University of Utah Health investigator Perry Renshaw, MD, PhD, and colleagues combine epidemiology, animal models, and human neuroimaging to study how impaired brain bioenergetics affect psychiatric disorders. They first reported a link between altitude and suicide in the U.S., a finding since replicated in three other continents. People living at high altitude are exposed to hypobaric hypoxia, and the partial pressure of oxygen in arterial blood is reduced in people at 4,500ft (Salt Lake City, UT) compared to sea level. Both Hypobaric hypoxia and chronic hypoxic conditions such as pulmonary, cardiovascular, and sleep disorders and smoking are linked to depression. Preclinical studies found that hypobaric hypoxia disrupts brain serotonin and bioenergetic systems, with women being particularly vulnerable.
Using magnetic resonance imaging, researchers also found that, compared to sea level, humans at 4,500 feet exhibit deficits in creatine, a high energy neurometabolite. The Renshaw Lab subsequently conducted animal and human studies and observed that targeted creatine supplementation improved brain bioenergetics and reduced depressive symptoms. Future goals aim to define the mechanisms by which hypobaric hypoxia promotes depression and suicide risk, and to test new treatment strategies.
Altitude, gun ownership, rural areas, and suicide. Kim, N, Mickelson JB, Brenner BE, Haws CA, Yurgelun-Todd DA, Renshaw PF. Am J Psychiatry. 2011 Jan;168(1):49.
Incidence of major depressive episode correlates with elevation of substate region of residence. DelMastro, K, Hellem T, Kim N, Kondo D, Sung YH, Renshaw PF. J Affect Disord. 2011 Mar;129(1):376.
Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. Kondo DG, Sung YH, Hellem TL, Fiedler KK, Shi X, Jeong EK, Renshaw PF. J Affect Disord. 2011 December;135(1):354.
Hypobaric hypoxia induces depression-like behavior in female, Sprague-Dawley rats, but not in males. Kanekar S., Bogdanova OV, Olson PR, Sung YH, D’Anci KE, Renshaw PF. High Alt Med Biol. 2015 Mar;16(1):52.
Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression. Kondo DG, Forrest LN, Shi X, Sung YH, Hellem TL, Huber RS, Renshaw PF. Amino Acids. 2016 August;48(8):1941.
Increased anxiety and anhedonia in female rats following exposure to altitude. Sheth C, Ombach H, Olson P, Renshaw PF, Kanekar S. High Alt Med Biol. 2018 Mar;19(1):81.
Hypobaric hypoxia exposure in rats differentially alters antidepressant efficacy of the selective serotonin reuptake inhibitors fluoxetine, paroxetine, escitalopram and sertraline. Kanekar S., Sheth CS, Ombach HJ, Olson PR, Bogdanova OV, Petersen M, Renshaw CE, Sung YH, D’Anci KE, Renshaw PF. Pharmacol Biochem Behav. 2018 July;170:25.