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Treatment of individuals at clinical high risk for psychosis

Student thesis: Doctoral ThesisDoctor of Philosophy

People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that includes attenuated positive psychotic symptoms and impairments of social/emotional functioning. The CHR-P state is associated with a 20% risk of developing psychosis over a two-year period. However, treatment options remain limited—no licensed pharmacological therapies are currently available, and the comparative efficacy of the available treatments remains unknown. The purpose of this PhD was to address aspects of these outstanding issues in two distinct but complementary ways. 

Part 1 of this thesis provides an evidence synthesis of the CHR-P treatment literature. Following a qualitative introductory review, I used systematic review and network meta-analyses to compare and summarise the relative efficacy and acceptability of current treatments for (a) preventing transition to psychosis from a CHR-P state [Paper 1], and (b) reducing attenuated positive psychotic symptoms [Paper 2]. The results of Papers 1 and 2 indicated that, to date, there is a lack of evidence that any specific intervention is particularly effective over any others in preventing transition to psychosis from a CHR-P state or in reducing attenuated positive psychotic symptoms. These results also suggest a need to identify potential novel therapeutics that may better target the pathophysiological mechanisms underlying psychosis onset and that may thereby alter the course of the disorder. 

Part 2 of this thesis sought to examine the neurophysiological basis for the effects of a potential novel treatment strategy, the neuropeptide oxytocin, in an intranasal oxytocin vs placebo acute challenge study using magnetic resonance imaging. Part 2 starts with the rationale for selecting oxytocin from the numerous candidate compounds indicated for those at CHR-P, followed by a discussion of the oxytocinergic system and its links to psychosis and the CHR-P state. I then present two experiments that tested whether oxytocin modulated (a) resting cerebral perfusion using arterial spin labelling, with a particular focus on the hippocampus [Paper 3], and (b) neurochemical metabolite levels (particularly glutamate, and glutamate plus glutamine, Glx) in the hippocampus, thalamus, and anterior cingulate cortex, as measured using proton magnetic resonance spectroscopy [Paper 4]. The results of the two neuroimaging experiments suggested that oxytocin can modulate hippocampal perfusion in CHR-P individuals [Paper 3]— which is a key pathophysiological mechanism strongly implicated in psychosis onset— but does not appear to have effects on glutamate or Glx concentrations in the hippocampus, thalamus, or anterior cingulate cortex [Paper 4]. However, based on the hippocampal perfusion findings alone, oxytocin merits further investigation as a candidate novel treatment for this group. 

Part 3 of this thesis extends the discussion of the findings from Part 1 and Part 2. Here, I use the results of the evidence syntheses and wider literature to highlight a number of critical challenges, and proposed solutions, for future CHR-P treatment research. I then place the experimental oxytocin findings in the context of CHR-P pathophysiology, before bringing together the two distinct methodological approaches (evidence synthesis and experimental medicine) to show how both—combined—could facilitate a new era of improved interventional research in the CHR-P field.
Original languageEnglish
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Award date1 Jul 2019

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