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Background: Immune, metabolic, and cardiac alterations are well recognised in schizophrenia, however it remains unclear if these alterations are present once the influence of lifestyle factors are accounted for, if they occur in all patients or only a subgroup, and if these alterations occur to a similar magnitude as alterations observed within the brain. Furthermore, it is unclear if metabolic changes in psychosis are reflective of a pro-inflammatory state. Systemic inflammatory conditions such as rheumatoid arthritis are characterised by insulin resistance and paradoxical reductions in cholesterol levels. In this context, specific hypotheses tested in this thesis are as follows: 1) Compared with controls, antipsychotic naïve patients with first episode psychosis will present with insulin resistance and reductions in total and low density lipoprotein cholesterol levels, reflective of a pro-inflammatory state; 2) Compared with controls, antipsychotic naïve patients with first episode psychosis will present with elevated pro-inflammatory immune parameters even once lifestyle factors are accounted for, and these alterations will be typically observed in patients rather than only occurring in a subgroup; 3) Compared with controls, patients with schizophrenia will present with fibroinflammatory changes within the myocardium, even after accounting for traditional cardiovascular risk factors; 4) In psychosis, alterations in metabolic, immune, and hypothalamic-pituitary-adrenal axis markers will be of a similar magnitude to brain structural, functional, and chemical alterations. Methods and Results: Introductory chapter 1 summarises the physical health burden associated with schizophrenia, considers outstanding issues that the papers in this thesis aim to address, and describes the statistical and imaging techniques employed to do so. Chapter 2 sets out to clarify if there is evidence of disturbed glucose homeostasis in antipsychotic naïve patients with FEP once the confounds of lifestyle and medication have been removed. The Embase, Medline and PsycINFO databases were systematically searched for studies examining measures of glucose homeostasis in drug-naïve individuals with FEP compared with controls. Of 3660 citations retrieved, 16 case control studies comprising 15 samples met inclusion criteria. The overall sample included 731 patients and 614 controls. Standardised mean differences in fasting plasma glucose, plasma glucose post-OGTT, fasting plasma insulin, insulin resistance, and HbA1c were calculated. Fasting plasma glucose (g = 0.20 (95% CI 0.02 – 0.38, p = 0.03)), plasma glucose post-OGTT (g = 0.61 (95% CI 0.16 – 1.05, p = 0.007)), fasting plasma insulin (g = 0.41 (95% CI 0.09 – 0.72, p = 0.01)) and insulin resistance (HOMA-IR) (g = 0.34 (95% CI 0.14 – 0.54, p = 0.001)) were all significantly elevated in patients compared with controls. Chapter 3 sets out to clarify if there is evidence of lipid dysregulation in antipsychotic naïve patients with FEP, even once the confounds of lifestyle and medication have been removed. The Embase, Medline and PsycINFO databases were systematically searched for studies examining lipid and adipocytokine parameters in individuals with FEP compared with controls. Studies reported fasting total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides and leptin levels. Of 2070 citations retrieved, 20 case-control studies met inclusion criteria including 1167 patients and 1184 controls. Total cholesterol (g = -0.19; 95% CI = -0.32 - -0.06; p = 0.005) and LDL cholesterol (g = -0.22; 95% CI -0.35 - -0.09; p = 0.001) levels were significantly decreased in patients versus controls. Triglyceride levels were significantly increased in patients versus controls (g = 0.14; 95% CI 0.00 – 0.28; p < 0.05). However, HDL cholesterol (g = -0.22; p = 0.07) and leptin (g = -0.05, p = 0.78) levels were not altered in patients versus controls. Chapter 4 sets out to clarify if there is evidence of immune dysregulation in antipsychotic-naïve first episode psychosis (FEP) after controlling for environmental/demographic confounders. It also examines for evidence of an immune subgroup of patients. The Embase, Medline and PsycINFO databases were systematically searched for studies examining blood cytokines, C-reactive protein, and white cell counts in individuals with FEP compared with controls. Means and variances were extracted and analysed using multivariate meta-analysis of mean and variability of differences. Outcomes were: 1) variability in patients relative to controls, indexed by variability ratio (VR) and coefficient of variation ratio (CVR); 2) mean differences indexed by Hedges g; 3) Modal-distribution of raw immune-parameter data using Hartigan’s unimodality dip test. 35 studies reporting on 1263 patients and 1470 controls were included. Variability of interleukin-6 (IL6) (VR:0.19), tumour necrosis factor−α (TNFα)(VR:0.36), interleukin-1β (VR:0.35), interleukin-4 (VR:0.55), and interleukin-8 (VR:0.28) was reduced in patients. Results persisted for IL6 and IL8 after mean-scaling. 94% and 100% of raw data were unimodally distributed in psychosis and controls respectively. Mean levels of IL6 (g=0.62), TNFα (g=0.56), interferon-γ (IFNγ) (g=0.32), transforming growth factor- β (g=0.53), and interleukin-17 (IL17) (g=0.48) were elevated. Sensitivity analyses indicated this is unlikely explained by confounders for IL6, IFN γ, and IL17. Chapter 5 describes a cardiac MRI study which set out, as its primary objective, to examine for evidence of inflammation/fibrosis within the hearts of patients with schizophrenia. 31 participants (14 patients and 17 controls) underwent cardiac MRI assessing myocardial markers of fibrosis/inflammation, indexed by native myocardial T1 time, and cardiac structure (left ventricular (LV) mass) and function (left/right ventricular end-diastolic and end-systolic volumes, stroke volumes, and ejection fractions). Participants were physically fit, and matched for age, gender, smoking, blood pressure, BMI, HbA1c, ethnicity, and physical activity. Compared with controls, native myocardial T1 was significantly longer in patients with schizophrenia (effect size, d=0.89; p=0.02). Patients had significantly lower LV mass, and lower left/right ventricular end-diastolic and stroke volumes (effect sizes, d=0.86-1.08; all p-values <0.05). There were no significant differences in left/right end-systolic volumes and ejection fractions between groups (p > 0.05). Chapter 6 considers whether psychosis should be considered a multisystem disorder. First, a systematic meta-review of Pubmed was conducted to summarize effect sizes for both CNS (focusing on brain structural, neurophysiological, and neurochemical parameters) and non-CNS dysfunction (focusing on immune, cardiometabolic, and hypothalamic-pituitary-adrenal (HPA) systems) in FEP to determine summary effect sizes for each organ system individually. Case control data was extracted for 165 studies making up these meta-analyses, comprising a total sample size of 13,440. Conclusions: Chapter 7 considers the outcomes of the preceding 5 chapters. Specific conclusions are as follows: 1) Glucose homeostasis is altered from psychosis onset and in the absence of antipsychotic treatment, indicating that patients are at increased risk of diabetes mellitus; 2) Total and LDL cholesterol levels are reduced in FEP, indicating that high rates of hypercholesterolemia in patients with chronic schizophrenia is secondary and potentially modifiable. In contrast, triglycerides are elevated in FEP. Hypertriglyceridaemia is a feature of type 2 diabetes mellitus, therefore this finding adds to an increasing evidence base of glucose dysregulation in this cohort; 3) Elevated blood cytokines are observed in psychosis after accounting for confounds, supporting the theory that the condition is pro-inflammatory, however the hypothesis of an immune-subgroup in psychosis is not supported by analyses of variability or modal distribution; 4) Cardiac imaging outcomes suggest a diffuse fibro-inflammatory myocardial process in patients that is independent of established CVD-risk factors and could contribute to the excess cardiovascular mortality associated with schizophrenia; 5) Alterations in non-CNS systems in FEP are broadly similar in magnitude to a range of CNS alterations, which could be interpreted as psychosis representing a multi-system disorder. Chapter 7 also considers if immune and cardiometabolic alterations seen in psychotic illness can be explained by a single pathoaetiological model. This draws on evidence from the field of rheumatology where systemic pro-inflammatory conditions are associated with insulin resistance, paradoxical reductions in cholesterol levels, and cardiac fibrosis. Future directions are also considered, including the need to define if cardiac alterations are the effect of antipsychotic treatment or are intrinsic to schizophrenia, and if early intervention for management of glucose dysregulation in FEP is warranted.