Veterans Affairs

Drug candidate for PTSD and treatment resistant depression

A tobacco metabolite plus an antioxidant may provide improved treatment outcomes and lower side effects

Medical & Biotechnology

The Department of Veterans Affairs has developed a novel pharmaceutical drug therapy for treating mental health conditions. The research and intellectual property rights are available to companies for the development of new health care products through a license agreement.

A U.S. Army soldier smokes a cigarette in Vietnam. (Peter P. Ruplenas/Army)

Stress from noxious stimuli occurs when an individual is unable to cope with overwhelming physical or psychological demands. The ability to quickly change behavior and the underlying brain activity in response to threatening stimuli is crucial for survival. While acute stress can be beneficial in recruiting adaptive responses to cope with a stressful situation, prolonged stress can result in maladaptation that can be a risk factor for mental illness and both cognitive and motor deficits that further diminish the quality of life.

Therapies currently in use for stress-induced depression often do not work. The pharmacological approaches include anxiolytics, antidepressants, and antipsychotics, that have many undesired side effects.

Current evidence suggests that cotinine – an alkaloid found in tobacco – can reduce anxiety and depression in subjects with stress-induced depression. The main target of cotinine is the nicotinic acetylcholine receptors (nAChRs). ACh is the main agonist of the nAChRs, and one of the most important neurotransmitters in the central nervous system (CNS) and peripheral nervous system.

Cotinine has also been shown to increase the expression of the glial fibrillary acidic protein (GFAP) in the hippocampus and frontal cortex of mice. GFAP cells are also found in the CNS and include astrocytes. They are critical to maintaining our resilience to stress. Post-traumatic stress disorder, chronic psychological stress, and major depressive disorder have been found to associate with a significant decrease in glial fibrillary acidic protein immunoreactivity in the hippocampus of rodents.

With the above background, VA researchers are pursuing a therapeutic approach to depression and PTSD with cotinine and an antioxidant delivered intranasally. Intranasal administration of CNS drugs is acquiring increasing attention because of the therapeutic advantages in reducing the time of action of the drugs, and decreasing systemic effects.

An animal study showed that intranasal cotinine prevented stress derived symptoms and the morphological abnormalities in GFAP+ cells which are critical to resilience to stress. The treatment helps to improve cognitive abilities and dramatically decreases depressive-like behavior and anxiety. The addition of an antioxidant, in one example, Krill oil, prevents oxidative stress, lowers the deleterious effects of stress on brain function, and improves cognitive abilities.

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