Aim: The overall aim was to create knowledge about what it means to live with bipolar disorder from an existential perspective, both for individuals with the diagnosis and for their close relatives.Method: An existential perspective in this context entails that it is explored and described from a lifeworld perspective of individuals who in various ways experience that which is termed as bipolar disorder. The lifeworld phenomenological approach Reflective Lifeworld Research (RLR) was used in the four empirical studies. Meaning-oriented interviews and analysis were conducted following the leading methodological principles of the chosen scientific approach. A synthesis, based on lifeworld hermeneutic existential philosophy, then presents how it is possible to understand the perspective of individuals with bipolar disorder and their close relatives as a coherent whole.Findings and conclusions: A magnitude and complexity of experiencing, which means that life with bipolar disorder is characterized by extra dimensions, specific tension and contradictions, has been elucidated. Knowledge of the meaning of these aspects enables for the persons with the illness and for their close relatives to understand, to put words to, and to communicate how their life is and what they need, which in turn enhances their ability to influence their lives. It also increases the opportunities for professional caregivers to develop care, both in content and organization, so that it can meet the actual needs of those concerned in an adequate way.Living with bipolar disorder means so much more than the usual description with changes between episodes of depression and mania. The diagnosis “bipolar disorder” thus appears to be an inadequate label that only reflects the more obvious and visible dimensions of the illness, while those that characterize life in its entirety remain hidden.The thesis also shows that the importance of the common everyday life of persons with bipolar disorder and their close relatives should be highlighted as the most important factor in a liveable existence. A change in the view of mental health care is thus needed; a change that is characterized by consensus, collaboration and transparent communication between the person with the illness, their close relatives and mental health care. The common goal should be about meeting actual needs, and to strengthen a profound connectedness in order to make everyday life more liveable. / Disputationen sker den 2012-11-16, Sal Myrdal, Hus K, Växjö, kl. 10:30.

This study applies statistical models to mood in patients with bipolar disorder. Three analyses of telemonitored mood data are reported, each corresponding to a journal paper by the author. The first analysis reveals that patients whose sleep varies in quality tend to return mood ratings more sporadically than those with less variable sleep quality. The second analysis finds that forecasting depression with weekly data is not feasible using weekly mood ratings. A third analysis shows that depression time series cannot be distinguished from their linear surrogates, and that nonlinear forecasting methods are no more accurate than linear methods in forecasting mood. An additional contribution is the development of a new k-nearest neighbour forecasting algorithm which is evaluated on the mood data and other time series. Further work is proposed on more frequently sampled data and on system identification. Finally, it is suggested that observational data should be combined with models of brain function, and that more work is needed on theoretical explanations for mental illnesses.

Bipolar disorder is a heritable psychiatric disorder, and several of the genes associated with bipolar disorder and related psychotic disorders are involved in the development and maintenance of white matter in the brain. Patients with bipolar disorder have an increased incidence of white matter hyper-intensities, and quantitative brain imaging studies collectively indicate subtle decreases in white matter density and integrity in bipolar patients. This suggests that genetic vulnerability to psychosis may manifest itself as reduced white matter integrity, and that white matter integrity is an endophenotype of bipolar disorder. This thesis comprises a series of studies designed to test the role of white matter in genetic risk to bipolar disorder by analysis of diffusion tensor imaging (DTI) data in the Bipolar Family Study. Various established analysis methods for DTI, including whole-brain voxel-based statistics, tract-based spatial statistics (TBSS) and probabilistic neighbourhood tractography, were applied with fractional anisotropy (FA) as the outcome measure. Widespread but subtle white matter integrity reductions were found in unaffected relatives of patients with bipolar disorder, whilst more localised reductions were associated with cyclothymic temperament. Next, the relation of white matter to four of the most prominent psychosis candidate genes, NRG1, ErbB4, DISC1 and ZNF804A, was investigated. A core haplotype in NRG1, and three of the four key single nucleotide polymorphisms (SNPs) within it, showed an association with FA in the anterior thalamic radiations and the uncinate fasciculi. For the three SNPs considered in ErbB4, results were inconclusive, but this was consistent with the background literature. Most notable however, was a clear association of a non-synonymous DISC1 SNP, Ser704Cys, with FA extending over most of the white matter in the TBSS and voxel-based analyses. Finally, FA was not associated with a genome-wide supported risk SNP in ZNF804A, a finding which could not be attributed to a lack of statistical power, and which contradicts a strong, but previously untested hypothesis. Whilst the above results need corroboration from independent studies, other studies are needed to address the cellular and molecular basis of these findings. Overall, this work provides strong support for the role of white matter integrity in genetic vulnerability to bipolar disorder and the wider psychosis spectrum and encourages its future use as an endophenotype.

Although psychological research into manic experiences is increasing, it remains an underresearched phenomenon. In particular, there is a dearth of qualitative research exploring these experiences in a clinical sample of people diagnosed with Bipolar Disorder. This study examined six participants’ experiences of mania using Interpretative Phenomenological Analysis. Through semi-structured interviews, the participants provided detailed accounts of how they made sense of and experienced their manic states. Three master themes were described: “A mixed relationship with mania,” “A separate and controlled self”, and “The struggle to be different.” The first master theme explored the participants’ mixed and ambivalent relationship with their manic experiences. These were viewed as both alluring and dangerous, but overall the perceived costs had outweighed the benefits, for all but one of the participants. Most participants described losses in relation to giving up their manic experiences, as well as losses related to the destructive consequences of their episodes. The second master theme examined perceptions of mania as a separate, uncontrollable phenomenon, over which they had little influence. It was hypothesised that these explanations served to relieve these participants from underlying negative emotions, such as guilt, regret, shame and selfstigma. The third master theme described how manic experiences had represented struggles to be different. These included a struggle against society; a struggle to experience a preferred self; and a struggle to access very unique experiences or abilities. A number of issues were discussed in relation to the above themes. These included positive and conflicting appraisals of high moods; loss; entrapment and helplessness; ambivalence; negative moral emotions and a preferred manic identity. A range of therapeutic approaches were suggested as potentially helpful for some of these issues. These included Motivational Interviewing, Narrative, Constructivist and Compassion therapies. Additionally, the findings of the study provided support for existing therapies for Bipolar Disorder; particularly Cognitive-Behavioural Therapy (CBT) and Interpersonal & Social Rhythm Therapy (IPSRT).

Major depressive disorder (MDD) and bipolar disorder (BD) are psychiatric diseases that affect behavior and impair cognition. A gene important to these disorders is the brain derived neurotrophic factor (BDNF) which is involved in processes controlling neuroplasticity. Previous studies have suggested that BDNF expression levels have to be finely regulated for normal mental health and cognition. This study therefore aimed to identify cis-regulatory elements that regulate BDNF promoter IV (BP4), which plays a role in mood and cognition, and investigated how polymorphisms in these cis-regulatory elements might alter BP4 activity contributing to MDD and BD. BP4-LacZ transgenic mice and primary neuron cultures were used to show that BP4 was active in the hippocampus, cortex and amygdala and responded to PKC, KCl and Wnt signaling activation. Using comparative genomics, two highly conserved regions were identified, BE5.1 and BE5.2, which contain the rs10767664 and rs12273363 polymorphisms respectively. Reporter gene assays in primary cultures derived from these brain structures showed that BE5.1 and BE5.2 were responsible for “filtering” or “gating” the effects of different combination of activated signal transduction pathways on BP4. Thus, BE5.1 increased BP4 response to forskolin in cortical cultures while abolishing BP4 response to PMA in hippocampal cultures. Similarly, BE5.2 permitted BP4 response to KCl and combined forskolin and PMA treatment, but not individual forskolin and PMA treatment nor LiCl in cortical cultures. Significantly, the minor allele of rs12273363, which has been associated with MDD and BD susceptibility, acted as a more potent repressor of BP4 response to neuron depolarization by KCl and PKA/PKC activation in different primary cultures. The possible relevance of these findings to the role of altered BDNF expression in MDD and BD are discussed.

Bakgrund: Bipolär sjukdom är en kronisk sjukdom som medför lidande för individen. Sjukdomen kännetecknas av återkommande maniska och depressiva perioder. Den påverkar individens livsvärld och hens upplevelse av sin hälsa. Sjuksköterskan har en betydande roll i att stödja dessa patienter. Syfte: Syftet är att beskriva patienters upplevelser av att leva med bipolär sjukdom. Metod: En kvalitativ metod användes och baserades på sex självbiografier som analyserades med innebördsanalys. Resultat: I resultatet framkom fem teman. Dessa är: upplevelsen av att leva i becksvart mörker och det klaraste ljus, att uppleva skam, upplevelsen av att förlora kontrollen över sitt liv, att uppleva rädsla samt betydelsen av trygghet och stöd för att minska ensamheten. Diskussion: Personer med bipolär sjukdom upplever både hälsa och ohälsa beroende på vart i sjukdomen de befinner sig. Familjen och samhället har en inverkan på hur individen upplever sin tillvaro. Med stöd från en sjuksköterska kan personerna delvis kontrollera sin sjukdom. Deras verklighet förändras ständigt och stöd från sjuksköterskan är betydelsefullt. Konklusion: Personer med bipolär sjukdom upplever starka känslor som påverkar deras liv. För att personerna ska känna sig sedda och bekräftade måste sjuksköterskan visa öppenhet inför individens unika livsvärld. / Background: Bipolar disorder is a chronic disease that entails suffering for the individual. The disease characterized by recurrent manic and depressive episodes. It affects the individual's lifeworld and his or her's health experience. The nurse has a significant role to support these patients. Aim: The aim is to describe patients' experiences of living with bipolar disorder. Method: A qualitative method was used and was based on six autobiographies analyzed with meaning analysis. Results: The results showed five themes. These are: the experience of living in the pitch-black darkness and the clearest light, the experience of shame, the experience of losing control of their life, the experience of fear and the sense of safty and support to reduce loneliness. Discussion: People with bipolar disorder experience both health and illness, depending on their current state of disease. The family and society have an impact on how the individual experience their existence. With support from a nurse the person can achieve control of the disease. Their reality is constantly changing and support from a nurse is important. Conclusion: People with bipolar disorder experience strong emotions that affect their lives. For people to feel seen and recognized the nurse must show candidness to the individual's unique lifeworld.

Aim: The overall aim was to create knowledge about what it means to live with bipolar disorder from an existential perspective, both for individuals with the diagnosis and for their close relatives. Method: An existential perspective in this context entails that it is explored and described from a lifeworld perspective of individuals who in various ways experience that which is termed as bipolar disorder. The lifeworld phenomenological approach Reflective Lifeworld Research (RLR) was used in the four empirical studies. Meaning-oriented interviews and analysis were conducted following the leading methodological principles of the chosen scientific approach. A synthesis, based on lifeworld hermeneutic existential philosophy, then presents how it is possible to understand the perspective of individuals with bipolar disorder and their close relatives as a coherent whole. Findings and conclusions: A magnitude and complexity of experiencing, which means that life with bipolar disorder is characterized by extra dimensions, specific tension and contradictions, has been elucidated. Knowledge of the meaning of these aspects enables for the persons with the illness and for their close relatives to understand, to put words to, and to communicate how their life is and what they need, which in turn enhances their ability to influence their lives. It also increases the opportunities for professional caregivers to develop care, both in content and organization, so that it can meet the actual needs of those concerned in an adequate way. Living with bipolar disorder means so much more than the usual description with changes between episodes of depression and mania. The diagnosis “bipolar disorder” thus appears to be an inadequate label that only reflects the more obvious and visible dimensions of the illness, while those that characterize life in its entirety remain hidden. The thesis also shows that the importance of the common everyday life of persons with bipolar disorder and their close relatives should be highlighted as the most important factor in a liveable existence. A change in the view of mental health care is thus needed; a change that is characterized by consensus, collaboration and transparent communication between the person with the illness, their close relatives and mental health care. The common goal should be about meeting actual needs, and to strengthen a profound connectedness in order to make everyday life more liveable.

Bakgrund: Bipolär sjukdom är en kronisk, komplex psykisk sjukdom som kännetecknas av perioder med mani och depression. Sjukdomen påverkar hela den drabbades liv och även dess familj och närstående. Som sjuksköterska kan man möta dessa patienter på alla olika vårdinrättningar och det är betydelsefullt att ha kunskap om sjukdomen för att kunna ge god och personcentrerad vård. Syfte: Syftet med litteraturstudien var att beskriva patienters erfarenheter av att leva med bipolär sjukdom samt att beskriva de inkluderade artiklarnas datainsamlingsmetod. Metod: Denna litteraturstudie har en deskriptiv design. Två databaser användes vid sökningen av artiklar och tolv artiklar inkluderades. Artiklarna granskades och sammanställdes av båda författarna. Huvudresultat: Erfarenheterna av att leva med bipolär sjukdom beskrevs av många som en lång väg till diagnos, att acceptera sjukdomen, svårigheter i att bilda en uppfattning av den egna självbilden, sjukdomens påverkan på relationer till andra, känsla av stigmatisering från både den drabbade själv och omgivningen, hantering av det dagliga livet samt sjuksköterskans betydelse för välmående och hantering av sjukdomen. Artiklarna som resultatet grundar sig på hade intervjuer, terapisessioner och enkät som datainsamlingsmetod. Slutsats: Att få diagnosen bipolär sjukdom erfors av patienter som en stor och bestående livsförändring både för den drabbade och dess närstående. Sjukdomen gav svårigheter i det dagliga livet, till exempel att behålla relationer till andra, bibehålla ett jobb och de erfor stigmatisering utav omgivningen. Som sjuksköterska kan kunskap och förståelse för sjukdomen leda till bättre omvårdnad. / Background: Bipolar disorder is a chronic, complex mental illness characterized by periods of mania and depression. The symptoms have an impact on the entire lives of the affected, and even to their families and relatives. As a nurse, you might meet these patients at all the different health facilities, and it is very important to have knowledge about the disorder to provide good care. Purpose: The purpose of this study was to describe patients' experiences of living with bipolar disorder and to describe the included articles´ data collection methods. Method: This literature study has a descriptive design. Two databases were used during the search of articles and twelve articles were selected. The articles were reviewed and compiled by both authors. Main results: The experiences of living with bipolar disorder were many; such as a long way to getting the diagnosis and to accept the disorder, difficulties in forming an idea of one´s own self-image, the effect the disorder has on the relationship with others, the sense of stigma from both the person with the disorder and from the environment, dealing with daily life, as well as the nurse´s importance to the patients well-being and management of the disorder. Conclusion: To be diagnosed with bipolar disorder experienced by patients as a great and permanent change of life for both the patients and their relatives. The disorder resulted in difficulties in daily life, such as maintaining relationships with others, maintain a job and they experienced stigma out of the surroundings. As a nurse, knowledge and understanding of the disorder can lead to a better care.

Bipolär sjukdom är en sjukdom som gör att den drabbade pendlar mellan maniska och depressiva episoder. Den upplevda sjukdomen påverkar inte bara den drabbade utan även familjemedlemmar och närstående i den drabbades vardag. Arbetet för att hjälpa de drabbade familjerna är viktigt för sjuksköterskan, då ett väl fungerande stöd från sjukvården kan underlätta hälsan för de inblandade drastiskt. Syftet med studien var att belysa vad det innebär att leva i en familj där en förälder lider av bipolär sjukdom. En litteraturstudie genomfördes och resultatet baseras på̊ elva vetenskapliga artiklar. Efter att artiklarna hade analyserats framkom tre kategorier: risker, bördor samt stöd. Resultatet visade att det på många sätt behövs hjälp från sjukvården för att familjer där en vuxen lider av bipolär sjukdom ska kunna få en fungerande vardag. Det fanns många risker och de närstående bar på ett flertal bördor. Genom att stötta familjerna med samtalsstöd, information och avlastning gjorde man det dagliga livet uthärdligt. / Bipolar disorder is a disorder who makes the victim oscillate between manic and depressive episodes. The perceived disease affects not only the afflicted but also the family members and relatives of the affected’s life. Efforts to help the affected families is important for the nurse, for a well-functioning support from health care can ease the health of those involved drastically. The aim of the study was to highlight what it means to live in a family where a parent is suffering from bipolar disorder. A literature review was conducted and the results are based on eleven scientific articles. After the articles had been analyzed three categories emerged: risks, burdens and support. The results showed that in many ways, help is needed from health care to families where an adult suffering from bipolar disorder for them to be able to get a functioning daily life. There were many risks and the related was carrying multiple burdens. By supporting the families with counseling, information and relief they made daily life bearable.

To align the neuropsychological functioning of our adult euthymic patient group with that reported in previous studies on euthymic bipolar disorder (BD), we used a neuropsychological battery that examined sustained attention (Rapid Visual Information Processing Task), verbal memory (California Verbal Learning Task), executive functioning (Intradimensional-Extradimensional Shift Task, Barrett Impulsivity Task, and Framing Task), and emotion responsiveness/regulation (Positive Affect/Negative Affect Scales, Behavioral Inhibition/Behavioral Activation Scale, and Affective Lability/Affective Intensity Scales) in patients versus healthy volunteers (HV). Our results corroborated existing evidence of reduced sustained attention, impaired verbal memory and executive functioning, and abnormal emotional responsiveness and regulation in euthymic BD relative to healthy controls (Chapter 2). To investigate how abnormal development of brain function in BD leads to deficits in decision-making, motor inhibition, and response flexibility, we examined child and adult BD using a novel risky decision-making task, and used cross-sectional (age x diagnosis) functional magnetic resonance (fMRI) designs to examine neural activation associated with motor inhibition and response flexibility in BD relative to HV. During the risky decision-making task, adult euthymic BD patients were no different from healthy controls in their proportion of risky lottery choices over a range of competing lotteries. This matched behavioral performance was associated with similar prefrontal and striatal brain activation between the patient and control groups during response, anticipation, and outcome phases of decision-making (Chapter 3). These results are different from previous studies that have shown increased risk taking during decision-making in euthymic BD. Similarly, young BD patients were no different from age-matched healthy and patient controls in their pattern of decision making during the risky choice task. This was evidenced by a similar number of risky lottery selections over the range of changing expected values between the young BD group and control groups (Chapter 4). Using a cross-sectional, fMRI analytic design during the stop signal task, we found that child and adult BD showed similar behavioral performance to child and adult HV during motor inhibition. However, this matched behavioral performance was associated with abnormal neural activation in patients relative to controls. Specifically, during unsuccessful motor inhibition, there was an age group x diagnosis interaction, with BD youth showing reduced activity in left and right ACC compared to both age-matched HV and adult BD, and adult BD showing increased activation in left ACC compared to healthy adults. During successful motor inhibition there was a main effect of diagnosis, with HV showing greater activity in left VPFC and right NAc compared to BD (Chapter 5). These neuroimaging data support existing laboratory-based evidence of motor inhibition impairments in BD relative to HV, and indicate brain dysregulation during motor control is important to BD pathophysiology. A previous behavioral study showed impaired response flexibility in young BD patients relative to age-matched controls when using the change task. Here, we used the change task during fMRI to examine response flexibility in child and adult BD compared to child and adult HV. We found that patient and control groups showed similar change signal reaction times in response to change cues. However, this matched behavioral performance was associated with abnormal age group x diagnosis activations in brain regions important in signal detection, response conflict, response inhibition, and sustained attention. Specifically, during successful change trials, child BD participants showed frontal, parietal, and temporal hyperactivation relative to healthy children and adult BD, while adult BD showed hypoactivation in these regions relative to healthy adults. These novel fMRI findings during the change task indicate impaired neural activation during response flexibility may be important to the pathophysiology of BD development.