ABSTRACT 1. Introduction: For a significant number of patients with depression, current antidepressants – such as selective-serotonin uptake inhibitors (SSRIs) - are ineffective. However, evidence from animal models suggests that 5HT4 agonism may be able to effectively augment SSRI treatment. To explore the potential antidepressant augmentation effect of PF-04995274 - a novel, highly-selective 5-HT4 receptor partial agonist developed by Pfizer – we will use an experimental medicine model developed by our group. Our previous work has found that citalopram – an SSRI – produces early changes in emotional processing which are critical to subsequent clinical outcomes. Therefore, we will assess whether 7 day administration of PF-04995274 (in addition to ongoing SSRI treatment) produces similar changes; results indicating antidepressant-like effects, expressed as an increase in accurate perception and memory of positive versus negative stimuli, would support future assessment of 5HT4 agonists for treatment of resistant-depression. 2. Methods: Depressed patients, who have failed to respond to current SSRI treatment, will be randomized (double-blind) to PF-04995274 (15mg) or placebo, for 7 days.