Poor air quality is associated with higher rates of several psychiatric disorders, new research suggests.

Analyzing large datasets from the United States and Denmark, investigators found significant correlations between air pollution and bipolar disorder in both countries and between air pollution and depression, schizophrenia, and personality disorder in Denmark.

Dr Andrey Rzhetsky

"If we know which environmental insults can trigger disease, we can probably prevent it in some patients, especially if we know they are genetically vulnerable," corresponding author Andrey Rzhetsky, PhD, professor of medicine and human genetics, University of Chicago, Illinois, told Medscape Medical News.

The findings were published online August 20 in PLOS Biology.

A Complex Mixture

Heritability explains the development of psychiatric disorders to a large extent, but "it's never 100%," and it is increasingly evident that environmental insults play an important role, Rzhetsky said.

Air pollution is a complex mixture of small particulate matter, gases, metals, and organic contaminants generated by natural erosion of stones and human-made materials, exhaust of transport vehicles, industrial activity, and fires.

There's already evidence from human, animal, and in vitro studies that airborne pollutants can end up in the brain and are implicated in the etiology of neurologic and psychiatric disorders.

For the current study, the researchers carried out two analyses, one using US data, and the other Danish data.

It was impossible to have the same design for the two datasets, said Rzhetsky. He added that the two countries have different cultures and diverging approaches to healthcare, population tracking, and environmental monitoring.

US Analysis

For the US analysis, the investigators used the IBM MarketScan health insurance claims database, which includes inpatient and outpatient claims, medical procedures, and prescription medications for more than 151 million patients, for the period from 2003 to 2013.

Their analysis included the quality of air, water, and land (for example, chemicals in the soil) and the "built" environment (for example, vehicular traffic, transit access, and pedestrian safety).

To quantify air pollution, the researchers used the Environmental Protection Agency air quality index, which is a summary measure of 87 potential air pollutants. Rzhetsky noted that for this analysis, the researchers had air quality measurements at only one time point and at a county level.

The researchers transformed environmental predictors into septiles, with Q1 indicating the best quality and Q7 the worst quality.

This analysis assessed four psychiatric illnesses — bipolar disorder, major depression, personality disorder, and schizophrenia — and two neurologic disorders — Parkinson disease (PD) and epilepsy. The neurologic disorders were included to act as a control, and "we did not expect to find an association," said Rzhetsky.

Results showed that, compared with the best air quality, the worst air quality was associated with about a 27% increase in the rate of bipolar disorder (95% credible interval, 15% – 40%; P < 10−4).

For major depression, there was an increase of 6% in the diagnosis rate in the worst vs best air quality regions.

The US data also showed a correlation between personality disorder and poor land quality, but not air pollution.

There was no association between poor water quality or "built" environment and psychiatric illnesses, nor was there a link between any type of pollution and epilepsy or PD.

Childhood Exposure

For the Danish analysis, the researchers used national treatment and pollution registers that included more than 1.4 million individuals born from 1979 through 2002 who were living in Denmark at their 10th birthday.

They studied the association between childhood exposure to air pollution and the same four psychiatric disorders included in the US analysis, but did not assess neurologic disorders.

The investigators performed principal components analysis on 14 air quality indicators to obtain a summarized measure of exposure to air pollution. They again transformed this exposure into septiles, with Q1 representing the least exposure and Q7 the highest exposure.

With the Danish registers, the researchers were able to follow each person's movements over time and access historical pollution data at 1 km by 1 km cell size. This allowed them to estimate the exposure to air pollution at the individual level, which is "much more precise" than the county level exposure used in the US analysis, Rzhetsky said.

Results showed that the rate of all four psychiatric disorders rose with increasing levels of exposure to air pollution. The strongest association was for personality disorder, for which there was a 162% increase (95% confidence interval, 142% – 183%; P < 2 × 10−16) in the rate for category Q7 compared with category Q1.

For bipolar disorder, the estimated rate was 24.3% higher in the Q7 group vs the Q1 group.

Suspect Pollutants

Subanalyses of the data included a "correction for spatial dependency," which took into consideration the proximity of US counties that may have shared environments, and a "harmonization" of the two datasets.

These additional analyses generally supported the robustness of the main findings, the study authors note.

The most likely mechanism by which pollutants engender psychiatric illnesses is through neuroinflammation. "We have quite a bit of evidence on this from animal studies, for example in dogs, and anecdotal evidence in humans," Rzhetsky said.

The investigators note that it is impossible to pinpoint specific airborne compounds that might lead to mental illnesses; it is likely that multiple pollutants contribute to negative effects on the human nervous system in an additive or synergistic way.

However, there are "some suspects," including small ambient particles, which can enter the lungs and bloodstream or cross the blood brain barrier, said Rzhetsky. "They can also go through the olfactory system to the brain, which is a more direct route because we have olfactory neurons in our nose," he added.

He's convinced that halting neuroinflammation can reverse psychiatric symptoms.

However, this needs to be verified, which could be challenging. Rzhetsky noted that clinical trials cannot be carried out because it is "completely unethical" to expose individuals to poor environmental conditions for the purposes of a study.

Intriguing Possibility

In an accompanying editorial, John P. A. Ioannidis, MD, director, Prevention Research Center, Stanford University, California, and director of the Meta-Research Innovation Center at Stanford, writes that a causal association between air pollution and mental diseases is an "intriguing possibility" and that the current study is a valuable contribution to this area of research.

The investigators "have offered a brilliant exploratory analysis with interesting hypothesis-generating hints for bipolar disorder and possibly other psychiatric diagnoses," Ioannidis writes.

But he notes some shortcomings of the study, including the fact that the datasets' "enormous sample sizes" do not guarantee validity.

"Analysis of big data can draw absurd conclusions because of fundamental deficiencies in the quality of the data," he writes. "The US database is approximately 100-fold larger than the Danish one, but the latter is of better quality."

Other notable differences include the variations between the datasets in exposure measurements and the number of variables used to define air pollution.

In addition, the strength of the observed associations is "modest"; although the effect sizes are larger in the Danish data, they never reach relative risks greater than 3, Ioannidis notes.

"However, this is not necessarily a weakness. It has been argued that most true causal effects are modest or even small/tiny; too-large effects may simply point to errors and biases," he writes.

The researchers also "seem to interpret their results as being replicated across countries," he writes. "However, with the exception of bipolar disorder, the point estimates are strikingly dissimilar between the US and Denmark, and 95% confidence intervals do not even overlap."

It would be useful to have analyses conducted by other investigators, including those who may have "skeptical views" about the association of air pollution and mental health, Ioannidis concludes.

"Remarkable" Bipolar Findings

Commenting for Medscape Medical News, Elizabeth Haase, MD, Carson Tahoe Health, Carson City, Nevada, who is a member of the American Psychiatric Association's Caucus on Climate Change, said that the study was interesting and that its illustrations were particularly impressive.

"Just the maps themselves, showing the distribution of mood disorders and schizophrenia across the US and the distribution of healthy environments of different kinds, is fascinating," said Haase, who was not involved with the research.

She agreed with Ioannidis that the Danish analysis is "a little bit cleaner" than the US one, partly because it took into account childhood pollution exposure. Early neuroinflammation, or genetic damage in early years, may be a significant risk factor for later pathology, she said.

Haase was also impressed with the way the Danish data narrowed down air pollution exposure "to within 1 km, rather than the whole county, which is much more specific."

She added that it was "remarkable" that the findings for bipolar disorder were so consistent. She noted that until now, there have not been any studies of bipolar disease and air pollution. "This has been a major deficit in the field," she said.

Haase stressed that there are options for controlling air pollution that could lessen neuroinflammation. These include producing clean energy, controlling industrial pollutants, and reducing use of fossil fuels.

There is "very clear evidence" that diseases become less severe in areas of the United States where coal plants have been shut down, she said.

The study was funded by the NordForsk project 75007, the DARPA Big Mechanism program, the National Institutes of Health, and a gift from Liz and Kent Dauten. The study authors, Ioannidis, and Haase have reported no relevant financial relationships.

PLoS Biol. Published online August 20 2019. Full article, Editorial

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