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.
Public Health Relevance Statement: 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.
Project Terms: Adult; Affect; Amino Acids; analog; Anesthetics; Animal Model; antidepressant effect; Antidepressive Agents; Anxiety; aspartate receptor; Atrophic; Attention; base; Behavioral; Behavioral Paradigm; beta-Alanine; Biological Markers; Bipolar Disorder; Brain region; Brain-Derived Neurotrophic Factor; Calmodulin; Chronic; Cognition; Cognitive; conditioning; conventional therapy; Data; Dendritic Spines; depression model; depressive behavior; depressive symptoms; design; Development; disability; Discrimination; Disease; Dose; Down-Regulation; Engineering; Enhancers; executive function; Family; fear memory; Feasibility Studies; Female; field study; flexibility; forced swim test; Functional disorder; Goals; Half-Life; heart damage; Hippocampus (Brain); Hour; Human; Immunoblot Analysis; Impairment; Infusion procedures; Injections; Intravenous; Ketamine; Lactams; Lead; Learning; Legal patent; life time cost; liver injury; Long-Term Depression; Long-Term Effects; Long-Term Potentiation; Major Depressive Disorder; male; Measures; Memory impairment; Mental Depression; Modeling; Mood Disorders; Morphology; Motor Activity; mouse model; Mus; Neurons; neurotrophic factor; Neurotrophic Tyrosine Kinase Receptor Type 2; novel; novel strategies; novel therapeutics; Nucleus Accumbens; off-patent; optimal treatments; Pathway interactions; Patients; Peptide Hydrolases; peptidomimetics; Periodicity; Permeability; Pharmaceutical Preparations; Phase; Phenotype; Phospho-Specific Antibodies; Phosphotransferases; Population; preclinical efficacy; preference; Prefrontal Cortex; Property; Receptor Signaling; renal damage; Resistance; Safety; Side; Signal Pathway; Signal Transduction; social defeat; Specificity; stability testing; Stress; Structure; Study models; subcutaneous; Sucrose; Synaptic plasticity; System; Tail Suspension; Testing; Therapeutic; Therapeutic Effect; Toxic effect; treatment effect; Treatment Efficacy; Treatment Protocols; treatment-resistant depression; Vertebral column; web site
