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Schizophrenia, bipolar disorder and major depression are common, heritable neuropsychiatric conditions and yet the source of the inherited risk remains largely unknown. This thesis focuses on two complementary strategies for identifying and characterising the genetic component of these illnesses: homozygosity mapping in consanguineous pedigrees, and genetic and neurobiological investigations of candidate genes identified by the analysis of structural chromosomal abnormalities carried by patients with psychiatric diagnoses. In a family of a cousin marriage, five of six offspring presented with a rare combination of schizophrenia, sensori-neural hearing impairment and epilepsy. Two loci were located on chromosomes 22q13 and 2p24-25 where a series of markers were homozygous by descent (HBD). Five further HBD loci were identified in a second, related family where four of five offspring had hearing loss. However, there was no overlap of the HBD intervals in the two families, and sequencing coding regions of candidate genes failed to identify causative mutations. A second study investigated the candidate gene ABCA13 identified at a breakpoint region on chromosome 7 in a patient with schizophrenia who carried a complex chromosomal rearrangement. Re-sequencing exons encoding the highly conserved functional domains identified eight potentially pathogenic, rare coding variants. Case control association studies involving cohorts of schizophrenia, bipolar disorder and major depression revealed significant associations of these variants with all three clinical phenotypes, and follow-up in relatives displayed familial inheritance patterns. Disruption of ABCA13, expressed in human hippocampus and frontal cortex, implicates aberrant lipid biology as a pathological pathway in mental illness. A third study focused on GRIK4, a candidate gene previously reported disrupted in a patient with schizophrenia who carried a chromosome abnormality. A deletion in the 3’UTR of GRIK4, encoding the kainate receptor subunit KA1, was identified as a protective factor for bipolar disorder. Using post mortem human brain tissue from control subjects, KA1 protein expression patterns were characterized in the hippocampal formation, amygdala, frontal cortex and cerebellum. KA1 expression was found significantly increased in subjects with the protective allele, supporting the hypothesis that reduced glutamatergic neurotransmission is a risk factor in major psychiatric illnesses. Together, these novel discoveries define aspects of the genetic contribution to mental illness, implicate specific dysfunctional processes and suggest new directions for research in the quest to find rationally based treatments and preventative strategies for some of the most common and disabling psychiatric disorders.

Purpose The aim of the systematic review and meta-analysis was to determine the magnitude and strength of the loneliness-psychosis relationship, and to synthesise current evidence. The aim of the empirical investigation was to establish whether, in older people, loneliness may increase proneness to auditory hallucinations and perceiving visual human-like features in ambiguous stimuli. Methods For the meta-analysis a search of electronic databases was conducted (PsychINFO, MEDLINE, EMBASE and Web of Science). Studies were included if they reported usable data relating to the association between loneliness and psychotic symptoms. A random effects meta-analysis was used to compute a pooled estimate of the correlation, together with 95% Confidence Intervals (CI). Study quality and outcome quality were systematically assessed using adapted versions of the Agency for Healthcare Research and Quality (AHRQ) tool and GRADE approach, respectively. For the empirical study, a parallel group experimental design with random allocation to experimental conditions was employed. Participants (62 healthy adults aged 65 and above) were assigned to one of the two conditions – the experimental condition or a control condition. A loneliness induction procedure was employed in the experimental condition whereas participants in the control condition completed a neutral task. A logistic regression was conducted to evaluate performance on auditory and visual tasks across the groups and an odds ratio was calculated. Results Thirteen studies were included in the meta-analysis, providing data from 15,647 participants. A moderate association between psychosis and loneliness was observed (k=13, N=15,647, r=0.32, 95% CI 0.20, 0.44; I2 97.56%; moderate quality evidence). Whether loneliness was assessed by single-item or a more comprehensive measure had no moderating effect on the estimate. The experimental study revealed that participants in the neutral condition were significantly less likely to hear words in ambiguous stimuli than those in the experimental condition (OR = 0.70, 95% CI 0.51 – 0.94, p < 0.05). Exploratory analysis revealed that higher scores on the state loneliness measure were associated with an increase in the likelihood of hearing words (OR=1.17, 95% CI 1.01-1.35, p = 0.03). No effect of loneliness induction was found on perceiving human-like features in ambiguous visual stimuli. Conclusions The meta-analysis confirmed a significant positive relationship between loneliness and psychosis, while the experimental study suggested that loneliness may have a causal role in the development of subclinical auditory experiences in older people. Further studies examining whether loneliness is involved in proneness to other psychotic experiences would be beneficial.

A qualitative methodology was employed to explore the narratives of clients with a diagnosis of schizophrenia. These were used to obtain a subjective perspective on the course of schizophrenia and its impact on a person's sense of self Narratives from a nominated relative provided an alternative perspective on this process and thus served to increase the validity of the findings. Research questions specifically addressed the process of making sense of the experiences over time and the role of professionals within this, the impact on sense of self and the impact on relationships with others. Semi-structured inter-views were conducted with 16 participants. These were audiotaped, transcribed then grounded theory was used to analyse the data. Results were used to build a stage model which charts the process over time. It is tentatively hypothesised that earlier vulnerabilities in the formation of self are expressed during adolescence due to the developmental need to separate from parents and develop an adult identity. Implications for clinical work and services are discussed.

A key feature of many psychiatric disorders, including schizophrenia and bipolar disorder, are pervasive deficits in several domains of cognition. Episodic memory is one of the most consistently observed cognitive deficits exhibited by patients with schizophrenia, and can be a predictor of overall functional outcome. Several neuroimaging studies have assessed episodic memory in psychosis, however the neural mechanisms underlying this deficit remain somewhat unclear. Studying the impact of rare genetic variants of large effect can offer a powerful method to further our understanding of the pathophysiology of psychiatric disorders. One such gene, DISC1 (Disrupted in Schizophrenia 1) is a putative susceptibility gene for a spectrum of major psychiatric disorders such as schizophrenia, bipolar disorder and major depression. DISC1 was originally identified in a large Scottish pedigree, in which it is disrupted by a balanced translocation between chromosomes 1 and 11, and this translocation confers a dramatically increased risk of major psychiatric disorder. However, the impact of this translocation on brain imaging measures is largely unknown. The rarity of this variation results in small group numbers for analysis, however rare variants are likely to have large neural effects. This thesis offers a unique investigation into the effects of the t(1;11) translocation, by examining fMRI of members of the original Scottish pedigree. Four groups of participants; 19 family members (8 with the translocation, 11 without), 30 patients with schizophrenia, 11 patients with bipolar disorder and 40 healthy controls underwent a functional MRI episodic memory encoding and recognition paradigm. Data processing and statistical analyses were performed using the standard approach in SPM8. The primary aim of this work was to investigate functional activation during episodic memory in individuals with and without the translocation, to examine the impact of the t(1;11) translocation. Analyses were also performed to examine differences between controls and patients with schizophrenia and bipolar disorder, to compare the effects of the translocation to the effects of a having a psychotic illness. During encoding of neutral scenes, translocation carriers showed greater activation of the left posterior cingulate, right fusiform gyrus and right superior frontal gyrus compared to non-carriers. During recognition, carriers showed greater activation in the right fusiform gyrus, left posterior cerebellum, right superior temporal gyrus, left anterior cingulate, right ventrolateral prefrontal cortex (VLPFC) and right dorsolateral prefrontal cortex (DLPFC). For both contrasts, no regions were found to be more active in family members without the translocation when compared to carriers. There were no significant differences between the groups in terms of their performance or reaction time on encoding and recognition conditions. Compared to healthy controls, patients with schizophrenia demonstrated increased activation during encoding in the inferior parietal lobe bilaterally, and decreased activation during recognition in a region encompassing the caudate nucleus and anterior cingulate cortex. Patients with bipolar disorder showed no difference in activation compared to controls during encoding, and increased activation during recognition in a region encompassing the caudate and anterior cingulate, extending to the inferior frontal lobe and insula. There was also a significant difference between patients with schizophrenia and bipolar disorder during recognition, with patients with bipolar disorder again showing increased activation in the caudate extending to the anterior cingulate cortex. These findings support previous research suggesting overactivation of fronto-limbic and striatal structures including the anterior cingulate and caudate in bipolar disorder, with a relative underactivation in schizophrenia. This thesis presents the first evidence of functional alterations during episodic memory in association with the translocation, primarily in fronto-temporal regions. Brain regions that were over activated in translocation carriers have been shown to be involved in memory encoding and recognition, and are known to be affected in patients with major psychiatric disorders and unaffected relatives. Family members with the translocation demonstrated a more similar pattern of activation during recognition to patients with bipolar disorder compared to schizophrenia, perhaps due to the fact that most diagnoses in the carriers were of an affective disorder rather than a schizophrenia-related psychosis. Based on these findings it can be argued that the translocation has an influence on brain activations in areas associated with episodic memory processes. These findings begin to provide a better understanding of the neural effects of the t(1;11) translocation, and highlight the significance of rare but biologically informative genetic variants in understanding psychosis.

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The available evidence suggests insomnia is common in individuals who experience psychosis. Poor sleep within this population has been associated with numerous detriments to mental health and well-being. Nevertheless, the majority of work to date has focused on chronic presentations, with few studies investigating the role of insomnia in recently onset psychosis. Understanding and treating psychosis following the first presentation is important to promote recovery and prevent the development of long-term illness. This work therefore aimed to utilise mixed methods to comprehensively investigate insomnia in early psychosis. It is presented in a series of five research papers, supplemented by additional chapters to provide an introduction, additional methodological details and general discussion. Paper one presents a systematic review, which aimed to synthesise the relevant literature with regards to the nature and correlates of insomnia in early psychosis. Paper two utilised qualitative methods aiming to understand the experience of insomnia, its impacts and experiences of help-seeking in early psychosis. Paper three aimed to investigate the nature of insomnia symptoms in first episode psychosis, compared to a healthy control group, using actigraphy and sleep diary measurement over a 14-day period. Paper four aimed to investigate how poor sleep was associated with next-day mental health and functioning, presenting data from an electronic diary study conducted alongside the sleep profiling presented in paper three. Paper five aimed to assess the acceptability of a Brief Behavioural Treatment for Insomnia (BBTI) delivered to a first episode psychosis group. Findings across studies indicated insomnia to have a wide range of detrimental outcomes, indicating the treatment of insomnia may be an important target for relevant mental health services.