Speaker 3: Maura Furey, USA

Background: Conventional antidepressant therapy has remained virtually unchanged for the past 50 years. The discovery of the rapid and potent antidepressant effects of the NMDA receptor antagonist ketamine has kindled interest in pursuing new and novel mechanisms for the treatment of depression. The cholinergic neurotransmitter system is implicated in affective illness, whereby a cholinergic agonist rapidly produces depressive symptoms in currently manic bipolar patients and worsens depressive symptoms in unipolar patients. Here studies evaluating the antidepressant effects of the anticholinergic, scopolamine, and potential biomarkers of response will be discussed. Methods: Currently unmedicated unipolar and bipolar patients participated in double-blind, placebo-controlled, crossover infusion studies using scopolamine (4mg/kg). Prior to each infusion patients completed the Profile of Mood State (POMS) and Visual Analog Scales (VAS) self-rating scales, and were assessed clinically using the Montgomery-Asberg Depression Rating Scale (MADRS). Following a single-blind placebo lead-in session, patients participated in a functional magnetic resonance imaging (fMRI) study while they performed a face-identity and face-emotion working memory task. Clinical efficacy was assessed by measuring change in MADRS over sessions. Biomarker analyses included: 1) baseline self-ratings were used in a discriminant function analysis to identify linear combinations of individual items that predict clinical response, and 2) whole brain task specific blood oxygen level-dependent (BOLD) signal at baseline was correlated with the magnitude of treatment response to scopolamine. Results: Clinically, patients showed a rapid and robust antidepressant response following the first administration of scopolamine that exceeded the placebo response. The discriminant analysis based on baseline self-ratings separated responders from non-responders in both the unipolar and bipolar diagnostic subgroups. Baseline BOLD response in the bilateral middle occipital cortex, selectively during the emotion working memory task, correlated with the magnitude of treatment response. Conclusion: These results indicate that antimuscarinic action by scopolamine produces rapid antidepressant effects, and that both clinical ratings and BOLD signal measured prior to treatment may predict clinical outcome. These findings implicate cholinergic and visual processing dysfunction in the pathophysiology of MDD, and suggest that both patient self-ratings and neural activity in the visual cortex may provide useful biomarkers for the identification of patients who will respond favorably to scopolamine.