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Schizophrenia has long been a contested and controversial psychiatric diagnosis. Over the last six decades, research has consistently demonstrated that Black, Asian and Minority Ethnic (BAME), specifically people of Black African and/or Black Caribbean descent in the United Kingdom (UK) are more likely to face mental health inequalities and be diagnosed with schizophrenia in comparison to other ethnic groups (Fernando, 2002; 2008; 2010; Read & Dillon, 2013b; Nazroo, 2020). However there has been a paucity in research into the lived experience of receiving a diagnosis of schizophrenia. This research seeks to contribute to the field of counselling psychology and allied professions by exploring the lived experience of receiving a diagnosis of schizophrenia amongst this specific population. The phenomenon was investigated by adopting Interpretative Phenomenological Analysis (IPA) (Smith, Flowers & Larkin, 2009). Semi-structured interviews were conducted with eight participants and subsequently analysed using IPA. The Six-Stages of Analysis was used (Smith et al., 2009) as a process of interacting with the data within an inductive and iterative cycle (Smith, 2007). The consisted of close interaction between the researcher and the text, using line-by-line analysis of each participant’s transcribed interview (Smith et al., 2009). The findings revealed that participants were engaged in a range of meaning-making processes regarding their experiences relating to the diagnosis. Four super-ordinate themes emerged from the data: ‘Schizophrenia is a form of social control’, ‘Living with schizophrenia is a dynamic sentence’, “A spiritual dimension to this experience” and ‘Being Black in the mental health system’. The findings highlighted that receiving a psychiatric diagnosis is not a static event located at one point in time. Rather it is a multifaceted process that is engaged with by the recipient on multiple levels beyond the diagnosis. The implications for Counselling Psychology and allied fields are reviewed, as well as limitations and suggestions for future research were discussed.

Recent theories in the field of computational psychiatry regard schizophrenia (SCZ) and autistic spectrum disorders (ASD) as impairments in Bayesian inference performed by the brain. In Bayesian terms, perception is a result of optimal real-time integration of sensory information (’likelihood’), which is intrinsically noisy and ambiguous, and prior expectations about the states of the world (‘prior’), which serve to disambiguate the meaning of the sensory information. Priors capture statistical regularities in the environment and are constantly updated to keep up with any changes in these regularities. The extent to which prior or likelihood dominate perception depends on the uncertainty with which they are represented, with less uncertainty resulting in more influence. Individuals with ASD and SCZ might show impairments in how they update their priors and/or how much uncertainty there is ascribed to prior and likelihood representations, leading to differences in inference. While this Bayesian account can be argued to be consistent with many previous experimental findings and symptoms of SCZ and ASD, recent experimental work inspired by these ideas has produced mixed results. In this work, we investigated possible Bayesian impairments in SCZ and ASD experimentally by addressing some of the methodological limitations of the previous work. Most notably, we used an experimental design that allows to disentangle and quantify separate influences of priors and likelihoods, and we tested both SCZ and ASD patient groups as well as autistic and schizotypy traits in the general population. We administered a visual motion perception task that rapidly induces prior expectations about the stimulus motion direction, leading to biases and occasional hallucinations that can be well described by a Bayesian model. In this task, autistic traits were found to be associated with reduced biases, which was underlied by more precise sensory representations, while the acquired priors were not affected by autistic traits. Patients with ASD, however, showed no evidence of increased sensory precision, while there also were no impairments in the acquisition of priors. We also found no effects in the acquisition of priors or sensory representations along schizotypy traits and in patients with SCZ. However, under conditions of high ambiguity SCZ patients were less likely to hallucinate the stimulus than controls. The second part of the thesis is focused on further exploratory analyses conducted using these same datasets. First, we investigated post-perceptual repulsion effects in our task and whether they were related to trait or group differences. We found clear evidence of repulsion from the cardinal directions. In addition to that, we found evidence for a repulsion from the central reference angle, which was randomly selected for each participant and which could only be inferred from the stimulus statistics. Furthermore, we found the repulsion from the central reference angle to be reduced along schizotypy traits. Interestingly, in both SCZ and ASD groups this repulsion was also found to be negligible. While these results are exploratory, they might point to a trans-diagnostic features of ASD and SCZ. Second, we investigated within-trial dynamics of evidence accumulation by constructing a Continuous Choice Drift Diffusion Model (CDM) – an extension of the classical binary choice drift diffusion model. The results of this model showed that increased sensory precision along AQ found in a Bayesian model was underlied by faster drift rates, while slower responses and reduced hallucinations in SCZ were explained by a larger decision threshold. In addition, this model provided a more complete characterization of the performance in this task (by including reaction times) and it serves to emphasize the importance of accounting for exposure to stimulus duration and judgement time in future studies investigating Bayesian inference. Together, this work provides novel experimental evidence that speaks to the hypothesis of impaired Bayesian inference in ASD and SCZ. Furthermore, the analysis of reference repulsion effects and within-trial dynamics provide additional insight related to SCZ and ASD differences that extend beyond the Bayesian framework.

The t(1;11) translocation is a mutation unique to a Scottish pedigree, members of which have been diagnosed with schizophrenia, bipolar disorder, recurrent major depressive disorder and other related disorders. The translocation is significantly linked to increased risk of these diagnoses. It disrupts three genes, only one of which, DISC1, encodes a protein. A number of experiments have explored the function of DISC1 as a molecular scaffold and developmental regulator. DISC1 and its interactors have roles in processes of relevance to psychiatric disease. These include neuronal precursor proliferation, migration and integration in the developing and adult brain, neurite outgrowth, mitochondrial activity, which is particularly important in neurons due to their high energy demands, and intracellular trafficking, especially critical in neurons due to their highly elongated morphology. Although various DISC1 mutations have been investigated in the past, it is only with advances in technology that neural cells derived directly from translocation carriers, and therefore carrying the translocation plus their genetic background, have been generated and analysed. In addition a recently described mouse model mimics the effects of the translocation upon DISC1 expression. It does so by removing endogenous Disc1 exons corresponding to those distal to the breakpoint in translocation carriers, and fusing the remaining endogenous 5’ Disc1 genomic sequence to human chromosome 11 genomic sequence distal to the translocation breakpoint. The result is a chimeric gene with 5’ mouse Disc1 joined to a segment of human DISC1FP1, the non-coding fusion partner of DISC1 located on chromosome 11. This leads to loss of wild-type Disc1 and prediction of chimeric transcripts encoding aberrant C-terminally truncated forms of Disc1. This thesis builds on the work of previous researchers to characterise the RNAsequenced transcriptome of ‘cortical’ neurons derived from induced pluripotent stem cells from various members of the pedigree. Both heterozygous and homozygous mutant mice have also been utilised to generate RNA-sequencing data from the hippocampus and cortex. The thesis not only describes the differential expression of genes and exons, but also carries out a series of analyses to examine whether proportions of certain cell types are altered, as well as whether differentially expressed genes are highly associated with specific cell types. RNA-Seq data have been analysed for differential expression at the gene and individual exon level using DESeq2 and DEXSeq, respectively. This has revealed over 1,200 differentially expressed genes in human neurons carrying the translocation, which predict changes to functions relating to intracellular transport and synaptic activity. In addition, a number of genes have been verified by RT-qPCR as being differentially expressed in these neurons. These include genes of known relevance to schizophrenia such as DRD2, which encodes the D2 dopamine receptor, NTRK2, which encodes the BDNF receptor NTRK2, and BBS1 which encodes the DISC1 interactor and centrosomal protein BBS1. The human neurons also show significant overlap with previously published dysregulated genes in human neurons carrying other DISC1 mutations, as well as with genes associated with schizophrenia by large-scale genome wide association and copy number variation studies. Human neuron RNA-Seq data have also been examined for evidence of local effects of the translocation upon gene expression, and no obvious strong effect was found. The pattern of gene dysregulation in heterozygous mutant mouse cortex overlaps with that of the mutant human neurons. Gene expression changes in the mutant mouse cortex have also been verified by RT-qPCR in the genes Arc and Avp, and the list of implicated genes also shows overlap with genes associated with schizophrenia by large-scale genome wide association and copy number variation studies. An RNA-Seq deconvolution analysis was carried out to look for evidence of altered proportions of cell types at both the broad and more specific cell type level. This compared the observed expression of hundreds of genes in in the RNA-Seq samples against their expression in publically available RNA-Seq data of specific cell types. There does not appear to be any strong and consistent effect of the t(1;11) or mouse mutation on cell proportions. However, the data indicate greater than expected dysregulation of genes that are highly enriched in specific cell types. This includes certain subtypes of astrocyte. Mutant mouse cortex also shows dysregulation of genes associated with several subtypes of interneuron and pyramidal neuron, including parvalbumin positive interneurons. This indicates that, while the proportions of cell types appears to be unaffected by the translocation or mouse mutation, specialised cellular functions may be perturbed. To conclude, this thesis highlights a number of processes which appear to be disturbed by the translocation and mouse mutation. In all models, RNA-Seq evidence suggests signalling pathways of known relevance to psychiatric disease have been affected without significant alteration of cell proportions. This concurs with histological analyses of the mouse model by previous researchers. This thesis also describes the overlap between genes implicated in the study of this unique mutation as well as those implicated by studies seeking common or rare mutations predisposing to schizophrenia, supporting the hypothesis that different genomic risk variants and mutations converge upon certain molecular pathways that are especially important in this illness. The implication that the t(1;11) may alter the activities of certain cell types is also notable and future work can elucidate the cell-specific effects of the translocation.

Schizophrenia is a severe neuropsychiatric disorder which is within the top ten causes of disability in the developed world. While we currently do not fully understand the aetiology of schizophrenia, a wealth of genetic, epigenetic, and epidemiological evidence suggests a neurodevelopmental origin, and that dysregulation of the immune system and infection can play a role in aetiology. This has been supported throughout the last decade and the “big data” revolution. Genetic and epigenetic data gathered through genome and epigenome wide association studies, have identified over 100 genetic risk loci for schizophrenia. Further to this there have been a number of epidemiological studies examining the effect of environmental risk factors to schizophrenia. However, many of these genetic, epigenetic, and environmental risk factors have no clear mechanism by which they cause disease. Many of these studies published present evidence for the “risk factor” involvement but fail to validate their findings in model systems, to establish how these risk factors cause disease. The main aim of this thesis was to develop functional assays and methods to validate genetic, epigenetic, and environmental risk factors in human cellular based models to elucidate how these risks can contribute to disease. From this work I have developed a protocol for knocking out risk genes, and have identified a role for the schizophrenia risk gene AS3MT in neuronal development. I have also developed several pipelines to validate epigenome wide association studies, and link how changes in DNA methylation can affect gene expression, at both the regional level and at individual genomic loci. And finally, I have examined what effect, if any, the active component of cannabis, which is an established environmental risk factor for schizophrenia, has on the DNA methylome, to understand how environmental risk can cause disease. In summary, the work presented in this thesis represents the movement from large scale (epi)genetic analysis and statistics to functional lab validation. This thesis contains several methods for the functional validation of identified (epi)genetic risk loci and risk factors for schizophrenia in a cellular model. From this we can now begin to explore how these changes in genetics, epigenetics, and environmental risk factors biologically link to the development and progression of schizophrenia and other neuropsychiatric disorders.

Neuroinflammation and dysregulation of glutamate in schizophrenia A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Biology, Medicine and Health by Catherine J Gregory, June 2019 Background: Schizophrenia is a mental illness with a lifetime prevalence of 7 in 1000 people. In some, symptoms can persist despite treatment with antipsychotic medication, leading to a poor quality of life. There has been a drive to better understand the pathophysiology behind schizophrenia, with the hope of developing more effective treatments. There is good evidence for a role of hypofunction of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) in schizophrenia, as well as for a role of neuroinflammation. However, how these processes may vary across the illness duration and with antipsychotic exposure is unclear. In particular, how these processes may be linked is uncertain. There is emerging evidence that they may be linked via neuroinflammation-mediated activation of the kynurenine pathway of tryptophan degradation and the production of neuroactive metabolites such as the endogenous NMDAR antagonist kynurenic acid. However, no study to date has measured neuroinflammation and NMDAR hypofunction in the same patients. Methods: Patients with recent onset (n=20) and chronic (n=21) schizophrenia were recruited along with age- and sex-matched healthy controls (n=19). Positron emission tomography (PET) and the 18kDa translocator protein (TSPO) radioligand [11C]-(R)-PK11195 measured TSPO availability as an indication of microglial activation, a putative measure of neuroinflammation. 1H magnetic resonance spectroscopy (MRS) measured concentrations of glutamate, glutamine and gamma-aminobutyric acid (GABA) as an indication of NMDAR function, as well as myo-inositol, a putative glial marker. Results: In the first study of its kind, we found a positive correlation between TSPO availability and glutamate in antipsychotic-free patients with recent onset illness, which was not present in antipsychotic-exposed or chronic patients. We also found a reduction in TSPO availability in antipsychotic-free recent onset schizophrenia compared to controls but no difference in antipsychotic-exposed or chronic patients. We found no difference in glutamate, glutamine or GABA between recent onset or chronic schizophrenia and controls. We found a weak positive correlation between myo-inositol and TSPO availability in schizophrenia but no difference in myo-inositol concentration between patients and controls. Conclusions: Our results provide evidence for a link between TSPO availability and glutamate concentration in antipsychotic-free recent onset schizophrenia. This association appears to be moderated by antipsychotic medication. The lack of group differences in TSPO availability or glutamate suggest that significant neuroinflammation leading to glutamatergic dysfunction may only be present in a subset of schizophrenia, such as those with treatment resistance. Further investigation is needed in this cohort of patients. We also found preliminary evidence in support of a role for myo-inositol as a potential MR marker of microglia, but further confirmatory evidence is needed.

Non-affective-psychosis tends to have a relapsing and remitting course. Relapses have profound adverse consequences for individuals and are costly to health services. Early signs interventions use timely prediction of relapse to prompt preventative action with the aim of averting, or lessening the impact of, relapse. The aim of this thesis was to investigate whether early signs interventions are efficacious and how they might be improved. To this end, existing studies testing early signs interventions were reviewed and four empirical studies were conducted. These studies examined the facilitators of, and barriers to, early signs interventions and tested whether adding 'basic symptoms' to conventional early signs and using smartphone technology to monitor these hypothesised predictors improves relapse prediction. Chapter 1 of the thesis outlines the importance of relapse prevention, provides background information about early signs, basic symptoms and symptom monitoring apps, and outlines the theoretical context of the thesis. Chapter 2 provides a detailed critical analysis of the methods used in the thesis and describes additional methods that were not covered in the five published PhD papers that are presented in Chapters 3 to 7. Findings from these papers are integrated with each other and with the wider literature in the discussion section of the thesis (Chapter 8), followed by an analysis of their theoretical, clinical and research implications. A systematic review of trials using early signs to target medication or psychosocial support (Chapter 3) showed that there is scope to further refine such interventions. Relapse rates were higher when targeted medication was used as an alternative to adequately dosed maintenance medication; although, not as high as when no medication was used. Targeted psychosocial interventions showed promise but there were insufficient studies of high enough quality to draw firm conclusions. To examine how early signs interventions might be improved, the thesis examined potential facilitators and barriers. Qualitative interviews with patients who had recently relapsed (Chapter 4) suggested that early signs monitoring may be easier for those who have the assistance of a family member or carer, an integrating recovery style, higher levels of insight and a good rapport with clinicians. Conversely, early signs monitoring may be more difficult for those with cognitive difficulties, low levels of literacy, a sealing over recovery style, a lack of insight, and high levels of residual psychotic symptoms. Some participants had encountered service-related barriers when attempting to seek help for an emerging relapse in the past; the capacity of a service to respond quickly to early signs is fundamental to a successful early signs intervention. With regard to relapse prediction, a systematised review of prospective cohort studies (Chapter 3) showed that conventional early signs have modest predictive validity and that studies using a wider variety of predictors and more frequent early signs assessments predicted relapse most accurately. Accordingly, the later PhD studies aimed to broaden the range of predictors (by adding basic symptoms) and to facilitate more frequent monitoring (using a smartphone app). The PhD findings supported the hypothesis that adding basic symptoms to conventional early signs improves relapse prediction. In retrospective interviews (Chapter 5), 74% of participants reported basic symptoms that began or increased in the three months before relapse. Prospective reports (Chapter 7), gathered using a smartphone app, showed that basic symptoms predicted increases in some psychotic symptoms items three weeks later, and that adding basic symptoms to early signs improved prediction in most cases. Prospective findings (Chapter 7) also indicated that using a smartphone app to assess early signs, basic symptoms and psychotic symptoms on a weekly basis was feasible and valid; qualitative interviews (Chapter 6) demonstrated that this method was largely acceptable to a sample with established psychosis. Therefore, app-facilitated assessment of these variables is recommended in future research; for example, a large-scale prospective cohort study or a trial of an early signs intervention incorporating both conventional early signs and basic symptoms.

Associations between schizophrenia and violence are well-documented, but there is little epidemiological evidence concerning homicide perpetration risk in this patient population. Such information can inform risk management and help services to target specific interventions. This study utilised the National Confidential Inquiry into Homicide and Suicide by People with Mental Illness (NCISH) consecutive case series of all convicted homicide perpetrators in England & Wales and incorporated three interrelated studies: (i) nested case-control study of homicide by patients with schizophrenia, which compared male patients with schizophrenia who were convicted of homicide to matched control patients with schizophrenia who had not perpetrated homicide; (ii) case series of male patients who were diagnosed with schizophrenia and convicted of homicide compared to a randomly selected age-matched comparison group of male patients with schizophrenia who died by suicide; (iii) case series of convicted homicide perpetrators classified according to Hodgins' (2008) typologies of violent offenders with schizophrenia. The findings generated confirm the association between a diagnosis of schizophrenia and homicide and highlight heightened risk in the presence of co-morbid personality disorder, dual diagnosis, non-adherence with medication and disengagement with services.

Background/Aims: People with a diagnosis of psychosis often experience stigmatising social encounters. These social encounters may influence the beliefs people hold, as research suggests that people develop a range of processes in an attempt to interpret information about both themselves and others. The internalisation of negative stereotypes about psychosis is one process used to explain how people's beliefs are influenced. Cognitive models highlight the relationship between self and social knowledge and mood. How people process social information might therefore have an important role in pathways to distress in psychosis. There is limited understanding of how different expressions of emotional distress might relate to the processing of social information. This research portfolio therefore has two aims. Firstly it aims to systematically review literature on the relationship between internalised stigma and distress for people with a schizophrenia spectrum diagnosis. It also aims to explore the relationship between attachment style, reflective functioning, personal beliefs about illness, and emotional distress in people who experience psychosis. Method: These two aims are addressed through two studies. The first study is reported in Chapter 1, where literature exploring the relationship between internalised stigma and measures of emotional distress was systematically reviewed. For this review, a search of electronic databases was conducted, included studies were assessed for quality, and results were outlined through a narrative synthesis. The empirical project reported in Chapter 2 employed a cross-sectional design to gather quantitative data from people who had a diagnosis related to psychosis. Mediation modelling was then used to explore cognitive appraisals as mediatory variables between attachment anxiety and emotional distress whilst controlling for psychotic symptomatology as a potential confounding variable. Results: Thirty studies were included in the systematic review, with over half of these being cross-sectional in design. Systematic review findings indicate a significant association between internalised stigma and depression, however the association with other measures of distress was inconsistent. Limited data was therefore available regarding the utility of cognitive interventions focusing upon internalised stigma for improving symptoms of distress in psychosis. Results from the empirical study indicate associations between attachment anxiety, cognitive appraisals, and emotional distress but not reflective functioning. Personal beliefs about illness regarding shame and control were found to mediate the relationship between attachment anxiety and distress. Conclusions: When reviewed systematically the relationship between internalised stigma and distress remained unclear. This is due in part to methodological limitations of included studies which did not allow the exploration of whether these negative beliefs about the self in relation to others around them leads to distress. However, findings from the empirical study suggested personal beliefs about illness could influence the relationship between attachment and emotional distress. Future interventions focusing upon internalised stigma as a vehicle for improving symptoms of distress in psychosis might therefore target perceptions of shame and control whilst recognising a wider range of outcomes for distress.

It is now accepted that Schizophrenia, a neurodevelopmental disorder which affects around 1% of the population, is influenced by both genetic and environmental risk factors. Schizophrenia is evidenced as being heritable with twin-heritability estimates of around 80%. Recently, the disorder has been demonstrated to be polygenic in nature; many genetic variants with individually small effects contribute to the overall phenotypic variation. Furthermore, cannabis use, adverse events, urbanicity, obstetric complications and migration, are five environmental risk factors that have been evidenced as being associated with an increased risk of developing the disorder. Abnormalities in brain structure are also well evidenced in individuals with schizophrenia, in particular, reduced cortical thickness, volume and surface area have been linked to those with schizophrenia when compared to healthy controls. It has been posited that these cortical alterations may predate disorder onset, for example, disruptions in brain development may be a function of experiencing schizophrenia-associated genetic and environmental risk factors. However, the link between genes, environment and brain structure within schizophrenia remains unclear. In this thesis, we aimed to examine whether genetic and environmental risk factors for schizophrenia directly impact cortical brain structure. Methods and Results The current aims were assessed using measures of cortical thickness, volume and surface area, as defined by FreeSurfer, in three separate studies. Firstly, ANCOVA models were applied to a case-control sample, the Scottish Family Mental Health (SFMH) study, ncontrols/npatients = 41/58) to determine whether PolyGenic Risk Scores for Schizophrenia (PGRS-SCZ) are associated with lower cortical thickness both globally and within regions of interest (frontal and temporal lobes) as well as to examine whether the effects of experiencing an accumulation of the five environmental risk factors (outlined above) is associated with greater cortical thinning (Chapter Two). The results indicated that an increased PGRS-SCZ was related to lower, global cortical thickness in the whole sample and not a result of group differences. With regards to environmental effects, the more environmental risk factors experienced, the lower the cortical thickness, this was specific to the temporal lobe. Secondly, to further investigate the link between environmental risk factors of schizophrenia, we focused on birth weight as a proxy for obstetric complications (Chapter Three). Linear mixed effects regression (LME) models were used to assess whether birth weight was associated with cortical thickness, surface area and volume in a UK Biobank (UKB) sample (n = 1,680). We then applied Mendelian Randomisation (MR) to determine if birth weight-associated genetic variants were causally related to cortical structure. The results in this chapter suggested that higher weight at birth was associated with larger cortical volumes and surface area, both globally and in several cortical sub-regions. In contrast, a negative association was found between birth weight and cortical thickness in the lateral occipital parcel. MR analysis suggested a causal link of birth weight, as indexed by genetic variants, and insular lobe cortical volume as well as surface area globally, in the insular lobe and in middle temporal, medial orbitofrontal and inferior frontal gyrus parcels. Lastly, we tested whether the same association between PGRS-SCZ and cortical thickness (outlined in Chapter Two) could be replicated within a subset of UKB (Chapter Four). For this, we again utilised LME models using the second genetic data release of UKB (n = 2,864). We tested this globally, lobarly and within 27 bilateral cortical parcels for each of these parameters. We found a higher PGRS-SCZ to be associated with lower global cortical volume and thickness as well as insular lobe cortical thickness. To further test potential environmental influences (as outlined in Chapter Three) on these effects, we used a liner regression model to test for a relationship between PGRS-SCZ and birth weight as well as LME models to test for interactional effects. No relationship was found between PGRS-SCZ and birth weight nor were there any significant interactions found between PGRS-SCZ and birth weight on cortical structure Conclusion Together, these studies highlight the fact that both genetic and environmental risk factors for schizophrenia may, indeed, directly but differentially impact cortical brain structure. This information may help us to further understand the progression of the disorder but also, by identifying and addressing these risk factors early, we may be able to minimise the impact that the disorder can have on cortical brain structure; particularly in relation to potentially modifiable factors, such as birth weight. We also highlight the importance of using large samples and replications in order to examine such relationships.

In the context of developmental psychopathology and the psychological and social risk factors associated with psychosis and 'schizophrenia', this thesis proposes that early attachment interactions underlie the development of reflective function and emotion regulation which contribute to the emergence of negative symptoms. Attachment, reflective function and emotion regulation have been associated with mental health difficulties characterised by emotion dysfunction and interpersonal problems. However, there is very little research examining these factors in relation to the development of negative symptoms, perhaps due to historical conceptualisation of negative symptoms as 'non-affective' phenomena. Therefore, less research has been performed into possible interpersonal affective mechanisms driving negative symptoms than other disorders. Two studies, each using a quantitative cross-sectional design were used to examine the following primary questions: 1) Does attachment insecurity predict negative symptoms? 2) Is this relationship mediated by reflective function and emotion regulation? 3) Is psychological distress associated with negative symptoms? Secondary questions were: 1) Do attachment, reflective function and emotion regulation predict psychotic experiences? 2) Does self-agency mediate the relationship between attachment and negative symptoms? The first empirical study was a large-scale survey of 1647 participants aged between 16 and 35 years recruited online from the general population. Participants completed questionnaires measuring attachment, reflective function, emotion regulation, negative symptoms and distress. Data was analysed using univariate statistics, multivariate statistics and structural equation modelling. Results demonstrated that attachment insecurity predicted negative symptoms and this relationship was partially mediated by emotion regulation. Reflective function also predicted negative symptoms and distress significantly covaried with negative symptoms. Self-agency also acted as a partial mediator between attachment, reflective function and negative symptoms. Attachment, reflective function and emotion regulation also predicted psychotic experiences. Method The second empirical study examined attachment, reflective function, emotion regulation and negative symptoms in a help-seeking population of 52 young adults attending mental health and third sector services in Edinburgh and the Lothians. Participants were administered the Clinical Assessment Interview of Negative Symptoms (CAINS), Comprehensive Assessment of At-Risk Mental States (for psychosis) (CAARMS), and the Adult Attachment Interview (AAI) scored for attachment and reflective function. Participants also completed questionnaires measuring distress, emotion regulation, interpersonal problems and self-agency. Data was analysed using appropriate univariate statistics, multivariate statistics and path analysis. The sample was divided into three groups according to psychosis: non-at-risk mental state (n=17), at-risk mental state (n=18) and first-episode psychosis (n=17). Results The sample was characterised by high levels of distress, interpersonal problems, attachment insecurity, dysfunctional emotion regulation and low reflective function. Attachment insecurity significantly predicted reduced reflective function which mediated the relationship between attachment insecurity and negative symptoms. Emotion regulation was not predicted by attachment or reflective function, nor did it predict negative symptoms. Distress significantly covaried with negative symptoms. Discussion These results highlight the importance of investigating the underlying psychological mechanisms and considering the role of affect in the development of negative symptoms. Attachment insecurity, emotion regulation and reflective functioning play a role the emergence of negative symptoms which are related to psychological distress. Therefore, to improve understanding and treatment of negative symptoms, it is important to focus on these interpersonal affective mechanisms and consider how they interact with distress to contribute to negative symptoms.

Physical exercise is widely accepted as having a plethora of physical and psychological benefits for the general population, including weight management, cardio-metabolic risk reduction, mood improvement and cognitive enhancement. This broad spectrum of beneficial effects has led to considerable research interest into how exercise may be applied with clinical care and treatment of people with severe mental illnesses, such as schizophrenia. Indeed, exercise interventions have been found to improve outcomes in people with schizophrenia, perhaps through providing effective adjunctive treatment for the various physical and mental health issues which are not resolved (or even worsened) by antipsychotic treatment. Exercise may be particularly useful when implemented in the early stages of schizophrenia, i.e. first-episode psychosis (FEP), in order to prevent obesity and cardiometabolic diseases from arising, and facilitate psychosocial recovery before enduring disability takes hold. However, the feasibility and effectiveness of exercise in this population is not well understood. In this thesis, I combine both meta-analytic and experimental methods to examine the effectiveness of physical exercise as an adjunctive treatment for the symptoms and cognitive dysfunction associated with psychotic disorders, and to investigate the feasibility of using individualised exercise training as an intervention in FEP. Furthermore, using both qualitative and quantitative data sources, I investigate the factors which may influence the effectiveness of exercise interventions for people with psychotic disorders, and explore motivations and barriers towards physical activity in this patient group. My investigations show that exercise can be used to target unmet treatment needs in FEP (i.e. improving negative symptoms and cognition), which may facilitate early recovery. However, results also indicate that exercise effectiveness is ultimately dependent upon participants achieving and maintaining sufficient weekly amounts of activity, therefore emphasizing the importance of developing acceptable interventions. I further show, using both qualitative and quantitative data sources, that social support and autonomy are critical factors determining exercise adherence - with individualised exercise training presenting an effective method for fulfilling these requirements, and promoting exercise engagement in FEP. I conclude by commenting on developments within the literature, identifying outstanding questions and discussing the clinical implications of the evidence to date, along with proposing a novel and potentially feasible system for providing exercise treatments to people with FEP, in order to improve physical health and facilitate recovery.

This thesis aimed to explore neuroleptic medication discontinuation, with particular focus on aspects relevant to clinicians. Papers 1 and 2 have been prepared for submission to journals and are in line with journal requirements. To ensure consistency throughout this thesis some minor formatting and stylistic changes have been made. Paper 1 is a systematic review aiming to examine and synthesise evidence on the relationship between the therapeutic alliance and neuroleptic medication adherence in individuals with experience of psychosis. Eighteen empirical papers were identified for inclusion in this review, seventeen of which reported positive associations between therapeutic alliance and neuroleptic adherence. However, further research using high quality designs and advanced statistical methods are required before it is possible to conclude the true extent and potential mediators of the relationship between alliance and adherence. Paper 2 utilised grounded theory method to examine clinicians' perspectives of decision-making concerning neuroleptic medication discontinuation. Twelve in-depth interviews were completed with Psychiatrists and Mental Health Nurses and a theoretical model was developed depicting a complex process of decision-making for clinicians working with service-users wishing to discontinue neuroleptics. The process of making decisions about neuroleptic discontinuation was found to be subjective and dependent on clinicians' previous experiences and judgements regarding potential risk factors. The clinical and research implications are discussed with reference to existing literature. Paper 3 provides a critical appraisal and reflective account of papers 1 and 2 and was not written for publication. This includes evaluation of the research area, methodological decisions, strengths and weaknesses, implications for future research and practice and personal reflections of the research process.

Abnormal activation of brain microglial cells is widely implicated in the pathogenesis of schizophrenia. The disrupted balance of microglia phenotypes has been hypothesized to influence the clinical course of the disease and affect symptom severity. Previously, the pathophysiology of microglial activation was considered to be intrinsic to the central nervous system. We hypothesised that due to their perivascular localization, microglia can also be activated by factors present in circulating blood. We applied a high-content functional screening platform, to characterize alterations in microglial intracellular signalling cascades induced by schizophrenia patient serum relative to control serum. Using automated sample preparation, fluorescent cellular barcoding and flow cytometry, the applied platform is capable of detecting multiple parallel cell signalling responses in microglia. First, we exposed a human microglia cell line to serum isolated from first-onset drug-naïve schizophrenia patients (n=60) and healthy controls (n=79). We were able to show that peripheral blood serum obtained from schizophrenia patients induced differential microglial cell signalling network responses in vitro. We subsequently assessed whether antipsychotic drug-treatment can normalise the abnormal microglial signalling responses previously identified by exposing microglia cells to serum from antipsychotic treated schizophrenia patients (n=15) and controls (n=17). In addition, in order to assess microglia activation in vivo, we obtained positron emission tomography (PET) imaging data from collaborators, who used a radiotracer to assess potential altered microglia activation in patients suffering from schizophrenia. Finally, as a proof of concept study, we attempted to validate these findings by assessing the effect of serum collected from first-onset drug-naïve schizophrenia patients (n=9), controls (n=12) as well as serum isolated from the same patients subjected to six weeks of clinical treatment with the antipsychotic olanzapine (n=9). This study aimed to identify normalisation of previously detected differences in microglia signalling pathways based on successful in vivo treatment. We demonstrate that peripheral blood serum isolated from schizophrenia patients, independent of their treatment status, is sufficient to trigger microglial cell signalling network responses in vitro, which are indicative of altered STAT3 signalling. We further explored the composition of the serum for differential expression of analytes, previously associated with neuropsychiatric disorders, and the utility of the detected microglial cellular phenotype as a target for novel drug discovery.

Over the past few decades, epidemiological evidence has accrued to establish variance in psychosis risk across both geographical locations and demographic characteristics such as the excess risk in migrants and their descendants. Yet, the causes of this variation in rates between places and ethnic groups are still unclear, and I aimed to address this in this thesis. I conducted a systematic review and meta-analyses to synthesise existing literature on psychosis incidence in the six countries included in the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study: England, The Netherlands, Spain, France, Italy and Brazil. I subsequently analysed data from two parts of the EU-GEI study: a 17-centre service-based incidence study of psychosis, and a case-control arm utilising community volunteers. In the latter, I aimed to explain excess risk in ethnic and religious minorities using a theoretical sociocultural distance model I developed using literature from the social sciences. Here, I proposed that culturally distant minorities were particularly at risk of social exclusion, and this outsider experience led to increased psychosocial disempowerment (a lack of control over one’s life), which increased psychosis risk. I also explored if this model could explain any excess risk in those with increased genetic African ancestry in England. Incidence varied substantially between the studies included in the systematic review, although methodological differences could not be excluded as an explanation. The EU-GEI incidence study confirmed substantial variation by place, and demonstrated a higher incidence in ethnic minorities and for young men, as well as in areas characterised by a low percentage of owner-occupied housing. The sociocultural distance model could explain most of the excess psychosis risk in ethnic minorities, although some excess risk remained, particularly in the Black ethnic group. Social and cultural distance appeared to be more important predictors than psychosocial disempowerment, suggesting that chronic social injustices rather than acute stress play an important role. This model did not explain excess risk in religious minorities: those following any religion retained an excess risk. It could explain the excess risk in those with increased genetic African ancestry, although this was a small, exploratory sample and this will need replicating in larger studies. This thesis demonstrated, for the first time, that excess risk in ethnic minorities could be explained by the sociocultural distance model. Overall, the findings from this thesis confirm substantial variation in psychosis risk by person and place, and suggest that the social reality of the environment plays a crucial role in explaining this.

1H-Magnetic Resonance Spectroscopy (MRS) is a MRI paradigm that allows the levels of specific metabolites to be estimated in vivo [1]. This means that insights into the biochemical changes associated with a rare genetic change that raises the risk of mental disorders, and the impact of having a mental disorder, can potentially be made. In this study the levels of glutamate and N-acetyl-aspartate (NAA) were measured at 3T field strength in three separate voxels: right dorsolateral prefrontal cortex (DLPFC), left DLPFC and the anterior cingulate cortex (ACC). This thesis reports that members of a family that carry a unique t(1;11)(q42.2;q14) translocation that affects DISC1 have a substantially raised risk of developing a range of mental disorders, including bipolar affective disorder, schizophrenia and depression. A genetic change that leads to an increase in the susceptibility to a range of mental disorders is in line with other genetic studies that have been recently reported [2, 3]. The translocation was associated with a significant reduction in right DLPFC glutamate (mean difference= -2.11, CI= -0.24: -3.98, p=0.029) and left DLPFC NAA (mean difference= -1.97, CI= -0.34: -3.61, p=0.020). Changes in these metabolites offer some support to studies in cells and rodents trying to understand the impact of the t(1;11) translocation. More specifically the results offer support to studies that have linked alterations in DISC1's molecular biology to changes in glutamate receptors and mitochondrial function [4-6]. The results need to be interpreted with some caution due to the small sample size and the lack of a significant effect in the bilateral DLPFCs. People with a major mental disorder were also found to have significantly lower levels of glutamate in the left DLPFC (F=3.16, p=0.047). When compared to controls the reductions were significant in the people with a diagnosis of schizophrenia (mean difference= -0.86, CI= -0.19: -1.51, p=0.012), but not in people with bipolar affective disorder. Glutamate levels were significantly correlated with negative symptoms in people with schizophrenia (SANS r= -0.44, CI= -0.07: - 0.70, p= 0.024). The effect of experiencing depressive symptoms was also evaluated due to support for a link in previous studies [7, 8]. Whist the participants were not recruited due their experience of depressive symptoms, metabolite levels were found to be significantly associated with depressive symptoms in all participants with a mental disorder (all three voxels, both NAA and glutamate p < 0.05). The experience of depressive symptoms is not the same experiencing a depressive episode though, and further work may offer more insights into the association between metabolite changes and experience of depression. These findings provide insights into the relationship between diagnosis, current psychopathology and genetic risk in major mental disorders. The thesis provides some support that MRS imaging can be used to try understand neurobiological changes that are associated a genetic change, which is in turn linked to range of mental disorders. Interpreting the results of MRS imaging studies in humans remains challenging due to the complexity of the molecular biology that underpins the estimated metabolite levels, but where there has been a wide range of translational study into a specific protein (or genetic change) MRS may offer further information to help understand any effect in vivo.

Background: Inability to retain participants in a clinical trial poses a threat to clinical research as it can lead to a number of issues ultimately affecting generalisability, validity and reliability of the study. Patients with schizophrenia have been reported as particularly difficult to engage and retain in research and psychiatric treatment. This thesis aimed to improve the current understanding of the retention of people with schizophrenia in trials evaluating complex interventions. Methods: This thesis adopted a mixed method design. Quantitative methodology was used to identify the scale of attrition and to explore potential predictors of dropout. This included a systematic review and meta-analysis and a separate meta-analysis of individual patient data. Qualitative methodology was used in two studies to explore the perspectives of both trial staff and former trial participants on the factors important for retention and effective practices and strategies. Results: The results of the systematic review and meta-analysis demonstrated the rates of dropout from studies to be higher than from experimental interventions. Dropout from interventions significantly increased as the number of intervention sessions increased. The individual patient data meta-analysis found retention to be higher at the final follow-up assessment than at the penultimate one. The effect of arm allocation almost reached statistical significance pointing to the possibility of participants in the active arm having higher odds of completing the final follow-up than those in the control arm. Two qualitative studies identified barriers and facilitators to retention related to factors related to participant, researcher, study, and wider context. Some of the identified barriers were specific to schizophrenia. Conclusion: Attrition is a phenomenon that should be anticipated by trialists and prevented with the use of multiple strategies. The extent to which dropout can be minimised depends on a number of factors associated with the participant, researcher, study, and context.

Proteomic profiling studies of schizophrenia have the potential to shed further light on this debilitating and poorly understood condition which affects up to 1% of the world’s population. However, recent studies suggest that the field of proteomics in general has been hindered by poor application of bioinformatic strategies, contributing to the failure of many findings to validate. In the context of schizophrenia research, there is therefore a need for a more robust application and integration of existing statistical approaches to proteomic datasets, as well as the development of new methodologies to offer solutions to current challenges. The aims of this thesis were multi-fold. Many studies have stipulated the need for new diagnostic and prognostic strategies to aid psychiatrists, particularly in predicting disease conversion from the prodromal phase. Proteomic data from serum samples was used to investigate the potential for statistical models based on biomarker panels to offer a new and clinically relevant approach. Models were trained based on either differential protein (chapter 3) or peptide (chapter 4) expression levels between schizophrenia patients and controls, as measured through multiplex immunoassay or targeted mass spectrometry technologies. In chapter 4, an SVM model based on 21 peptides was identified that is both highly sensitive and specific as a diagnostic and prognostic tool in symptomatic individuals. Furthermore, in recent years, few preclinical innovations have been made in schizophrenia research in either in vitro or in vivo studies, resulting in a standstill in the development of treatments. In chapters 5 and 6 of this thesis, proteomic information from a novel cellular model of schizophrenia was analyzed. In chapter 5, cell signalling alterations in vitro were identified which may underpin dysfunctional microglial activation in at least a subgroup of patients, thus representing new drug targets in the CNS. Subsequent analysis identified compounds which have the potential to ameliorate the observed changes. Lastly, in chapters 7 and 8, a novel systems biology methodology was developed for the functional comparison of proteomic changes in brain tissue from existing preclinical rodent models of psychiatric disorders to those in human post-mortem samples, providing a new means of overcoming some of the translational hurdles of preclinical psychiatric research. The application of different bioinformatic strategies to a range of proteomic datasets in this thesis has yielded a number of findings which have enhanced the understanding of schizophrenia pathophysiology and provide a platform for future studies towards the goal of improving outcomes for patients affected by this disorder.

The aim of this thesis was to explore the relationships between worry, rumination, psychotic symptoms and sleep disturbance. The thesis is presented as three papers; a systematic literature review, an empirical study and a critical appraisal. The systematic literature review in paper one gathered findings from clinical studies on the role of worry and rumination in psychosis. Robust evidence was found for a positive association between worry and persecutory delusions but not auditory hallucinations. Little evidence was found for a relationship between rumination and persecutory delusions or auditory hallucinations, yet conclusions remained tentative due to the limited number of studies in this area. The empirical study in paper two used experience sampling methodology (ESM) to investigate the relationship between objective, actigraphy defined, sleep disturbance and next-day worry, rumination and psychotic symptoms in people experiencing psychosis. Sleep disturbance did not predict worry, rumination or psychotic symptoms. Worry and rumination predicted concurrent auditory hallucinations and worry additionally predicted concurrent persecutory delusions. Effect estimates were small, as was the sample size, meaning the findings must be interpreted with caution. The critical appraisal in paper three evaluates and reflects upon the entire research process for both the literature review and empirical study. Strengths and weaknesses of the research are considered as well as implications for theory, clinical practice and future research.

This thesis aimed to explore the construct of stigma and its relationship with experiences of psychosis. In particular, it sought to investigate the role of assessment, lived experience, and therapeutic response to stigma, with those who experience psychosis. To achieve these objectives multiple methods were utilised including qualitative interviews, cross-sectional and longitudinal methods, systematic narrative synthesis and meta-analysis, and a feasibility randomised controlled trial. Chapter one provides a review of the stigma literature applied to people who experience psychosis. Chapter two provides an overview of the methodology utilised in this thesis and outlines the six academic papers which comprise the bulk of this thesis. Chapter three (Study 1) describes a systematic narrative synthesis and meta-analysis of psychosocial interventions for internalised stigma in psychosis. This review identified that no current trials of psychosocial intervention improved internalised stigma, but low-quality evidence limited the conclusions drawn. Further research examining psychosocial interventions is required. Chapter four (Study 2; n=79) outlines the development of semi-structured interview measure of stigma (SIMS) in psychosis. A reliable, valid and clinically relevant measure of stigma was developed specifically for people who experience psychosis. Chapter five (Study 3; n=25) outlines a qualitative exploration of stigma experiences with psychiatric inpatients who experience psychosis. This study identified three superordinate themes of 'stigmatising social environments and networks', 'stigmatised person with psychosis', and 'stigma interactions'. Chapter six (Study 4; n=79), explored relationships between stigma and psychological factors in psychosis. It identified that internalised shame and self-esteem were significant mediators between the relationships of experienced and perceived stigma with depression, hopelessness and recovery. Based on the evidence examined in chapters one to six, chapter seven (Study 5) outlined an integrative cognitive model of internalised stigma in psychosis. Chapter eight (Study 6), based on the model described in chapter seven, describes a feasibility randomised controlled trial (n=30) that was conducted examining the efficacy and acceptability of a brief internalised stigma CBT intervention, comparing it to a psychoeducational intervention, with acute inpatients who experience psychosis. The intervention was shown to be feasible and acceptable but a larger definitive trial is required. Finally chapter nine outlines an overall discussion and reflections on the previous chapters.

The aim of this thesis was to explore which day-time pre-sleep factors contribute to night-time sleep disturbance in the context of insomnia and psychosis. It is presented to the reader as three separate papers. 1) A systematic literature review exploring the utility of physical activity interventions for improving sleep outcome for people presenting with insomnia disorder and insomnia symptoms. 2) An empirical study investigating which day-time pre-sleep factors contribute to sleep disturbance for people with psychosis.3) A critical appraisal and personal reflection of the whole research process. Paper one presents a systematic review of the existing literature that explores physical activity interventions for improving sleep outcome for people presenting with insomnia disorder and insomnia symptoms. Thirteen articles were identified which met the review criteria. The mythological quality and evidence derived from the studies was mixed; however, there was evidence that exercise has the potential to improve sleep outcomes for people with insomnia disorder and insomnia symptoms. Recommendations for future research were suggested along with potential clinical implications which arose from the review. The empirical study presented in paper two used experience sampling methodology to explore which day-time pre-sleep factors contribute to night-time sleep disturbance for 21 people with psychosis. Physical activity, social interaction and sleep preoccupation served as primary variables, whereas negative affect, stress, arousal, napping, and psychotic symptomatology served as exploratory variables. Multilevel modelling was performed to evaluate associations between these predictor variables and objective sleep parameters including Total Sleep Time (TST), Sleep Efficiency (SE) and Sleep Fragmentation (SF). Social interaction was the only significant predictor found; increased social interaction predicted increased TST and increased SE the following night. Methodological strengths and limitations, clinical implications and ideas for future research are also discussed. Paper three provides the reader with a critical reflection of the whole research process, including a discussion of the background literature, rationale for topic choice, methodological and personal reflections, clinical implications, and directions for future research.

Schizophrenia is a neuropsychological disorder in which the neural systems which regulate attention allocation, primarily the dorsolateral prefrontal cortex, are dysfunctional, resulting in deficient gating of attention to irrelevant inputs from the environment. This sensory processing dysfunction hinders goal-directed behaviour to the extent that the subsequent cognitive deficits of schizophrenia prevent many chronic patients from leading normal lives. It is the onus of neuroscience to understand the nature of deficits induced by the disorder, thus providing target mechanisms for remediation of those deficits in patients. To accomplish this, manipulations in rats with relevance to schizophrenia are examined in assays with translation to human neurobiology and behaviour. In this thesis, three manipulations with relevance to schizophrenia, were examined for attentional regulation in the attentional set-shifting task, and similar assays, to determine how different forms of schizophrenia-related pathology influence attentional regulation and behavioural flexibility. The foremost findings of the experiments herein were that manipulations inducing schizophrenia-related neurobiology, resulted in impaired performance in extradimensional set-shifting and reversal learning. These deficits were found following: acute inhibition of the mPFC in adult rats, in adult rats who had been exposed to a glutamate receptor antagonist during the neonatal period of development, and/or in adult rats who had gestational disruption of neuron proliferation. Across all three manipulations, a clear behavioural pattern of deficient sensory gating, evidenced by responding to irrelevant stimuli during the set-shifting task was found. These findings suggest that at the core of the cognitive deficits in schizophrenia is the ‘loosening of associations' such that patients suffer the inability to regulate attention, and limit sensory processing to relevant information. The subsequent aberrant learning about irrelevant information then impairs performance during goal-directed behaviours.

This thesis explored the ways in which people experiencing psychosis respond to their distressing experiences. Mixed methodology was used to address the research questions. Chapter two included a thorough systematic review and meta-analysis to investigate the relationship between safety seeking behaviours and psychosis. This review concluded that safety seeking behaviours, avoidance and resistance were associated with increased distress whereas engagement was associated with reduced distress. The review also highlighted some conceptual difficulties with differentiating between safety seeking and coping in this population. Study one, a qualitative exploration of how people respond to the experience of psychosis is presented in chapter four. This study found three key themes relating to perceived importance of responses, accuracy of threat appraisals and perceptions of ability to control experiences. An overarching theme of fighting a daily battle to maintain functioning was also identified. This analysis provided some support for the model of safety seeking responses but also demonstrated additional complexities in the way that people respond to their distressing experiences. Chapter five presents study two, the development and validation of a measure of responses to psychosis. Principal Components Analysis identified three subscales: threat monitoring and avoidance, social control and reassurance seeking and conscious self-regulation attempts. The subscales were found to have good internal consistency and convergent validity. To build on this work, study three used Structural Equation Modelling to test an integrative cognitive and metacognitive model of voice hearing (chapter six). In support of this model, it was found that voice hearing predicted beliefs and beliefs predicted responses and negative affect. Responses were not predicted either by voice hearing or negative affect. It was also found that both schematic beliefs and meta-worry mediated the relationship between avoidance and negative affect. Finally, in study four, presented in chapter seven, the response styles of attentional avoidance and attentional focusing were manipulated in response to an ambiguous auditory task in an experimental study. It was found that the attentional avoidance response resulted in a significantly greater increase in words heard during the task. However, the manipulation did not have an impact on distress levels. This thesis has demonstrated significant relationships between response styles, distress, appraisals and voice hearing. This, therefore, confirms the important role of responses to unusual experiences in models of psychosis. It appears that avoidance is likely to be unhelpful however, it should not be assumed that other responses are either helpful or unhelpful as this is likely to be person and context specific. The clinical and research implications of this are discussed.

Introduction: Impaired neurocognition, especially social cognition, predicts disability in schizophrenia. Early intervention to target impairment is theoretically attractive as a means to minimise chronic disability. Many trials confirm that Cognitive Remediation (CR) produces meaningful, durable improvements in cognition and functioning but few interventions remediate social cognition or focus on the early stages of schizophrenia. Methods: A systematic review and meta-analysis of 11 randomised controlled trials (RCTs) of CR in first episode psychosis (FEP) was completed. A randomised controlled pilot trial was then conducted to investigate a combined CR and social cognition training (CR+SCT) intervention in FEP compared to CR alone, assessing cognition, functioning and symptoms at baseline and follow-up. Qualitative feedback was also obtained in a nested feasibility and acceptability study to assess engagement, intervention suitability and attrition. Results: In the systematic review and meta-analysis, random effects models revealed a non-significant effect of CR on global cognition in FEP. However, there was a significant effect on functioning and symptoms, which was larger in trials with adjunctive psychiatric rehabilitation and small group interventions. In the pilot trial, the CR+SCT group had significantly better social functioning scores post-treatment, especially on the interpersonal relationships scale, however there was no significant effect on social cognition. CR+SCT also improved visual learning and set-shifting. There was no specific effect on symptoms. The nested feasibility and acceptability study found CR and CR+SCT to be acceptable and feasible for early intervention in psychosis service users, with high engagement rates and high user-reported satisfaction. Users perceived improvements in neurocognition and reported using strategies learnt during CR in daily life. Conclusions: Meta-analysis suggests that CR is beneficial in FEP. Evidence from the pilot trial shows that a CR intervention enhanced with SCT can improve functioning more than CR alone and that such an intervention is feasible and acceptable. A larger RCT is required to explore the full benefits of a CR+SCT intervention compared to CR and treatment as usual.

Schizophrenia is a complex mental disorder characterised by positive symptoms such as hallucinations and psychosis, negative symptoms such as avolition and anhedonia, and cognitive defects. Schizophrenia risk has a genetic component, and it is likely that this is caused by interaction between numerous genes with individually small effects. Environment also plays a role; factors associated with schizophrenia include drug use, prenatal stressors and living environment. Candidate genes linked to schizophrenia have been identified through recent GWAS of human populations with the disorder, including ANK3, TCF4 and CACNA1C. GWAS associations alone are not sufficient to identify these as definitive risk genes for the disease. In order to validate these findings, animal models (in particular the mouse) can be used to study the effect of mutations in these genes of interest. Knockouts of these genes in the mouse are lethal, so we have used the ENU mutagenesis DNA archive at MRC Harwell to screen for additional allelic variants expressing more subtle and varied behavioural phenotypes. Endophenotypes associated with schizophrenia and bipolar disorder, such as anxiety, cognitive deficits and sensorimotor gating deficits, can be characterised in these mutants and, together with molecular characterisation, this can validate these genes as risk factors. While mutations in Ank3 and Tcf4 proved to be non-functional, two mutations in Cacna1c have been associated with anxiety phenotypes and differences in EEG power spectra, as well as causing a cardiac phenotype.

Purpose: A systematic review and meta-analysis was conducted to identify what factors have been investigated as correlates of the 4 key domains of treatment decision making capacity (TDMC) in people who have experienced psychosis (understanding, reasoning, appreciation, communication) and to provide estimates of the magnitude of these correlations, taking into account study quality. A novel empirical study was conducted to test the hypothesis that variance in psychosis-specific cognitive biases (including the well-established ‘jumping to conclusions’ bias) would account for unique variance in TDMC domains in those with psychosis, after taking into account the known contribution of symptoms and insight. A secondary aim of the empirical study was to examine for the first time the relationship between TDMC and personal recovery in this group, and post hoc analyses of the relationship between cognitive biases, emotional distress and TDMC were also conducted. Methods: Electronic databases were systematically searched for literature on the schizophrenia and psychosis and treatment decision making capacity. Pooled estimates of correlation were estimated for factors with data from three or more studies, and both study and outcome quality were systematically assessed. A cross-sectional observational study was conducted, and individuals with psychosis completed measures of TDMC, cognitive biases, psychotic symptoms and recovery. Multiple regression was used to examine the primary and secondary hypotheses, and mediation analyses were used to conduct the post hoc analyses. Additional data from a parallel study was incorporated to increase power. Results: Twenty-four studies met inclusion criteria for the systematic review and meta-analysis. Low to moderate quality evidence suggested that the ability of people with psychosis to understand treatment-relevant information was strongly associated with overall psychotic symptom severity, verbal cognitive functioning and years of education, but not depression (moderate quality evidence). Low quality evidence suggested reasoning was strongly associated with verbal cognitive functioning and moderately associated with symptoms. Appreciation was associated with symptoms, but it and communication were generally poorly studied. Findings from the empirical study suggest that cognitive biases, and the Jumping to Conclusions bias in particular, predicts a moderate amount of the variance in the understanding and reasoning TDMC domains, but did not add predictive power to a model containing symptoms, insight, and cognition. The appreciation domain was strongly predicted by cognitive biases, insight, and cognition. TDMC was not found to be correlated with personal recovery and post hoc analyses did not find that emotional distress mediated any relationship between cognitive biases and TDMC. Conclusions: The meta-analysis confirms there is a robust association between symptoms and TDMC in psychosis, as currently conceived. The empirical study suggests cognitive biases may be related to TDMC, even after taking into account the contribution of symptoms. Larger studies, perhaps employing experimental procedures, are required to clarify the exact nature of this relationship. The lack of any relationship between TDMC and service-user defined recovery from psychosis is notable, and lends support to those calling for a conceptualisation of TDMC that takes greater account of this concept.

Schizophrenia is often a debilitating psychiatric disorder, characterised by both positive and negative symptoms, and cognitive and psychosocial impairments. The established disorder has been associated with a number of brain abnormalities, however it is at present unknown whether these brain changes occur prior to onset of schizophrenia, or in unaffected relatives with a familial vulnerability to develop the disorder, or only in those at high risk that go on to develop the disorder. Furthermore, most studies have been conducted cross-sectionally, which may have obscured subtle longitudinal changes in familial high risk individuals, and these studies tend to have focused on localized cortical gray matter , and thus it is unclear whether they affect different cortical parameters differentially. Prospective familial high risk studies utilizing surface based MRI programmes provide a good method to investigate this. In the Edinburgh High Risk Study, structural magnetic resonance imaging (MRI) scans of 150 young individuals at familial high risk of schizophrenia, 34 patients with first-episode schizophrenia and 36 matched controls were obtained. Of the high risk participants with scans suitable for analysis, 17 developed schizophrenia after the scans were taken, whilst 57 experienced isolated or sub-clinical psychotic symptoms, and 70 remained well. We used Freesurfer to extract volumetric and surface-based measurements of several cortical and localized sub-cortical regions with the aim of assessing whether any alterations found were present in all those at high risk, or selectively in the high risk cohort based on future clinical outcome, or only in those experiencing their first-episode of psychosis. It was found that those experiencing their first episode of schizophrenia exhibited significantly more widespread brain alterations compared to those at high risk or controls, both on a more global cortical level and in more localized regions of the cortex, with cortical thickness being generally thinner than in the other groups, and cortical surface area and gyrification increased compared to the other groups. An increased global surface area was also shared with the HR[ill] group, suggesting that this could be a marker that is predictive of future transition to psychosis. Within the high risk cohort, some brain alterations seemed to present as general vulnerability markers, specifically in the temporal lobe at baseline, whilst longitudinally both localized and global cortical alterations distinguished the high risk cohort from the control group, and a different developmental trajectory of the hippocampus was also found. These findings show that some brain alterations may be more accurately characterized as general vulnerability markers of the disorder, whilst some are specifically present in patients who have experienced their first episode of schizophrenia, whilst some also occur before disorder onset in those at high risk that go on to develop schizophrenia. The findings have some clinical implications, as they suggest that it is possible to assess who at high risk will go on to develop schizophrenia based on brain structural alterations. This may provide clinicians with an early window of opportunity for intervention, as it has been found that early intervention may improve patient's prognosis. The findings also have important implications for the understanding of the underlying eitology of schizophrenia, as they suggest that some of these alterations are present before illness onset, and not associated with medication effects, thus potentially lying on the causal path of developing schizophrenia.

Over the past years early detection and intervention in schizophrenia have become a major objective in psychiatry. Early intervention strategies are intended to identify and treat psychosis prior to fulfilling diagnostic criteria for the disorder. To this aim, reliable early diagnostic biomarkers are needed in order to identify a high-risk state for psychosis and also predict transition to frank psychosis in those high-risk individuals destined to develop the disorder. Recently, machine learning methods have been successfully applied in the diagnostic classification of schizophrenia and in predicting transition to psychosis at an individual level based on magnetic resonance imaging (MRI) data and also neurocognitive variables. This work investigates the application of machine learning methods for the early identification of schizophrenia in subjects at high risk for developing the disorder. The dataset used in this work involves data from the Edinburgh High Risk Study (EHRS), which examined individuals at a heightened risk for developing schizophrenia for familial reasons, and the FePsy (Fruherkennung von Psychosen) study that was conducted in Basel and involves subjects at a clinical high-risk state for psychosis. The overriding aim of this thesis was to use machine learning, and specifically Support Vector Machine (SVM), in order to identify predictors of transition to psychosis in high-risk individuals, using baseline structural MRI data. There are three aims pertaining to this main one. (i) Firstly, our aim was to examine the feasibility of distinguishing at baseline those individuals who later developed schizophrenia from those who did not, yet had psychotic symptoms using SVM and baseline data from the EHRS study. (ii) Secondly, we intended to examine if our classification approach could generalize to clinical high-risk cohorts, using neuroanatomical data from the FePsy study. (iii) In a more exploratory context, we have also examined the diagnostic performance of our classifier by pooling the two datasets together. With regards to the first aim, our findings suggest that the early prediction of schizophrenia is feasible using a MRI-based linear SVM classifier operating at the single-subject level. Additionally, we have shown that the combination of baseline neuroanatomical data with measures of neurocognitive functioning and schizotypal cognition can improve predictive performance. The application of our pattern classification approach to baseline structural MRI data from the FePsy study highly replicated our previous findings. Our classification method identified spatially distributed networks that discriminate at baseline between subjects that later developed schizophrenia and other related psychoses and those that did not. Finally, a preliminary classification analysis using pooled datasets from the EHRS and the FePsy study supports the existence of a neuroanatomical pattern that differentiates between groups of high-risk subjects that develop psychosis against those who do not across research sites and despite any between-sites differences. Taken together, our findings suggest that machine learning is capable of distinguishing between cohorts of high risk subjects that later convert to psychosis and those that do not based on patterns of structural abnormalities that are present before disease onset. Our findings have some clinical implications in that machine learning-based approaches could advise or complement clinical decision-making in early intervention strategies in schizophrenia and related psychoses. Future work will be, however, required to tackle issues of reproducibility of early diagnostic biomarkers across research sites, where different assessment criteria and imaging equipment and protocols are used. In addition, future projects may also examine the diagnostic and prognostic value of multimodal neuroimaging data, possibly combined with other clinical, neurocognitive, genetic information.

Cognitive deficits are the single strongest predictor of the functional outcome in patients with schizophrenia. Current treatments are largely ineffective in improving cognitive impairments and promising pre-clinical research has mostly failed to translate clinically. Despite the advances provided by rodent models, the neurobiological basis of cognitive deficits in schizophrenia is poorly understood. Therefore, this thesis proposes a zebrafish model for studying cognitive impairments of schizophrenia. Although more evolutionarily distant to humans compared to the rat, the zebrafish has emerged as a popular vertebrate model of human disorders due to its genetic tractability, complex nervous system and elaborate behavioural repertoire. We investigated the effects of genetic alterations and neurodevelopmental disruption on behaviour and learning in zebrafish. Using both disc1 mutant lines and sub-chronic phencyclidine (PCP) on larvae from 6-10 dpf, we were able to assess behavioural changes as a function of developmental age. In particular, this thesis aimed to develop appropriate behavioural assays to assess zebrafish learning and executive function relevant to disorders seen in human patients with schizophrenia. It was possible to demonstrate robust learning across several domains, namely, reversal, classical avoidance and non-associative learning, alongside locomotor and anxiety-related behaviours. There were varied deficits associated with each of the two – genetic (disc1 gene mutation) and environmental (sub-chronic PCP) – manipulations, consistent with observations in rat research. Together, the research in this thesis demonstrates that a zebrafish model exhibits behaviour resembling that of mammalian models of schizophrenia and provides a foundation for the utility of zebrafish in examining cognitive impairments associated with schizophrenia.

The negative symptoms of schizophrenia include impoverished speech, affective blunting, an inability to anticipate pleasure, asociality, and amotivation. Current effective treatment options are limited, which is a significant issue given their strong association to functional impairment. The primary aims of this thesis are to explore areas which may inform the design of clinical trials addressing these symptoms, build upon recent advances in negative symptom assessment, and further understand the impact of negative symptoms on outcomes. A meta-analysis examining the longitudinal course of negative symptoms demonstrated a consistent reduction in negative symptoms over the study period in all treatment conditions examined, including in studies which adopted different eligibility criteria to minimise the presence of secondary negative symptoms. A comparison of different eligibility criteria revealed that whilst these criteria reduce the association between negative and depressive symptoms, their association to positive symptoms remains largely unaffected, and can substantially reduce the proportion of available participants. Given existing negative symptom assessment tools have been identified as a significant barrier in the development of new treatments, a comparison of assessment methods was performed. Results revealed the Clinical Assessment Interview for Negative Symptoms to be a more sensitive instrument, and a better predictor of functional impairments, relative to the negative subscale of the Positive and Negative Syndrome Scale. Findings described here also demonstrate that the link between negative symptoms and subjective quality of life may be stronger than previously assumed, relating exclusively to experiential deficits. Finally, manic and positive symptoms, rather than negative symptoms, were found to be associated with inpatient treatment appraisal, an important factor in treatment outcomes. Overall, this thesis describes key findings which demonstrate the importance of the appropriate assessment of negative symptoms of schizophrenia, shine new light on symptom progression over time, and highlight a need to further refine clinical trial inclusion criteria.

Schizophrenia is a severe and debilitating disorder, primarily treated with antipsychotic medications. Weight gain is a serious side-effect associated with most second generation antipsychotic drugs such as clozapine. The mechanism behind clozapine-induced weight gain remains poorly understood, but changes in eating behaviour and energy homeostasis may be involved. Recently, genome-wide association studies have identified a number of genetic variants associated with obesity risk; however the effects of these risk variants on clozapine-induced weight gain have not been investigated. This doctoral thesis focused on the following research questions: (1) Does schizophrenia share a genetic link with obesity? (2) Can various antipsychotics alter the expression of obesity-related genes? (3) What is the initial signalling event by which clozapine could induce a change in mRNA expression of the obesity-related genes? The major findings from this work included that there was no demonstrable association between obesity-related variants and schizophrenia, and that low and intermediate doses of clozapine (0.125 μg/ml and 0.25 μg/ml) induced changes in mRNA expression of a panel of obesity-related genes in U937 cells. This effect was not observed in cells treated with haloperidol. However, the mRNA expression of most obesity-related genes tested was also altered by treatment with olanzapine in most obesity-related genes tested but only in one gene when treated with risperidone. Treatment with 5-HT promoted an increase in mRNA expression of some obesity-related genes, which was similar to the treatment with 0.25 μg/ml clozapine although this effect was not apparent with a combination of clozapine and 5-HT. Changes in mRNA expression in clozapine-treated cells were likely mediated by the IP3 signalling pathway. In conclusion, the mechanism behind weight gain in patients treated with either clozapine or olanzapine is multi-factorial: this study suggests that there may be an additional risk factor that could facilitate antipsychotic-induced weight gain: the altered the mRNA expression of obesity-related genes.

The inhibitory circuitry of the prefrontal cortex (PFC) is involved in working memory and modulation of brain oscillations. Alterations in this network and especially GABAergic cells that express cholecystokinin (CCK), parvalbumin (PV), or somatostatin (SST) may underlie some of the cognitive deficits observed in schizophrenia. To assess the involvement of CCK+, PV+, and SST+ interneurons in PFC-dependent behaviours, we selectively inactivated these in prelimbic and infralimbic PFC via virus-mediated expression of tetanus toxin light chain (TeLC). We found that functional removal of CCK+ or PV+, but not SST+ neurons leads to specific impairments in working memory, and these represent the main cognitive domains affected in schizophrenia. PV-TeLC and CCK-TeLC mice displayed significant Y-maze alternation index reduction (p < 0.05). Targeting of PV+ prefrontal cells causes anxiety-like phenotype. Moreover, PV+ and SST+, but not CCK+ interneurons, appear to play a role in latent inhibition. Functional removal of CCK+, PV+ and CCK+ cells from PFC does not affect circadian activity and does not cause anhedonia. The involvement of PV-network in generation of neuronal activity and acetylcholine homeostasis was assessed. For neurophysiological recordings, each arm of the Y-maze divided into two equal-sized zones – proximal (close to the central decision point) and distal (far end). Zone entry was event-mapped onto continues local field potential recordings from medial PFC and CA1 region of the hippocampus. PV-TeLC animals displayed significantly lower prefrontal power in the decision zone. This suggests that the PV-TeLC animals are unable to modulate neuronal activity depending on the cognitive demand. Functional removal of prefrontal PV+ interneurons also leads to disturbed acetylcholine homeostasis. These results show that prefrontal GABAergic cells drive different behaviours and control task-relevant neuronal activity in different brain regions engaged with working memory such as hippocampus. Similar signalling anomalies may thus underlie cognitive deficits found in schizophrenia.

The empirical aim of this heuristic study was to explore the psychotherapeutic experiences of those with a ‘schizophrenia’ diagnosis. The epistemological aim was to deconstruct the structures of knowledge underpinning the diagnosis. The ‘personal knowledge’ drawn from the researcher’s own experience of working as a psychotherapist and filmmaker with individuals who had the diagnosis, and of being a psychiatric patient in the past, was used as a way of furthering these aims. Along with the work of Moustakas and Polanyi, key discourses used were Heidegger, Laing and contemporary critical clinical discourses. Eight participants with a ‘schizophrenia’ diagnosis took part in open-ended, conversational interviews that yielded substantial detail about the phenomenon. A multiperspective chronological narrative of early life experience, ‘schizophrenic’ breakdown, treatment and recovery emerged during the analysis of data, and is preserved in the composite depiction of the group experience. It was found that exploring the meaningfulness of experiences was a core driver of recovery, and psychotherapy was most helpful when it facilitated this exploration. By contrast, psychotherapy, and treatment as a whole, that obstructed this exploration were found unhelpful. These findings led to the argument that, what is termed ‘personal meaning’, may be a key factor in recovery from ‘schizophrenia’, and psychotherapy that was helpful seemed characterised by Heidegger’s concept of ‘anticipating care’. Treatment governed by ‘medical meaning’ and ‘intervening care’, meanwhile, are argued to prolong a crisis of ‘personal meaning’, and potentially facilitate an ‘acute’ phase of ‘schizophrenia’, rather than recovery. This conclusion raises critical questions about NICE guidelines for ‘schizophrenia’, which seem rooted in ‘medical meaning intervening care’. As well as facilitating an ‘understanding’ approach (in Heidegger’s sense) to researching experience, one key outcome arising from the researcher’s autobiographical connection to the research was learning more about his own experiences, and how to speak about them.

Sleep disturbance is a prevalent complaint amongst individuals with a diagnosis of schizophrenia. However, very little research has explored the effects of sleep difficulties on the experience of psychotic symptoms and functioning. Therefore, this thesis provides a detailed examination of the role of sleep disturbance in people with a diagnosis of schizophrenia. It is presented in three papers: (1) a systematic review; (2) an empirical study and (3) a critical evaluation and reflection on the research process. Paper one presents a systematic review of the relationship between objective and subjective sleep disturbance and psychosis severity, within the context of schizophrenia-spectrum diagnoses. Twenty six papers were identified through electronic database searches and reference list searches of relevant articles and reviews. All papers met pre-defined inclusion and exclusion criteria. Both objective and subjective sleep disturbance was associated with increased psychosis severity; however, evidence was weak-to-moderate in quality as few studies controlled for confounders. Recommendations for future research were suggested to improve the quality of prospective studies aiming to elucidate the sleep-psychosis relationship. Paper two presents the first, well-controlled, longitudinal examination of the relationship between objective and subjective sleep parameters, next-day psychotic symptoms and functioning. Objective and subjective sleep parameters were assessed across six days and nights of actigraphy and completion of morning sleep diaries. Using Experience Sampling Methodology (ESM), assessments of mood, psychotic symptoms and functioning were completed five times each day, by twenty-two participants with a schizophrenia-spectrum diagnosis. All objective and subjective sleep parameters predicted impaired next-day functioning, which remained significant after controlling for symptom severity. Reduced sleep efficiency and increased sleep fragmentation predicted next-day auditory hallucinations, while increased sleep fragmentation and reduced sleep quality predicted next-day paranoia and delusions of control. A proportion of all significant relationships between sleep and next-day variables were mediated by morning negative affect. Paper three describes a critical evaluation and reflection of the research process. This includes reflections on key methodological decisions and their underlying rationale, personal reflections on the completion of papers one and two and discussion of the overall findings within the context of clinical practice. Paper three concludes that sleep disturbance appears related to symptom severity and impaired functioning in people with a diagnosis of schizophrenia. Sleep could therefore represent a key target for therapeutic intervention, which has the potential to enhance both symptomatic and functional recovery.

Poor insight has clinical significance as a predictor of non-adherence to treatment, increased number of relapses, hospitalisations, recovery and risk of violence. Empirical research has led to advances in the redefinition, knowledge and understanding of insight in psychosis. However, the use of a wide range of definitions and measures has created difficulties in interpreting research findings, without clarifying the concepts being measured and evaluating the quality of their associated assessment tool. Therefore, the aim of the first piece of work, a Systematic Review (SR), was to identify and describe the constructs of insight in psychosis and their assessment tools and briefly evaluate their psychometric properties. Insight in psychosis is particularly relevant to Forensic Mental Health Services, given its link with offending behaviour and risk to others. However, outside of those provided by risk appraisal tools, there are no current guidelines that specifically target the assessment, or intervention, of insight. Therefore, the second piece of work, a research project (RP), aimed to explore current practices, as described by experienced clinicians. The SR identified twelve assessment tools and fourteen papers for detailed analysis. Twelve theoretical constructs were identified, the most prominent being awareness of mental illness and awareness of the need for treatment. Other prominent theoretical constructs included awareness of negative consequences of illness and awareness of generic or specific symptoms. However, few of the subscales associated with each theoretical construct were supported by empirical evidence. Further work to clarify aspects of insight that are important areas for intervention, along with the provision of data to support these, should continue to be a focus for on-going research. The RP was a qualitative design using Thematic Analysis. Data was collected by semi-structured interviews from 11 qualified Clinical Psychologists working in Forensic Mental Health Services across Scotland. The RP identified three overarching themes. The first “risk related” illustrated the influence of risk to other when assessing and treating patients. The second “holistic approach” illustrated that insight or mental illness was rarely looked at in isolation. The third theme “no specific or satisfactory unified approach” illustrated the diversity of the conceptualising, assessment and treatment of insight. Opportunities exist to develop a more uniformed approach and to introduce or develop outcome measures for interventions.

Schizophrenia is a relatively poorly understood, debilitating psychiatric disorder affecting around 0.5% of the population worldwide. The main characteristics of the disease are hallucinations, delusions and cognitive impairment such as difficulty in learning. It has been recently suggested that Disrupted-in-Schizophrenia-1 (DISC1) might be one of the main genetic risk factors for this disease. Mouse Disc1 has been implicated in brain development, mainly in neurite outgrowth, integration of newborn neurons, neuronal precursor proliferation/differentiation and neuronal migration. Disc1 function in the cortical excitatory cells was studied in fair detail but there is little data on Disc1 role in cortical interneuron development. In this study I have investigated development of the cortical interneurons in 21 days old mice with ENU-induced point mutations in the mouse Disc1 sequence - L100P and Q31L; previously characterized as ‘schizophrenic-like’ and ‘depressive-like’ respectively. Bin analysis was performed on five brain regions: frontal and central primary somatosensory (fSSp and SSp respectively) cortices, ventral auditory (vAud) cortex, visual (Vis) cortex and medial prefrontal cortex (MPFC); for four major interneuronal markers: parvalbumin (PV), somatostatin (STT), calretitnin (CLR) and glutamate decarboxylase 67 (GAD67). A significant decrease in PV (protein and mRNA) expression was observed in a subclass of the cortical interneurons in the fSSp, SSp, vAud and Vis cortices of L100P homozyogous (L100P) and heterozygous (L100P +/-) mouse brains when compared to their wild-type (WT) littermates. No such difference in the PV positive cells was found in the MPFC in the L100P mouse brain. Other interneuronal markers expression was not different in the L100P and L100P +/- brain from that in the WT littermate controls. Furthermore, there was no significant difference in any of the interneuronal markers expression in the Q31L mouse brain cortex. A minor change in the relative distribution of the interneurons (GAD67 positive cells) was found in the L100P but not Q31L brain. With no difference in the number of the interneurons and the nature of PV expression regulation, the cell non-autonomous effect of L100P Disc1 on this subpopulation of intereneurons was investigated. Overexpression of the mouse Disc1-100P in utero in the radial glia cells born at E14.5 (future layer II/III and IV excitatory cells) resulted in a significant decrease in the PV positive cells in all of the electroporated regions (fSSp, SSp, vAud and Vis cortices) when compared to mouse WT Disc1 overexpression. Furthermore, a decrease in the PV cells on the contralateral side was observed in the SSp and Vis cortices. This study demonstrates that mouse Disc1 is involved in the generation of parvalbumin expressing interneurons within the cortex in a cell non-autonomous way. The L100P point mutation in Disc1 led to downregulation of parvalbumin, which in turn would result in abnormal inhibitory properties of this interneuron subtype.

Computational modelling has been gaining an increasing amount of support from the neuroscience community as a tool to assay cognition and computational processes in the brain. Lately, scientists have started to apply computational methods from neuroscience to the study of psychiatry to gain further insight into the mechanisms leading to mental disorders. In fact, only recently has psychiatry started to move away from categorising illnesses using behavioural symptoms in an attempt for a more biologically driven diagnosis. To date, several neurobiological anomalies have been found in schizophrenia and led to a multitude of conceptual framework attempting to link the biology to the patients’ symptoms. Computational modelling can be applied to formalise these conceptual frameworks in an effort to test the validity or likelihood of each hypothesis. Recently, a novel conceptual model has been proposed to describe how positive symptoms (delusions, hallucinations and thought disorder) and cognitive symptoms (poor decision-making, i.e. “executive functioning”) might arise in schizophrenia. This framework however, has not been tested experimentally or against computational models. The focus of this thesis was to use a combination of behavioural experiments and computational models to independently assess the validity of each component that make up this framework. The first study of this thesis focused on the computational analysis of a disrupted prediction-error signalling and its implications for decision-making performances in complex tasks. Briefly, we used a reinforcement-learning model of a gambling task in rodents and disrupted the prediction-error signal known to be critical for learning. We found that this disruption can account for poor performances in decision-making due to an incorrect acquisition of the model of the world. This study illustrates how disruptions in prediction-error signalling (known to be present in schizophrenia) can lead to the acquisition of an incorrect world model which can lead to poor executive functioning or false beliefs (delusions) as seen in patients. The second study presented in this thesis addressed spatial working memory performances in chronic schizophrenia, bipolar disorder, first episode psychosis and family relatives of DISC1 translocation carriers. We build a probabilistic inference model to solve the working memory task optimally and then implemented various alterations of this model to test commonly debated hypotheses of cognitive deficiency in schizophrenia. Our goal was to find which of these hypotheses accounts best for the poor performance observed in patients. We found that while the performance at the task was significantly different for most patients groups in comparison to controls, this effect disappeared after controlling for IQ in one group. The models were nonetheless fitted to the experimental data and suggest that working memory maintenance is most likely to account for the poor performances observed in patients. We propose that the maintenance of information in working memory might have indirect implications for measures of general cognitive performance, as these rely on a correct filtering of information against distractions and cortical noise. Finally the third study presented in this thesis assessed the performance of medicated chronic schizophrenia patients in a statistical learning task of visual stimuli and measured how the acquired statistics influenced their perception. We find that patient with chronic schizophrenia appear to be unimpaired at statistical learning of visual stimuli. The acquired statistics however appear to induce less expectation-driven ‘hallucinations’ of the stimuli in the patients group than in controls. We find that this is in line with previous literature showing that patients are less susceptible to expectation-driven illusions than controls. This study highlights however the idea that perceptual processes during sensory integration diverge from this of healthy controls. In conclusion, this thesis suggests that impairments in reinforcement learning and Bayesian inference appear to be able to account for the positive and cognitive symptoms observed in schizophrenia, but that further work is required to merge these findings. Specifically, while our studies addressed individual components such as associative learning, working memory, implicit learning & perceptual inference, we cannot conclude that deficits of reinforcement learning and Bayesian inference can collectively account for symptoms in schizophrenia. We argue however that the studies presented in this thesis provided evidence that impairments of reinforcement learning and Bayesian inference are compatible with the emergence of positive and cognitive symptoms in schizophrenia.

The experiments described in this thesis involved the sleep, circadian and behavioural characterisation of two schizophrenia-relevant transgenic mouse models, both of which are models of altered glutamatergic function. Although schizophrenia cannot be recapitulated in rodents, the study of transgenic mouse models can yield insights into the roles of schizophrenia candidate genes in brain function and dysfunction. D-amino acid oxidase knockout (Dao-/-) mice do not express DAO, a glial peroxisomal enzyme that catalyses the degradation of D-amino acids including D-serine. In turn, D-serine is the primary endogenous co-agonist of the synaptic N-methyl-D-aspartate receptor, an ionotropic glutamate receptor that is strongly implicated in learning and memory, which may be hypoactive in schizophrenia. Given evidence of DAO overactivity in schizophrenia, DAO inhibiting drugs have been proposed as a potential treatment for the disorder. To assess the behavioural consequences of Dao inactivation, Dao-/- mice were subjected to a range of psychiatrically-relevant behavioural tests. Anxiety-like behaviour was increased in Dao-/- mice, while short-term memory performance was enhanced. By contrast, long-term spatial memory acquisition was unaltered in Dao-/- mice. However, the Morris watermaze performance of Dao-/- mice was critically dependent on the radial distance of the hidden platform from the side-wall. Analyses of spatial swimming behaviour revealed that Dao-/- mice demonstrated an increased preference for the periphery of the watermaze arena, which may be another manifestation of heightened anxiety. Prepulse inhibition testing revealed a complex interplay between genotype, sex and stress levels. Likewise, genotype-by-sex interactions were evident in the Morris watermaze and the novelty-suppressed feeding test. Dao-/- mice showed no evidence of sleep or circadian rhythm disruption (SCRD). Taken together, these results suggest that DAO inhibition might ameliorate the memory deficits of schizophrenia patients, although these effects may not extend to long-term associative memory. In addition, these benefits could come at the cost of heightened anxiety. Our data also imply that DAO inhibitors might have different effects in male and female patients. Metabotropic glutamate receptor 2 & 3 double-knockout (Grm2/3-/-) mice lack the inhibitory autoreceptors mGlu2 and mGlu3, which are encoded by the genes Grm2 and Grm3, respectively. Based on the results of genome-wide association studies, Grm3 is amongst the strongest schizophrenia candidate genes. The Grm2/3-/- mouse was used to assess the 'shared neuropathophysiology' hypothesis of SCRD in schizophrenia. This theory posits that the high co-morbidity of schizophrenia and SCRD stems from dysfunction in common brain mechanisms that underpin both pathologies. Consistent with this hypothesis, Grm2/3-/- mice displayed significant SCRD, characterised by reduced sleep duration and increased sleep fragmentation. They also demonstrated increased sensitivity to the circadian effects of light. These data are consistent with the 'shared neuropathophysiology' hypothesis, and tentatively suggest that mGlu3 dysfunction could contribute to SCRD in schizophrenia. Since memory performance is also impaired in Grm2/3-/- mice, this model could be an ideal tool with which to investigate the relationship between sleep disruption and cognitive performance. Finally, Grm2/3-/- mice displayed perturbed wheel-running rhythms under a standard light/dark cycle, despite the fact that their home-cage activity rhythms were unaltered in the absence of a running wheel. Although the basis of this phenotype is unclear, these data speak to the debate about the suitability of running-wheels as a circadian assay for psychiatrically-relevant mouse models.

Introduction This thesis has two aims. The first was to systematically review the literature on the effect of computer assisted cognitive remediation (CACR) for schizophrenia on psychosocial functioning, with a focus on methodological quality and efficacy. The second aim was to evaluate the implementation of CACR in a high secure forensic setting. Method Database searches and hand searches returned 16 randomised controlled trials of CACR that included a functional outcome measure. These were reviewed against predefined quality criteria and effect sizes were calculated. In addition, an uncontrolled pre-post test design was used to evaluate the implementation of CACR in a high secure forensic hospital. Attrition rates, predictors of attrition, and participant feedback were evaluated, along with symptom and functional outcomes. Results The systematic review found a range of methodological limitations. Studies that did not share these limitations did not provide evidence that CACR improves psychosocial functioning. However, CACR may be effective in improving functional outcomes when delivered alongside interventions targeting functional skills. The experimental study found a high attrition rate; poor adherence to the treatment protocol; no clinical, risk or demographic factors to distinguish treatment completers from those dropping out during treatment; and few improvements to performance on treatment activities or functional outcome measures. Conclusion The systematic review indicates that more methodologically rigorous research is required. Future studies with a general psychiatric population should examine the effect of CACR delivered in conjunction with interventions that aim to develop functional skills. Motivational deficits may have undermined the outcomes of the experimental study and it will be important to ensure the delivery of CACR in forensic psychiatric settings is designed to incorporate strategies for enhancing motivation. In addition, using CACR to target functional outcomes may be inappropriate within a high secure forensic setting. The role of CACR as in managing risk and enhancing the outcomes of other interventions should be explored.

Schizophrenia is a complex and severe psychiatric disorder with positive symptoms, negative symptoms and cognitive deficits. Preclinical neurobiological studies showed that alterations of dopaminergic and glutamatergic neurotransmitter circuits involving the prefrontal cortex resulted in cognitive impairment such as working memory. Functional activation and functional connectivity findings of functional Magnetic Resonance Imaging (fMRI) data provided support for prefrontal dysfunction during fMRI working memory tasks in individuals with schizophrenia. However, these findings do not offer a neurobiological interpretation of the fMRI data. Biophysical modelling of functional large-scale networks has been designed for the analysis of fMRI data, which can be interpreted in a mechanistic way. This approach may enable the interpretation of fMRI data in terms of altered synaptic plasticity processes found in schizophrenia. One such process is gating mechanism, which has been shown to be altered for the thalamo-cortical and meso-cortical connection in schizophrenia. The primary aim of the thesis was to investigate altered synaptic plasticity and gating mechanisms with Dynamic Causal Modelling (DCM) within functional large-scale networks during two fMRI tasks in individuals with schizophrenia. Applying nonlinear DCM to the verbal fluency fMRI task of the Edinburgh High Risk Study, we showed that the connection strengths with nonlinear modulation for the thalamo-cortical connection was reduced in subjects at high familial risk of schizophrenia when compared to healthy controls. These results suggest that nonlinear DCM enables the investigation of altered synaptic plasticity and gating mechanism from fMRI data. For the Scottish Family Mental Health Study, we reported two different optimal linear models for individuals with established schizophrenia (EST) and healthy controls during working memory function. We suggested that this result may indicate that EST and healthy controls used different functional large-scale networks. The results of nonlinear DCM analyses may suggest that gating mechanism was intact in EST and healthy controls. In conclusion, the results presented in this thesis give evidence for the role of synaptic plasticity processes as assessed in functional large-scale networks during cognitive tasks in individuals with schizophrenia.

This thesis has been prepared in the paper based format and includes a systematic review, a novel empirical piece of research and a critical reflection. The thesis focuses on the implementation of the National Institute for Health and Clinical Excellence’s (NICE) guidance recommendations for the psychological interventions for those people suffering from schizophrenia. Papers 1 and 2 have been prepared for submission in ‘Psychology and Psychotherapy: Theory, Research and Practice’ and the ‘Journal of Mental Health’ respectively. Paper 1 includes a systematic literature search and narrative synthesis exploring if the recommendations for psychological interventions for schizophrenia were being met. Rates of implementation for Cognitive Behavioural Therapy (CBT) and Family Intervention (FI) were compared. The barriers against implementation and the strategies aimed at improving implementation were reviewed. Rates of implementation varied from 4% to 100% for CBT and 0% to 53% for FI. Previously reported barriers to implementation were found, with organisational barriers being most common. Implementation strategies discovered included training packages for CBT and FI. Rates of implementation are below recommended levels suggesting inequalities in the provision of psychological interventions for schizophrenia are present. Strategies to improve implementation that are comprehensive and supported from all levels of the NHS are considered to be most effective. Paper 2 reports a quantitative piece of research exploring if behaviourally specific and plain English language guidance can improve healthcare professional intentions to perform actions in line with recommendations for schizophrenia. An independent measure, single blind, randomised controlled design was used to disseminate guidance in two formats; the ‘original’ and ‘alternative’. Self-report measures revealed no significant results when comparing the original guidance to the alternative for the cognitive determinants of behaviour, actual behaviour change, or comprehension and satisfaction with the guidance. Behaviourally specific and plain English language does not affect intentions or behaviour to implement recommended guidance for the provision of psychological interventions for schizophrenia. A more multi-factorial approach including organisational culture may be required. Paper 3 is a critical reflection of the submitted papers and research process as a whole. Strengths and limitations of the included studies, the findings in the context of wider research, implications for clinical practice and future research are discussed.

Bipolar affective disorder and schizophrenia are highly heritable psychiatric illnesses and the leading causes of worldwide disability. The orbitofrontal cortex (OFC) is a region of the frontal lobe with wide spread connectivity with other brain areas involved in reward, motivation and emotion. Evidence from various neuroimaging, genetic, post-mortem and brain lesion studies suggest that orbitofrontal cortex may play a role in pathophysiology of mental illnesses. This thesis sought to investigate the pathogenesis of major psychiatric illnesses through the investigation of orbitofrontal morphology in schizophrenia and bipolar disorder and through its associations with brain structure and function. Orbitofrontal morphology and its structural and functional associations were examined in healthy controls, patients with schizophrenia or bipolar affective disorder, and those at high genetic risk using functional and structural MRI. In the first study we found that the orbitofrontal type III is more frequent and the orbitofrontal type I is less common in the right hemisphere in patients with schizophrenia while in patients with bipolar disorder type III appears more often in both left and right hemispheres. We then sought to examine the relationship of orbitofrontal morphology to disease risk in a study of 146 people at high risk of developing schizophrenia and 110 people at high risk of developing bipolar disorder. We discovered that in the unaffected high risk groups the orbitofrontal type III predicted the development of later psychiatric illnesses, when combined with anterior cingulate morphology. Finally we showed, in a further study, that OFC morphology was associated with measures of schizotypy, brain structure, brain function and cognition. In conclusion, orbitofrontal morphology is linked to major psychiatric disorder and has significant structural and functional associations. As orbitofrontal sulcogyral patterns are formed in early life a fuller awareness of their relevance to brain function holds out the prospect that we could use such measures as an indicator of vulnerability to the development of illness later in life. This work points to the potential for the foundation of a theory of predictive associations between morphological patterns and the development of psychosis.

Background: Attachment theory represents a developmental framework which proposes that early relationships with primary caregivers have an enduring effect on interpersonal relationships, affect regulation and psychological functioning throughout the lifespan. It has been suggested that this occurs via the influence of internal representations regarding the self, others and relationships, which form the basis of an attachment style in adulthood. Attachment has been conceptualised as a constructive theoretical basis from which to consider psychological mechanisms underlying the emotional distress, interpersonal problems and difficulties in affect regulation commonly associated with psychosis. Aims: A systematic literature review was conducted investigating the current research findings regarding adult attachment style in psychosis and clinical correlates of this. An empirical study used a cross sectional design to investigate the role of adult attachment style in emotional recovery in psychosis. It was hypothesised that attachment insecurity would be associated with higher levels of depression and symptom related distress. Interpersonal problems and emotion regulation were also investigated and it was predicted that these variables would mediate the relationship between attachment insecurity and increased emotional distress. Method: Individuals with psychosis (n=70) completed self report measures of adult attachment style, interpersonal problems and emotion regulation. Clinician rated measures of depression and symptom related distress were also completed. Results: The literature review revealed that adult attachment style is of relevance in psychosis as consistent findings of greater attachment insecurity in psychosis compared with non clinical populations have been reported. Adult attachment insecurity has been associated with a number of clinical outcomes in exploratory research. The empirical study found support for hypothesised associations between attachment insecurity and greater emotional distress. Predicted relationships were also supported between attachment insecurity and higher rates of interpersonal problems and more use of expressive suppression as an emotion regulation strategy. Interpersonal problems significantly mediated the relationship between attachment insecurity and emotional distress. The hypothesised mediating role of emotion regulation was not supported. Conclusions: Findings of the empirical study suggest that insecurity in adult attachment style is an important variable in understanding emotional distress in individuals with psychosis and that difficulties in interpersonal functioning, as a mediating factor in this relationship, may represent a useful focus in clinical work.

24 million people worldwide are affected by schizophrenia. Its complex psychopathology, including changes in perception, can incur substantial personal distress and economic burden. Finding appropriate treatment that attracts voluntary adherence is an ongoing challenge for clinicians to prevent relapse and poor prognosis. This thesis conceives the psychiatrist-patient alliance - mediated through talk - as an intervention point that demands analytic attention. Conceptualising ‘good’ communication is however hindered by a lack of a) conceptual clarity on its constituents b) knowledge of what actually happens in psychiatric encounters. Abstract ideals of ‘Patient Centredness’ and ‘Shared Decision Making’ are widely endorsed as beneficial to adherence, but do not pragmatically translate into specific practices, conducive to training. Following a preparatory systematic review, this thesis addresses a gap in literature by observing psychiatric communication in 3 mixed method studies. Synthesising coding methodologies and statistical analyses with principles of conversation analysis, two studies explore the association - and explanatory mechanism - between adherence and specific communication practices: patient other-initiated repair and psychiatrist questions. Treatment decisions, the precursor to adherent behaviour, are also examined: alternative resources that psychiatrists employ and their interactional consequences are mapped, with a focus on patients’ overt resistance. The findings collectively extend knowledge on medical interaction and demonstrate the utility of a novel approach to outcome research in field dominated by cross sectional studies. Clinical, methodological and theoretical contributions are yielded relating to six themes 1) the consequentiality of psychiatrists’ communicative choices 2) the manifestation of alliance and adherence in clinical talk 3) orientations to experiential expertise and the contingencies of antipsychotic medication adherence 4) reconceptualising ‘good’ communication: misalignment as key to clinical success 5) evidence of the interaction order in schizophrenia 6) reconciling the nuances of naturalistic interaction with global clinical outcomes.

Genome wide association studies have provided evidence for a significant association between ZNF804A (zinc finger protein 804A) - specifically the intronic single nucleotide polymorphism (SNP) rs1344706 - and schizophrenia, but little is known about the function of the gene or the effects of the SNP. By studying post-mortem human brain tissue, I characterised ZNF804A immunoreactivity in adult and foetal human brain and investigated effects of diagnosis and rs1344706 genotype on ZNF804A mRNA and protein expression. Secondly, I looked in a large sample of healthy volunteers (n=922) at the effects of rs1344706 on brain structure using volumetry and voxel based morphometry (VBM). Furthermore, I recruited healthy volunteers who were either homozygous for the risk allele or homozygous for the non-risk allele (n=50). They participated in magnetoencephalography (MEG) and magnetic resonance (MR) sessions in which brain activity was measured during a working memory task, a visual processing task, and rest. Using magnetic resonance spectroscopy, also neurotransmitter levels were assessed. The experiments conducted for this thesis showed for the first time that ZNF804A immunoreactivity can be detected in both foetal and adult human brain and that it is mainly localised to layer III pyramidal cells, with a granular subcellular distribution throughout the cytoplasm. No effect of rs1344706 on mRNA and protein expression was found. In our structural MRI study, rs1344706 did not affect macroscopic brain structure as measured by volumetry and VBM, and given the large sample size, this seems a convincing negative. However, we did find that rs1344706 alters prefrontal-hippocampal connectivity, with increased connectivity being observed in risk homozygotes. Additionally, using MEG, we found an effect of ZNF804A genotype on hippocampal connectivity in the theta band (4-8Hz), with non-risk homozygotes displaying more connectivity. This finding provides a first clue as to the mechanisms that might underlie the previously observed effects of rs1344706 on prefrontal-hippocampal connectivity. Future studies will need to elucidate the actual function of the ZNF804A protein, in order to bridge the gap between the molecular and neuroimaging findings described in this thesis.

Background: The first aim of this thesis was to systematically review the evidence for the impact of interpersonal trauma in childhood on appraisals of auditory hallucinations in adulthood. Informed by this systematic review and cognitive models of psychosis, potential moderators of the relationship between trauma and distress were proposed. Hypotheses: It was hypothesised that the experience of interpersonal trauma in childhood would predict ‘self blaming’ and ‘danger to self’ appraisals made by voice hearers about their auditory hallucinations. It was predicted that these appraisals would interact with the use of avoidant and non avoidant coping strategies and that this would predict wellbeing. Method 1 and results: In order to measure voice appraisals, the Interpretation of Voices Inventory was adapted. It was completed by one hundred and thirteen voice hearing participants and confirmatory factor analysis was used to test the predicted factors. Most items covaried with their respective factors acceptably. A number of items did not load well and it was recommended that they be removed from the measure. The amended factor structure improved the fit of the measure to an acceptable standard. Method 2 and results: Sixty two participants completed additional measures of interpersonal trauma in childhood and wellbeing. Structural equation modeling provided support for a link between severity of childhood trauma and ‘danger to self’ appraisals. ‘Danger to self’ appraisals predicted the use of acceptance based coping and this predicted wellbeing. Independent of this model, interpersonal coping was shown to predict the use of psychological explanations for the experience of auditory hallucinations. Psychological explanations did not predict acceptance or wellbeing. Discussion: It may be clinically helpful to test acceptance based interventions using ‘danger to self’ appraisals as an outcome measure in the future. Possible factors that may have influenced the results were reflected on. The potentially negative impact of insight on wellbeing was discussed. Stigma was highlighted as a potential barrier to non avoidant coping

The aims of this study were to explore professionals’ and clients’ experiences of diagnosis and treatment of auditory verbal hallucinations with a view to identifying important clinical issues for counselling psychologists. Six professionals, three psychologists and three psychiatrists, who had worked with people who hear voices, alongside four clients who hear voices, volunteered and participated in a semi-structured interview. These interviews were transcribed and analysed using Interpretative Phenomenological Analysis (IPA) as described by Smith, Flowers and Larkin (2009). A table of super-ordinate and sub-ordinate themes was created as a result of this analysis. A number of themes arose from both groups of participants’ experiences. The main themes that arose for the professionals was: professional ambivalence; varying theories on causes of voices; perspectives on diagnosis and formulation; perspectives on medication; thoughts on working therapeutically; and, thinking on recovery. The themes that arose from the clients’ experiences were feelings about diagnosis and experiences of treatment. This research concludes that there is professional ambivalence in working with people who hear voices that is caused by a lack of certainty about the causes of the phenomenon alongside a lack of training in working with clients who have symptoms of psychosis. This impacts clients in several ways. The clients in this study were not offered the option to have any involvement in their own care and none of them were offered therapy as a treatment option. The study also concludes that psychiatric diagnosis does not consider all pertinent information related to clients’ issues which can lead to inconsistency in the diagnosis of clients who hear voices.

Introduction: An increased incidence of schizophrenia among migrant and ethnic minority groups has been established. Ethnic minorities have poorer access to and outcomes from evidence based psychosocial interventions compared to the majority population. The overall aims of this thesis was to explore culturally adapted psychosocial interventions for migrant and ethnic minority schizophrenia sufferers, and use the results of these investigations to develop culturally adapted cognitive remediation (CR) to meet the needs of South Asian first episode sufferers. Methods: A systematic review and meta-analysis of previous randomised controlled trials (RCTs) investigated the quality, methods and effectiveness of culturally adapted psychosocial interventions for schizophrenia. Interviews, analysed using framework analysis, explored the acceptability, and perceived accessibility, of CR to the target population. CR for first episode psychosis was then adapted to target South Asian sufferers' needs and participants' satisfaction and engagement measured in a feasibility study. Results: The systematic review identified 17 RCTs of culturally adapted psychosocial interventions for schizophrenia. Meta-analysis of culturally adapted Family Intervention (caFI) compared to Treatment As Usual (TAU) showed no reduction in relapse risk. There were non-significant reductions in risk and number of hospitalisations during the intervention and significant shortening of total time in hospital. Meta-analysis of culturally adapted Social Skills Training (caSST), compared to TAU showed improvements in medication and symptom management but no effects when compared to a time-matched psychosocial intervention. Results must be interpreted with caution due to the small number of trials included and limitations in their analyses. Cultural adaptations made to the interventions were similar across trials. This allowed for the development of a measure systematically recording the methods used in culturally adapting interventions. Scale items included: language, therapeutic alliance, teaching style, manual content, family, treatment goals, explanatory models of illness, help seeking behaviour, delivery, stigma, societal context and cultural tenets. Emergent themes from qualitative interviews with ten South Asian first episode schizophrenia sufferers included: help seeking for psychosis, sociocultural influences on help seeking, experience of cognitive deficits, and recommended cultural adaptations to CR. CR was well received by all respondents. Level of acculturation and the influence of family and illness beliefs were associated with distinct pathways to care. A feasibility study of culturally adapted cognitive remediation (caCR) for first episode South Asian psychosis patients resulted in high levels of service user satisfaction, therapeutic alliance and participant retention rates. The majority (87.5%) reported cognitive benefits and a boost in self-esteem. Conclusions: The scale of cultural adaptations for psychosocial interventions for schizophrenia will provide a framework for those developing culturally adapted interventions for migrant or ethnic minority communities and a means to record the degree and type of adaptation. CaCR was acceptable to first episode South Asian psychosis sufferers. A larger trial is required to investigate this intervention's efficacy in terms of cognitive and global functioning.

Schizophrenia is a severe and chronic disorder in many cases. The illness can impact on the whole family. Family interventions are a psychosocial treatment for schizophrenia. A robust evidence base has developed supporting the use of family interventions, as reduced relapse and other clinical benefits can be produced. The majority of service users in forensic services suffer from schizophrenia. Yet little is known about the need, acceptability or feasibility of family intervention in forensic services. The over-arching goal of this programme of research was to review the literature for family intervention and conduct a comprehensive needs assessment, with a final aim to resolve the barriers of implementation of family intervention within forensic services. Meta-analysis indicated that the efficacy of family interventions resulted in positive outcomes in reduced relapse and psychotic symptoms, and improved knowledge and relationships. Family interventions were found to be applicable to the psychological needs of forensic service users. Problems were identified with staff training and supervision on forensic wards, with few wards providing family intervention as part of treatment for schizophrenia. Relatives of forensic service users expressed a need for family intervention. Staff highlighted that the barriers to family intervention were associated with insufficient time, poor support, lack of training, deficient information sharing, and geographic limitations between family homes and the forensic units. Staff offered solutions to implementing family intervention that related to revised policy and improved supervision. Relatives and staff held positive attitudes toward family intervention with open-minded attitudes towards the use of a web camera to facilitate family intervention in forensic services (e-FFI). The fourteen week web based family intervention (e-FFI) feasibility study generated reduced levels of stress, stigma and expressed emotion with improvements in the family’s knowledge of schizophrenia, personal health and an acceptance of forensic services. E-FFI was administered with ease achieving positive feedback from the family and the forensic service.