Identification of Causes and Treatment for Chronic Depression in a Rodent Model of Gulf War Illness
Abstract
It is estimated that approximately 25% to 33% of the nearly 700,000 U.S. Soldiers deployed during the 1990-1991 Gulf War suffer from an unexplained chronic multi-system and multi-symptom disorder known as Gulf War Illness (GWI). A major challenge from the Gulf War Illness Research Program is to design high-impact research that will improve the health and lives of Veterans who suffer from GWI. Our research efforts are aimed at addressing these important issues by developing this project that has the potential to yield new molecular mechanisms and treatment approaches for our GWI-suffering Veterans. The most common of the debilitating GWI symptoms are neurological disorders including anxiety, depression, and memory impairments. Recent studies have shown that mood disorders including major depression, dysthymia, and anxiety are more prevalent in deployed First Gulf War Veterans, who are twice more likely to suffer from depressive symptoms than non-deployed Soldiers from the same era. The current treatment recommendation by the Institute of Medicine for GWI depression includes a combination of antidepressant medication and psychotherapy. However, treatment of depression in the general population is limited by the fact that there is a delay of weeks to months for the onset of therapeutic effects with conventional antidepressants, and many patients do not achieve sustained remission of depressive symptoms. The situation is further complicated in GWI Veterans that may have therapy-resistant depression. Veterans with GWI continue to suffer from chronic depression and other neurological symptoms despite current treatment efforts. In light of this reality, there is an urgent need to identify molecular mechanisms underlying the development and expression of GWI and use this knowledge to develop novel, effective GWI treatments. Given the unique set of deployment circumstances that led to the development of GWI, we hypothesize that depression associated with GWI may in fact represent a unique neuroplasticity phenomenon and therefore require drugs that act differently than conventional antidepressants if we are to effectively treat this GWI morbidity. Our research has offered a novel molecular target for therapeutic intervention in GWI. We have developed a rodent model of GWI neurological morbidities following chronic, low-dose exposure to organophosphate and nerve agent surrogate DFP (diisopropyl fluorophosphates) and postulate that sustained elevations in neuronal calcium could underlie synaptic plasticity changes that express themselves as behavioral abnormalities of depression and anxiety in GWI rats. Preliminary results from our laboratory indicate that increased influx of extracellular calcium through NMDA-R (N-methyl-D-aspartate receptor) trigger sustained release of calcium from intracellular stores responsible for maintaining chronically elevated calcium levels in GWI rodents. Initial studies from our research further indicate that NMDA-R antagonist ketamine at a low, sub-anesthetic dose was effective in not only lowering these calcium elevations but also produced a rapid and long-lasting antidepressant effect in GWI rats. Given the critical role calcium ions play in shaping synaptic plasticity and modulating behavior, these pathological changes may be responsible for GWI neurological symptoms. Our observations have taken on new meaning in light of recent evidence that ketamine exerts a rapidly acting antidepressant effect in major depression. More than 20 years have elapsed since the end of the First Gulf War and it is unacceptable that we do not have effective therapies for GWI-suffering Veterans. Gulf War Veterans are frustrated and appear to scour internet sites that are now offering ketamine therapies for relieving depression. Several news and media outlets report that ketamine clinics are popping up around the country and are treating patients who are able to pay out of pocket. While “some of the cli
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710573
Entities
People
- Laxmikant S. Deshpande
Organizations
- United States Army
- Virginia Commonwealth University