When the Covid-19 pandemic hit, one of the biggest questions was: Why do some people get so much sicker than others? It’s a question that has forced researchers to confront some deep mysteries of the human body, and come to conclusions that have startled them.
By the fall of 2020, psychiatrists were reporting that among the many groups who were high risk, people with psychiatric disorders, broadly, seemed to be getting more severe forms of Covid-19 at a higher rate. Katlyn Nemani, an NYU neuropsychiatrist, decided to dig deeper, asking: Just how much more at risk, and which conditions?
In January, she and a group of colleagues published a study of 7,348 Covid-19 patients in New York. One finding was stark: People with a schizophrenia spectrum diagnosis faced more than two and a half times the average person’s risk of dying from Covid-19, even after controlling for the many other factors that affect Covid-19 outcomes, such as cardiovascular disease, diabetes, smoking, obesity, and demographic factors — age, sex, and race.
“That was a pretty shocking finding,” Nemani says. The patients all were hospitalized in the same medical system, in the same region, which implies they weren’t receiving radically different treatments, she says. In sum, it all suggests that the risk was closely linked to the mental illness itself and not to some other variable.
Since then, more studies have come out — as well as meta–studies pooling the conclusions of those studies — showing worse Covid-19 outcomes among people with diagnosed mental health disorders including depression, bipolar disorder, and schizophrenia.
Some of this isn’t surprising; a lot of people with mental health issues experience a general increased risk of poor health outcomes. But the pandemic started to shine a brighter light on why, bolstering a hypothesis that’s been accruing evidence in recent years.
It appears that something in the body, something biological associated with these disorders, may be at play. “That suggests there’s a physiologic vulnerability there in these folks,” said Charles Raison, a psychiatrist and researcher at the University of Wisconsin Madison.
It’s not necessarily that people with schizophrenia or mood disorders are more likely to become infected with Covid-19. Rather, once they are infected, “the outcomes are worse,” Nemani says.
Depending on the study and the severity of the mental health diagnosis, people with these conditions are, roughly, between 1.5 and 2 times more likely to die of Covid-19 than average, after adjusting for other risk factors (unadjusted risk is even higher). The level of increased risk, Nemani says, is “on par with what we’re seeing for other well-established risk factors like heart disease and diabetes.”
What’s happening? Why would mental illness make someone more vulnerable to a respiratory disease?
Psychiatrists who study these mental illnesses say the culprit might lie in a connection between mental health and the immune system. They’re finding that mental health stressors could leave people more at risk for infection, and, most provocatively, they suspect that responses in the immune system might even contribute to some mental health issues.
There’s a lot that’s unknown here. But the pandemic is giving researchers a new window into these questions. And the research “might teach us something about how to protect these people from infection going forward,” Nemani says.
How the immune system can impact mental health
In September, the Centers for Disease Control and Prevention updated its list of underlying conditions that put people at higher risk for severe Covid-19, adding mood disorders — like depression and bipolar disorder — and schizophrenia spectrum diagnoses, a group that accounts for around 34 million Americans. It was a recognition of the growing evidence published by Nemani and colleagues across medicine, and prioritizes this group for vaccines and booster shots.
Roger McIntyre, a psychiatrist at the University of Toronto, is one of the co-authors of one of two systematic review studies that the CDC cited in its change. (Nemani is a co-author on the second.) To him, it’s no surprise that mental illness imparts an infection risk. “A thread that has been woven through many of these disorders is immune or inflammatory dysregulation,” McIntyre says.
That is, problems with the immune system tend to coincide with mental health issues. And problems with the immune system can lead people to have worse outcomes when it comes to SARS-CoV 2, the virus that causes Covid-19.
“Most of the time in medicine, it’s hard to have one singular explanation for anything,” he cautions. That’s especially true here in the discussion of why people with certain mental health issues might be more at risk for severe disease. People living with mental illnesses like schizophrenia, bipolar disorder, and major depression tend to have shorter-than-average life spans and worse health overall. They’re more at risk for heart disease and obesity; they smoke at higher rates. All these risk factors put people with these mental health issues — particularly schizophrenia — at higher risk of death from many causes, including severe infections.
The studies that have been conducted to date try to control for these factors, but it’s impossible to control for them all. Other factors like economic insecurity, added isolation brought on by the pandemic, access to diagnostic testing, or behaviors at the individual level that are hard to account for in studies could play a role.
But the scientific literature does find links between mental health and immune system health. The biggest one: Studies have reported that many people with depression, bipolar, and schizophrenia (as well as other mental health issues not highlighted as Covid-19 risk factors by the CDC) have higher levels of inflammation throughout the body.
Inflammation is one of the body’s responses to dealing with dangerous invaders like the SARS-CoV-2 virus. Inflammation is literally a flood of fluids containing immune system cells. They get released from the blood into body tissues to help clear infections. This is why infected areas of the body get swollen.
When inflammation is short-lived, it can help clear out an infection. When it is chronic, it can cause problems. It wears on the heart and can contribute to illnesses like diabetes. When it comes to Covid-19, scientists suspect that underlying inflammation — or underlying dysregulation of the immune system — is what causes some patients’ bodies to overreact to the virus, causing the worst symptoms that can land people in hospitals and lead to death.
As Nemani explains, the inflammation tends to increase with the severity of the mental illness. “For people with depression, you see a small increase in systemic inflammation,” Nemani says. It grows higher in people with severe depression, and higher still in people with bipolar and schizophrenia. (All these conditions exist on a continuum, and there are more and less severe versions of each.)
So people with certain mental health issues might have chronic inflammation, and that could lead to poorer outcomes when it comes to Covid-19. The question is, why do they have chronic inflammation in the first place?
Part of the reason may simply be the chronic stress that comes from living with mental health issues, McIntyre and Nemani say. Stress can provoke an inflammatory response, as can a lack of sleep.
But it’s also possible that the immune system has a role to play in generating these diseases. “Beginning in about 2000, we began to show that inflammation can make people depressed,” Raison says. “The best evidence is that there have been a number of studies where inflammatory stimuli [such as drugs known to cause inflammation] of various intensity and durations have been given to people, and they tend to make people feel depressed and exhausted.”
In depression, McIntyre says, scientists often (but not always) find elevated markers of inflammation in the blood. “Now, it may not be the causative role, although it might be,” he says. “It may be the causative role in some people, and it may be playing more of a secondary role in other people.”
This just provokes another question: Why would the immune system change our mood and influence our exhaustion?
McIntyre makes an example of the common cold to explain. “When you have the common cold, I’m not saying you have depression, but what I’m saying is you have a lot of symptoms that look a lot like depression,” he says. “You feel tired, your sleep is disrupted, you lose your appetite. You’re probably not enjoying many things. You’re quite apathetic. Things are bland in your life. That’s the immune system that’s been activated, creating those symptoms. We think that for some people with depression, that can explain your depressive symptoms.”
That is, when your immune system isn’t working properly, it could contribute to, or even possibly generate, depressive symptoms.
Similarly, it’s possible that the immune system plays a role in generating schizophrenia. “There’s a theory that viral exposure while in utero is closely tied with developing psychotic illness or schizophrenia later on,” says Ellen Lee, a psychiatrist and researcher with the University of California San Diego. It’s possible that the mother’s immune response during the infection leaves a lasting impact on the child’s brain and immune system. Other studies have suggested that having a prior autoimmune disorder puts a person at risk for schizophrenia. But, Lee stresses, “There’s so much that we don’t fully understand.”
The bigger point, Lee says, is to recognize that schizophrenia is “a whole-body disorder.” “We see inflammation increase in the brain and we see inflammation increase throughout the body.” That leaves people with schizophrenia at risk of a whole host of chronic illnesses. “The inflammation worsens metabolic health, which then in turn usually leads to obesity and worse inflammation,” Lee says. “So it’s all kind of a cycle.”
How infections could precipitate mental health issues
The evidence for this theory — that immune issues can contribute to mental health disorders — is incomplete.
For one, Raison says that while it seems as though inflammation can contribute to depression, “it has not appeared that blocking inflammation is a particularly robust way to either treat or prevent these disorders.” So there’s a big piece of the puzzle missing there. Another missing piece: There are some cases of depression where inflammation does not appear to play a big role, says McIntyre, and there are probably many unrecognized or underrecognized causes or contributors to mental health issues.
Finally, the mental health conditions mentioned in this piece — depression, bipolar, schizophrenia — are not fully understood to begin with. Scientists just generally don’t understand how much biological overlap there is among them. With depression in particular, some scientists suspect it isn’t just one disease, but perhaps many different ones that manifest with similar, overlapping symptoms.
So the big picture is complicated and incomplete.
But if it is true that the immune system can influence the mind and vice versa, it opens up some important, fascinating questions.
For instance: Can getting sick, and the immune system reaction to fighting a virus, provoke changes in mental health? Our bodies get inflamed when we fight off an infection. Could that impact and even possibly cause or contribute to a mood disorder?
Past work suggests it could. An enormous study of the health records of 3.56 million people born between 1945 and 1996 in Denmark showed that a history of infection and autoimmune disorders predicted later diagnosis of mood disorders. More specifically, the study found that the more infections a person had, the more at risk they’d be for mental health issues later on; there could be a causal pathway here. That makes it seem like the infections themselves are a risk factor.
This also might be playing out in the pandemic. “It seems like having Covid puts you at higher risk for psychiatric illness after infection,” Nemani says. A February study of 69 million individual health records, published in The Lancet, found that “the incidence of any psychiatric diagnosis in the 14 to 90 days after Covid-19 diagnosis was 18.1 percent, including 5.8 percent that were a first diagnosis.” (The study made a few comparisons. Covid infections seem to precede more first time mental health diagnoses than breaking a bone, getting a kidney stone or a gallstone, and seem to precede more diagnoses than other infections like the flu.)
Exactly how this unfolds is not fully understood. Some of it might be due to the peculiarities of Covid-19 and how it can infect nervous system tissues, and is possibly a unique symptom of long Covid. (As reported in the Lancet study, Covid-19 patients were around twice as likely to develop a psychiatric illness for the first time compared to a control group of people who were sick with the flu.) But it also could be because many viral infections can nudge people’s mental health in a poor direction.
Consider the common cold example McIntyre laid out above. What if, after getting an infection, the lethargic wasting feeling doesn’t leave? There’s some suspicion that changes to the immune system, wrought by battling the virus, could do that.
Again, this is hardly settled science. But the pandemic presents these psychiatry researchers with an opportunity to ask these questions. When it comes to mental health risk after an infection, “what we’re going to need to do is tease apart what’s due to general stress from the pandemic itself — people losing people that they love, the stress of just getting the diagnosis itself, all of the life changes that came along with it — from the potential immune effects of the virus,” Nemani says.
More questions could be answered, too. “Looking ahead, we might be able to better understand how a viral infection can lead to new onset psychiatric illness,” she says. “If we can better understand that mechanism, we might be able to identify treatment targets that could potentially help treat psychiatric symptoms … and maybe even bolster the immune system of susceptible patients.”
Taking care of mental health can help communities prepare for outbreaks
Despite scientists having an incomplete picture of the science here, they believe it’s still useful to know that mental health issues can be a precursor to infection risk, or vice versa.
Recently, public health researchers at Yale published a study that found a county-level correlation between people’s general mental well-being and confirmed cases of Covid-19. Whereas the meta-reviews mentioned above looked at infection risk for actual diagnoses, this study looked at a more general measure of “poor mental health days.” It’s a self-reported measure that simply has people recall “the number of days that you are kind of feeling down or had some emotional issues,” Yusuf Ransome, the Yale epidemiologist who led the study, says.
In this study, “poor mental health days” is used as a way to take the mean mental health temperature of a region, and it does seem to be correlated to outbreak risk. At this zoomed-out level of analysis, it’s even harder to determine causality. But at least, Ransome says, it suggests that when it comes to the intersection of mental health and infection, we shouldn’t just focus on issues that rise to the level of a diagnosis.
“When we are only focusing on clinical manifestations, we might miss sort of the much more lay version of how people are experiencing mental health,” he says. “We need to look at even the most basic indicators of mental well-being. We don’t necessarily need to have the whole population diagnosed by a clinician for depression to understand the severity of the impact.”
To identify communities where mental health is overall poor, he says, is to potentially target them for interventions and outreach to help deal with future viral outbreaks.
For now, the scientists who research this intersection of mental health and the immune system want the public to know that mental health disorders can be whole-body disorders. They don’t just impact the brain. And for that, they applaud the CDC’s decision to recognize these disorders as being risk factors for severe Covid-19. A lot of people with such disorders are underserved by health care in general.
“People with mental health disorders — especially schizophrenia, severe depression — they don’t receive primary care interventions as often as other people,” Nemani says. “The fact that the CDC updated their high-risk list to include some of these mental health conditions was just, you know, a really great thing that really might help save lives.”
It’s hard to think of any silver linings in the pandemic, but one is the potential to gain knowledge. “We have a single virus at a single point in time, infecting so many people at a scale that we’ve never seen before,” Nemani says.
If scientists can use the pandemic to learn even more about the nature of these mental illnesses and how they interact with the immune system, more future lives could be saved, too.