Atypical antipsychotic-induced weight gain is a significant impediment in the treatment of schizophrenia. The primary aim of the empirical work presented in this thesis, is to develop a rodent model of atypical antipsychotic-induced hyperphagia and weight gain, in order to investigate the behavioural and neurochemical mechanisms underlying these drug-ettects on humans.

This thesis described the development of a pragmatic, randomized clinical trial evaluating the safety and efficacy of antipsychotic treatment in schizophrenia. In the perspective of highlighting some critical issues of the trial design, the thesis focused on the trial's planning and conduct and on the preliminary analysis of the first followed-up subjects. Having experienced significant problems in patient recruitment a survey on perceived inclusion barriers and antipsychotic preference was performed. Investigators mainly complained about system-related barriers, and believed in the superiority of second-generation antipsychotics. Taking the cue from these results, strategies were adopted in order to reach the planned target of 800 subjects. Remedial actions included study promotion activities, education initiatives and bursaries, and resulted in a significant improvement of the recruitment rate. Nevertheless, we had to reduce the sample to one third of the original size. The second part of the thesis focused on the concept of end points using a secondary analysis of existing data and a preliminary analysis of GiSAS trial data. The assumption that differences in discontinuation rates reflect differences in effectiveness was reinforced by the results of a pharmaco-epidemiological study comparing the use of reboxetine and SSRIs in a large population sample. The established lack of efficacy of this antidepressant was mirrored by a higher proportion of treatment discontinuations. We explored the baseline characteristics of 114 included subjects and compared the baseline and follow-up variables between those who discontinued study drugs at follow-up and those who did not. Discontinuers' worse outcome was mainly attributable to self reported side-effects. This thesis highlighted some critical issues on the execution of a pragmatic trial in schizophrenia. The feasibility of the trial design and the concept of endpoints were critically analyzed. The trial mechanism is now fully functional and most problems of its implementation have been identified and contained.

Objective: This study aimed to provide a preliminary investigation of the mediators of change in an Acceptance and Commitment Therapy (ACT) intervention for people distressed by hearing voices. According to ACT it is the relationship one has to their unwanted experiences that impacts upon distress and valued living. The cognitive mediation model proposes that it is beliefs about the voice/s and the self that is causally related to distress and diminished life circumstances. Consequently, Cognitive Therapy (CT) aims to alter such beliefs. This study investigates the shared and distinct mediators of change in these two models. Design: Following a four-week baseline four participants who were distressed by hearing voices engaged in a 12-week ACT intervention. ACT and CT- process measures were completed at every session. Outcome measures were completed at the end of each phase. A qualitative Change Interview was conducted at the end of the intervention. Results: Two of the four participants responded to the intervention. They demonstrated reliable changes on measures of general psychological flexibility, psychological flexibility in relation to hearing voices, and in beliefs about voice omnipotence. No meaningful changes were demonstrated on a measure of positive and negative self-beliefs. Changes appeared to occur during the Acceptance phase of the therapy. Conclusions: This study provided further support for ACT as a promising intervention for people distressed by hearing voices. ACT appears to impact upon psychological flexibility, as hypothesized, as well as the content of beliefs about voices, possibly through the development of meta-cognitive awareness. Tentative findings suggest that changes may occur following the introduction of acceptance and mindfulness based techniques. In addition, findings suggest clients presenting with significant interpersonal difficulties may not benefit from ACT or may require a longer-intervention. Clinical implications and suggestions for future research are discussed.

Background: Clozapine, the treatment of choice in treatment-resistant schizophrenia, is not effective in up to half of patients. Aims of this thesis were: to verify whether clozapine augmentation with amisulpride, an atypical antipsychotic with preferential affinity at doparninergic D2-like receptors, is clinically effective; to test the prediction that changes in D2-like receptor availability might explain that improvement; to explore clinical and receptor availability characteristics of good clozapine responders. Methods: Study 1: Thirty-three patients with schizophrenia, partially or non-responsive to clozapine, had augmentation with amisulpride using an open label design. Study 2: Ten patients recruited from study 1 underwent 123I_IBZM SPET scans at baseline and after 10-12 weeks on amisulpride augmentation, to assess striatal D2-like receptor binding potential. Ten matched controls had one 123I-IBZM scan. Scanning was carried out using a Picker Prism 3000XP triple headed SPET camera. Study 3: Ten "good" responders to clozapine monotherapy were matched to patients in study 2 and had one 123I-IBZM scan. Results: Study 1: Twenty-eight subjects (85%) completed 6 months' augmentation. There was a statistically significant improvement from baseline in clinical rating scales and no change in side-effects. 71% and 32% of patients showed a 20% and 50% reduction in BPRS respectively. Study 2: Patients had mean striatal D2-like receptor occupancy of 47% at baseline, which increased with amisulpride augmentation to 59%. Study 3: Clozapine responders were on much lower doses of clozapine (331 mg/day) with lower s-clozapine levels (0.26 ng/L). Their D2-like occupancy was 45%. Conclusion: The augmentation led to substantial improvement in both positive and negative symptoms and was well tolerated. It raised D2-like binding to likely "threshold levels" for response. Some patients require both the broad receptor occupancy profile of clozapine and a higher degree of D2-like receptor occupancy than can be provided by clozapine alone.

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