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Persistent depression is a debilitating health condition with a poor prognosis even in the context of current gold-standard pharmacological and psychological interventions. A better understanding of the mechanisms contributing to its maintenance is needed to facilitate the development of more targeted psychological interventions. Bayesian predictive processing models of depression propose that negative emotional and physiological outcomes arise in depressive illness as a result of disturbed interoceptive precision estimation in depressed individuals; however, evidence from the clinical and cognitive neuroscience literatures suggests the hypothesis that sensory precision is attenuated in persistent depression across sensory modalities in general. A series of studies was designed to index sensory precision across somatic and auditory modalities and to identify the level at which any disruption manifested in persistently-depressed participants relative to controls. Study 1 (Chapter 3) measured baseline signal discriminability under conditions of focused attention. Study 2 (Chapter 4) measured the impact of failures of voluntary attention on signal discriminability. Study 3 (Chapter 5) used a simulation approach to model sensory precision in the first two studies and to identify mechanisms which could successfully predict the data. Studies 4 (Chapter 6) and 5 (Chapter 7) measured attentional capture by task-irrelevant and predictive sensory cues respectively. Study 6 (Chapter 8) partially replicated Studies 4 and 5 and used the resulting data to estimate the group-level sensory precision and salience parameters of a predictive processing model of precision optimization. The results suggest that sensory precision is attenuated in persistent depression across sensory modalities, and that this attenuation results from disturbances of voluntary and involuntary attention rather than baseline perceptual sensitivity. Under conditions of voluntary attention, reduced sensory precision may result from efforts at resource conservation; and under conditions of involuntary attentional capture, it may be related to a loss of target discriminability and salience. Conversely, the bottom-up salience of somatic stimuli was uniquely enhanced among depressed participants and was predicted by high anxiety and by low interoceptive sensibility. These findings open up new avenues for investigation of the mechanisms underlying persistent forms of depression, and have direct implications for clinical practice with respect to psychological intervention.

This thesis seeks to encourage an anthropology of psychology through an ethnographic account of evidence-based psychological therapy in the United Kingdom. It examines the ‘Improving Access to Psychological Therapies’ (IAPT) service established in 2008 as part of the National Health Service (NHS) and is based on 18 months of fieldwork conducted between 2016 and 2018 amongst mental health professionals and therapists-in-training. Through the invention of IAPT, 'Cognitive Behavioural Therapy' (CBT) and other cognate therapies such as 'Mindfulness' have become a hallmark of ‘evidence-based’ psychological healthcare. This research takes up the question of their acclaimed scientific status and asks how, and with what effects, psychological therapies have become conceivable and workable within the framework of evidence-based medicine (EBM). Divided into six chapters, the thesis offers a series of ethnographic reflections on some of the effects of the institutionalisation of evidence-based psychological therapy and the scientific persuasions that have made it possible. This research thus investigates the principles underlying psychological therapy, how they are conveyed through training and conferences, and how practitioners make sense of them in their everyday work. It examines some of the histories and logics that underscore the invention of IAPT, how psychological therapies align with dominant discourses in biomedicine concerning treatment and evidence, and some of the assumptions concerning ideas of selfhood that are implicit in them. We will see how professionals acquire particular skills and sensitivities in order to become therapists, how within specific professional contexts they debate and disagree with each other, yet also how they produce certain forms of critique and contextualisation familiar to social scientists. The ethnography shows that whilst psychological therapies – from ‘CBT’ to ‘Mindfulness’ – have become recognised as effective interventions for a range of mental health problems, they have also generated their own empirical tensions and uncertainties. We follow these ethnographic realities as we move from some of the ambitions and problems of the IAPT service to the contexts of research, education and training of therapists. The thesis argues that the epistemic success of CBT as the benchmark model of psychological healthcare in the UK rests on a persuasive, recursive move: CBT introduces accountability and measurement at the heart of its proposed vision of mental health – enacted through particular therapeutic practices of self-reporting and self-inspection – and this, in turn, enables it to demonstrate its value and validity in the terms set by the conventions of ‘evidence-based’ practice. As a result, psychotherapeutic care has been reconstituted as a highly manualised, standardised and quantifiable intervention. It is the quest for objectivity and scientific validation that requires psychological therapy to be enacted as an object of scientific testing and accountability by way of rendering the human subjecthood at the core of its practice amenable to measurement and intervention. Such an ambition is not new in psychology, as we shall see, but it has been revivified in new and interesting ways through the promises and persuasions of evidence-based psychological therapy. The thesis thus contributes to anthropological studies of scientific epistemologies and therapeutic practices and suggests a way of treating ethnographically common psychological realities, including those found in the conceptual worlds of anthropologists.

Autism Spectrum Conditions (henceforth, autism) refers to a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication, difficulties in adjusting to unexpected change, alongside unusually narrow interests and repetitive behaviour, and sensory hyper-sensitivity. Twin and family-based studies have consistently identified high heritabilities for autism and autistic traits, with recent studies converging at 60 – 90% heritability. Common genetic variants are thought to additively contribute to as much as 50% of the total risk for autism. In this thesis, I investigate the contribution of common genetics variants (including SNPs, and InDels) to autism and related traits. In Chapter 1, I discuss the recent advances in the field of autism genetics, focussing on the contribution of common genetic variants to the risk for autism. Chapters 2 – 7 report the results of various studies investigating the genetic correlates of autism and related traits. In Chapter 2, I surveyed the evidence for 552 candidate genes associated with autism, and conducted a meta-analysis for 58 common variants in 27 genes, investigated in at least 3 independent cohorts. Meta-analysis did not identify any SNPs that were replicably associated with autism in the Psychiatric Genetics Consortium genome-wide association study (PGC-GWAS) dataset after Bonferroni correction, suggesting that candidate gene association studies are not statistically well-powered. In Chapters 3 – 7, I conducted genome-wide association studies (GWAS) for 6 traits associated with autism: self-reported empathy (N = 46,861, Chapter 3), cognitive empathy (N = 89,553, Chapter 4), theory of mind in adolescents (N = 4,577, Chapter 5), friendship satisfaction (Neffective = 158,116) and family relationship satisfaction (Neffective = 164,112, both Chapter 6), and systemizing (N = 51,564, Chapter 7). GWAS identified significant loci for self-reported empathy, systemizing, friendship and family relationship satisfaction, and cognitive empathy. Genetic correlation analyses replicably identified a significant negative genetic correlation between autism and family relationship satisfaction and friendship satisfaction, and a significant positive genetic correlation between autism and systemizing. In addition, there was a negative genetic correlation between autism and self-reported empathy. Chapter 8 draws all of these studies together, concluding that there may be at least two independent sources of genetic risk for autism: one stemming from social traits and another from non-social traits. I discuss some future directions about how this can be leveraged using polygenic scores from multiple phenotypes to potentially stratify individuals within the autism spectrum, and both the strengths and limitations of the reported studies.

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.

Psychotic symptoms are prevalent in a wide variety of psychiatric and neurological disorders. Yet, despite decades of research, the neurobiological mechanisms via which these symptoms come to manifest themselves remain to be elucidated. I argue in this thesis that using a mechanistic approach towards understanding psychosis that borrows heavily from the predictive coding framework, can help us understand the relationship between neurobiology and symptomology. In the first results chapter I present new data on a biomarker that has often been cited in relation to psychotic disorders, which is glutamate levels in the anterior cingulate cortex (ACC), as measured with magnetic resonance spectroscopy. In this chapter I aimed to replicate previous results that show differences in glutamate levels in psychosis and health. However, no statistically significant group differences and correlations with symptomology were found. In order to elucidate the potential mechanism underlying glutamate changes in the anterior cingulate cortex in psychosis, I tested whether a pharmacological challenge of Bromocriptine or Sulpiride altered glutamate levels in the anterior cingulate cortex. However, no significant group differences were found, between medication groups. In the second results chapter I aimed to address a long-standing question in the field of computational psychiatry, which is whether prior expectations have a stronger or weaker influence on inference in psychosis. I go on to show that this depends on the origin of the prior expectation and disease stage. That is, cognitive priors are stronger in first episode psychosis but not in people at risk for psychosis, whereas perceptual priors seem to be weakened in individuals at risk for psychosis compared to healthy individuals and individuals with first episode psychosis. Furthermore, there is some evidence that these alterations are correlated with glutamate levels. In the third results chapter I aimed to elucidate the nature of reward prediction error aberrancies in chronic schizophrenia. There has been some evidence suggesting that schizophrenia is associated with aberrant coding of reward prediction errors during reinforcement learning. However it is unclear whether these aberrancies are related to disease years and medication use. Here I provide evidence for a small but significant alteration in the coding of reward prediction errors that is correlated with medication use. In the fourth results chapter I aimed to study the influence of uncertainty on the coding of unsigned prediction errors during learning. It has been hypothesized by predictive coding theorists that dopamine plays a role in the precision-weighting of unsigned prediction error. This theory is of particular relevance to psychosis research, as this might provide a mechanism via which dopamine aberrancies, might lead to psychotic symptoms. I found that blocking dopamine using Sulpiride abolishes precision-weighting of unsigned prediction error, providing evidence for a dopamine mediated precision-weighting mechanism. In the fifth results chapter I aimed to extend this research into early psychosis, to elucidate whether psychosis is indeed associated with a failure to precision-weight prediction error. I found that first episode psychosis is indeed associated with a failure to precision-weight prediction errors, an effect that is explained by the experience of positive symptoms. In the sixth results chapter I explore whether the degree of precision-weighting of unsigned prediction errors is correlated with glutamate levels in the anterior cingulate cortex. Such a correlation might be plausible given that psychosis has been associated with both. However, I did not find such a relationship, even in a sample of 137 individuals. Thus I concluded that anterior cingulate glutamate levels might be more related to non-positive symptoms associated with psychotic disorders. In summary, a mechanistic approach towards understanding psychosis can give us valuable insights into the disease mechanisms at play. I have shown here that the influence of expectations on perception is different across disease stage in psychosis. Furthermore, aberrancies in prediction error mechanisms might explain positive symptoms in psychosis, a process likely mediated by dopaminergic mechanisms, whereas evidence for glutamatergic mediation remains absent.

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.

Psychotic experiences (PEs) occur in the general population, beyond psychotic disorders. PEs are a risk factor for mental ill health in young people but can occur benignly in selected samples of adults. Environmental factors predispose to PEs but their underlying mechanisms are not well-understood. Progress in understanding PEs may be limited by diverse conceptualisations, imprecise measurement and a lack of explanatory frameworks that can bridge the gaps between aetiological factors, their effects on the brain and their behavioural manifestations. In this thesis, I undertook a comprehensive investigation of the measurement, health implications, aetiology and computational mechanisms of PEs in adolescents and young adults using data from two large cohort samples, supplemented with smaller-scale behavioural studies. I first investigated the measurement of PEs. I assessed and optimised the measurement of PEs in young people by two self-report instruments. I then used latent variable modelling to show that a self-report and interview instrument measured the same underlying psychotic phenomena. Both instruments were able to measure severe PEs, while the self-report questionnaire also measured more mild psychotic phenomena. I then investigated the health implications of PEs. Using cluster analysis in both cohorts, I found replicable patterns of PEs at similar levels of intensity and persistence but with and without depressive symptoms and with varying risk of mental disorder. Paranoid ideation was more associated with depressive symptoms than non-paranoid unusual perceptions and beliefs. Childhood adversity was associated with both PE-prone groups, but later social support from family and friends was far higher in those with PEs and low depressive symptoms than those with PEs and high depressive symptoms. Subsequently, I investigated the role of the social environment in the development of PEs and psychopathology using longitudinal structural equation modelling. I found that asocial dispositions increased or preceded increase in PEs over one year, mediated by detriment to social support. Conversely, PEs did not precede or increase asociality. I then showed that dimensions of PEs and depressive symptoms were promoted by childhood adversity but differentially affected by later social support, with paranoid ideation being more influenced by support than non-paranoid unusual perceptions/beliefs. Finally, I investigated specific mechanisms of PEs in two behavioural studies. In the seventh study, I used computational modelling of reward learning to link PEs to reduced ability to modulate learning by confidence, replicating computational effects of a pharmacological model of psychosis. I also used a novel visual task to show that the manifestation of PEs as anomalous perceptions versus anomalous beliefs might be explained by over-reliance on different types of prior knowledge in perceptual inference. These results suggest that different conceptual approaches to PEs might be synthesised despite issues with their measurement. PEs in young people, while not entirely benign, are heterogeneously associated with psychopathology. Importantly, they characterise a minority of young people who are at very high transdiagnostic risk of mental illness but also occur without distress in young people, often in the context of a supportive social environment. Health outcomes in young people with PEs are predicted and potentially modified by social functioning and social relationships. PEs might arise from atypicalities in how the influences of information sources on perception and belief-updating are modulated according to their reliabilities.

Schizophrenia and major depressive disorder (MDD) are disabling, poorly understood conditions with inadequate diagnostic and therapeutic technologies. They are characterized by clinical and epidemiological heterogeneity between male and female patients. Females have a higher prevalence of MDD, and in schizophrenia males have a higher incidence, earlier onset, more negative symptoms, and a worse prognosis and response to antipsychotic medication in schizophrenia. A better understanding of sex differences in these patients is needed to provide insight into biological mechanisms in these conditions and develop better diagnostic tools and therapies for males and females. This thesis sought to examine molecular sex differences in control subjects and in schizophrenia and MDD patients by profiling serum and prefrontal cortex (PFC) brain tissue. Multiplex immunoassay and microarray technologies were used to measure concentrations of proteins and small molecules in serum and gene expression in brain, respectively. Extensive differences in serum molecular concentrations were found between males and females experiencing a menstrual cycle, using oral contraceptives, and after menopause. These were involved in immune, metabolic, and endocrine processes and may play a role in driving sex differences in susceptibility and other characteristics of mental disorders. Furthermore, the hypothalamic-pituitary-gonadal (HPG) axis was altered in MDD and first onset, antipsychotic naive schizophrenia patients. Biological processes involving response to steroid hormone stimulus and estradiol were enriched among differentially expressed genes in the PFC in schizophrenia. However, investigation of sex-dependent differences in PFC gene expression in schizophrenia was limited by the small number of female samples available. Finally, higher serum concentrations of a number of immune and inflammatory molecules were associated with MDD and schizophrenia in males only and this may have consequences for immune hypotheses of these disorders. The research undertaken in this thesis has advanced the understanding of the mechanisms potentially involved in schizophrenia and MDD in males and females. Furthermore, sex and female hormonal status should routinely be taken into account during design and analysis of psychiatric molecular data to increase the reproducibility of such studies. This research shows that failing to consider these in biomarker studies can result in a high proportion of false positive findings and obscure important sex-dependent markers of mental disorders.

This dissertation presents results from the first quantitative population based study exploring prevalence of Common Mental Disorders (CMDs), psychotic symptoms and Hazardous Drinking (HD) and factors associated with each outcome in a large group of first generation economic 'immigrants' in Santiago, Chile (i.e. born in Peru) compared with a geographically matched sample of 'non-immigrants' (i.e. born in Chile). A total of 1,293 adult householders were assessed in a two-stage survey [Inner Santiago Health Study (ISHS)] using the Revised Clinical Interview Schedule (CIS-R), the Psychosis Screening Questionnaire (PSQ), the Alcohol Use Disorders Identification Test (AUDIT) and the Warwick-Edinburgh Mental Well-being Scale (WEMWBS). Participants screening positive for psychosis were assessed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). As a framework for comparison, this dissertation includes Systematic Reviews and meta-analyses of literature reporting prevalence of psychotic disorders, CMDs and Alcohol Use Disorders/HD in immigrants from Latin America and the Caribbean (LAC), and in the general populations of Peru and LAC. Results reveal the magnitude of untreated mental health problems (i.e. CMDs, psychotic symptoms and HD) in the community, particularly CMDs among women and HD among men and the consistency of discrimination as a risk factor for CMDs and psychotic symptoms among 'immigrants'. They also show a lower overall one-week estimated prevalence of any ICD-10 'any CMD' and higher mental wellbeing among 'immigrants' compared with 'non-immigrants' and a similar estimated annual prevalence of 'any psychotic symptom' or HD between 'non-immigrants' and 'immigrants' despite higher exposure of 'immigrants' to socioeconomic disadvantage. Prevalence estimates for ICD-10 'major depression' and 'any anxiety disorder' in 'immigrants' appeared higher than pooled prevalence estimates calculated for the Peruvian general population and prevalence estimates for ICD-10 'major depression' and 'any anxiety disorder' in 'non-immigrants' higher than pooled prevalence estimates in the LAC general population. These findings provide evidence that first generation economic Peruvian immigrants to Chile are not at higher risk of mental health problems when compared with local population, providing direct policy implications for Chile and the LAC region.