Background and objectives Mortality is higher in people with severe mental illness than others. An important policy goal is to reduce this ’mortality gap’. The objectives of this thesis were to investigate whether the gap has reduced in recent years in people with bipolar disorder or schizophrenia, to quantify the extent of ’avoidable mortality’ in these people, and to investigate whether the excess mortality risk extends to people with a physical illness as a main diagnosis and comorbid SMI. Method Three separate record linkage studies were undertaken study using Hospital Episode Statistics and death registration data about patients discharged from inpatient care in England between 1999 and 2007. Results Findings showed that the mortality gap widened over the last decade for people with bipolar disorder and schizophrenia. For people discharged with bipolar disorder the SMR increased from 1.3 to 1.9 between 1999 and 2006 (Poisson test of trend, P=0.06). Whilst for people discharged with schizophrenia the SMR increased from 1.6 to 2.2 (P<.001). Potentially avoidable deaths comprised 59-2% and 60.2% of all deaths in people with a diagnosis of bipolar disorder and schizophrenia respectively. The results showed that comorbidity with mental illness in people with a main diagnosis of CVD causes between 12-46% excess deaths compared with those without mental comorbidity, and between 43-68% excess deaths in people with a main diagnosis of Diabetes. Conclusion The total burden of premature deaths in these populations is substantial and increasing. excess in SMI by about 50%, but not eliminate it entirely. These results strongly point to the need for better understanding of the reasons for the persistent mortality gap; and for continued action to target risk factors for both natural and unnatural causes of death in people with SM.

There is a significant gap in the literature in relation to the experience of receiving a psychiatric diagnosis and in particular, in relation to receiving a diagnosis of bipolar disorder. The present study therefore aimed to get an in-depth understanding of the experience of receiving a diagnosis of bipolar disorder. Specific areas of interest were participants’ subjective experience of receiving a diagnosis of bipolar disorder, participants’ understanding of their diagnosis, participants’ experience of how well (or not) the diagnosis fitted their experiences, participants’ perceived consequences of having a diagnosis and any particularly helpful or unhelpful aspects in relation to the way the diagnosis was imparted. In collecting and analysing data, this study aimed to utilise a qualitative cross sectional design set within a social constructionist framework. Semi-structured interviews were carried out and transcripts were analysed using IPA (Smith & Osborn, 2003; Smith, 2007; Smith et al. 2009). A purposive sample of service users was used, in keeping with IPA requirements to have a small and fairly homogenous sample. The sample consisted of seven women and two men all of whom had received a diagnosis of bipolar disorder within the last year. The reported findings are based on the participants’ accounts of their experience of receiving a diagnosis of bipolar disorder and the meaning they attach to this experience, as well as the researchers’ own interpretation of these accounts. In essence, the findings can be described in terms of three master themes: 1. ‘Establishing fit between the diagnosis and subjective experiences’, 2. ‘Evaluating the utility of carrying the diagnostic label’ and 3. ‘The role of diagnosis in searching for solutions for one’s difficulties’. While these results broadly support findings from previous studies, they differ in terms of the central position of the process of establishing fit between diagnosis and personal experiences and in terms of the relevance of perceived stigma for this particular group of participants. The study also highlights the importance of the role of the client-clinician relationship in terms of establishing fit and instilling hope which has implications for the acceptance of the diagnosis and engagement with services. Finally, further implications and directions for future research are discussed.

Genetic studies have led to the identification of several candidate genes, some novel and others established, that may contribute to the risk of developing neuropsychiatric disorders. For example, dopamine receptor genes are established candidates for a number of psychiatric disorders such as Parkinson’s Disease, alcohol addiction and mood disorders. On the other hand, a gene of unknown function, AUTS2 (Autism susceptibility candidate 2), has recently been associated with alcohol consumption in a GWAS meta-analysis performed by our group. Interestingly, it has been associated with a broad range of neuropsychiatric disorders including autism, epilepsy and schizo-affective disorders. This thesis looked to address two broad aims: to establish lentiviral-mediated gene delivery technique in vivo by delineating the role of two well characterised Dopamine receptors D2R and D3R and to functionally characterise the role of AUTS2. By successfully establishing lentiviral mediated gene manipulation in vitro and in vivo, this thesis presents data for a similar role of nucleus accumbens D2R and D3R in novelty-induced locomotion while these receptors have a differential function in the regulation of light-induced locomotor behaviour in rats. Additionally, using molecular biology and in silica methods, this thesis demonstrates that AUTS2 is a nuclear protein and presents indications of its function as a neurodevelopmental gene with a potential role in neural migration, although its specific role has yet to be corroborated. Collectively, findings from this thesis will increase our understanding of the genetic link with brain function and behavioural traits. This will therefore have implications for overall neuropsychiatric research, as it will help understand molecular mechanisms underlying these conditions and possibly direct in the identification of potential therapeutic targets.

Classical proteomic techniques have been used in medicine for biomarker discovery and have recently entered the arena of neurodegenerative disorders. Biomarkers for disorders such as Huntington’s, Parkinson’s and Alzheimer’s diseases are currently being developed and tested for use in early detection, disease progression, prognosis and response to treatment. However, psychiatric disorders have been less researched to date. In this thesis, a classic proteomic approach was used (1) to examine alterations in molecular pathways determined by a well known high-risk schizophrenia (SCZ) gene (DISCI); (2) to assert the effects of antipsychotic medication in the brain and plasma of F344 rats; and (3) to canvass the plasma of psychotic patients searching for biomarkers of the disease. It was found that DISCI modulated the expression of dihydropteridine reductase, a key enzyme for biogenic amine synthesis and that of peptidyl-prolyl isomerase A, a protein involved in apoptosis. Antipsychotic treatment in rats exerted an effect on glucose and lipid metabolic pathways, mitochondria! function, immune system response, neuronal migration, differentiation and apoptosis. Alterations in calcium signalling pathways were detected in the plasma of psychotic patients, indicated by a significant reduction in plasma levels ofgelsolin and an increment of S100B.

People with psychosis commonly have poorer social networks and social support than the general population. However, qualitative social network features (e.g. presence of a confidant, perceived social support) are under-researched in first episode psychosis. Also, mechanisms through which poor relationships and support make symptoms and functioning in psychosis worse are largely unknown. This study aimed to investigate social network features and perceived social support in people with first episode psychosis, and also examined if the association between loneliness and paranoia was mediated by anxiety. Thirty eight people with first episode psychosis were recruited for a cross-sectional study. The study used questionnaire and interview measures to assess symptoms, functioning and availability of and satisfaction with perceived social support. Additionally, qualitative social network features (loneliness, and presence of a confidant) were measured. A mood-induction task involved watching anxiety-inducing pictures and neutral/happy pictures on a computer screen. Visual analogue scales assessed changes in paranoia, anxiety and loneliness. A mediation analysis then tested whether anxiety mediated between loneliness and paranoia. Results indicated that poor perceived social support, loneliness and the absence of a confidant were strongly associated with psychosis and depressive symptoms. The mediation analysis revealed that anxiety may be one potential mediator between loneliness and paranoia. Exploratory regression analyses further revealed that participants without a confidant were more likely to feel lonely when triggered into anxiety than those with a confidant. Finally, participants had temporarily raised paranoia when triggered into anxiety, and those with higher current negative symptoms felt more paranoid after anxiety-induction thus providing tentative experimental evidence for recent cognitive models of psychosis. In line with previous studies, results showed that poor perceived social support, loneliness and the absence of a confidant were associated with more symptoms and poorer functioning. First episode patients appear to be more susceptible to feeling lonely when anxious. Anxiety may be one pathway through which loneliness affects paranoia. Potential clinical implications are discussed.

Persecutory delusions are one of the most common and distressing symptoms of psychosis. Many studies indicate an association of persecutory delusions with depression. A direct role for depression-related cognitive factors in the maintenance of persecutory delusions has not been systematically examined, despite such processes being implicated in a cognitive model. To determine whether depression in people with persecutory delusions is associated with the same cognitive factors implicated in major depressive disorder, and to examine these factors as predictors of the persistence of persecutory delusions over time. A systematic literature review formed the basis of two linked studies: one cross-sectional and one longitudinal. In the first study, 60 participants with persecutory delusions and schizophrenia spectrum diagnoses were classified into two groups, according to whether or not they met ICD-10 criteria for major depression. Assessments were made of delusions, depression and key cognitive factors from the literature: schematic beliefs, avoidance, rumination, memory specificity and problem solving. The groups’ scores were compared, and the same comparisons were made between 30 participants with non-psychotic depression and 30 non-clinical controls. For the second study, 54 participants with delusions were re¬assessed six months later, and predictors of symptom persistence were examined. 50% of participants with persecutory delusions met diagnostic criteria for major depression. With baseline paranoia levels controlled, higher baseline depression predicted higher paranoia six months later. Negative schematic beliefs about the self and problem solving deficits predicted the persistence of both paranoia and depression over time. Coexisting depression predicts the persistence of persecutory delusions, suggesting a causal association. Trials are warranted of depression-related therapeutic techniques for people with delusions, including those that target negative schematic beliefs about the self. An improved understanding of the mechanisms that maintain paranoid beliefs can enable the development of better treatments.

Aims: To address gaps in the humanitarian needs assessment and mental health research field, the Humanitarian Emergency Settings Perceived Needs (HESPER) Scale was developed, a valid and reliable scale to assess the perceived needs of adult populations affected by humanitarian emergencies in low- and middle-income countries. Methods: A previously developed draft version of the HESPER Scale was pre¬tested in the United Kingdom (UK) with seven refugees from the Democratic Republic of the Congo (DRC), and was then pilot-tested in small samples (122 participants in total) with displaced Iraqi people in Jordan, and with the local populations in Gaza and Sudan, to assess the scale’s feasibility, intelligibility, comprehensiveness and cultural applicability, and to determine the suitability of training materials. A revised version of the HESPER Scale was subsequently field-tested in larger samples (817 participants in total) with displaced Iraqi people in Jordan, with people displaced following an earthquake in Haiti, and with Bhutanese refugees in Nepal, to assess its psychometric properties, as well as testing its application in measuring perceived needs and in providing data to predict mental health outcome. Results: Participants during pilot-testing found the list of HESPER items to be comprehensive and relevant, suggesting face validity and content validity of the scale. During field-testing, inter-rater reliability, test-retest reliability and internal consistency of the HESPER Scale was good to excellent across the three sites. Most HESPER items correlated as was predicted with related questions of both a quality-of-life instrument and a distress scale, demonstrating criterion (concurrent) validity of the scale. The HESPER Scale was also able to provide useful data on perceived needs in the three field-sites, with few gender differences. Number of perceived unmet needs and number of past traumatic events were both associated with symptoms of common mental.

While psychotic disorders are thought to involve a disruption of cortico-cortical and cortico-subcortical connections, it is unclear whether this is a correlate of the disorder itself or is related to risk factors for the disorder. In this PhD thesis, I examined the integrity of cortical connections, the pattern of cortical morphology in two unique MRI datasets that have been collected over the last five years: one from a large sample of twins with and without schizophrenia, and another from a cohort of subjects with prodromal signs of psychosis, scanned before and after the onset of the disorder. The main hypothesis of this work is that abnormal cortical connectivity will be evident in subjects at risk of psychosis, but to a lesser degree than in patients with psychosis. Diffusion Tensor Imaging (DTI) and T1-weighted images were acquired for both samples. DTI is a brain imaging technique that aims to reconstruct white matter connections between cortical areas and assess their microstructure. T1-weighted imaging enables the examination of cortical shape changes that may result from abnormal connections. I applied to MRI data of both samples a voxel-brain morphometry analysis to DTI data, probabilistic tractography and a method for the assessment of cortical morphology. The principal result of my analysis confirmed the main hypothesis of this study. Further work revealed that abnormal connections are evident before the onset of psychosis and that these abnormalities may underlie the risk of developing psychosis.

The Buddhist philosophy from which mindfulness-based approaches originate proposes a system of understanding whereby inherent suffering stems from attachment to a rigid and unchanging concept of self. Though this notion of selfhood is afforded centrality within such traditions, as well as having been a predominant concern in the history of theoretical psychology, our modern research interests and clinical applications have seemingly preferred to focus on operationalisable constructs, such is their relative amenity to empirical study, whilst at the same time, an interest in the clinical application of mindfulness is abound. As such - and with MBCT as currently the most evidenced of mindfulness-centred clinical protocols - we consider the extent to which the benefits apparent may pertain directly to, and be more clearly understood in terms of, this broader theme of change in conceptualisation of and relationship with self, commensurate in particular with the key Buddhist tenets of Dukkha, Anicca and Anatta (inherent suffering, transience of forms, and non-self). Our motivation is to explore the context within which well-researched content-based mechanisms of change in MBCT (e.g. cognitive reactivity and self-compassion) may operate. Explorative interviews investigating processes of change experienced were conducted with 21 subjects; comprising current MBCT patients, previous MBCT patients, and Clinical Psychologists in Training, with a Grounded Theory methodology employed in data collection, abstraction, and integration of theory. Findings indicate a dynamic three-phase process of change; capturing the accounts of individuals firstly in gaining insights into "how I am constructed and controlled", secondly in "getting to know my experience", and finally in "knowing myself differently". The constituent categories of these central concepts (which make up our explanatory scheme) are described and illustrated in detail. Our findings and interpretations are suggestive that MBCT does indeed promote change in conceptualisation of, and relationship with selfhood, potentially through processes seemingly well aligned with the Three Marks of Existence outlined in Buddhist philosophies. Implications, both theoretical; regards the prominence of context versus content in psychological literature, and clinical; with respect to the issue of working therapeutically - and more explicitly - with selfhood, or personhood, are considered. Links are made with existing research into known change mechanisms in MBCT, as well with prominent clinical models, in particular CBT, ACT and PBCT. Finally, wider structural inferences and potential future research are suggested.

Having a diagnosed psychotic disorder affects a persons’ ability to participate in everyday life. An admission to hospital and deterioration of mental health are disruptions in life that can result in further skill loss and decrease in daily routine. The purpose of this study was to develop and pilot an intervention to improve occupational performance for people with a diagnosed psychotic disorder. The intervention aimed to address specific problems with occupational performance following discharge from hospital. The study consisted of two stages. The first stage of the study combined four sub-studies to develop an intervention using best available evidence. A literature review of occupational performance and psychosis, focus groups with staff and service users, a systematic review of interventions and a literature review of models of occupational performance were completed to gather the evidence to inform the intervention. The second stage of the study used a quasi-experimental controlled study design to evaluate the developed intervention. A process evaluation was also carried out to assess the implementation of the intervention in clinical practice. This study generated new knowledge regarding what is known about the problems of occupational performance following discharge from hospital and interventions to address these problems. A stepped intensity 16 week manualised intervention Graduating Living skills Outside the Ward, GLOW, was developed. The results of the pilot study indicated that participants in the intervention group, showed a greater improvement on the primary measure when compared to treatment as usual. Barriers to recruitment were encountered in this study. Results of the pilot study showed that GLOW is an acceptable intervention to both service users and staff. The intervention was shown to have preliminary evidence of effectiveness. This indicates that GLOW merits further investigation to evaluate its effectiveness. The study recommends methods to increase participation of clinical staff in research.