From the very beginning of the pandemic, it has been clear that COVID can have as profound an impact on mental health as it does on physical well-being.

Rates of depression and anxiety have spiked around the globe, even among those who’ve never been sick. For those who have been infected, the risk is higher. People who’ve had COVID-19 and have recovered are more likely to be diagnosed with depression or anxiety in the year after their illness, and they’re more susceptible to sleep problems and substance abuse, too.

For a small subset of those patients, the connection can be especially sudden and severe. For more than two years, doctors around the world have published case reports describing COVID-related psychosis, telling stories of previously healthy individuals who suddenly develop symptoms like hallucinations or violent delusions.

And the causes are still not clear.

In so many ways, the pandemic has whipped up a perfect storm for mental health issues. There’s the stress and isolation of pandemic living, and there are millions of people dealing with the fallout of an infection and long COVID. Loss, fear, uncertainty and physical pain have upended many people’s lives.

But researchers increasingly believe there is a biological underpinning to the COVID-related mental health crisis as well. The virus puts people at greater risk of health problems like inflammation and blood clots that can take a toll on the brain. There’s also some evidence suggesting the virus may directly enter the brain itself — though that research is still very preliminary.

Regardless, it is clear that the relationship between COVID and mental health issues is complex. Mental health experts have known for some time that people with schizophrenia or mood disorders, like depression, may be at greater risk for getting really sick if they are infected with COVID. The why, again, isn’t known.

It is possible, for example, that people with schizophrenia have underlying immune system disturbances that increase their risk of severe illness if they are infected with COVID-19. But researchers haven’t ruled out the very real possibility that it could be something else. Social determinants of health, like economic stability or access to health care, could also be factors. Those kinds of stressors can put people at greater risk of certain mental health issues, and can also increase the likelihood of severe illness if they get COVID.

There are no solid estimates on how many people around the world have developed sudden-onset psychosis after a COVID infection, but the available data shows that it is rare. Still, mental health experts say it is an important issue to track because there’s still so much they do not understand about it.

Most case reports are puzzling, in that they’ve cropped up in individuals with no previous mental health issues, and the symptoms are severe. Case studies have described patients becoming physically and verbally aggressive, seemingly out of the blue. Some came to believe their health care providers are out to kill them. Others began hearing voices. With psychotic disorders — a category that includes schizophrenia — people become detached from reality, and can experience hallucinations and delusions.

“There’s still a lot we don’t know about the relationship between COVID-19 and psychosis. What we do know is that there are many causes of psychosis, including infection,” said Dr. Cristopher Bartley, an immunopsychiatrist at the University of California San Francisco who worked on a 2021 study looking at three teenagers with COVID who developed severe and sudden psychiatric symptoms.

Bartley explained that other viruses, such as herpes simplex, can cross into the central nervous system and cause severe complications like autoimmune encephalitis — basically, inflammation of the brain that can cause psychosis. But he cautioned that the evidence at this point that SARS-CoV-2 (the virus that causes COVID) can directly infect brain cells is “weak.”

One hypothesis that Bartley said is gaining traction is the idea of autoimmune psychosis. The SARS-CoV-2 virus basically wreaks havoc on the immune system to the point where the body starts attacking itself, including the central nervous system. But that theory, at this point, is by no means a perfect one, Bartley emphasized. Doctors aren’t finding the kinds of biomarkers of autoimmune psychosis that would support the idea.

“This COVID-19 psychosis is mysterious,” Bartley said. “Most cases seem to occur out the of the blue and we don’t know why.”

Mental health experts stress that researchers need to take the phenomenon seriously, if for no other reason than the virus is not going anywhere.

Psychosis itself remains under-treated, with many people waiting years before seeking help. So it is possible that in some cases the timing of people’s psychosis is coincidental, Bartley said. About 3.5% of people experience a psychotic episode at some point in their lives, making it more common than many realize.

It is too soon at this point to tell what the long-term outlook is for people who develop severe symptoms of psychosis after COVID infection. There are some reasons to be hopeful, however.

“Fortunately, there are a number of cases where COVID-19 psychosis seems to resolve without intervention,” Bartley said. “We don’t have indications yet that SARS-CoV-2 leads to schizophrenia, which is a stable lifelong form of psychosis. This is reassuring.”

Still, much about why some otherwise healthy people develop this kind of severe response remains a mystery — which makes treatment and prevention difficult.

Psychosis can be treated through a combination of therapy and antipsychotic medications. Sometimes it’s necessary for people to receive care in a hospital or rehab setting. In the case of chronic conditions like schizophrenia, there are ways to manage it throughout a person’s life.

But in order to help, doctors and researchers must understand the root causes. And with post-COVID psychosis, there are more questions than answers at this point.

“There’s still a lot,” Hartley said, “that we don’t know.”

Experts are still learning about COVID-19. The information in this story is what was known or available as of publication, but guidance can change as scientists discover more about the virus. Please check the Centers for Disease Control and Prevention for the most updated recommendations.