High altitudes may elevate inflammation, increasing risk of depression, suicide

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Even a moderate increase in altitude can have some severe effects on the human mind and body. (AP Photo/Niranjan Shrestha)

Living at even moderately high altitudes could be a risk factor for depression and suicide, according to researchers who ran experiments on rats at sea level in California and at one mile high in Colorado. 

The study, published April 21 in Progress in Neuro-Psychopharmacology and Biological Psychiatry, followed 320 young adult rats during acclimation periods ranging from one to five weeks. The researchers looked at biomarkers for inflammation that are potentially key indicators of depression and suicidal behavior, finding that the biomarkers did not dissipate during the study period. In other words, the rats did not acclimate as expected. 

"There's a knowledge gap we're filling with this particular study," Christopher Lowry, an associate professor with the University of Colorado in Boulder and corresponding author of the study, told The Academic Times. "The evidence that there's increased inflammation at altitude is mostly based on very high altitude — people at base camps for mountain climbing. So it's hard to make the case, based on [those studies], that people who live at what we consider normal altitudes in Western states have higher inflammation than someone at sea level.

"But that's what emerged from this study," he continued. "The case for persistent increase in biomarkers of inflammation is very compelling. This was somewhat unexpected. We didn't anticipate how significant these differences would be and how long-lasting." 

What's behind the effect? Hypoxia, a condition that occurs when tissue is deprived of oxygen, is closely related to inflammation. It's often experienced by mountain climbers in thin-air environments, but it's possible to enter a mildly hypoxic state at lower elevations. That could explain the persistence of biomarkers for inflammation the team observed in rat subjects, Lowry said: "We have to assume that's the likeliest candidate — the differences in available oxygen in the two locations." 

"We know there are cells that line the airways in the lungs that are essentially oxygen detectors that respond to partial air-pressure loss," he continued. "So it's not hard to imagine that there's a physiological response to oxygen availability that could drive changes in nervous system functioning. But that's complete speculation."   

Previous studies led by Shami Kanekar at the University of Utah have linked hypoxia to depression-like behavior in female rats, though not in male rats, and shown that antidepressant medications are less effective at altitude. Those studies simulated high-altitude conditions with pressurized chambers, but Lowry and his colleagues are the first researchers to ship rodent subjects from sea level to high altitude. 

"We had one team of investigators who did the experiment at both locations," Lowry said. "The same people who ran the experiments in Boulder ran the same experiments in La Jolla [California]. We know the investigators have a big impact on behavior in these types of models. You can't have different people running the experiments. Likewise, the equipment matters, so they literally drove to La Jolla and took the equipment with them." 

Each rat ran through a battery of tests in California and Colorado, including several designed to monitor anxiety-like behaviors; the researchers did not observe significant changes in anxiety between sea level and high altitude. Subjects were also tested for anhedonia — the inability to experience pleasure — by making a sugary beverage available, which revealed the most significant changes in behavior. "The animals housed at high altitude, whether they were male or female, responded by a lower sucrose preference," Lowry said. "This was the most striking and persistent difference between the two altitudes." In other words, at high altitudes, rats of both sexes were less interested in sweet drinks they would typically find pleasurable.

While there isn't a direct relationship between depression and suicide — many factors are involved — the available evidence makes it "clear that high altitude is a risk factor for suicide," Lowry said. "Some people have made the argument that, at least in the Western United States, if you live at higher altitude, you have increased access to guns and more lethal means of suicide, which is in some part true. But that really doesn't exclude the possibility that there are biological factors that haven't been carefully evaluated that could put people at high risk." 

Lowry stopped short of recommending that depression-prone people should consider relocating from mountainous states to sea level. But he emphasized that the risk is real for people living in the West. "Is this an overwhelming risk? No," he said. "On the other hand, knowledge is power: If you know there's a risk, perhaps that awareness can help people take steps that limit their chances of negative outcomes." 

The study, "Evaluation of the effects of altitude on biological signatures of inflammation and anxiety- and depressive-like behavioral responses," published April 21 in Progress in Neuro-Psychopharmacology and Biological Psychiatry, was authored by Kadi T. Nguyen, Chloé A. Gates, James E. Hassell Jr., Christine L. Foxx, Stephanie N. Salazar, Amalia K. Luthens, Andrea L. Arnold, Brooke L. Elam, Ahmed I. Elsayed and Jon D. Reuter, University of Colorado; Mathias Leblanc and Sean E. Adams, The Salk Institute for Biological Studies; and Christopher A. Lowry, University of Colorado, Veterans Health Administration and Military and Veteran Microbiome: Consortium for Research and Education. 

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