Genetic studies of schizophrenia have often been frustrated by the aetiological and pathological complexity of the disorder. One research strategy to address this issue is the use of endophenotype markers. The aim of this PhD thesis is to explore the validity of selected candidate endophenotype markers for schizophrenia by establishing the evidence that they may have some or indeed any relationship with the genetic risk for the disorder. I have studied a unique twin and family population, to describe the distribution of a variety of deficits as candidate markers in patients, their unaffected co-twins and relatives, and healthy controls, to explore the evidence for genetic and environmental influences on their distribution. I selected neurological soft signs, personality and social development, grey and white matter cerebral volumes, and regional neural activity during a phonological verbal fluency task. The results were most compelling for the developmental and verbal fluency markers, supporting their role as endophenotype markers. In comparative terms, this may relate more to methodological factors, than the markers inherent properties. All of the markers demonstrated that they met many endophenotype criteria.

In this thesis, allocentric spatial memory was investigated in healthy volunteers with average and high levels of schizotypal traits assessed using the Schizotypal Personality Questionnaire. Functional and structural MRI was used to investigate the neural correlates of allocentric spatial memory in schizotypal personality. Allocentric spatial memory is reported to be impaired in schizophrenia and this is thought to be related to alterations in hippocampal function and structure. Previous literature suggests individuals with schizotypal personality traits have a similar cognitive and neural profile to schizophrenia spectrum disorders for example reduced hippocampal volumes and compromised cognition. It was therefore hypothesised that high schizotypy would be associated with worse performance on these tasks and a different pattern of functional activation in the hippocampus and parahippocampal gyrus compared to controls. No behavioural differences were observed on the cognitive measures in this thesis. Investigation of brain function revealed decreased volume of the right hippocampus and bilateral medial frontal gyrus and increased volume of the posterior cingulate, superior temporal gyrus and anterior prefrontal cortex, in line with previous literature. Functional MRI revealed decreased activation of the right hippocampus during memory encoding and increased activation of the hippocampus bilaterally during memory retrieval in high schizotypy compared to controls. Memory retrieval was also associated with increased activation of the anterior cingulate gyrus, inferior frontal gyrus and insular cortex in this group. Further, activation of the right hippocampus is related to better performance across allocentric spatial memory tasks in controls but this relationship is absent in high schizotypy.

Rare copy number variants (CNV), defined as deletions and duplications of genetic material over 1,000 base pairs in length, have become the focus of considerable interest in psychiatric disorders, where a proportion of individuals harbour rare and de novo events not usually seen in controls. We have performed a genome wide association study of copy number variation in 3,106 cases of recurrent depressive disorder, 1,731 controls screened for a lifetime absence of psychiatric disorder, and 5,619 population controls from phase 2 of the Wellcome Trust Case Control Consortium. Analysing our data with the PennCNV method, we found an enrichment of rare deletion CNVs in our case cohort, especially when compared to our screened control cohort. This finding was supported by further analysis with the iPattern method, but not by the QuantiSNP method. We followed up a selection of cases and controls with a comparative genomic hybridisation (CGH) array focussed on the region 22qll.2, which is a neuro-gene rich region of the human genome under current active evolutionary selection and resident to a deletion syndrome which commonly manifests with psychiatric disorders. We found no significant differences in CNV burden between our case and control cohorts. Finally we ran association analyses with our CNV call sets, including a high quality intersected call set derived from all three methods, against various phenotypes obtained from a combined database of all studies that contributed samples to this GWAS. We found no associations that survived Bonferroni correction for multiple testing.

Background: Many service users with psychosis will live with and/or maintain regular contact with informal carers. Findings from a small number of studies suggest that a significant number of carers of people with psychosis experience posttraumatic stress symptoms (Barton & Jackson, 2008; Loughland et al. 2009; Boye & Malt, 2002). However, it is unclear how these symptoms relate to a broader range of carer characteristics. The application of a stress and coping framework, including components from the cognitive model of PTSD (Ehlers & Clark, 2000) may help us to understand the relationships between posttraumatic stress symptoms and well-being in carers, and in turn help to shape interventions for both carers and service users. Aims: In a sample of carers of people with psychosis the study aimed to explore posttraumatic stress symptoms, including intrusive imagery, and to examine the relationship between posttraumatic stress symptoms, well-being and caregiving experiences. Methods: Thirty-two carers of people with psychosis completed self-report questionnaires and short interviews assessing posttraumatic stress symptoms, negative caregiving appraisals, appraisals of trauma, avoidant coping style, social support, expressed emotion, physical health and sleep quality. Results: Almost half (n = 15; 44%) of the participants reported symptoms of posttraumatic stress. Posttraumatic stress symptoms were associated with negative appraisals of caregiving, negative appraisals of trauma, greater levels of avoidant coping, and lower reported physical health. Associations between posttraumatic stress symptoms and social support, expression emotion and sleep quality, were not found. Negative intrusive images were identified in 35% (n = 11) of carers. Images were appraised as vivid and moderately to extremely distressing; and elicited strongly held negative beliefs about the self, others or the world. Conclusions: This study supports existing research to suggest that carers of people with psychosis can experience posttraumatic stress symptoms related to their caring role. It also lends support for the application of a stress and coping framework to understand relationships between posttraumatic stress symptoms and carer characteristics. Conclusions are limited by a relatively small sample and cross-sectional design. Future research is needed to assess causal relationships and the role of other factors implicated within theoretical models of stress and coping. The findings indicate that posttraumatic stress symptoms should be considered when designing and implementing interventions to meet carer needs and improve outcomes for both carers and service users.

Developing empathy has become a central component of cognitive behavioural treatment programmes for offenders, who it is argued have victim empathy deficits. It is therefore important to evaluate the effectiveness of these interventions. Research is moving towards utilising victim empathy measures as the most effective tools for this purpose, although evidence has been mixed regarding their psychometric properties. The Victim Empathy Response Assessment (VERA) was developed as a victim specific measure to assess cognitive and affective empathy in forensic settings. Limited validity has been demonstrated using an adult male forensic and community sample. Following participant feedback suggesting how to increase the validity of the tool a second video prototype VERA(ii) was developed. This study aimed to evaluate the validity of the VERA(ii) with 51 non-offending adult community males. Participants viewed the VERA(ii) whilst simultaneously providing physiological measurements of skin resistance level (SRL) and heart rate (HR). Following this they completed the VERA(ii) cognitive and affective empathy questionnaires, also the Wechsler Abbreviated Scale of Intelligence, Eysenck Personality Questionnaire Revised - Short Form, Eysenck Impulsiveness, Venturesomeness and Empathy Questionnaire, Maudsley Violence Questionnaire and the Story Comprehension Task. Wilcoxon signed-ranks tests demonstrated a significant difference between cognitive and affective empathy and SRL from mean baseline to mean total SRL after viewing the VERA(ii). However, Spearman’s Rho Correlations found no significant associations between physiological measures and total cognitive or affective empathy. A significant negative correlation was found between cognitive empathy and MVQ Machismo, and a significant positive correlation was found with the Story Comprehension Task. No other significant associations were demonstrated. Overall, the results of the current study have provided limited evidence for the validity of the VERA(ii). Limitations of the study have been highlighted and discussed with regards to theoretical and clinical implications. Recommendations for future research have subsequently been presented. The original intention of this research was to validate the VERA(ii) using a non-offending adult male community sample and adult male in-patient offenders. However, unfortunately due to practical difficulties severely limiting the recruitment of the offending group this part of the study could not be fully completed. The study therefore focuses upon a community sample only.

Background: Bipolar Disorder (BD) is one of the leading causes of disability worldwide. Much of the disability associated with BD is linked to the early onset of the disorder, typically between 16 and 30 years of age. The aim of the PhD was to examine whether subclinical manic symptoms are associated with subsequent onset BD and to identify the longitudinal trajectories associated with conversion to syndromal BD. Methods: I analyzed data from TRAILS (TRacking Adolescents’ Individuals Lives Survey), a prospective population based study of 2,230 Dutch adolescents. Participants were assessed with the Child Behaviour Checklist 6-18 (CBCL 6-18) at ages 11, 13 and 16 years and were administered the Composite International Diagnostic Interview (CIDI) at age 19. The prevalence rate for BD in TRAILS was 5.4%. Results: I developed and validated a new scale, the Child Behaviour Checklist-Mania Scale (CBCLMS) to capture subclinical manic symptoms. The CBCL-MS consists of 19 items of the CBCL 6-18 selected by an expert panel to map onto the DSM criteria for Mania. The CBCL-MS had a four factor structure that was interpretable and temporally stable, and presented with good reliability and discriminative ability for BD. Based on assessments with the CBCL-MS at age 11, a Latent Class Analysis extracted three classes, representing an asymptomatic class (n=862), a mildly symptomatic class (n=845) and a highly symptomatic class (n=199). Membership in the highly symptomatic class was associated with a 7-fold increase in the odds for subsequent BD. Non-conversion to BD for members of this class was characterised by a decreasing longitudinal trajectory of subclinical manic symptomatology. Conclusions: These results support the concept of “alarm symptoms” in BD, as highly deviant childhood manic symptoms were associated with a subsequently greatly elevated risk of BD, and for initiatives to identify underlying BD at an earlier and more amenable stage. However, there was little support for a detectable prodromal phase for BD.

Policy and professional guidance in England have emphasised the importance of Therapeutic Relationships (TRs) in community mental health care, yet there is no comprehensive model to guide practice or understand the process through which stronger TRs are generated. This thesis investigated TRs in community mental health for individuals with psychotic disorders and was embedded within the CRIMSON trial: a randomised controlled trial of the Joint Crisis Plan (JCP) intervention. JCPs contain service users’ treatment preferences for future care, which are jointly decided with clinicians. Qualitative analyses addressed participants’ views of TRs and JCPs. Quantitative analyses addressed the predictive utility of TRs for outcomes, associations of TRs and the effect of JCPs on service user and clinician-rated TR. Results suggested that significant ambiguity persists regarding what can and should be provided in community mental health, resulting in unhelpful experiences for service users and clinicians. A new model of TRs - Consistent Respect - was developed; it presents TRs as bi¬directional processes, jointly affected by clinicians’ and service users’ experiences of interactions and their roles defined by the wider context; the latter often being a barrier to the development of strong TRs. JCPs significantly improved service users’ appraisals of TRs by providing a structured protocol through which routine role enactments were limited and clinicians could demonstrate Consistent Respect. Positive effects were lost when there were deficiencies in the implementation of JCPs and/or engagement of clinicians. In conclusion, improving TRs through JCPs could facilitate better outcomes and more satisfactory treatment experiences for service users and clinicians. Changes in policy and practice are indicated to facilitate transparent goals and roles for clinicians and respectful interactions with service users.

There is ample evidence that patients with psychosis are more likely to use illicit substances than the general population, with cannabis being the most popular. Research has also shown that cannabis use is associated with poor prognostic outcomes in patients with an established psychotic disorder. It is important to understand the reasons patients with psychosis endorse for their cannabis use and findings so far point towards an ‘alleviation of dysphoria’ model rather than the ‘self-medication’ hypothesis. It is not known how the level of motivation to change cannabis use can affect patients’ actual use. Lack of validated readiness to change questionnaires for use with psychotic populations makes it essential to develop and validate such measures. The aim of this thesis was to evaluate the reasons for cannabis use and its effects on psychotic outcomes in a patient cohort with first-episode psychosis. The association between cannabis use and other illicit drug use was also investigated. Readiness to change was evaluated as a predictor of cannabis use outcomes using two questionnaires. The main finding was that cannabis use was not associated with psychotic outcomes but was related to other illicit drug use. With regards to reasons, patients chose enhancement and social motives as most important for their cannabis use providing support for the ‘alleviation of dysphoria’ model. Preliminary analysis showed no clear pattern of association between readiness to change and cannabis use outcome. Utility of two readiness to change measures for use with patients with psychosis was not validated. These findings add to the small evidence base that cannabis use is not associated with prognostic outcomes in psychosis. No evidence for the self medication hypothesis was observed. Readiness to change was not associated with cannabis use outcomes signifying the need for using validated measures to assess motivation in psychotic populations.

The main aim of my doctoral work was to investigate the extent to which neuroanatomical and neurofunctional alterations previously reported in patients with chronic schizophrenia represent neurobiological markers of vulnerability to psychosis or are specifically associated with the onset of the disease. To this purpose, I have applied a range of neuroimaging techniques and analytical approaches to the study of 21 individuals with an At Risk Mental State (ARMS), 26 patients with a First Episode of Psychosis (FEP) and 24 matched healthy controls. I initially focused on the characterisation of neuroanatomical alterations by performing a comparison between voxel-based morphometry and cortical thickness measurements. I then moved on to the investigation of alterations of regional activation and interregional coupling within a network of fronto-temporal regions, using a standard functional Magnetic Resonance Imaging (fMRI) and a Dynamic Casual Modelling (DCM) analysis respectively. Subsequently, I characterised white matter integrity of fronto-temporal connections by performing a virtual in vivo interactive dissection of the main white matter tracts thought to connect temporal, cingulate and frontal regions. Finally, I explored the relationship between fronto-temporal structural connectivity and interregional coupling by performing a correlation analysis between the subject-specific measurements of white matter integrity and functional connectivity. The results of the present multimodal investigation suggest that regional fronto-temporal neuroanatomical and neurofunctional alterations precede the emergence of psychosis, consistent with a neurodevelopmental model of the illness, while most dysconnectivity alterations within the same network may only appear in the presence of active and severe symptoms or as illness progresses. Findings are discussed in relation to their implication for: (i) current neurobiological models of the disease and (ii) the identification of neurobiological markers which could inform early diagnosis.

Numerous studies report significant biological and cognitive alterations in chronic schizophrenia (ChSz) patients relative to healthy controls (HCs). More recently, similar,albeit less severe, changes have been reported in subjects with a recent first episode of psychosis (FEP), and those at clinical high-risk, referred to as the at-risk mental state (ARMS). The clinical impact of such findings has been limited, however, driven in part by the univariate analyses employed by the majority of studies, which allow inference at the group level only. Support vector machine (SVM) is one alternative multivariate analysis, which, able to provide inference at individual level, has high potential for translation into a clinical setting. Here, I employed a multimodal approach comprising genetic, structural magnetic resonance imaging (sMRI), diffusion tensor imaging, functional MRI, and cognitive data, in order to investigate the capacity of each modality to distinguish FEP and ARMS subjects from HCs, and each other, both at the group, and the single-subject level, using standard univariate and multivariate SVM analyses respectively. Since the clinical potential of SVM is ultimately governed by its classification accuracy, I also performed an empirical comparison of four integrative methods, proposed to enhance classification through data integration. Collectively, the results provide relative support to the notion that FEP and the ARMS may be characterised by genetic, neuroanatomical, neurofunctional and cognitive alterations similar to those observed in ChSz, albeit less severe. With respect to neuroanatomy, and neurofunction moreover, they suggest such changes may be both subtle, and spatially diffuse. The achievement of only modest classification accuracies, however, suggest that the modalities investigated here have only limited diagnostic power with respect to early-stage psychosis, though it remains that they may be able to provide useful information for predicting conversion to psychosis or treatment outcome, a prospect which could be investigated by future studies.