COVID-19 and Psychosis: Is There a Link?

Michael Vlessides

May 08, 2020

Since the start of the COVID-19 pandemic, most of the research into the SARS-CoV-2 virus has focused on its direct effects on the body with the aim of finding effective treatments and, ultimately, a cure. However, researchers Emily Severance, PhD, and Robert Yolken, MD, are investigating a potential secondary, long-term impact of COVID-19 exposure — greater susceptibility to psychosis.

"Over the years there have been data showing an association between exposure to general respiratory viruses such as the flu and subsequent psychotic episodes. This association was especially evident in studies of the aftermath of the great influenza of 1918," Severance, assistant professor of pediatrics, Johns Hopkins University, Baltimore, Maryland, told Medscape Medical News.

Against this background, the investigators conducted a 2011 study to determine "whether or not this association with psychosis was specific to influenza, or if other respiratory infections like the coronavirus might also have similar consequences," said Severance.  

The researchers examined the response of immunoglobulin G against four human coronavirus strains common at the time. Results showed that more than 90% of adults diagnosed with psychoses had high levels of antibodies to one or more of the viruses, and that all four coronaviruses were more seroprevalent in patients versus controls.

Multivariate analyses suggested that two of the coronaviruses — HKU1 and NL63 — may confer particular risk for neuropsychiatric disease.

The current study will build on these earlier findings. The researchers plan to examine adult case-control comparisons of the four less severe coronaviruses (229E, NL63, OC43, HKU1) and quantify the seroprevalence of the more severe forms of the virus, MERS, SARS-CoV-1, and SARS-CoV-2, in patients with psychiatric disorders versus controls.

Growing Body of Evidence

There is a substantial body of literature linking exposure to various pathogens with the subsequent development of psychiatric disorders. One of the most well studied is the parasite Toxoplasma gondii, which is implicated in a number of neuropsychiatric disorders, most notably, schizophrenia.

"It's an esoteric area of the literature, but it really has a lot of evidence to support a connection between the infectious disease process and the development of psychiatric disorders," said Severance.

One possible explanation for this association is that neurotropic pathogens travel directly to the brain and have direct effects on brain cells. Indirect effects on the brain also occur from the body’s heightened immune response during the infectious disease process.

However, said Severance, some of the most convincing evidence comes from research in pregnant women. As previously reported by Medscape Medical News, children born to women who contract influenza during pregnancy have nearly a fourfold increased risk of having bipolar disorder later in life.

"So the pathogen contribution to psychoses is likely through a neurodevelopmental mechanism, but that doesn't exclude other possibilities, including that what we're observing is a direct effect of the virus entering the brain during adulthood," said Severance.

The new study will use banked blood samples from thousands of individuals with psychiatric disorders, while simultaneously collecting new samples. To date, the researchers have focused their efforts on developing assays for the study.

"Our next step is to make sure that our system is operative following testing with appropriate controls, including people that we know have COVID-19 and the other coronaviruses, and as well the proper negative controls. Once we have a carefully tested set of assays, we'll be able to start screening samples," said Severance.

Results Within the Year

The investigators are interested in understanding the extent of cross-reactivity in the human immune system toward the different viruses. They also plan to start experiments to examine the extent to which SARS-CoV-2 and other coronaviruses enter the brain.

"This will allow us to more finely interpret our seroprevalence studies to better tease out lifestyle versus direct brain effects of the virus," said Severance.

Interestingly, the study may also yield some information about the genesis of the COVID-19 outbreak.

"We have some samples from the time point when COVID-19 was emerging, at least in this geographic area. This will also allow us to get at the question of whether COVID-19 has been circulating before the actual recorded date of entry into the United States, particularly in individuals with serious psychiatric disorders," she added.

The current intense focus on addressing the immediate effects of the COVID-19 outbreak has limited the researchers' access to resources and manpower. Nevertheless, they hope to have study results within the year.  

Severance would not speculate on the current investigation's potential findings, though she noted that previous research in the area has helped solidify the link between exposure to pathogens such as coronavirus and the subsequent development of psychiatric disorders.

"I think it really illuminates the very vulnerable nature of a lot of people with mental illness. If they're exposed to these viruses at increased rates, we need to address that, and develop and implement the infrastructure where those that need help can be identified and treated," she said.

"Crucial" Research

Commenting for Medscape Medical News, Tom Pollak, PhD, MRCPsych, King's College London, UK, who is not involved in the research, said that pandemic viral infections have long provided clues to the origins of psychotic disorders such as schizophrenia.

"Most psychiatrists will be able to remember learning that at a population level, exposure to virus while in utero increases a baby's risk of developing schizophrenia later in life, but in fact evidence from previous pandemics such as the 1918 Spanish flu suggests that these viruses may have a more immediate effect, resulting in cases of acute psychosis at, or soon after, the time of infection," said Pollak.

"Nobody knows for sure whether these represent the direct effects of the virus on the brain, systemic inflammation due to infection, or some sort of post-viral immune activation," he added.

Pollak went on to explain what while clinicians hope the mental health burden of COVID-19 will not be as severe as that of the 1918 flu pandemic, studies such as this are a crucial part of a coordinated response.

"If the study is able to demonstrate a link between viral exposure and psychosis, this would mandate further investigation into the immune basis of psychotic disorders, potentially with huge public health implications or even implications for the development of novel treatment strategies for some people with psychosis."

Severance and Pollak have reported no financial conflicts of interest.

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