Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly-defined neurobiological basis. Animal models with greater translational reliability and validity are essential to develop improved therapies and aid understanding of disease aetiology. This thesis utilised the well-established isolation rearing developmental disruption model of schizophrenia in the rat as the base for producing novel ‘dual-hit’ combination models of the disease, with the aim of improving disease validity and model robustness. Pharmacological insults were added to the isolation rearing model, first in the form of prenatal administration of the antimitotic agent methylazoxymethanol (MAM), and subsequently perinatal treatment with the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). The resulting ‘dual-hit’ models were assessed for behavioural and neurobiological validity to schizophrenia, and the incurred deficits challenged with the atypical antipsychotic risperidone and the putative adjunct therapy lamotrigine. Combination of isolation rearing and prenatal MAM on gestational day 17 did not produce more robust behavioural deficits than isolation rearing alone, but did cause marked reductions in hippocampal volume, akin to those observed in the clinic. Addition of perinatal PCP treatment on post-natal days seven, nine and eleven to the isolation rearing protocol produced more robust behavioural deficits, with limitations. Baseline hyperlocomotion in a novel arena in three cohorts was accompanied by an elevated locomotor response to acute PCP treatment, highlighting sensitization. Visual and spatial learning deficits were observed in the novel object discrimination task, whilst fear-motivated conditioning was impaired in a conditioned emotional response paradigm. Preattentional processing was also somewhat deficient in combination-treated animals in the prepulse inhibition of acoustic startle paradigm. Inconsistent deficits in visuo-spatial learning and cognitive flexibility were observed in a Morris water maze task. Acute treatment with the atypical antipsychotic compound risperidone at 0.5mg/kg caused marked sedation. At lower doses, pretreatment 30 mins prior to behavioural testing elevated prepulse inhibition and reversed emotional conditioning deficits, and returned baseline locomotor activity to levels similar to control. There was no effect on visual reference memory deficits. Conversely, pretreatment with the sodium-channel blocker lamotrigine reversed a deficit in visual reference memory, but had no effect on sensorimotor gating or fear-motivated conditioning. These data suggest that the combination of isolation rearing and perinatal PCP treatment to rats produces a model of schizophrenia-like symptoms that possesses some validity to the human condition, but lacks the desired robustness of a preclinical model. Further validation and improvement may allow this model to become a useful tool in on-going preclinical research.

Objectives: People who identify as transgender are reported to experience high levels of mental health problems in comparison to people who do not identify as transgender. The minority stress model has been used to explain these high prevalence rates. But this model was designed to be used in lesbian, gay and bisexual (LGB) populations (Meyer, 1995, 2003). Researchers have applied some of the hypothesised processes of the model to people who identify as transgender. However, evidence testing the minority stress model in this population is limited. The model postulates that minority stress processes (namely, distal stress, internalised stigma, vigilance and concealment) lead to adverse mental health outcomes. It also states that coping and social support moderate and ameliorate the stress processes. However research on this aspect is inconclusive, with other researchers stating that coping and social support meditate the relationship between internalised stigma and psychological distress. In light of the current literature, this research aimed to test the application of the minority stress model in a sample of people who identified as transgender. It also aimed to test the moderating and mediating roles of coping and social support. Furthermore, this research endeavoured to develop an alternative model (i.e. based on the findings and the literature). Methods: A cross-sectional design was used. Participants were recruited from transgender forums, social groups, transgender events and social media. Those who identified as transgender, under the umbrella term, were invited to complete an online survey (N = 270; mean age = 27.5). The majority of participants (60.4%) described their gender identity as trans women. Results: Multiple linear regression, mediation and moderation analyses were conducted. Results showed that, individually, all the stress processes (distal stress process, internalised stigma, vigilance and concealment) were significantly associated with psychological distress. However, when assessed in combination, only certain stress processes emerged as being significant. With internalised stigma emerging as being significant in all the regression models (i.e. depression, anxiety and stress). No moderation effects were found for coping and social support. Instead, passive coping and social support were found to partially mediate the relationship between internalised stigma and psychological distress. Structural equation modelling was also used to develop hypothesised models based on this data. Conclusion: Limited support was found for the minority stress model within this sample. Hypothesised models were developed instead, to highlight the stress processes involved in depression, anxiety and stress. However, future research is warranted to test these models.

Smoking remains a major cause of morbidity and mortality. In 2013/2014, 454,700 hospital admissions in the UK amongst persons 35 years and over were estimated to be attributable to smoking. This accounts for 4 per cent of all hospital admissions in this age group. In 2013, 17% (78,200) of all deaths in adults aged 35 and over were estimated to be caused by smoking[1]. Reducing smoking therefore, remains a major priority for governments and health systems like the UK National Health Service (NHS). Following the publication of the Government’s White Paper, Smoking Kills[2] in 1998, a comprehensive tobacco control strategy was implemented. This strategy was aimed at reducing uptake of smoking and increasing quitting among existing smokers, and involved a combination of population tobacco control interventions (such as price rises, an advertising ban and smoke-free legislation) combined with treatment for dependent smokers through the NHS. A Tobacco Control Plan for England was also produced in 2011 which explained the government’s strategy to reduce smoking through the new public health system[3]. This plan outlined commitments to implement legislation to end display of tobacco in shops, to encourage smokers to quit and remaining quit by using effective forms of support and implementing a policy of using tax to maintain the high price of tobacco. Effective forms of support may be behavioural, pharmacological or a combination of both[3]. In the UK, support is often delivered by stop smoking services (SSS), although smokers, who wish to, may obtain smoking cessation medication from their GP[4]. These SSS have been shown to be cost effective, but the majority, 85% of smokers attending the services, have relapsed by one year. The nature of nicotine addiction means that smoking is a chronic relapsing condition[5], with many smokers unable to sustain abstinence. Smoking relapse rates can be extremely high (up to 90% in the first 3 months)[6], and only 3%-5% of unsupported/untreated quitters maintain their quit attempt for 6 months or longer[7]. This high relapse rate reflects the addictive nature of cigarette smoking and underscores the importance of finding effective relapse prevention interventions for use in routine practice, which can be delivered alongside or after acute cessation has ended. There is no universally accepted definition of what interventions to prevent relapse to smoking (relapse prevention interventions - RPIs) should comprise; many smoking cessation programmes simply modify the content of existing, cessation-orientated support and deliver these as relapse prevention[8]. The paucity of information regarding provision of smoking relapse prevention is in contrast to the wide availability of evidence for the use of acute cessation treatments which has grown rapidly over recent decades. A variety of effective treatments now exist which can increase the chances of stopping smoking up to fourfold compared with no support[9], but research suggests that relapse prevention interventions and treatments are not as widely known or even used. At the time the research was conceived, there was very little information about the effectiveness of RPIs. A number of studies had investigated effectiveness of behavioural support, pharmacotherapies, and combination treatments, as forms of relapse prevention or maintenance treatment, and one Cochrane Review[8] found no evidence for the effectiveness of behavioural RPIs, but this may have been because the review combined smoking outcomes obtained at different follow-up time points after quitting and this may have obscured real effects of RPIs. The review found insufficient evidence for the effectiveness of extended treatment with bupropion and weak evidence for the effectiveness of nicotine replacement therapy for relapse prevention. There was, therefore, a need to examine current literature and synthesize data from a wide variety of studies, using a different approach from that used in the Cochrane Review to enhance interpretation of findings. In addition to ascertaining whether or not RPIs are effective, there was also a need to explore feasibility of provision within local Smoking Cessation Services. No study had explored feasibility of provision of RPIs within Stop Smoking Services, and whether these interventions would be acceptable to smokers trying to quit, mainly because the use of relapse prevention interventions in a local smoking cessation service was not only relatively new and unproven, there was also no information regarding smokers’ perceptions of relapse prevention interventions Abstinence and relapse during a quit process is still poorly understood, especially relapse after the use of a smoking cessation aid. A few studies had investigated patterns of relapse and abstinence in smokers who quit smoking unaided and two reviews[7 10] found that the majority of relapse occurred in the first two weeks of starting a quit attempt. The majority of smokers who wish to quit smoking use some form of evidence based treatment. It was therefore important to explore patterns of relapse in smokers who have attempted to quit smoking with the aid of a smoking cessation treatment. The work presented here is for the degree of PhD by publication and is based upon five publications in high quality peer reviewed journals between 2009 and 2015. I am the lead author on four of the included papers and the final and corresponding author on one paper. The research forms a coherent body of work informing the evidence base on smoking relapse prevention interventions (RPIs). This has contributed to the evidence base around four key aspects of smoking relapse prevention: knowledge, views and beliefs, effectiveness of smoking relapse prevention interventions, feasibility of delivery of RPIs within UK Stop Smoking Services, and abstinence and relapse patterns amongst smokers who quit smoking with the aid of a pharmacological smoking cessation treatment. Systematic reviews, meta-analysis, quantitative research and qualitative research were used to generate the data which supported the exploration of the four themes outlined below. Specifically, the published works have identified: • Knowledge, Understanding, Views and Beliefs: there was no shared understanding of what relapse prevention meant to Stop Smoking Service professionals or the kinds of interventions that should be used for this, but a willingness to provide such treatments was apparent. (Agboola SA, Coleman, T and McNeill, A. (2009). Relapse prevention in UK Stop Smoking Services: a qualitative study of health professionals' views and beliefs. BMC Health Services Research. 9:67 and Agboola SA, Coleman TJ, Leonardi-Bee J, McEwen A and McNeill A (2010). Provision of relapse prevention interventions in UK NHS Stop Smoking Services: a survey. BMC Health Services Research 10:214) • Effectiveness of smoking relapse prevention interventions: A pooled analysis of randomized controlled trials of nicotine replacement therapy, bupropion and varenicline showed that these interventions are effective for relapse prevention. A meta-analysis of four studies of nicotine replacement therapy found that smokers who used NRT for relapse prevention were 1.56 times more likely to remain abstinent at six months follow-up compared to placebo (95% confidence interval 1.16 to 2.11). A pooled analysis of four studies of bupropion showed evidence for effectiveness at long term follow-up (12 to 18 months) with an odds ratio of 1.49 (95% confidence interval 1.10 to 2.01). A single study of varenicline also demonstrated evidence for effectiveness for relapse prevention. (Agboola S, McNeill A, Coleman T and Leonardi-Bee, J (2010). A systematic review of the effectiveness of smoking relapse prevention interventions for abstinent smokers. / Addiction 105, 1362–1380) This was the first time that RPIs had been proven effective, and now that there appeared to be evidence of efficacy, it was appropriate to investigate feasibility of introducing these into routine clinical practice (next study). • Feasibility of delivering relapse prevention: A study investigating the feasibility, uptake and acceptability of offering nicotine replacement therapy (NRT) as a relapse prevention intervention (RPI) within UK Stop Smoking Services, showed that NRT can be added to existing treatment protocols, and that of 260 SSS clients who were eligible and offered this intervention, 44% (95% confidence interval 38% to 50%) accepted the offer. • Abstinence and relapse patterns: A pooled analysis of 19 trials of varenicline showed that varenicline recruits smokers into abstinence following the target quit date to a greater extent than placebo (point prevalence abstinence increased from 32% [95% confidence interval 25% to 40%] in week two to 54% [95% confidence interval 48% to 61%] in week 12). A higher immediate relapse rate following varenicline treatment discontinuation was also observed, which implied that there would be smokers who would benefit from a longer course of treatment.

This thesis presents an instrumental case study of a National Health Service (NHS) mental healthcare trust in relation to race related equality policy in the delivery of secondary mental healthcare in England. The study takes a constructionist ontological position, and an interpretivist epistemology. Semi-structured interviews were conducted with the 20 participants working at three different levels of the organisation. These include strategic leaders: Chief Executive Officer, Operational Director, Director of Nursing Quality and Patient Experiences, Director of Learning and Development, Head of Human Resources, Equality and Diversity Lead; service level middle managers: General Manager, Modern Matron, Team leader, Manager of the Recovery College; and frontline practitioners: clinical directors, psychiatrist, occupational therapist, staff nurses, community psychiatrist nurse, Recovery College instructor, all working in an adult mental healthcare setting of the organisation. Narrative interviews were also conducted with eight members of the Pakistani community living in the local service area to gain their perspectives on mental illnesses and mental health services. The study was conducted because national race equality policy expects NHS mental healthcare organisations to change their culture and deliver equitable, culturally appropriate and satisfactory mental health services to all members of society, including those who identify themselves as ‘BME’ groups. However, there is evidence in the policy and research literature of inequalities in mental healthcare experienced by service users who identify themselves as being from ‘BME’ groups in England. This study, therefore, explores how a NHS mental healthcare Trust is trying to bring about cultural changes in order to meet the expectations of policy as well as meeting the needs of service users of ethnic background. For example, on the organisational side, the study explored vision and strategy as well as interventions for bringing about organisational change and the views of the participants on this change. The views from the members of the Pakistani ethnic group highlight how mental illnesses are perceived and responded to within this ethnic group. Data obtained from the staff group were analysed using a thematic framework approach. Resultant themes include: interpretation of racial equality policy in the organisation; organisational vision and strategy for change; and the challenges, barriers and facilitators to achieving the stated vision on racial equality in the service provision, especially for people of Pakistani ethnic group. The analysis benefited from the organisational development literature in analysing the data. Data obtained from the members of the Pakistani community were analysed using a thematic narrative approach. This data reflected ways in which mental health/illness is perceived and responded to within this group including: the social identity claims that people of Pakistani ethnicity make when perceiving and responding to mental illnesses; the extent to which they associate themselves with western and/or eastern models of mental illnesses; and their identification as an ethnic group with diverse and multiple social identities. Social identity literature is used to analyse and interpret this data. The relationship between the organisational data and the ethnic group data is discussed, and a way forward is suggested for bringing about the expected cultural change to the organisation in order to meet the mental health needs of ‘BME’ groups in England. The instrumental organisational case study, along with perspectives of the service users, have served to underline the challenges for the organisation on a day-to-day basis as they attempt to meet the expectations of policy, as well as the views and expectations of people of Pakistani ethnicity.

Smoking is the leading avoidable cause of mortality and serious disability worldwide. The prevalence of smoking varies greatly between the 27 European Union (EU) Member States as does the implementation of tobacco control policies. The main aims of this thesis were to investigate the extent of the variation between and the reliability of measures of smoking prevalence, the relation between prevalence and tobacco control policy implementation, the country characteristics associated with policy implementation, and a detailed analysis of the association between cigarette prices and smoking prevalence.

Growing interest in the research community has been shown in clinical neuroscience to assess neurotransmitter profiling both in healthy and diseased subjects. A large body of research in this field focuses on schizophrenia to characterise its glutamatergic level according to the most recent hypothesis of NMDA (N-Methyl-D-aspartic acid) receptors hypofunction. Magnetic Resonance Spectroscopy (MRS) is able to detect some of the most common neurotransmitters but a number of issues, such as low signal to noise ratio (SNR), spectra overlapping and line broadening prevents MRS from being clinically relevant for neuropsychiatry. Four important aims were considered relevant for this work. Firstly, we aimed to compare the reliability of conventional and timing-optimized sequences for the detection and measurement of most of the visible metabolites and, in particular, for glutamate (Glu), glutamine (GIn) and gamma-aminobutyric acid (GABA) to assess the best available sequence for a study in schizophrenia. Secondly, we also intended to investigate whether glutamatergic activity might predict the oscillatory activity and how this link might survive or not in schizophrenia. Thirdly, we wanted to study whether the well known animal model of schizophrenia, the rearing in isolation model, exacerbates the effect of ketamine and determines more profound changes on neurotransmitter profile in rats. Fourthly, a further goal focuses on the improved data acquisition and on the data processing to reliably resolve GABA and to be able to quantify a wider range of metabolites. To address those points five studies were performed. The first work (Chapter 3) describes a study of reproducibility on sequences which have been reported in the literature to be capable to detect Glu and GIn. The study was performed on 14 healthy subjects by scanning them twice and repositioning between the two scans. The absolute percentage difference was then computed to assess the accuracy per sequence and metabolite. A good compromise was found in PRESS sequence (TE=80 ms) which was exploited subsequently for the following study on schizophrenic patients (Chapter 4). Twenty-seven early stage schizophrenic patients and twenty-three aged-matched controls were recruited to undergo a protocol including, in two separate sessions, MRS and electroencephalography (EEG). Anterior Cingulate Cortex Glu was found to predict the induced theta activity in healthy controls but not in patients. Furthermore, the NAA values have also been found to be reduced in schizophrenia and linked to N100, an Event Related Potential (ERP) which is well known to be decreased in schizophrenia. Following on from the findings of the study on the early stage of schizophrenia, further investigations were undertaken to study the psychotic state occurring in the disease via a functional MRS, where 25mg/kg of ketamine (NMDA antagonist) injection was administered to two groups of rats. The two groups were group-housed and reared in isolation. This work was able to show increase of prefrontal GIn levels in both groups but showed a selective GABA decrease only in isolated rats. It would have been very interesting to be able to detect GABA changes in the study at 3T but the used protocol did not allow its accurate quantification. Simulations and reliability tests (Chapter 6)were then utilized to optimize a standard sequence to obtain an accurate and reliable GABA concentration. The optimized sequence reproduces the quantification with 12% of accuracy. The preliminary results of the last study (Chapter 7) give an evidence of the potential of combined use of Monte Carlo, Levenberg-Marquardt and NNLS methods embedded in a novel fitting approach for two-dimensional spectra. The three appendices at the end of this work illustrate the details of some of the algorithms and softwares used throughout the studies.

This thesis explores the role of a large-scale brain network comprising of the insula and anterior cingulate cortex in the pathophysiology of psychosis using structural and functional neuroimaging. Primarily, anatomical changes affecting the grey matter structure and patterns of dysconnectivity involving the insula are investigated. Various meta-analytic studies have reported consistent reduction in insular grey matter across various psychotic disorders. Despite these robust observations, the role played by this brain region in the generation of psychotic symptoms remains unexplored. In this thesis, using a meta-analytic approach, the relevance of insula for the clinical expression of psychosis is highlighted. Further, significant reduction in the cortical folding of the insula was noted in patients with schizophrenia. Reduced gyrification is accompanied by reduced functional connectivity between the insula and the rest of the brain. Using an effective connectivity approach (Granger Causal Analysis), the primacy of insula in driving the dorsolateral prefrontal cortex is demonstrated in healthy controls; this relationship is significantly affected in schizophrenia amounting to aberrant connectivity within a putative salience-execution loop. Reduced primacy of the salience-execution loop relates to illness severity. It is argued that the insula, as a key region of the salience network, plays a crucial role in the generation of symptoms of psychosis. The evidence in support of this theory is discussed, together with its implications for clinical practice aimed at reducing the burden of psychosis.