Mania isn’t a mental illness unto itself, but it is a defining feature of bipolar disorder. People can experience extreme levels of emotion, disruptions in sleep pattern and energy levels, and exhibit odd behaviors during a manic episode.
In her 1997 book, An Unquiet Mind, clinical psychologist Kay Redfield Jamison described one such episode she had where even the parking lot of UCLA’s Medical Center in the middle of the night was fodder for overstimulation. “I was on the run," she wrote. "Not just on the run but fast and furious on the run, darting back and forth across the hospital parking lot trying to use up a boundless, restless, manic energy. I was running fast, but slowly going mad.”
About 2.8 percent of US adults have bipolar disorder, and of those, almost 83 percent are considered seriously impaired. But when researchers try to understand these kinds of complex psychiatric disorders, they often hit a wall. Studies that look at the DNA of people with bipolar disorder have found some genetic risk factors, but bipolar disorder suffers from “missing heritability”—a problem with many psychiatric conditions where genes alone don’t explain or predict who will develop a disease.
This is leading researchers to look to environmental factors that might influence the onset of psychiatric illness. Since we can change the environment more easily than we can our genes, this is a great place to look for preventative and therapeutic possibilities.
This is how asking patients “Have you ever eaten locally procured dry cured meat” came about in the first place.
In a new study out today from Johns Hopkins University, researchers found an association between nitrate-treated meat products—like beef jerky, salami, hot dogs—and mania. They analyzed more than 1,000 people with and without psychiatric illness, and found that those who were hospitalized for a manic episode had more than three times the odds of having eaten those kinds of meats, compared to healthy controls. In follow-up experiments in rats fed diets with added nitrates, the researchers saw similar mania-like behaviors in only the rats that received nitrates.
What are nitrates? Food writer Bee Wilson, in a recent article for The Guardian, says the tell for their presence is “the pinkness of bacon”, or that similar rouge in ham, salami, jerky—all these meats have been treated with nitrates, which act as preservatives. Nitrate-treated meats have been recently associated with an increased risk of a variety of kinds of cancer.
Robert Yolken, a professor of neurovirology in pediatrics at the Johns Hopkins University School of Medicine and the senior author on the new paper, tells me he didn't set out to examine the effects of nitrate-cured meats on bipolar disorder. His colleagues have been collecting data for about ten years, looking for any environmental exposures that might be associated with a variety of psychiatric problems, including bipolar disorder, but also schizophrenia, and major depression.
Yolken was initially interested in whether an exposure to undercooked meat might influence a psychiatric illness. He tells me that the nitrate-treated meats were included as controls to those undercooked meats. “So, yes, it was surprising for us when we analyzed the data,” he says. The processed meats were the strongest signal of any of the foods that they had data on. (The undercooked meats did not end up showing an association.)
When he saw the results, he says he thought of two explanations: That eating the meats was either affecting the concentration of nitrates in the central nervous system or leading to changes in the gut microbiome (the population of bacteria that live in the digestive tract). There’s growing evidence that there is a connection between the intestinal tract and the brain, and in Yolken's previous work, he'd found that giving patients probiotics could increase the time between their hospitalizations.
To explore the altered microbiome hypothesis further, the team turned to rats. Seva Khambadkone, the first author on the study and a MD-PhD candidate at Johns Hopkins, tells me that in an animal model they could try to rule out other variables and determine whether it was really the nitrate in the meats or something else that was driving the association.
Mania is a complicated human state that involves a whole cluster of different symptoms. But Khambadkone says that psychomotor agitation, or physical and mental restlessness and purposeless movement, is a common feature. Khambadkone and others looked for versions of that in rats that they fed diets of nitrated-cured meat, and in a control group that didn’t get that type of meat. First they watched the rats over the course of a day, to look for their general activity levels, to see if they were more active and if their sleep patterns were abnormal—another common symptom of mania.
“We were able to see both," she says: "That the animals who were on the processed meat diet not only looked hyperactive more generally, but also they were hyperactive during the light-cycle period. Since rats are nocturnal, normally this is when they would be in more of a rest state.”
Khambadkone also exposed both groups of rats to a new environment, because it’s been thought in humans that novelty could trigger episodes of mania. The rats that were eating the nitrated meat showed greater hyperactivity in a new environment than the control rats.
Interestingly, Khambadkone says they also had a control group that ate the same amount of meat—but meat that was not processed with nitrate. These rats behaved more like the control group, suggesting that "it doesn’t seem to be the meat itself, but specifically the nitrates,” Khambadkone says. “The beauty of animal studies is that in humans we can look at correlations and associations but it’s more difficult to study pathophysiologically what’s going on in them. So in this study we were actually able then to take the brains from the rats and look within the brains to see what changes were, in a way that we obviously can’t do in people. And we were also able to look at the microbiome.”
In the brains, they saw gene expression changes in in the hippocampus, and they detected changes in the bacteria in the microbiome. Two of the microbes they found more of in the nitrate-fed rats, Lachnospiraceae and Erysipelotrichales, are part of a family of microorganisms that are associated with altered behavior and cognitive functioning in other experiments on animals, the paper noted. Khambadkone says that they’re discussing what their next moves are, but they’d like to see what happens in animal models that have those microbes altered without being fed nitrate: Would they see the same effects? Another lingering question: Do humans show similar microbiota changes?
Melvin McInnis, the director of the Heinz C. Prechter Bipolar Research Program at the University of Michigan, says he finds a microbiome explanation convincing. In bipolar disorders, he tells me, his own research and others are finding that there are distinct differences in the microbiomes of people that have it, compared to those who don’t. The question is whether this is solely influenced by diet choices, or if something is inherently different about their gut bacteria. It may be a combination of both, but it's a promising direction for future research.
Yolken thinks it's crucial to say that their results don't mean he can make any sweeping recommendations for people to change their diets yet. “I think that has to be done on an individual basis," he says. "The main thing that needs to get done in the human studies would be to look at additional populations, since this is just one population in Maryland. The best we can put together now is that this is on top of other factors, which are presumably genetic, and other environmental factors as well. The nitrates are interacting with all the other factors involved in people that have mania.”
McInnis agrees. He says this is not an explanation, nor the cure for bipolar disorder. It doesn’t fully explain why somebody gets manic. Rather than seeing these findings as a condemnation of specific diet choices, meat, or even nitrates—though future study is needed on all of these topics—the most crucial conclusion to draw from this work is the reaffirmation of the microbiome’s participation in the development of diseases like bipolar disorder. While we don’t completely understand all the factors that go into who gets these diseases and who doesn’t, it seems like the microbiome might play a significant role.
"The important fact here is that we still really truly, truly do not understand why someone develops an illness,” McInnis says. “You can have the risk genes for it, you can have any number of different risk factors and still not develop this disorder. One study does not prove something necessarily, but it’s helpful and it suggests to us that we need to be paying attention to that."
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