of life. Patients were assessed on cognitive aspects, functionality, global health, quality of life, and depressive, anxious, and neuropsychiatric symptoms. The results indicated that caregivers of BD patients experienced similar levels of burden (p=0.097) and higher levels of distress (p=0.019) as did caregivers of AD patients. In both groups, the ZBI was associated with impairment in patient\'s functionality, number of tasks completed for the patient, caregiver depression and anxiety consequently poor quality of life(r > 0.3; < 0.05). NPI-D was associated with the neuropsychiatric symptoms of patients in both groups (p < 0.001). BD caregivers\' perception of care has been associated with positive feelings of gratitude, well-being, and satisfaction; negative feelings such as tiredness, obligation and insecurity; and the feeling of conformity. Regarding the difficulties in patient care, the BD caregivers reported mood alterations; body hygiene tasks; lack of family support, time, patience and money. It is concluded that the evaluation of the neuropsychiatric functionality and neuropsychiatric symptoms of the elderly patient with BD can bring benefits to the professionals, as well as the inclusion of the evaluation of the caregiver burden and the distress of the caregivers. Our results point to the need to take care of the health of the caregiver, through psychosocial interventions, medical and psychological assistance, and the establishment of networks to support caregivers in the community

O Transtorno Afetivo Bipolar (TAB) é uma condição crônica, caracterizada pela existência de episódios agudos e recorrentes de alteração patológica do humor, que ocasiona grande impacto na vida do paciente, reduzindo seu funcionamento e sua qualidade de vida. O uso de medicamentos consiste em uma realidade necessária ao cotidiano da pessoa com TAB. Este estudo teve como objetivo compreender o significado da terapêutica medicamentosa para a pessoa com TAB, em sua perspectiva e na de seu familiar. Dada a natureza do problema, esta investigação utilizou uma abordagem qualitativa, tendo como referencial metodológico a Teoria Fundamentada nos Dados, à luz do Interacionismo Simbólico. Participaram do estudo 14 pessoas com TAB que estavam em acompanhamento em uma Unidade Ambulatorial de Transtornos do Humor de um hospital universitário e 14 familiares indicados pelas mesmas. A entrevista e observação foram utilizadas como principais estratégias de obtenção de dados. As entrevistas gravadas, após serem transcritas, foram codificadas em três etapas: codificação aberta, codificação axial e codificação seletiva. A análise comparativa dos dados resultou no fenômeno central: ?ESTANDO ENTRE A CRUZ E A ESPADA? em relação à terapêutica medicamentosa. Tal processo foi constituído pela integração entre categorias no modelo de paradigma de Strauss e Corbin, envolvendo a causa desencadeadora do fenômeno, o contexto em que o mesmo está inserido, as condições intervenientes, a estratégia de ação sobre o fenômeno e suas conseqüências. O fenômeno ESTANDO ENTRE A CRUZ E A ESPADA permitiu compreender que, para pessoas com TAB, existe uma situação de ambivalência em relação à terapêutica medicamentosa: no início, não reconhecendo o transtorno e, paralelamente, tomando muitos medicamentos. Como não se percebem doentes, geralmente não identificam motivos para utilizar medicamentos que lhes impõem como realidade conviver com o preconceito e com as perdas e limitações impostas tanto pelos seus efeitos colaterais quanto pelos sintomas do transtorno, sendo freqüente o abandono da terapia medicamentosa. Ao identificar a real necessidade do medicamento, evidenciada pela vivência de crises na ausência do mesmo, as pessoas com TAB percebem-se frente a um dilema entre as duas alternativas de vida em que se constituem a saúde e a doença. Nesse sentido, ao mesmo tempo em que depositam no medicamento o símbolo de sanidade, esse passa a ser a prova concreta e cotidiana de que possuem um transtorno mental e crônico. Este estudo permitiu, assim, compreender os fatores associados e determinantes da realidade vivenciada pelas pessoas com TAB em relação à terapêutica medicamentosa, possibilitando um salto na implementação de estratégias de intervenção nos serviços de saúde direcionadas à qualidade da assistência a esses pacientes / Bipolar Affective Disorder (BAD) is a chronic condition, characterized by the existence of acute and recurring episodes of pathological mood change, which causes a great impact on patients? lives, reduces their functioning and quality of life. Taking medication is a necessary reality in the daily lives of BAD patients. This study aimed to understand the meaning of medication therapy for these patients, according to their perspectives and those of family members. Given the nature of the problem, this research used a qualitative approach, based on Grounded Theory, in the light of Symbolic Interactionism. Study participants were 14 BAD patients who were followed at a Clinical Unit for Mood Disorders of a university hospital and 14 relatives they indicated. Interviews and observation were the main strategies for data collection. The recorded interviews were first transcribed and then coded in three phases: open coding, axial coding and selective coding. Comparative data analysis resulted in the central phenomenon: BEING BETWEEN THE DEVIL AND THE DEEP BLUE SEA with respect to medication therapy. This process was constituted by integrating categories in Strauss and Corbin?s paradigm model, involving the cause that triggered the phenomenon, the context in which it is inserted, intervening conditions, the strategy to act on the phenomenon and its consequences. The phenomenon of BEING BETWEEN THE DEVIL AND THE DEEP BLUE SEA allowed us to understand that, for patients with BAD, there is an ambivalent situation related to medication therapy. This is perceived, at first, by not acknowledging the disorder and, in parallel, by taking many drugs. As patients do not perceive themselves as ill, they generally do not identify, at this moment in the history of the disorder, motives to take drugs that impose the reality of living with prejudice and with the losses and limitations imposed by their collateral effects as well as by the symptoms of the disorders, with frequent abandonment of medication therapy. By identifying the real need for the drug, evidenced by the experience of crises when it is absent, patients with BAD find themselves faced with a dilemma between the two alternatives of life, which are health and disease. In this sense, patients place the symbol of sanity in the medication but, at the same time, it becomes the concrete and daily proof that they have a mental and chronic disorder. This study allowed us to understand associated and determinant factors of the reality BAD patients experience in relation to medication therapy, permitting a leap in the implementation of intervention strategies in health service directed at the quality of care for these patients

O Transtorno Bipolar [TB] é uma doença crônica e recorrente, que traz prejuízos significativos para o indivíduo. No idoso bipolar as recorrências são cada vez mais rápidas e os episódios mais longos, com um elevado risco de desenvolvimento de um quadro demencial, estando também estas associadas as alterações inerentes ao processo de envelhecimento. O presente estudo teve por objetivo comparar os benefícios da adição da Terapia Cognitivo Comportamental [TCC] e da Psicoeducação [PE], em grupo, ao Tratamento Padrão [TP] terapêutica farmacológica convencional do TB em idosos. Realizou-se um estudo controlado, com a amostra distribuída por conveniência e avaliação cega das medidas de desfecho. Os instrumentos utilizados foram o Protocolo de Pesquisa para a caracterização sociodemográfica e o histórico clínico, a Escala de Depressão Geriátrica, a Escala de Avaliação de Mania de Young Modificada, o Questionário de Crenças Irracionais, o Inventário de Sintomas de Stress para Adultos Lipp e o Inventário de Qualidade de Vida. Os critérios de inclusão para o estudo foram ter TB tipo I ou II, com idade igual ou superior a 60 anos, estar eutímico ou em remissão parcial dos sintomas, a ausência de um quadro demencial ou de delirium. Os participantes foram distribuídos em três grupos, o da adição da TCC ao TP, o da adição da PE ao TP e apenas o TP. Os participantes foram avaliados antes e após a intervenção. As intervenções em grupo ocorreram em 21 encontros semanais, com uma hora e trinta minutos de duração cada. Participaram do estudo 26 idosos bipolares, com a média etária de 66,6 anos, sendo a maioria do sexo feminino (65,4%), casada (50%) e morando com o cônjuge (26,9%). Os resultados demonstraram a equivalência das amostras antes da intervenção. Após esta, observou-se no grupo da TCC uma redução significativa dos sintomas de mania (p=0,034), do padrão de crenças irracionais (p=0,046) e da média das crenças pontuadas (p=0,019). Não houve mudanças significativas nos grupos da PE e do TP. Notou-se na amostra total um aumento significativo do nível de estresse (p=0,014) e da qualidade de vida na área da saúde (p=0,046), no período pós-intervenção. Quanto ao desfecho clínico, o grupo da TCC foi o que se manteve estável por um maior período de tempo, quando comparado com os demais grupos, mas isto não foi significativo. Neste estudo observou-se que o grupo da TCC foi o que mostrou melhores resultados e que se manteve em eutimia por um maior período de tempo. Embora os estudos de acompanhamento ao longo do tempo com idosos sejam difíceis de serem conduzidos, devido à maior desistência ao longo destes, sugere-se a realização de estudos longitudinais, controlados, que visem a desenvolver protocolos de intervenção para o tratamento dos idosos bipolares, proporcionando uma melhora na sua qualidade de vida e um envelhecimento saudável / The Bipolar disorder [BD] is a chronic and recurrent disease, which brings significant impairment to the individual. For the elderly bipolar patients, recurrences are even faster and episodes are, usually, longer and with a high risk of developing dementia symptoms. It is, also, associated with inherent changes during the process of aging. This study aimed to compare the benefits of adding cognitive behavioral group therapy [CBT] and psychoeducation group therapy [PE], in elderly bipolar patients under standard treatment [ST], i.e., conventional pharmacological therapy. The present study was a controlled one, with the sample distributed by convenience and with a blind evaluation of outcome measures. The instruments used were: a Research Protocol for the socio-demographic characterization and clinical history, the Geriatric Depression scale, the scale of Assessment of Modified Young Mania, the Irrational Beliefs Questionnaire, the Lipp Inventory of Stress Symptoms for Adults and Quality of Life Inventory. The study criteria for inclusion were patients with BD type I or II, who were clinically described as euthymic or in partial remission of symptoms, aged 60 years or over, in absence of dementia or delirium symptoms. Participants were distributed into three groups: (a) the addition of CBT to ST, (b) the addition of PE to ST and (c) only ST. Participants were assessed at baseline and at the end of the intervention. Group interventions occurred in 21 weekly meetings lasting an hour and thirty minutes long each. The participants were elderly bipolar (n=26), mean age of 66.6 years, most females (65.4%), married (50%) and living with the spouse (26.9%). The baseline evaluation showed an equivalence of symptoms among the patients. After the intervention, the CBT plus ST group showed a significant reduction of symptoms of mania (p = 0.034), a lower pattern of irrational beliefs (p = 0.046) and a lower score of punctuated beliefs (p = 0.019). There were no significant changes in the groups of the PE and the ST. Also, all participants showed a significant increase in the stress level (p = 0.014) and in quality of life concerning health area (p = 0.046). As for the clinical outcome, CBT Group remained stable for a longer period of time, when compared with the other groups, but this was not a significant result. Nevertheless, CBT group remained euthymic much longer and showed a better outcome compared to the other ones. Follow-up studies with elderly patients are difficult to be conducted due to the great withdrawal over time, as so, it is suggested controlled longitudinal studies, aimed to develop intervention protocols for the treatment of elderly bipolar, providing an improvement in their quality of life and a healthy aging

Evidências indicam que o estresse psicológico pode desempenhar um papel importante no desencadeamento e evolução do Transtorno Bipolar. Faz-se importante estudar as maneiras como os pacientes lidam com o estresse (Coping). Os objetivos deste estudo foram investigar as relações entre coping e traços de personalidade em bipolares e controles saudáveis; comparar estratégias e estilos de coping e traços de personalidade de pacientes bipolares com controles saudáveis; comparar estratégias de Coping nos pródromos da mania de pacientes bipolares I e II. Foram realizadas entrevistas diagnósticas e confirmada a eutimia dos pacientes resultando no total de 35 bipolares (foram considerados eutímicos pacientes com escore 12 na Escala de Avaliação de Mania de Young e 7 na Escala de Avaliação para Depressão de Hamilton). O grupo de comparação foi constituído por 40 indivíduos saudáveis do ponto de vista psiquiátrico. Foram avaliadas as habilidades de coping (Coping Inventory for Prodromes of Mania, Escala de Modos de Enfrentamento de Problemas e Brief COPE) e os traços de personalidade (Inventário de Personalidade NEO PI-R). As comparações das médias dos escores da escala Coping Inventory for Prodromes of Mania foram realizadas pelo teste Mann-Whitney. As comparações das médias dos escores das estratégias e estilos de coping e dos traços de personalidade foram realizadas por análises multivariadas de covariância. As associações entre estratégias e estilos de coping e traços de personalidade foram realizados pelos modelos de regressão linear múltipla. Os resultados mostraram que os bipolares apresentam mais estratégias e estilos de coping focalizados na emoção do que no problema, altos níveis de Neuroticismo e baixos níveis de Extroversão e Conscienciosidade. Foram encontradas associações positivas entre Neuroticismo e coping focalizado na emoção e negativas entre Neuroticismo e coping focalizado no problema (estratégias). Nos estilos de coping, foram encontradas associações positivas entre coping focalizado no problema e Conscienciosidade e negativas entre Extroversão e coping focalizado no problema. Estes resultados suportam a hipótese de que associações entre traços de personalidade e habilidades de coping desempenham um importante papel na modulação entre estresse e recorrência no Transtorno Bipolar / Evidence indicates that psychological stress may play a key role in triggering the onset and evolution of Bipolar Disorder. Investigations into the ways patients cope with stress are therefore valuable. The aims of this study were to: (i) investigate the relationship between coping and personality traits in bipolar and control subjects;(ii) compare coping strategies and style besides personality traits in bipolar patients against those of healthy controls;(iii) compare coping strategies between bipolar I and II patients in the prodromes of mania. Diagnostic interviews were conducted confirming euthymia among participants and detecting a total of 35 bipolar patients (scores 12 on the Young Mania Assessment Scale and 7 on the Hamilton Depression Rating Scale indicated euthymia). The control group for comparison comprised 40 psychiatrically-healthy individuals. Coping skills (Coping Inventory for Prodromes of Mania, Ways of Coping Checklist and Brief COPE) and personality traits (Personality Inventory NEO PI-R) were assessed. Mean scores on the Coping Inventory for Prodromes of Mania were compared using Mann-Whitneys test. Mean scores for coping strategies and styles as well as personality traits were compared by multivariate covariance analyses. Associations between coping strategies and styles and personality traits were determined by multiple linear regression models. Results showed that bipolar patients made greater use of emotion-focused strategies than problem-focused strategies, exhibited high levels of Neuroticism and low levels of Extroversion and Conscientiousness. Positive associations between Neuroticism and emotion-focused coping, and negative associations between Neuroticism and problem-focused coping (strategies), were found. Regarding coping styles, positive associations were identified between problem-focused coping and Conscientiousness, while negative associations were found between Extroversion and problem-focused coping. These results support the hypothesis that associations between personality traits and coping skills play a key role in the modulation between stress and relapse in Bipolar Disorder

Les troubles bipolaires (TB) sont des troubles chroniques, multifactoriels et multi-systémiques avec une morbidité, mortalité et fardeau socio-économique très élevée. Mieux comprendre le fond génétique et les facteurs environnementaux déclencheurs permettra d'améliorer le diagnostic et la prise en charge thérapeutique. La dysimmunité semble être parallèle à l'apparition, la progression ainsi qu'au développement de comorbidités psychiatriques et somatiques. L'inflammation chronique et l'activation de la microglie sont des mécanismes liant potentiellement l'infection et le stress pendant l'enfance avec la survenue d'un TB, en particulier la plus sévère forme d'apparition précoce. Les variants génétiques des récepteurs de reconnaissance de motifs moléculaires, première ligne de défense immunitaire, pourraient participer à la résilience/vulnérabilité aux facteurs de risque environnementaux tôt au cours de la vie. Nous avons exploré cette possibilité en analysant les associations génétiques entre des acteurs centraux de la réponse immunitaire innée, TLR2, TLR4 et NOD2 et les TB, en testant aussi l'hétérogénéité entre les sous-groupes d'apparition précoce et tardive. Étant donné que l'activation de ces voies augmente la production d'oxyde nitrique (NO) et en vue de son rôle dans l'inflammation, le stress oxydatif et la neurotransmission ainsi que son dysfonctionnement dans les TB et suicide, nous avons analysé simultanément des variants génétiques des trois isoformes de NO-synthase (NOS) chez les patients avec antécédents de conduites suicidaires. Nous avons trouvé que les génotypes TLR4 rs1927914 AA et rs11536891 TT sont significativement plus fréquents chez les patients tandis que l'allèle NOD2 rs2066842 T est significativement plus fréquent chez les témoins suggérant une vulnérabilité génétique à l'exposition aux pathogènes dans les TB. En plus, l'association avec TLR4 est restreinte au sous-groupe à début précoce et le génotype TLR2 rs3804099 TT est significativement plus fréquent chez les patients à début précoce qu'à début tardif, confortant l'hypothèse que les facteurs génétiques ont un poids plus important dans les TB d'apparition précoce. Des associations entre NOS1, NOS2 et NOS3 et TB n'ont pas été observées mais NOS3 rs1799983 T à l'état homozygote a été associé aux tentatives de suicide violentes, chez les patients à début précoce, apportant une preuve supplémentaire de l'implication de variants de NOS3 (endothéliale) dans les conduites suicidaires. En étudiant l'effet de l'interaction entre les variants génétiques de TLR2/TLR4 et les antécédents d'abus dans l'enfance mesurées par le Childhood Trauma Questionnaire (CTQ) sur l'âge de début des TB, nous avons observé un effet combiné du génotype TLR2 rs3804099 T avec antécédents d'abus sexuels sur la détermination d'un âge plus précoce d'apparition des TB. Les effets de l'abus sexuel dans l'enfance sur l'âge d'apparition des TB peuvent être accrus chez les porteurs du génotype TLR2 rs3804099 TT potentiellement médié par des voies liés aux réponses inflammatoires. Nos résultats sont en faveur d'un modèle « multiple-hit » dans lequel une vulnérabilité génétique liée au système immunitaire contribuerait à des réponses anormales aux infections périnatales baissant le seuil pour les effets adverses des stress ultérieurs. La confirmation de ces données par réplication dans des cohortes indépendantes est nécessaire. La caractérisation de la sévérité de la maladie, des phénotypes immunitaires et du type, intensité, fréquence et moment de survenue des stress doivent être prévues dans les futures études. Le développement de modèles animaux pourra aussi permettre de mieux comprendre les mécanismes impliqués à travers la manipulation expérimentale de la génétique et des conditions environnementales. Ces approches pourraient permettre l'identification de biomarqueurs et de signes cliniques prodromiques bien que des nouvelles stratégies de prévention et des cibles thérapeutiques. / Bipolar disorders (BD) are chronic, multisystem and multifactorial disorders with significant lifetime morbidity, mortality and socioeconomic burden. Understanding its genetic background and triggering environmental factors should improve diagnosis and therapeutic management. Immune dysregulation seems to parallel its onset and progression as well as the development of psychiatric and other medical comorbidities. Chronic low-grade inflammation and microglia activation are thought to be important mechanisms linking infection and childhood trauma with BD, in particular the more severe early-onset subform. Genetic variations in pattern-recognition receptors, the first line of immune defence, may thus participate in one's resilience/vulnerability to environmental exposures, particularly early in life. We explored that possibility by investigating genetic associations between central players of innate immune protection, TLR2, TLR4 and NOD2 and BD, taking into account the potential genetic heterogeneity between the early- and late-onset subgroups. Given that the activation of these pathways increases the production of nitric oxide (NO), a potent innate immune effector, by immune cells and taking into consideration the role of NO in oxidative stress and neurotransmission as well as its dysfunction in both BD and suicide, we simultaneously analysed variants of the three isoforms of nitric oxide synthase (NOS) genes with suicidal behaviour in BD. We found TLR4 rs1927914 AA and rs11536891 TT genotypes to be significantly more prevalent in patients than in controls. We also found that NOD2 rs2066842 T allele carrier state may confer some protection against BD as it was more prevalent in controls. These results suggest a genetic vulnerability to pathogen exposure in BD. We also found that the referred association with TLR4 was restricted to the early-onset subgroup and that a TLR2 genotype (rs3804099 TT) was significantly more prevalent in early- than in late-onset patients comforting the hypothesis that genetic factors are of greater importance in early-onset BD. While associations between NOS1, NOS2 and NOS3 with BD were not observed, NOS3 rs1799983 T in homozygous state was associated with violent suicide attempts, seemingly restricted to the early-onset BD bringing further evidence for the potential involvement of endothelial NOS genetic variants in the susceptibility to suicidal behaviour. By investigating the effect of potential interaction between TLR2 and TLR4 and childhood abuses as measured by the Childhood Trauma Questionnaire (CTQ) on the age at onset of BD, we observed a combined effect of TLR2 rs3804099 TT genotype and childhood sexual abuse on determining an earlier age at onset of BD by means of a Kaplan-Meier survival curve. The effects of childhood sexual abuse on age at onset of BD may be amplified in TLR2 rs3804099 risk genotype carriers through immune-mediated pathways.Altogether the present results comfort a multiple-hit model in which immune-related genetic susceptibility contributes to abnormal responses to perinatal infectious insults establishing a lower threshold for subsequent stress-triggered events. Confirmation by replication in independent BD cohorts is warranted. Characteristics of illness severity, immune phenotypes and detailed annotation of type, intensity, frequency and time of stress exposure should be documented in future studies involving large cohorts. Additionally, the development of animal models in conformity with the presented model would facilitate better understanding of the precise mechanisms involved by allowing specific manipulation of genetic and environmental conditions. These approaches may allow the identification of both biological and clinical prodromal manifestations and consequently lead to preventive strategies and novel therapeutic targets.

BACKGROUND - Bipolar disorder has been postulated as an explanation for King John's inconsistencies of leadership and vagaries of character. Changes in activity, matching those in mood, are core features of the condition. METHOD - A measure of King John's activity was derived from his travelling itinerary. Change Point Analysis (CPA) was used to detect significant changes in that travelling activity and from them, to identify clinically compliant, high and low, activity time periods. The results were tested against an alternative mathematical model (Bollinger Bands™), three alternative parameters and two comparator itineraries (familial & non-familial). Using primary historical sources and published analyses, bipolar symptoms were identified and their temporal relationship to the ICD-10 compliant CPA periods evaluated. The influence of circumstances was also evaluated using primary sources and a representative sequential sample (1200-1204). RESULTS - CPA identified 83 periods of changed travelling activity. These changes were mathematically independent of the availability of the historical sources that underpin the itinerary. From these, 37 high and 22 low periods complied with current diagnostic guidelines and demonstrated descriptive and statistical similarities to those found in the bipolar literature. Analyses using alternative mathematical modelling and different parameters showed similar changes; analyses of comparator itineraries showed a possible familial trait. Of the 17 bipolar symptoms identified, all were found in CPA periods of appropriate polarity. Of the 23 sequential periods, 10 showed evidence of behaviour that was difficult to attribute to circumstances. CONCLUSIONS & OUTCOMES - The pattern of changes in King John's activity are highly suggestive of bipolar disorder with primary historical sources describing synchronous bipolar behaviour. This may alter our understanding both of King John and of Magna Carta. Change Point Analysis merits greater consideration when analysing time based data, as does the use of activity as an objective marker of human behaviour.

Bipolar disorder (BD) and major depressive disorder (MDD) are characterised by a fundamental disturbance of mood, with strong support for overlapping causal pathways. Structural brain and neurocognitive abnormalities have been associated with mood disorders, but it is unknown whether these reflect early adverse effects predisposing to mood disorders or emerge as a consequence of illness onset. The Bipolar Family Study is well-suited to examine the origin of structural brain and neuropsychological abnormalities in mood disorders further. The volumes of subcortical brain regions, cortical thickness and surface area measures of frontal and temporal regions of interest and neuropsychological performance over a two-year time interval was compared at baseline and longitudinally between three groups: young individuals at high risk of mood disorders who subsequently developed MDD during the follow-up period (HR-MDD), individuals at high risk of mood disorders who remained well (HR-well), and healthy control subjects (HC). The longitudinal analysis of cortical thickness revealed significant group effects for the right parahippocampal and right fusiform gyrus. Cortical thickness in both of these brain regions across the two time points was reduced in both high-risk groups relative to controls, with the HR-MDD group displaying a thinner parahippocampus gyrus than the HR-well group. Moreover, a significant interaction effect was observed for the left inferior frontal and left precentral gyrus. The HR-well subjects had progressive thickness reductions in these brain regions relative to controls, while the HR-MDD group showed cortical thickening of these areas. Finally, longitudinal analyses of neuropsychological performance revealed a significant group effect for long delay verbal memory and extradimensional set-shifting performance. Reduced neurocognitive performance during both tasks across the two time points was found in the HR-well group relative to controls, with the HR-MDD group displaying decreased extradimensional set-shifting abilities as compared to the HC group only. These findings indicate, that reduced left parahippocampal and fusiform thickness constitute a familial trait marker for vulnerability to mood disorders and may thus form potential neuroanatomic endophenotypes. Particularly strong thickness reductions of the parahippocampal gyrus appear be linked to an onset of MDD. Moreover, progressive thickness reductions in the left inferior frontal and precentral gyrus in early adulthood form a familial trait marker for vulnerability to mood disorders, potentially reflecting early neurodegenerative processes. By contrast, an absence of cortical thinning of these brain regions in early adulthood appears to be linked to the onset of MDD, potentially reflecting a lack or delay of normal synaptic pruning processes. Reduced long delay verbal memory and extradimensional set-shifting performance across time constitute a familial trait marker for vulnerability to mood disorders, likely representing disturbances of normal brain development predisposing to illness. These findings advance our understanding of the origin of structural brain and neurocognitive abnormalities in mood disorders.

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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