DESCRIPTION (provided by applicant): The recent escalation in suicide rates amongst veterans is of urgent concern, likely reflecting high rates of both major depression (MDD) and treatment-resistant depression (TRD). Higher rates of MDD and suicide are linked to living at altitude as well as with chronic hypoxic disorders (COPD, asthma, smoking), implying that chronic hypoxia intensifies MDD status, increases the prevalence of TRD and elevates suicide risk. Using a novel translational animal model for hypoxia-related depression, we plan to test the efficacy of current standard of care (SOC) antidepressants (AD) in chronic hypoxia, and also to explore alternative therapeutic options for MDD in chronic hypoxia, with a special focus on women. This proposal thus meets 3 out of 8 priority research areas of interest to the BLR&D program: Suicide Prevention, Women's Health and Risky Behaviors (Smoking). People residing at altitude or those with hypoxic disorders (COPD, asthma, smoking) are exposed to chronic hypoxia. In animal models, hypobaric hypoxia (the low oxygen levels experienced at altitude) lowers brain serotonin levels, and low brain serotonin can reduce the efficacy of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed ADs and the ADs of choice for the veteran population. Using a novel animal model, we find that after a week of housing at altitude (4500, 10,000 or 20,000ft), female rats show significantly more depression-like behavior (DLB) in the FST vs. at sea level, with motor behavior in the open field test (OFT) unchanged. Future studies will analyze DLB in rats with the FST and the sucrose preference test and further will evaluate locomotor effects of treatments with the OFT. In our model, hypobaric hypoxia also lowers brain striatal serotonin and forebrain total creatine (a brain bioenergetic marker) in rats, and reduces efficacy of the SSRI fluoxetine (Prozac(r)) in the FST. A similar drop in forebrain creatine levels is also seen in people residing at altitude (4500 ft) vs. at sea level. Our overarching hypothesis therefore is that chronic hypoxia may cause neurochemical deficits in people, leading to increased rates of MDD and TRD, and higher suicide risk, implying the need for therapeutic options specific to MDD in chronic hypoxia. We thus plan to initially test for efficacy of SOC ADs from serotoninergic and noradrenergic classes in hypobaric hypoxia, towards optimizing SOC AD use in veterans with chronic hypoxia. We then plan to test dietary augmentation with 5-hydroxytryptophan (5HTP, to enhance brain serotonin levels), creatine (to enhance brain bioenergetics), and a combination of 5HTP+creatine, each ±SSRI treatment, as options to reduce MDD and improve SSRI efficacy in TRD in veterans in chronic hypoxia. Data from these studies are expected to serve to significantly reduce suicide risk in the veteran population. A chronic disease, depression is particularly prevalent amongst veterans...