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Major depressive disorder is associated with dysfunctional motivation, reward and cognitive processing. A clinical feature of depression is low motivation but it remains unclear whether this reflects a fundamental impairment in basic incentive motivation or a higher level deficit in integrating cognitive and emotional information in complex situations. The focus of this thesis was to investigate the behavioural and neural bases underlying the processing of reward-related and motivational processes in major depression; in particular, the influence of variable reward magnitudes on incentive motivation and the interaction between information processing and response to reinforcement.

The upregulation of alpha 7 nicotinic acetylcholine receptors (α7 nAChRs) are putatively reported to play a role in in vivo cortical spreading depression-elicited neuroprotection. In this study, a reliable in vitro spreading depression model was created for studying this phenomenon. In contradiction to previous studies, it was, however, shown that functional α 7 nAChRs are down-regulated upon chronic depolarisation with KCl, although the activity of this receptor subtype remained essential for the preconditioning mechanism. Evidence was provided for a differential mechanism underlying protection against NMDA-mediated and hypotonic-shock induced cell loss. Non-pharmacological upregulation of the α 7 nAChRs in pure neuronal cortical cultures by means of a recombinant adenovirus led to the increased cell death subsequent to an excitotoxic glutamate insult. In addition, in order to study the relationship between α7 nAChRs and its function-dependent regulator Ric3, a novel anti-Ric3 antibody and a recombinant adenovirus expressing the ric3 gene were created. Ric3 was found to be expressed in many important brain structures, including hippocampus, perhinal cortex, thalamic and hypothalamic paraventricular nucleus, structures implicated in both cognitive and emotional behaviours. Interestingly, Ric3 was also expressed in the choroid plexus, a non-neuronal cell type not known to α 7 nAChRs, indicating additional roles for this protein. The recombinant constructs expressing ric3, α 7 nAChRs and dual ric3/ α 7 nAChRs were all validated in vitro.

The thesis comprises of three sections relating to ethnic discrimination and depression. The first is a literature review on the relationship between discrimination and depression in Black and minority ethnic (BME) communities. The second is a research report, which considers the utility of the concepts of external shame and belongingness in explaining the relationship between ethnic discrimination and depression. The third is a critical reflection on the process of the research. Literature review: The review found evidence of a cross-sectional association between discrimination and depression, but there was a lack of methodologically robust prospective studies. Subtle forms of discrimination were found to be as important as blatant forms. Ethnic identity was found to be a generally protective factor in the relationship between discrimination and depression. The process of perceiving discrimination was found to be complex and related to ethnic identity. The utility of considering depression in terms of positive and negative affect was recommended. Research Report: This section reports on a cross-sectional study that used self-report measures. The study sampled White British (WB) and BME students. The results supported a social ranking model of the relationship between discrimination and mood. External shame was found to mediate the relationship between ethnic discrimination and negative affect for the BME and WB groups and with positive affect for the BME group. The BME group was found to report a greater frequency of ethnic discrimination than the WB group. Ethnic discrimination had a greater psychological effect on the BME group than the WB. The results did not support belongingness to ethnic community mediating the relationship between discrimination and mood for either group.

Recent findings indicating higher than expected levels of psychopathology amongst British South Asian women over the last decade provided a rationale to investigate the links between acculturation/cultural identity and psychological distress (specifically depression) and the experience of shame. Ninety British South Asian women were drawn from the general population of five culturally diverse cities in the UK and completed measures of acculturation/cultural identity (AIRS-B), psychological distress (GHQ-28) and shame (ESS). Hypotheses and explanations generated in the previous literature to account for the high incidence of mental health problems among British South Asian women were critically examined to assess their usefulness in understanding the cultural factors implicated in the causation of psychological distress. Theoretical and empirical links between the constructs were discussed in relation to evolutionary models of shame (Gilbert, 1997, Lewis, 1987) and Berry's (1980, 1997) bi-dimensional model was applied to the two-way interaction process between minority and majority cultures to determine the psychological adaptation of individuals living in a bi-cultural context. Results indicated that acculturation strategy and level of cultural identity were related to psychological distress and depression but these relationships were mediated by the intervening mechanism of shame. Full or partial identification with South Asian culture was related to higher levels of shame and the vulnerability to experience shame (shame prone-ness) was associated with psychological distress, specifically depression. A preliminary model of possible relations between the different psychological constructs was developed from the findings of the study. The relations between acculturation/cultural identity and shame illuminated the complex processes involved in shaping an individual's sense of self and provided a tentative understanding of the dynamics involved in the development of psychological distress for British South Asian women.

'Cognitive inflexibility', evidenced by impaired set-shifting and inhibitory control, is a well established feature of acute depression. The extent to which inflexibility is a 'state' characteristic, present only during active depression, or an underlying 'trait' vulnerability that precedes the disorder's emergence and increases risk of onset, relapse and recurrence, is however uncertain. Clarification of its status as a potential risk marker is an important research and clinical objective in the development of early detection, intervention and prevention strategies. The first paper is a systematic methodological review of recent studies investigating set-shifting and inhibitory control in remitted depression and at-risk samples. While some studies report deficits in remission and in at-risk twins, the findings overall are inconsistent and are confounded by methodological limitations in terms of neuropsychological test administration and sample matching and heterogeneity. Given the paucity of at-risk investigations, the findings do not provide a convincing body of support for either 'cognitive scars' that persist in remission, or underlying vulnerabilities, nor do they clarify the state-trait debate. Further research in at-risk populations is recommended, but methodologically improved and more consistent study design and test selection is essential. The second paper investigated whether cognitive inflexibility and attentional bias for negatively valenced information, as candidate disorder risk factors, might be observed in never depressed 16-20 year old offspring at genetic risk of depression, but not controls. No differences between groups were observed in terms of set-shifting or inhibition of prepotent responding in relation to neutral stimuli, or of biased attentional orientation. Evidence was, however, observed of inefficient inhibitory control of attention and responses to negatively valenced stimuli in at risk participants, consistent with the possibility that deficits in affective inhibitory control are vulnerability candidates. Implications of the findings, together with study limitations and recommendations for future research are considered.

There have been few investigations of the goals of depressed individuals despite the well-documented effects of depression on motivation. This study focused on two aspects of goals in particular, approach and avoidance motivation, and self- concordance. The aim was to find out whether, in line with neurobiological theories of depression (F owles, 1988,1994), decreased approach motivation and increased avoidance motivation would be evident. A secondary aim was to investigate whether the goals of depressed individuals would be less self-concordant than non-depressed individuals. A depressed (n=26) group was recruited from Primary Care and Mental Health Trust sites, and compared with a non-depressed (n=33) group recruited from the community. Participants listed approach and avoidance goals, chose two of each and wrote down their underlying reasons for adopting these goals. They then rated their anticipated affect upon successful goal attainment and completed a measure of self-concordance for each goal. At face value, there were no differences between the groups in terms of numbers of approach and avoidance goals generated. However, when underlying reasons were examined, the expected relationships between depression, decreased approach motivation and increased avoidance motivation were found. As predicted, the goals of depressed individuals were also less self-concordant than those of non-depressed individuals. These results suggest that, although individuals with depression are engaged in pursuit of the same types and numbers of goals as non-depressed individuals, their reasons for goal pursuit are more negative in terms of avoidance motives and acting for non self-concordant reasons. 3

One approach to defining well-being - psychological well-being (PWB; Ryff, 1989) - encompasses six dimensions of positive functioning: Autonomy; Environmental Mastery; Personal Growth; Positive Relations with Others; Purpose in Life and Self-Acceptance. Previous research has not clarified the relationship between depression and the dimensions of PWB in a clinical sample. This study's first aim was to compare PWB self-report scores from a group of depressed participants with a non-depressed group. Previous studies have found that people with depression show specific deficits in anticipating future events. A second aim was to further investigate future thinking in depressed individuals by examining the well- being value of anticipated future events in terms of their expected impact on PWB dimensions. A depressed group (n=26) was recruited from a psychological therapies service and compared with a non-depressed control group (n=26) recruited from the community. Participants completed the scales of PWB (Ryff, 1989) and an adaptation of the Future Thinking Task (MacLeod, Rose & Williams, 1993) asking them to identify two events they were looking forward to and two events they were not looking forward to for each of three future time periods. Probe questions elicited what would be good (positive events) or bad (negative events) about these events. Responses were coded for the six dimensions of PWB. The depression group scored significantly lower on all self-reported dimensions of PWB than the control group, with particular deficits in Environmental Mastery and Self-Acceptance. Anticipated positive events made the greatest perceived contribution to Positive Relations with Others and anticipated negative events had the greatest perceived detrimental effect on Environmental Mastery and Positive Relations with Others. There were no significant differences between the groups on the anticipated impact of future events, suggesting that the structure of future thinking in terms of its perceived impact on' PWB is unaltered by depression.

Depressive disorders are prevalent and costly but there is a lack of evidence on how best to select treatments for mild to moderate depression in primary care. Illness beliefs have been shown to affect the outcome from physical illness, but there is limited information on the beliefs of patients who are depressed. It is not known whether beliefs influence outcome from depression and whether this is mediated through medication adherence. The Beliefs about Depression questionnaire (BDQ), based on Leventhal common sense model (CSM) of illness beliefs, was developed from existing qualitative and quantitative data. An initial 76 Item questionnaire was tested on 334 primary care patients with diagnosis of depression and principal component analysis was used to reduce the number of items. The shortened questionnaire (sBDQ) was tested for construct and criterion validity by comparison with existing measures. Test- retest reliability was carried out at two weeks and internal consistency of subscales calculated. A six month longitudinal study was carried out on a cohort of primary care patients with a new episode of depression in the previous six months. Baseline measures were completed and 224 (76%) completed follow-up questionnaires at six months. The primary outcome was the change in depression scores measured by the Hospital and Anxiety Scale - depression subscale (HAD-D). Secondary outcomes were measures of anxiety, functioning, use of medication and use of services. These latter two outcomes were measured both by participant self-report and information from the GP computer systems. Results show that beliefs at baseline contributed to the prediction of depression severity at six months measured by HAD-D or PHQ-9. Severity scores at six months were increased by initial severity but decreased in participants who believed that exercise or activity could control their depression (self-efficacy behaviour). Beliefs about medication did not influence outcome of depression but did predict medication usage. The meaning and possible implications of these findings are discussed in relation to existing literature. Faculty of Medicine Primary Care and Population Sciences Doctor of Philosophy Are patient beliefs important in determining adherence to treatment and outcome for depression? Development and testing of a brief questionnaire to measure beliefs about depression in primary care Dr Jeannette Lynch