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Objectives To determine 1) mortality and morbidity in people with bipolar disorder, and 2) the impact of maintenance medication on relapse/reoccurrence and adverse events. Methods Objective 1: I conducted a meta-analysis of studies examining mortality in bipolar disorder populations. I then carried out a cohort study in United Kingdom primary care electronic health records to understand rates of mortality and morbidity in bipolar disorder relative to the general population. Objective 2: I completed a network meta-analysis of the efficacy of maintenance mood stabiliser medications (lithium, valproate, olanzapine and quetiapine) in preventing relapse. I then carried out a series of cohort studies in primary care electronic health records. These studies examined 1) the effectiveness and tolerability of these medications, 2) the rates of renal, endocrine, hepatic and metabolic adverse events, and 3) the rates of self-harm, accidental injury and suicide. Propensity score methods were used to address issues of confounding. Results Objective 1: All-cause and cause specific mortality was elevated in people with bipolar disorder (summary standardised mortality ratio 2.05; 95% CI 1.89 to 2.23). In a cohort of 17,341 with bipolar disorder, mortality rates increased from the mid-2000s relative to the general population (hazard ratio increased by 0.14 per year; 95% CI 0.10 to 0.19). Objective 2: Trials comparing lithium, valproate, olanzapine, quetiapine and placebo did not show superiority of one drug. In the electronic health records cohort studies individuals prescribed lithium went for longer before treatment failure (for example valproate had hazard ratio 1.20; 95% CI 1.10 to 1.32 compared with lithium), had increased mild (but not severe) renal failure (hazard ratio for valproate: 0.56; 95% CI 0.45 to 0.69 compared with lithium), hypo- and hyperthyroidism and hypercalcemia rates. However, they had lower rates of clinically significant weight gain (hazard ratio for >15% weight gain with valproate: 1.62; 95% CI 1.31 to 2.01 compared with lithium) and there was no difference in hepatotoxicity, cardiovascular events or diabetes mellitus rates. Additionally, people taking lithium had lower self-harm (hazard ratio for alternatives: 1.51; 95% CI 1.21 to 1.88 compared to lithium) and accidental injury rates. Conclusions Bipolar disorder is associated with increased mortality and morbidity, and the mortality gap with the general population has widened in recent years. Despite limited trial evidence, lithium appears to offer the best opportunity for mood stabilisation. Lithium is associated with increased renal and endocrine dysfunction, but these risks are offset by the potential of more frequent weight gain with alternative drugs. Furthermore, lithium may be associated with specific anti-suicidal effects. These risk and benefits should be considered when individual treatment decisions are made.

Cardiovascular disease (CVD) is the leading cause of death amongst people with severe mental illness (SMI) and drives substantial portion of the 15-20 year deficit in life expectancy experienced by this group relative to the general population. Statins form a core part of CVD prevention in the general population, but the evidence-base for people with SMI is unclear. Evidence on the effectiveness of statins for primary prevention of CVD was systematically searched but did not identify any studies investigating CVD events or associated mortality in people with SMI; therefore highlighting the need for studies on the long term impacts of statin prescribing. Two analytical studies were undertaken using longitudinal data from The Health Improvement Network (THIN) primary care database to investigate: 1) CVD screening and statin prescribing in people with and without SMI and 2) to explore the effectiveness of statins for CVD prevention in individuals with SMI. Collectively the work has established that CVD screening and statin prescribing is increasingly accessed by individuals with SMI at levels that are comparable to people without similar mental health conditions. The results from this study provide the first evidence that statin prescribing to people with SMI is associated with statistically significant reductions in total cholesterol (of 1.2mmol/L for up to 2 years, p < 0.001). There were small non-significant reductions in the rate of combined MI and stroke (0.89; 95% CI; 0.68-1.15) and all-cause mortality 0.89 (95% CI; 0.78, 1.02). This study provides evidence that statin prescribing to people with SMI may have a magnitude of effectiveness that is broadly similar to the general population.

Introduction: Provision of support for people bereaved by suicide has become a key priority for suicide prevention strategies in many developed countries. Few studies have measured whether suicide bereavement increases risk of suicidal behaviour compared with bereaved controls. Methods: I sampled 659,572 staff and students at 37 UK higher education institutions in 2010. Via mass email, I invited adults who had experienced a sudden bereavement to complete an online survey measuring post-bereavement suicidal ideation and attempts, and other psychosocial outcomes. Inclusion criteria were: current age 18-40 years, and sudden bereavement of a close contact since the age of 10 years. Multivariable regression was used to compare those bereaved by suicide to two reference categories: those bereaved by natural causes and those bereaved by unnatural causes. Results: Of 3,432 eligible respondents, 614 adults were bereaved by suicide, 712 by sudden unnatural causes of death, and 2,106 by sudden natural causes. Compared with adults bereaved by natural causes, adults bereaved by suicide had a similar risk of suicidal thoughts, poor social functioning, non-suicidal self-harm and incicdent depression, but a significantly increased risk of suicide attempts (AOR=1.65; 95% CI=1.12-2.42; p=0.01), drop-out from work or education, and subjective stigma. Compared with adults bereaved by unnatural causes, adults bereaved by suicide had a similar risk of all the above outcomes, except for an increased risk of poor social functioning and subjective stigma. For all the associations identified, risks were elevated in both relatives and non-relatives. Discussion: My findings suggest that there are some risk similarities in suicidality between young adults exposed to suicide bereavement and those exposed to other violent bereavements. Implications: The needs of young adults in the UK bereaved by unnatural deaths may also need consideration in suicide prevention policy.

Background: Cannabis use amongst those with first episode psychosis (FEP) is prevalent and associated with negative outcomes. However, a move to cannabis abstinence amongst problematic cannabis users from this group is not uncommon. The aim of this thesis was to improve understanding of the factors influencing achievement of cannabis abstinence in FEP assuming the findings would assist in the development of more effective treatments for persistent cannabis users. Methods: Three pieces of research were undertaken to meet the aims of the thesis including: (i) a systematic narrative synthesis of the cannabis abstinence literature; (ii) a qualitative study with a sample of former problematic cannabis users with FEP investigating participant’s views of factors that contributed to their cannabis abstinence and their recommendations for treatment for persistent users and; (iii) a quantitative study of the influence of cannabis using contacts and conflict in social networks on cannabis abstinence. Results: Methodological weaknesses challenged efforts to develop a cohesive synthesis of existing cannabis research. Within the research, health concern is the most frequently endorsed factor underpinning the shift to cannabis abstinence followed by maturational factors incorporating role transitions and changing experiences and expectations of cannabis use. Similar factors were highlighted in the qualitative interviews though fell into chronological order with the initial health crisis of a first episode of psychosis or another keystone life event inducing a re-appraisal of future cannabis use. Thereafter, internal and external factors including aversive treatment experiences and social networks seemingly facilitate the successful achievement and maintenance of cannabis abstinence. Discussion: Opportunities to secure abstinence amongst problematic cannabis users are evident amidst the crisis of a first episode of psychosis. Timely intervention early in the course of psychotic illness with a broad, recovery orientated focus that includes input to social networks may improve the likelihood of sustained abstinence.