Major depressive disorder is a debilitating mood disorder that affects ~7% of US adults in their lifetime, costing the U.S. economy more than $200 billion a year. Drugs that increase monoaminergic signaling are the mainstay of depression therapy, but have a delayed onset of action and are only effective in about 50% of affected patients. Aberrant brain-derived neurotrophic factor (BDNF) signaling has been proposed to underlie the pathophysiology of major depressive disorder and Bipolar disorder. We have developed a novel family of cyclic peptidomimetic compounds that potentiate the BDNF pathways to produce rapid (within hours) antidepressant effects. Here, we propose a Phase I proof-of- concept and feasibility study for the use of our patented new drug, CN2097, for treating depression. There are three major goals that focus on preclinical efficacy. Aim 1 will test the stability of CN2097 analogues and evaluate toxicity. Aim 2 will evaluate the rapid and long-term effects of treatment with CN2097 in mitigating depressive behaviors using two extensively validated models: Chronic mild stress (CMS) and Chronic social defeat stress (CSDS). Aim 3 will examine the ability of CN2097 to correct impairments in the cellular mechanisms of depression that include signaling, neuronal atrophy and synaptic plasticity.

Major Depressive Disorder affects over 16 million of the US population and represents a major cause of disability worldwide. We have engineered a unique drug exerting rapid therapeutic effects on depression pathways. Here, we propose a Phase I proof-of-concept and feasibility study for the use of our patented new drug, CN2097, for treating depression. Results of this study will point to novel therapeutic treatment for this devastating disorder.