Title: Therapeutics Targeting Brain Bioenergetics may be Effective as Antidepressants in Altitude-related Treatment-Resistant Depression: Sex-based Animal Model Studies
Presenter: Shami Kanekar, PhD, University of Utah Department of Psychiatry and VISN19 Rocky Mountain MIRECC & US Department of Veterans Affairs
Contributors: H.J. Ombach (University of Utah Department of Psychiatry), J. Brown (University of Utah Department of Psychiatry), M.D. Hoffman (University of Utah Department of Psychiatry), R.E. Ettaro (University of Utah Department of Psychiatry), C.S. Sheth (University of Utah Department of Psychiatry), Y.H. Sung (University of Utah Department of Psychiatry); P.F. Renshaw (University of Utah Department of Psychiatry and VISN19 Rocky Mountain MIRECC & US Department of Veterans Affairs)
Brief Description: The physical effects of living at altitude increasing rates of depression
Keywords/Main Subjects: Mental health, environmental health, depression, altitude, major depressive disorder (MDD), suicide
Copyright: copyright Shami Kanekar ©2020
Living at altitude (inhypobaric hypoxia) increases risk for major depression (MDD). Healthy people living at 4,500ft exhibit lower levels of blood oxygen and forebrain bioenergetic markers vs. those at sea level, and MDD is linked to forebrain hypometabolism. We established an animal model to study altitude-related depression. In rats housed at sea level, 4,500ft or 10,000ft, depression-like behavior (DLB) increases with altitude in females, but not males, and most selective serotonin reuptake inhibitors (SSRIs) are ineffective antidepressants in both sexes. Since rats housed at altitude also exhibit forebrain hypometabolism, we tested bioenergetic compounds for antidepressant potential at altitude. Creatine is a bioenergetic compound which may improve brain energetics, and its lipophilic analog, cyclocreatine, may have improvedbrain access vs. creatine.
Rats housed at 4,500ft were given dietary creatine (4%w/w, 5wks) or cyclocreatine (1%w/w, 3wks), vs. food controls, then tested for DLB in the forced swim test. Blood and brain regions were assayed for creatine levels or serotonin.
Blood creatine levels increased significantly in creatine-treated males and females, butforebrain creatine (a bioenergetic marker)and depression status improved in females, but not males. Cyclocreatine was antidepressant in both sexes. Both treatments improved forebrain serotoninin females, but not males.
Rates of MDD and suicide increase demographically with altitude. Our studies suggest that hypobaric hypoxia may alter brain physiology to worsen rates of MDD, treatment-resistant depression and suicide. We find that improving brain bioenergetics may be an effective strategy to improve depression status in people at altitude.