Depression is a major psychological and neurobiological disorder in society, with a set of diversified symptoms and a complex pathophysiology. Understanding the causes and mechanisms of depression represents a major research challenge, due to the involvement of complex neural circuitry, various neurotransmitters, hormones, intracellular pathways and genetic factors. Neurobiologically realistic computational models allow us to integrate various available data types in a systemic way, account for underlying neural mechanisms, and make predictions of yet to be discovered biological parameters. This thesis focuses on the interaction of the monoaminergic and orexin/hypocretin systems, as for many years monoamines (serotonin and norepinephrine), and more recently, orexin, have been implicated in the etiology of depression. In particular, a major emphasis is on orexin-monoamine interactions. To assist in understanding the functional connectivity of monoaminergic and orexin systems, the work in this thesis develops and studies biologically based computational models at different levels of complexity .. Initially, hybrid firing-rate type models are presented. The simulation results show that baseline values found in different studies can coexist. Moreover, the influence of orexin's extracellular concentration dynamics has been explored in the circuitry, and correlations between the neuromodulator levels and neural firing activities are predicted. The influence of specific drugs (selective serotonin reuptake inhibitor antidepressants, orexin antagonist) has also been simulated in the neural circuit models. These studies are then followed by the development of a more detailed microcircuit model involving the orexin-serotonin system, where the direct and indirect interactions between the orexin and serotonergic neurons are investigated. In particular, autoreceptors are implemented, the local inhibitory GABAergic intemeurons are included into the model to mediate indirect interactions, and the influence of hypothesised connections and the time scales of their receptor types are studied. The model simulations demonstrate that the microcircuit is more stable if the connection from serotonin neurons to GABAergic neurons local to the orexin neurons is sufficiently strongly excitatory. It is also found that orexin receptors on local GABAergic neurons are not important to the system, and that the latter is resilient to 'knockout' of orexin neurons. Moreover, the connectivity timescales do not affect the steady state of the system but have significant influences on its transient behaviour. Finally, based on known electrophysiological properties, orexin and serotonergic spiking neuronal models are developed. More importantly, biologically realistic serotonin and orexin receptor induced currents are developed for the first time, allowing inter-neuronal interactions in a spiking neuronal network model. The model faithfully replicates the known spiking behaviour of the neurons, including the current-frequency curves. The simulation results also showed that the baseline activity and concentration levels found in different experiments can co-exist, just as in the previous more coarse-grained hybrid firing-rate model. Moreover, hypothesized model parameters of orexin concentration-vs-conductance curve (e.g. shift and slope factors) can significantly affect the network behaviour when their values are less than that of control. In addition, by simulating the 5-HTIA agonist effect, the model suggests that higher doses can lead to more synchronized slow oscillations of spiking activity among the 5-HT neuronal population. Overall, the neural circuit models developed at various levels shed light on the complex relationship between orexin and serotonergic systems, and contribute to bridging the gap between neuronal activities and behaviour.

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The aim of the study was to identify predictors of (a) successful engagement with self management for patients with depression and (b) successful outcome of treatment. A number of Key issues were highlighted, which could impact on the success of self help in primary care. These included the importance of issues of control and social functioning among patients with depression, the need to ensure that the context of primary care is viewed as a suitable location for mental health care.

Background: Social Mentality Theory has shown that dominant-to-subordinate self attacking thoughts are a key aspect of depression. These thoughts are thought to restrict access to self soothing systems in the brain. People who hear negative voices feel subordinate to them but the role of dominant self attacking has not been explored. Aim: To investigate the role of self attacking in negative voice hearing as compared to people with depression and healthy controls. Subsidiary aim: to explore the relationship between self attacking and factors associated with voice hearing. Hypotheses: It was hypothesised that negative voice hearers would engage in higher levels of self attacking than people with depression and non-psychiatric controls. It was further hypothesised that people with negative voices would engage in lower levels of reassuring thoughts as people with depression and significantly lower than healthy controls. Method: A cross-sectional 3 group design was used, comparing 16 negative voice hearers, 9 people with depression and 19 non-psychiatric controls. A parallel measure of self-attacking for voice hearing was developed. An exploratory study was conducted on relationships between the forms and functions of voice and self attacking and self compassion, beliefs about voices, and appraisals of self in relation to others and to the voice in terms of social power. Results: No significant difference was found between the Negative Voice Group and the, Depression or Healthy Control Group on measures of Self-Attacking or Self Reassuring Thoughts after depression and years of education were taken into account as covariates. Self-Attacking was found to be significantly associated with depression across groups. Exploratory analyses in the Negative Voice group revealed significant positive correlations between the Forms and Functions of Self- and Voice- Attacking with Beliefs About Voices and Distress. Persecutory Voice Attacking was significantly associated with Voice Power. Self-and Voice- Attacking were significantly negatively correlated with Self Reassurance and Self-Compassion. Conclusions: Self attacking thoughts were not found to be significantly higher in people who hear negative voices as compared to people with depression or healthy controls. Self-attacking thoughts were significantly related to depression across groups. Therefore, an alternative hypothesis that self-attacking thoughts is a transdiagnostic process implicated in depression experienced by all groups was considered. The present study was not suitably designed to test the hypothesis that a Social Rank Mentality patterns both self and voice attacks and subsequent depression and distress. Hypotheses generated from the exploratory study were that self attacking may be inversely related to self-reassurance and self-compassion in the voice hearing group. Voice-to-self relating may be significantly more hating and less reassuring than self-to-self relating. Voice-attacking may be more persecutory in perceived intention as compared to self-attacking which seemed more corrective in perceived function. If such findings are borne out by further studies, the clinical implications would be that therapy aimed at increasing a person's self-soothing capacity may be an effective treatment of distress in relation to harsh and critical voices.

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