Features and Occasionals

Your Brain on Altitude

By Alice Toler

Depression and suicide are serious problems in Utah. In 2012, 545 Utahns took their own lives—more than the number of people who died in auto fatalities. We aren’t alone in this disturbing ranking; in fact, Utah is squarely in the middle of the USA’s “suicide belt”—a geographical area which encompasses the Intermountain West. Suicide rates are similarly high in Wyoming, Montana, New Mexico, Colorado and Nevada.

Various causes have been advanced to explain these disturbing statistics: the prevalence of guns (which account for 50% of all completed suicides), the sparseness of the population, strict religious and cultural expectations, poor acceptance of gays and minorities, alcohol and drug abuse. But, after controlling for all of these factors that may indeed push any individual towards suicide, there is only one true commonality among cities such as Albuquerque, Reno, Salt Lake City, Denver and Billings: altitude.

In other high-elevation countries as well, altitude appears to correlate to depression and suicide, though serious research in this area is scant. The Himalayan countries are most well-known for their Buddhist traditions and their placid monks, but a Google search shows that both Nepal and Bhutan have a suicide problem, particularly among young women. One town in the highlands of Ecuador, Chunchi, has become known as “the village of the suicidal children.”

Utah had 20.9 deaths per 100,000 in 2012; an additional 3,968 Utahns were hospitalized for attempts. The highest rate was found in Wyoming: 29.6 deaths per 100,000. By contrast, Washington, DC came in at 5.7 and New York City at 8.3 (per 100,000).

Dr. Perry F. Renshaw, psychiatrist and biophysicist, was recruited from Harvard Medical School to become the Utah Science Technology and Research (USTAR) Professor of Psychiatry at the University of Utah’s Brain Institute in 2008. His previous and ongoing work using magnetic resonance spectroscopy to peek into the brains of addicts and people with mood disorders has been brought to bear on what Dr. Renshaw calls “The Utah Paradox”—Utah is consistently characterized as one of the happiest places in the United States; however, our rates of depression and suicide are also some of the highest. How do you reconcile this? Let’s start with the depression side of the equation.

It all has to do with “getting high”…high up in the mountains, that is. Salt Lake City’s air, at 4,500 feet, is thinner, and therefore has less available oxygen in it than the air at sea level. Where your coastline dweller is used to a 21% oxygen-rich atmosphere, here we’re only getting about 17.5%. That percentage drops to 16% in Park City, and dwindles towards 14% as you pass the 10,000-foot mark. The oxygen deficit in the Salt Lake Valley is enough to cause a mild chronic hypoxia (oxygen restriction) in the body, which causes a variety of reactions. First is a reduction in the amount of the neurotransmitter serotonin, which, among other things, is responsible for mood stability.

“Reductions in serotonin will make you more depressed and anxious, especially if you happen to be predisposed to those disorders,” says Dr. Renshaw. “We see this most commonly in recent transplants to Utah from lower-altitude states. It may happen as much as 30%-40% of the time. Even just knowing that those symptoms might occur is valuable.” If you understand that moving to Park City from Chicago might actually bum you out on a metabolic level, you won’t feel like it’s a personal failing (or blame it on the local culture) if it happens. And you can take steps to alter that balance.Renshaw Headshot copyPerry F. Renshaw, MD, PhD, MBA

Altitude also decreases brain levels of a nitrogenous organic acid called creatine. You may have heard about creatine as a supplement for athletes and body builders, but it is also a vital component of brain health, and it is a part of the way that the brain will heal itself from depression naturally.

“When I was in Boston working at McLean Hospital, we found this really strange pattern in the brains of people with major depression,” says Dr. Renshaw. “It was puzzling, because they had relatively high levels of phosphocreatine, which is one of the highest-energy compounds in the body, and relatively low levels of ATP, which is the businesslike molecule that fuels all sorts of processes inside cells.” The bodies of these depressed people were holding energy in reserve for some reason, and not using it.

“At first we thought this abnormal chemistry must be bad, but it actually turned out that depressed people who had this abnormal pattern of higher phosphocreatine in the brain would go on to get better. no matter what we treated them with. We could treat them with an SSRI [antidepressant], or behavioral therapy, or thyroid hormone—it didn’t matter. If they had high levels of phosphocreatine, they would get better.”

This creatine suppression at altitude is key in Dr. Renshaw’s research into possible remedies for the chronic hypoxia blues. “So we asked, could we artificially induce this pattern of brain chemistry? And it turns out that the nutritional supplement creatine monohydrate will do that for you. This supplement is already in widespread use—some 62% of all high school football players currently take it. If you give healthy people creatine monohydrate, their brains will develop more phosphocreatine and less ATP, which is exactly the signature we wanted.”

Dr. Renshaw and his team then studied the phenomenon in lab rats, putting creatine monohydrate in their food and testing them for depression-like behavior using what’s known as the rat swim test. Rats are put into a trough of water where they will naturally swim around to try to escape, and researchers measure the amount of time they make any movements beyond those just required to keep their heads above water. Basically, they are measuring how long it takes a rat to despair, and once it shows evidence of a negative mood, it’s taken out of the water bath, dried off, and allowed to recover. One swim test was performed before the creatine supplementation, and one afterwards. There was a re­mark­able lengthening in the amount of time the rats would attempt to swim after creatine supplementation, but oddly only in the female rats. “The male rats couldn’t have cared less,” says Dr. Renshaw, “but the female rats thought this was the most antidepressant thing they’d ever seen in their lives!

“But the real question,” he continues, “since rats are very different from humans in terms of the way their brains work, was to confirm these findings in a clinical trial. So some colleagues and I did a trial in South Korea with about 50 women who were, on average, middle-aged and depressed. Half of them got a standard Lexapro [SSRI antidepressant] therapy, and the other half got Lexapro plus creatine. In the Lexapro plus creatine group, the women got better twice as quickly, and they got better twice as much as the women who just got the standard SSRI. It was a profoundly positive result.”

After Dr. Renshaw and his wife moved to Utah, he and his team here started to study depression in adolescents. “One group with depression that responds terribly to [standard] treatment is adolescents, so we looked for some really depressed adolescent girls who had failed on treatments with antidepres­sants, and we gave them creatine. In about eight weeks they were on average 50% better, which in the world of depression treatment is an astonishing result. Our first co­hort of seven girls had all been out of school or work and most were suicidal. By the end of the study, none were suicidal and all reported feeling much more functional.” Renshaw credits his colleague, child psychiatrist Doug Kondo, who wrote the grant for the National Institute of Mental Health (NIMH) and who’s done most of the creatine work with kids.

“Once we had our grant, we wanted to know, how much creatine do you need? It turns out that all the doses we studied (two grams, five grams, and 10 grams per day) were effective. The body’s daily requirement for creatine is two grams, and your body can usually make about one gram, so you need about another gram from dietary sources.” Dietary creatine comes from eating the meat of vertebrate animals, so vegetarians and vegans may find themselves deficient. Vegan-friendly, lab-synthesized creatine supplements are widely available online and at health food stores.

Dr. Renshaw’s team has done studies that show a definitive decrease in brain creatine with altitude. Creatine supplementation may be something that works especially well in women; it may also work for men with altitude-related depression.

But what about Utah’s reputation as one of the happiest places in America? How can that follow from serotonin- and creatine-depressed chronic hypoxia?

Renshaw says this has to do with dopamine, a different neurotransmitter which is responsible for feelings of euphoria. Cocaine and methamphetamine both create a dopamine rush in the brain…and weirdly enough, chronic mild hy­poxia has also been shown to increase dopamine levels. “Dopamine is linked to addiction, rightly or wrongly,” says Dr. Renshaw, “but it’s also linked to anything we do that gives us a sense of pleasure or satisfaction. So having more dopamine in your brain is going to make every­one feel somewhat better about the things they’re doing and the activities they’re enjoying. Not, obviously, if they’re depressed, but if you’re not depressed, the sense of feeling better in the mountains is a real one.” And the effect is pretty striking.teamThe Brain Institute research team: Young-Hoon Sung, M.D., M.S.; Taeyoung Choi , M.D., Ph.D.; Perry Renshaw, M.D, Ph.D., M.B.A.; Douglas Kondo, M.D.; Xianfeng Shi, Ph.D.; Tae Suk Kim, M.D., Ph.D.; Andrew Prescot, Ph.D. Bottom row from left to right: Rebekah Huber, M.A.; Lauren Forrest, B.S.; Bethany Nickerson, B.S.; Olena Bogdanova, Ph.D.; Shami Kanekar, Ph.D; Sujung Yoon, M.D., Ph.D.; Tracy Hellem, RN, BSN

“ADHD [Attention Deficit Hyper­activity Disorder] is a classic dopa­mine disorder, and we usually treat it by increasing dopamine in the brain [using, for example, Ritalin or Adderall]. On the coasts near sea level, the incidence of ADHD will be around 10% in the population at large, but in the mountain states it’s only around 5%, suggesting that there’s a pretty big impact of altitude on brain dopamine systems.” So if you don’t feel depressed in the mountains, chances are you’ll feel a lot better here than you will anywhere else! And whether or not you get the creatine-and-serotonin hypoxic blues, or the dopamine-related hypoxic euphoria seems to come down to genetics.

All of this information about blood oxygenation and depression also begs the question—what about other things that cause mild hypoxia, such as smoking cigarettes?

“Smoking, asthma, and COPD [Chronic Obstructive Pulmonary Disease] all have been linked to increased incidence of depression and suicide,” Dr. Renshaw says. So can you improve your mood stability by running air filters in your house, keeping houseplants, and taking other measures that you would to clean up the atmosphere in your house? “Well, we don’t know,” he says. “That’s exactly the point where this part of the research is, and we want to shift gears and say okay, what can you do about this if you’re negatively impacted, other than move to the coasts? We’re cautiously optimistic that there is a way forward.” And certainly, if you’re depressed, quitting smoking is a very sensible step you can take to improve your mood.

How did Dr. Renshaw himself react to moving from sea level to the Utah altitudes? “I think I had a sense of profound satisfaction the first year, and part of that is because it had actually been a really good transition for me, but in retrospect I wonder if some of that was just having more dopamine in my brain. I’ll take what I can get if it’s on the good side! There was definitely, for me, a sense of real pleasure in the changes my family and I had been able to enact in our lives.”

Good science on supplements: What’s happening at Utah’s Brain Institute

Dr. Perry Renshaw and his team of researchers at the University of Utah’s Brain Institute are investigating more than just altitude-related depression. Their association with the Utah Science Technology and Research (USTAR) Initiative allows them to test other commonly available supplements and their effects on mood, wellbeing and addiction. These supplements aren’t being in­vestigated by large pharmaceutical companies because they cannot be patented.

USTAR is interested in supporting the development of innovations that will drive economic growth. In his work improving brain imaging techniques for improving diagnosis and treatment, Dr. Renshaw is able to investigate some of these intriguing but neglected supplements. “The NIH [National Institutes of Health] has an ambivalent stance about supplements, in part because there’s so little science, and of that little science, so much of it is bad. It’s hard to know how to fix the supplements field and identify products that are really safe and effective without doing a lot more research, and the problem is getting that research paid for.” Dr. Renshaw and his team are attempting to add what they can to the annals of good science on supplements.

In addition to considering the role of creatine in depression, Brain Institute researchers have been looking at uridine, a compound that’s found in mother’s milk, and its effects on the mood swings of bipolar disorder. They have also been investigating a nootropic supplement called “for its efficacy in treating addiction, particularly to methamphetamine.

“We’re very keen on uridine for bipolar,” Dr. Renshaw says. “It really seems to decrease mood symptoms quite quickly, within a couple of weeks. We’ve been working with a local company to try to get them interested in developing it as a product or treatment, because the effects have been amazingly strong.”

The results have been similarly promising for citicoline. “We’ve been studying it for close to 20 years, and it seems to have the ability to repair the brain,” Dr. Renshaw continues. “We studied adult methamphetamine users, and we showed that eight weeks of treatment with citicoline really does seem to help gray matter in the frontal cortex regrow itself. One of the problems that people who use stimulants have is that their ability to comply with treatment is proportional to their cognitive abilities.” Basically, the more meth or cocaine you use, the less executive function you’re going to have—the less ‘smart’ you’re going to be. “So these people’s ability to stay with the program, to remember what they’re doing, and to avoid drug cues is paramount. So we thought if we can repair the brain, that can have secondary benefits in terms of improving the effects of any other treatment [for addiction].”

Citicoline is also known to help the brain produce more dopamine and norepinephrine. “Both of these neurotransmitters have been associated with depression and substance abuse. Because it creates more dopamine, we think citicoline is likely to help in treating a variety of addictive behaviors.”

So, can you get high off citicoline? Is it possible to get addicted to it?

“It functions differently from a stimulant,” Dr. Renshaw replies. “A stimulant tremendously increases the release of dopamine from the synapses of your brain and will give you a very potent high, but what citicoline does is a little bit different. It increases the rate at which the neurons synthesize dopamine, but it doesn’t give you that flooding high. Really experienced users of stimulants say that when they take citicoline, they don’t feel any kind of high at all—there is no subjective difference [in that regard] between taking citicoline and taking a placebo, which is amazing.”

Bad air days and depression

Everyone who lives along the Wasatch Front knows that the altitude isn’t the only thing here that can decrease the amount of oxygen in your body. The Salt Lake valley is unfortunately infamous for its winter inversions and air pollution. Does air pollution correlate to increased depression and suicide among residents here? The answer, apparently, is yes.Bakian 3636 x

A new study out this year by the University of Utah’s Dr. Amanda Bakian, Director of the Utah Registry of Autism and Developmental Disabilities, shows a robust statistical correlation between certain types of air pollution and increased numbers of suicides. Increased nitrogen dioxide and fine particulate pollution both correspond to an uptick in suicides after the general population has been exposed for three days or so. The puzzling part about this result is that the suicides don’t take place mostly during the winter, when air pollution is worst, but in spring and fall, when the air usually isn’t that bad. These findings are consistent with other research that has been performed in Asia.

Depression is a complex condition, and the causes of suicide are multi-factorial, so socioeconomic status, physical health, genetics and psychiatric disorders all have to be taken into account as well. Perhaps in the winter the air is so bad that the depressed among us can’t muster the ambition to commit suicide? In any case, this existing correlation with air pollution gives us yet one more reason to clean up our air.

If you’re thinking of “trying this at home”

Nobody should start a new nutritional supplement or treatment program without first consulting their primary care physician, says Dr. Renshaw. Since he and his team at the Brain Institute are still researching the effects of these supplements on brain health, they are not in a position to make recommendations about dosage or administering. If you would like to stay up to date on the state of this ongoing research, however, you can follow along at Utahbrain.org.

“That said, Brain Institute studies found so far that one gram of a daily creatine supplement was sufficient for results—dramatically less than the five to 25 grams consumed by many athletes. Information about creatine, urinine and citicoline is available online; the supplements are available in many stores. Do your homework and talk with your doctor before deciding what’s best for you.

Alice Bain Toler is a local writer and visionary artist. She’s intensely interested in brain science as it pertains to understanding personality, depression, anxiety, trauma, and dementia.

This article was originally published on December 1, 2014.