Psychiatrists are finding links between infections and mental illness. They’re surprising

18th December, 2021.      //   Health  // 

Immune responses to viruses such as SARS-CoV-2 can have an impact on mental health and vice versa. Doctors are working to figure out how.

One of the most pressing issues following the Covid-19 outbreak was: Why do some people grow sicker than others? It’s a topic that’s driven scientists to address some profound secrets of the human body, leading to startling discoveries.

Psychiatrists reported in the fall of 2020 that, among the various high-risk groups, those with psychiatric illnesses appeared to be getting more severe types of Covid-19 at a higher incidence. Katlyn Nemani, a neuropsychiatrist at NYU, decided to investigate further, asking: How much more at danger, and under what conditions?

She and a group of colleagues in New York published a study of 7,348 Covid-19 patients in January. 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 — people with a schizophrenia spectrum diagnosis faced more than two and a half times the average person’s risk of dying from Covid-19.

“That was a startling discovery,” Nemani says. She claims that the patients were all hospitalized in the same medical system and in the same region, implying that they weren’t receiving drastically different treatments. Overall, it appears that the risk was directly tied to the mental illness itself, rather than to any other factor.

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.

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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.

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