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The genetic contribution to the aetiology of psychiatric illness is well-established; however, few variants that alter the encoded protein have been irrefutably identified as causative, leading to the hypothesis that variants affecting gene regulation may play a pathogenic role. This thesis focuses on two genes, Neuregulin 1 (NRG1) and Disrupted in Schizophrenia 1 (DISC1), for which there is strong genetic evidence for involvement in psychiatric illness, as well as evidence for altered expression in patients. Association analysis was carried out to assess the involvement of six intronic NRG1 single nucleotide polymorphisms (SNPs) in schizophrenia and bipolar disorder in two independent samples from the Scottish (Scottish 2; n = 307 control subjects, 303 schizophrenic patients, and 239 bipolar disorder patients and German populations (n = 397 control subjects, 396 schizophrenic patients, and 400 bipolar disorder patients). These SNPs form two haplotypes, one encompassing the 5’ and promoter region of the gene and the other located at the 3’ end of the gene, that were previously associated with schizophrenia and bipolar disorder in a Scottish sample (Scottish 1). The location of these haplotypes, together with the prior evidence for altered NRG1 expression in schizophrenia, suggested the potential involvement of regulatory variants. On combining the Scottish 1 and Scottish 2 samples (combined n = 765 control subjects, 682 schizophrenic patients and 601 bipolar disorder patients), a two- SNP haplotype spanning both coding and non-coding regions in the 3’ region was associated with schizophrenia (p = 0.0037, OR=1.3, 95% CI: 1.1-1.6) and the combined schizophrenia and bipolar disorder case group (p = 0.0080, OR=1.2, 95% CI: 1.1-1.5), with both these associations remaining significant after permutation analysis (p = 0.022 and p = 0.044, respectively). To further understanding of how DISC1, a leading candidate gene for schizophrenia that has also been implicated in other psychiatric disorders, is regulated the previously uncharacterised promoter region was assessed both bioinformatically and in vitro using the dual luciferase reporter assay. The region was found to lack canonical promoter motifs but to contain a CpG island, consistent with DISC1’s ubiquitous pattern of expression. A region located 300bp to -177bp relative to the transcription start site (TSS) was identified as contributing positively to DISC1 promoter activity, whilst a region -982bp to -301bp relative to the TSS was found to confer a repressive effect. FOXP2, a transcription factor which is mutated in a rare speech and language disorder and implicated in autism pathogenesis, was found to repress transcription from the DISC1 promoter. Two pathogenic FOXP2 point mutations reduced this transcriptional repression. Preliminary evidence for a bi-directional regulatory relationship between DISC1 and FOXP2 was observed: a mouse model of schizophrenia that carries a Disc1 L100P amino acid substitution and shows altered developmental Disc1 expression was also found to show altered developmental expression of Foxp2. These results further understanding of two genes whose altered expression might contribute to the pathogenesis of psychiatric illness.

The basic helix-loop-helix PAS domain transcription factor gene NPAS3 is a risk factor for psychiatric disorders. A knockout mouse model also exhibits behavioural and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 aetiopathology immunofluorescent and transcriptomic approaches were used. Npas3 was co-localised with Dcx, but not other neurogenesis markers, in the hippocampal subgranular zone - the site of adult neurogenesis. This implied that NPAS3 might be involved in maturing, rather than proliferating, neuronal precursor cells. Microarray analysis revealed that the transcriptional activities of NPAS3 and its truncated form (C-terminal deletion) in the HEK293 cell line are sensitive to circadian rhythm context. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was one of many NPAS3 target genes also shown to be regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental pathways. The transcriptional repression of multiple glycolytic genes indicated that NPAS3 has a second role in metabolic regulation. This finding was also confirmed by collaboration with a metabolomics research group at the University of Strathclyde. SOX11, a transcription factor known to play a role in neuronal and glial cell differentiation, was shown to be down-regulated by NPAS3. The set of genes targeted by SOX11 and their ontologies were deduced by a microarray analysis in a SOX11 overexpressing HEK293 cell line. Regulated genes include a previously established SOX11 target, known markers of neurogenesis as well as genes implicated in neuropsychiatric disorders. Multiple histone and zinc finger genes are regulated by SOX11, many of which were located in two clusters on chromosomes 6 and 19. The chromosome 6 cluster lies within a region of the genome showing the strongest genetic association with schizophrenia. SOX11 may alter localised expression competence and its targets induce a complex programme of chromatin remodelling and downstream gene expression changes to achieve the mature neuronal phenotype. This thesis details how transcription factors are involved in biological processes linked to psychiatric illness. The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of aspects of neurogenesis relevant to mental illness and may explain the innate and medication-induced susceptibility to diabetes reported in psychiatric patients.

Bakgrund: I Sverige beräknas 14-20% av befolkningen lida av psykisk ohälsa. Egenvård är handlingar som utförs i syfte att upprätthålla hälsa och är central inom den psykiatriska omvårdnaden. Sjuksköterskor möter personer med psykisk ohälsa i olika vårdsituationer och därför krävs kompetens om hur egenvård bör tillämpas i den psykiatriska omvårdnaden. Syfte: Att beskriva sjuksköterskors erfarenheter av hur egenvård tillämpas inom psykiatrisk omvårdnad. Metod: Kvalitativ intervjumetod med induktiv ansats tillämpades. Studien genomfördes inom öppen- och slutenvårdspsykiatrin i en mellanstor svensk kommun. Materialet bestående av nio intervjuer transkriberades och analyserades därefter med hjälp av konventionell innehållsanalys. Resultat: Sjuksköterskorna arbetade utifrån ett professionellt förhållningssätt i syfte att utbilda patienten och individanpassa vården. De beskrev att egenvård som begrepp sällan användes men att de tillskrev många omvårdnadshandlingar till just egenvård. Sjuksköterskorna beskrev att insikt, eget ansvar, motivation och delaktighet var förmågor som var avgörande hos patienten för en fungerande egenvård. Sjuksköterskorna erfor dock att en allt för stor tilltro till medicineringen och bristande kompetens hos vårdgivarna bidrog till att patienternas egenvård försummades då problem ofta löstes kortsiktigt och patienterna blev kvarvarande inom psykiatrin. Konklusion: Bland de intervjuade sjuksköterskornas var den generella uppfattningen att egenvårdsfilosofin inte har anammats inom den psykiatriska omvårdnaden, vilket resulterar i att patienterna blir kvar inom den psykiatriska vården under en obefogat lång tid genom att patienternas sjukdomsförlopp förlängs. / Background: In Sweden, 14-20 percent of the population has reduced psychiatric health. Self-care is actions done to maintain health and is crucial in psychiatric nursing care. Nurses meet people with reduced psychiatric health in care situations and therefore knowledge about how self-care should be used in the care of the psychiatric patient is important. Aim: The aim of this study was to describe nurses’ experience of how self-care is applied in psychiatric nursing care. Method: A qualitative interview study was conducted in out- and incare psychiatric care in a middle-size Swedish municipality. Nine interviews was transcribed and thereafter analyzed with a conventional content analysis. Result: The nurses was found to work from a professional approach in order to educate and individualize care. They described that the concept of self-care was rarely used but that they ascribed many actions of nursing care to self-care. The nurses described that insight, responsibility, motivation and participation were the determinant abilities of the patient for a functional self-care. Yet, nurses believed that a greater faith for the medication and lack of competence of the care givers contributed to neglection of the patients’ self-care when problems often were short-term solved and the patients remained in psychiatric care. Conclusion: In the group of interviewed nurses, the general opinion was that the concept of self-care not has been embraced in psychiatric nursing care. According to the nurses, it results in patients remaning in psychiatric care during an unjustified long time and that the course of illness becomes extended.

Chronic health problems are hypothesised to be a risk factor to child and adolescent mental health, due the consistent and continuing stress these health problems pose to normative patterns of development. However, this theory remains to be substantiated by empirical research. Moreover, a systematic review conducted as part of this research indicated that the empirical body is not one on which the validity of this theory can be adequately tested. The major question posed is whether the lack of high quality epidemiological data in the field is obscuring a true psychiatric risk associated with chronic illness in childhood and adolescence, or whether, in contrast, the theory of chronic health problems as a particular risk factor to child and adolescent mental health, is based on false premises. In order to provide a stronger insight into the association of chronic health problems to mental ill-health across the late childhood and adolescent period, this study used data from a large, representative British sample (the Avon Longitudinal Study of Parents and Children (ALSPAC)) and sensitive measures of mental health outcomes. Mediating factors in these associations were also identified, and a model of the association of chronic health problems to poor mental health outcomes in early adolescence was developed. In order to ensure that all findings were applicable across chronic health conditions, outcomes over this period for children with chronic illness more generally were compared to outcomes for children with asthma diagnoses. Children with chronic health problems presented with a disproportionate rate of psychiatric illness at 10 years, and these chronic health problems continued to be associated with poor mental health outcomes across the early to mid-adolescent period. The outcomes at 10 and 13 years were suggested to be mediated by factors non-specific to any diagnosis, specifically peer victimisation and health-related school absenteeism. Limitations to external validity in the research, and implications for public health and future research are discussed.

Schizophrenia, bipolar disorder and major depressive disorder are devastating psychiatric conditions with a complex, overlapping genetic and environmental architecture. Previously, a family has been reported where a balanced chromosomal translocation between chromosomes 1 and 11 [t(1;11)] shows significant linkage to these disorders. This translocation transects three genes: Disrupted in schizophrenia- 1 (DISC1) on chromosome 1, a non-coding RNA, Disrupted in schizophrenia-2 (DISC2) antisense to DISC1, and a non-coding transcript, DISC1 fusion partner-1 (DISC1FP1) on chromosome 11, all of which could result in pathogenic properties in the context of the translocation. This thesis focuses on the genome-wide effects of the t(1;11) translocation, primarily examining differences in gene expression and DNA methylation, using various biological samples from the t(1;11) family. To assess the genome-wide effects of the t(1;11) translocation on methylation, DNA methylation was profiled in whole-blood from 41 family members using the Infinium HumanMethylation450 BeadChip. Significant differential methylation was observed within the translocation breakpoint regions on chromosomes 1 and 11. Downstream analysis identified additional regions of differential methylation outwith these chromosomes, while pathway analysis showed terms related to psychiatric disorders and neurodevelopment were enriched amongst differentially methylated genes, in addition to more general terms pertaining to cellular function. Using induced pluripotent stem cell (iPSC) technology, neuronal samples were developed from fibroblasts in a subset of individuals profiled for genome-wide methylation in whole blood (N = 6) with an aim to replicate the significant findings around the breakpoint regions. Here, methylation was profiled using the Infinium HumanMethylation450 BeadChip’s successor: the Infinium MethylationEPIC BeadChip. The results from the blood-based study failed to replicate in the neuronal samples, which could be attributed to low statistical power or tissue-specific factors such as methylation quantitative trait loci. The differences in methylation in the most significantly differentially methylated loci were found to be driven by a single individual, rendering further interpretation of the findings from this analysis difficult without additional samples. Cross-tissue analyses of DNA methylation were performed on blood and neuronal DNA from these six individuals, revealing little correlation between cell types. DISC1 is central to a network of interacting protein partners, including the transcription factor ATF4, and PDE4; both of which are associated with the cAMP signalling pathway. Haploinsufficiency of DISC1 due to the translocation may therefore be disruptive to cAMP-mediated gene expression. In order to identify transcriptomic effects which may be related to the t(1;11) translocation, genome-wide expression profiling was performed in lymphoblastoid cell line RNA from 13 family members. No transcripts were found to be differentially expressed at the genome-wide significant level. A post-hoc power analysis suggested that more samples would be required in order to detect genome-wide significant differential expression. However, imposing a fold-change cut-off to the data identified a number of candidate genes for follow-up analysis, including SORL1: a member of the brain-expressed Sortilin gene family. Sortilin genes have been linked to multiple psychiatric disorders including schizophrenia, bipolar disorder and Alzheimer’s disease. Follow-up analyses of Sortilin family members were performed in a Disc1 mouse model of schizophrenia, containing an amino acid substitution (L100P). Here, developmental gene expression profiling was performed with an additional aim to optimise and validate work performed by others using this mouse model. However, results from these experiments were variable between two independent batches mice tested. Additional investigation of Sortilin family genes was performed using GWAS data from human samples, using machine learning techniques to identify epistatic interactions linked to depression and brain function, revealing no statistically significant interactions. The results presented in this thesis suggest a potential mechanism for differential DNA methylation in the context of chromosomal translocations, and suggests mechanisms whereby increased risk of illness is conferred upon translocation carriers through dysregulation of transcription and DNA methylation.

Background: This study explores the use of storytelling and patient narrative in mental health care. The focus is how the use of storytelling can reduce suffering and support the recovery process for individuals with psychiatric illnesses. The objective is to review research on the role of storytelling in promoting health, mitigating suffering, and fostering recovery in healthcare from a caring perspective. The study aims to answer the question of whether storytelling can reduce suffering in patient care. Design and Method: This study is a systematic literature review of qualitative studies that utilized the method meta-synthesis and thematic analysis. The authors searched for relevant articles, screened them based on inclusion and exclusion criteria, and extracted data using an inductive approach. A total of 15 articles were chosen, and the extracted data were analyzed to identify common themes and subthemes. Results: The main themes that emerged in the analysis of the fifteen articles were suffering, lifestory and the caring relationship and the subthemes were shame and stigma, loss of self and isolation, hope, meaning, growth, and recovery. Conclusion: A significant finding from the study is that the caring relationship between the nurse and the patient is important in order to provide a supportive context for the rewriting of the patient's life story, which in turn can contribute to the relief of suffering.

Introduktion: Patienter med psykisk sjukdom har ett ökat vårdbehov på grund av ökad risk för samsjuklighet. Detta gör att de är en patientgrupp vårdpersonal möter i alla delar av vården. Forskning visar att vårdpersonal kan känna en rädsla för patienter med psykisk sjukdom samt se dem som oförutsägbara.  Syfte: Syftet med litteraturöversikten är att undersöka hur personer med psykisk sjukdom upplever bemötande från vårdpersonal inom hälso- och sjukvården. Metod: Allmän litteraturöversikt baserad på tolv kvalitativa originalartiklar. Litteratursökning genomfördes i databaserna PsycInfo, PubMed samt CINAHL.  Resultat: Resultatet indelades i följande kategorier: Att inte bli trodd på, att bli bemött med ointresse, brist på respekt för patientens delaktighet och att inte bli lyssnad på. Personerna med psykisk sjukdom upplevde att vid många tillfällen att de inte blev tagna på allvar vilket skapade osäkerhet och självstigmatisering. Detta resulterade i att de var mindre benägna att söka vård. Deltagarna i studierna upplevde att de fick sämre bemötande, blev inte trodda på samt fick vänta längre på vård på grund av sin psykiska sjukdom. Positiva upplevelser av bemötande uttrycktes när patienterna haft en kontinuerlig vårdkontakt samt blivit bemötta med empati. Slutsatser: För att personer med psykisk sjukdom ska få ett gott bemötande krävs det att de känner sig prioriterade, blir lyssnade och trodda på samt känner sig delaktiga i sin vård. Den psykiska sjukdomen ska tas i beaktande dock inte överskugga andra problem och sjukdomar. Sjuksköterskor bör få utökad klinisk och teoretisk praktik inom ämnet psykiatri för att minska rädsla och fördomar och därmed främja ett bättre bemötande. / Introduction: Patients with mental illness have an increased need for care due to an increased risk of co-morbidity. This means that they are a patient group that health professionals meet in all parts of care. Research shows that healthcare professionals can feel a fear of patients with mental illness and see them as unpredictable. Aim: The purpose of this literature review is to investigate how people with mental illness experience encounters with healthcare professionals. Method: General literature review based on twelve qualitative original articles. A literature search was carried out in the databases PsycInfo, PubMed and CINAHL.  Results: The result was divided into the following categories: Not being believed, to be met with disinterest, lack of respect for patient participation and not being listened to. The persons with mental illness experienced on many occasions that they were not taken seriously, which created insecurity and self-stigmatization. This resulted them being less likely to seek care. The participants in the studies felt that they were categorized because of their mental illness, received worse treatment and had to wait longer for care because of this. It was perceived that healthcare professionals believed that patients with mental illness lied. Positive experiences of treatment were expressed by the patients when they had continuous care contact and were treated with empathy. Conclusion: In order for persons with mental illness to receive good treatment, it is necessary for them to feel prioritized, to be listened to and believed in, and to feel involved in their care. Categorization of patients with mental illnesses should be avoided. Nurses should receive increased clinical and theoretical practice in the subject of psychiatry to reduce fear and prejudice to promote better encounters with patients.

The aim of this study is to evaluate the outcome of adoptions and to study the gene-environment influences on psychiatric illness as well as sick-leave patterns. The material consists of 2 966 adopted persons born between 1917 and 1949, their 5 932 adoptive parents and 5 438 identified biological parents.Adopted persons had a higher incidence of personality disorders and substance abuse than non-adopted controls. Adopted men also had an increased incidence of neuroses. Adopted women had an increased sick-leave because of somatic complaints, especially upper respiratory tract infections and abdominal complaints of short duration. Somatization i.e. more than 2 sick-leaves/year because of somatic complaint together with nervous complaints was more frequent among adopted women. Women with somatization could be separated into 2 types according to the pattern of sick-leave. Type 1 ("high frequency") had frequent sick-leaves for psychiatric, abdominal and back complaints. They also had a high frequency of alcohol abuse. Type 2 ("diversiform") had more diverse complaints and had fewer sick-leaves because of nervous complaints.High frequency somatizers had biological fathers with teenage onset of criminality and frequent registrations for alcohol abuse. Diversiform somatizers had the same genetic background as adopted men with petty criminality or male limited alcoholism.No specific genetic influences on treated depression or substance abuse were found in this study. However, a non-specific vulnerability of the biological mother influenced on the risk of depression and substance abuse among adopted women.There were some indications that placement in the adoptive home between 6 and 12 months of age was associated with reactive neurotic depression in adult life. Otherwise early negative experiences in term of unstable placements before adoption did not significantly influence on psychiatric illness in adulthood.Affective disorders in the adoptive father were associated with treatment for depressions or substance abuse in the adoptee. Low social status in the part of the adoptive father increased the risk of somatization of both types in the adoptee. / <p>S. 1-80: sammanfattning, s. 81-236: 6 uppsatser</p> / digitalisering@umu