We propose a mechanistic clinical trial to identify molecular and imaging correlates of rapid action of intravenous subanesthetic dose of ketamine (KET). KET is a rapidly acting highly effective treatment for depression and frequently accompanying suicidality. However, its mechanism of rapid action remains unclear which has hindered development of methods to monitor its effects and development of new medications with similar efficacy but more favorable side-effects profile. A basic science bottom-up approach for identification and development of novel drug agents has a high degree of uncertainty. Therefore, a reverse translational approach that first identifies drug targets in humans holds promise. Our clinical translational program has developed a method to integrate drug related molecular, brain imaging and clinical changes in patients to identify novel drug targets for psychiatric illnesses. We have successfully used this method in vivo to characterize mechanism of action of lithium - a gold standard drug for bipolar disorder. In this application, we propose to apply the method to KET's mechanism of rapid action in the treatment of depression. Clinical efficacy of KET in depression and its complex effects on multiple brain physiological functions may be best deciphered using a network properties-metric approach. This approach is critical because it provides insight into the function of complex brain networks (e.g., graph theory metrics provide summary measures of whole-brain and local network properties), which is more likely to be closely linked to complex brain behavioral states such as depression. Furthermore, the relationship between neuroimaging effects of ketamine and its molecular effects in humans has been even less studied. This proposal addresses these important gaps in knowledge. We will study 90 depressed subjects (medication-free for 2 weeks) at baseline and after 3 alternate-day ketamine treatments. Thirty healthy controls will also be studies at two points but will not receive treatment. Subjects will undergo a structural scan, resting state functional magnetic resonance imaging (fMRI) and Diffusion Weighted Imaging (DWI) scans at baseline and at the two time-points. In addition to imaging, using an innovative approach, we will also collect living neurons from olfactory epithelium using a soft nasal brushing procedure to conduct molecular and gene expression analysis. We will acquire imaging on a state-of-the-art 7-T scanner and apply cutting-edge brain network properties analyses and correlate with molecular changes as well as changes in depression scores. We will conduct a mediation analysis to identify specific molecular/gene expression alterations which cause connectome changes which in turn lead to rapid antidepressant and antisucidal effects. This study will therefore provide unique data regarding imaging and molecular correlates of rapid antidepressant action of ketamine. In addition, this mechanistic clinical trial will provide a new paradigm for treatment monitoring and drug development of novel rapidly acting antidepressant therapeutic agents.
