| Summary: | Major Depressive Disorder (MDD) is a common, recurrent and disabling mental illness which is poorly treated by currently prescribed drug therapies. The discovery of treatment tools that target putative mechanisms of illness in depression is thus a clinical priority. Depression is characterised by hyporeactivity to reward and hyperactivity to aversive stimuli, which putatively reflects altered function in fronto-striatal-limbic brain regions innervated by monoamines. Yet, very few studies have used dopaminergic drugs to probe the association between neural reward- and especially penalty- signalling and depression. Such intervention designs are important for overcoming the limitations of correlational studies through randomization and experimental manipulation. Preliminary findings raise the intriguing possibility that dopamine antagonists with antidepressant properties may exert their effects via reward and/or penalty signal normalisation, however further studies are warranted. This thesis aims to address this knowledge gap by exploiting the advantages of a placebo-controlled design to examine how a novel D2 antagonist with antidepressant properties, lurasidone, modifies activity in the brain’s reward/penalty network in depression. We recruited 43 medication-naïve participants across the range of depression severity (Beck’s Depression Inventory –II score range: 0-43), including healthy volunteers, as well as people meeting full-criteria for MDD. In a double-blind placebo-controlled cross-over design, all subjects received either placebo or lurasidone (20mg) across two visits separated by one week. Functional magnetic resonance imaging (fMRI) with the Monetary Incentive Delay (MID) task assessed reward functions via neural responses during anticipation and receipt of gains and losses. The analyses focused on these two phases of reward processing as well as medication and depression effects on Prediction Error (PE), the brain’s key dopaminergic learning signal encoding the difference between reward or loss outcome and their anticipation. We hypothesised that subjects scoring high on depression would show a baseline difference in fronto-striatal activity which would be reverted by acute-dose lurasidone. Moreover, we sought to address a key concern in pharmacoimaging studies, namely that shifts in global or regional CBF could underlie changes observed in BOLD fMRI signal. We therefore also used arterial spin labelling (ASL), an imaging modality that allows the quantification of cerebral blood flow at rest, to disentangle global and regional CBF changes from BOLD fMRI signal. As such, this was the first investigation examining the acute effects of lurasidone in the human brain (across a spectrum of depression severity), on a well validated neuroimaging reward task, together with a concerted attempt to control for known potential confounds. Our findings showed that lurasidone altered fronto-striatal activity during anticipation and outcome phases of the MID task without modification of behaviour. There was a significant three-way Medication-by-Depression severity-by-Outcome interaction in the anterior cingulate cortex (ACC) after correction for multiple comparisons. Follow up analyses revealed significantly higher ACC activation to Penalty Outcomes in high- versus low depression participants in the placebo condition, with a normalisation by lurasidone. We found an opposite pattern of signal normalisation for Reward Outcomes in the ACC and Nucelus Accumbens (NAcc). Lurasidone enhanced ACC and NAcc signalling to positive feedback in depressed individuals, however, this pattern did not remain significant after stringent correction for multiple ROI comparisons. Instead, we found that lurasidone significantly increased NAcc activation in individuals with higher symptoms of anhedonia. For the PE analyses, we found support for a normalisation in reward-related PE encoding in the amygdala and penalty-related PE encoding in the ACC in one of the three PE models tested. Finally, sensitivity analyses demonstrated that comorbid anxiety symptoms, self-reported changes in sedation and state anxiety and increased striatal CBF under lurasidone did not confound lurasidone’s effects on reward and penalty processing in depression. Taken together, an acute dose of lurasidone normalises (reduces) neural ACC responses to negative outcomes and PE encoding, without modification of behaviour in individuals with elevated depressive symptoms. Lurasidone also normalises (increases) striatal (NAcc) responses to positive feedback as a function of anhedonia severity. Potential mechanisms at the receptor level are discussed with reference to activity at Dopamine D2 and Serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors. The results provide evidence for abnormalities in neural reward-penalty systems in depression and highlight the potential of targeted pharmacological treatments to normalise penalty and reward-related processing in depression. The thesis brings increased knowledge and precision to our understanding of the effects of lurasidone, during different phases of reward and penalty processing across the continuum of depression and anhedonia severity.
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