COVID-19 May Be Linked to Spontaneous Psychosis. Researchers Are Trying to Figure Out Why

One 33-year-old North Carolina mother with three children began to experience symptoms of COVID-19. A different set of symptoms developed four days later. She stopped sleeping well and started having paranoid delusions that people were tracking her through her cell phone—culminating in a frantic scene at a fast-food restaurant, in which she tried to pass her children through the drive-through window, where they’d be safe from the phones and other dangers.

The restaurant worker called 911 and the emergency medical service workers quickly arrived. They gathered the family and took them to Duke University Medical Center, Durham. Doctors were able to treat the mother immediately. “She was physically in the room, but she wasn’t making consistent eye contact,” says Dr. Colin Smith, who is now chief resident of the hospital’s internal medicine psychiatry program but was a second-year resident when he took care of the patient. “She was not really engaging all that much. Her thought processes were disorganized.”
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Smith and her other doctors acknowledged the following: The patient knew that her behavior was not typical and she had to make changes quickly.

There’s growing evidence that COVID-19 and new psychotic episodes are connected. North Carolina is the case. Report in British Medical JournalIn August 2020, the case report joins an array of medical journal cases that describe psychotic episodes after a COVID-19 diagnose. The July 2020 issue is available at BJPsyh Open, researchers reported that a 55-year old woman in the U.K., with no history of mental illness, arrived at a hospital days after recovering from a severe case of COVID-19 with delusions and hallucinations, convinced that the nurses were devils in disguise and that monkeys were jumping out of the doctors’ medical bags. Other researchers also wrote in April 2021. In BMJ Case ReportsA middle-aged British male, with no previous mental disorders, had presented at a London hospital suffering from auditory and visual hallucinations. He also banged his head against the walls, causing severe burns. He had been discharged from COVID-19, which had left him in the ICU for several weeks. A second case is published in Journal of Psychiatric Practice in March 2021, a 57-year-old-man turned up at Columbia University’s New York Presbyterian Hospital insisting that his wife was poisoning him, that cameras had been planted throughout his apartment, and that the patients in the hospital’s emergency department were being secretly murdered.

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“The situation was strikingly similar to one we’d expect from someone who had a schizophrenia spectrum illness,” says Dr. Aaron Slan, now a fourth-year psychiatry resident at Columbia University, who cared for the patient and co-authored the report. Slan says that this particular patient also had no mental illness history and was not too old to have schizophrenia. Schizophrenia typically strikes between the ages of 20-30 for men. A test at the hospital showed that the patient had COVID-19.

COVID-19-related psychotic breaks are rare—though researchers say that it’s too early to say exactly how rare—and plenty of experts believe that the connection between the two conditions, if any, is not causal. The 2021 review is available here. Neurological letters, a group of researchers in the U.K. casts doubt on the emerging body of work on the COVID-19-psychosis link as “beset by both small sample size, and inadequate attention to potential confounding factors,” such as heightened stress, substance abuse, and socioeconomic hardship.

Researchers are still investigating this link. A U.K. study was published in LancetIn October 2020, it was found that 10 of the 153 COVID-19 patients who had been diagnosed early during the pandemic experienced new-onset psychotic episodes. Seven others also developed psychiatric disorders including catatonia or mania.

An analysis Publication last August General Hospital PsychiatryWe took a wide-ranging view and analyzed 40 scientific articles. This included 48 people from 17 countries that experienced psychotic episodes due to COVID-19. The same as the Neurological letters paper, the authors of this study found plenty of other variables that might muddy the link between COVID-19 and psychosis—like stress, substance use, and medications—but the relationship still held.

“We see post-infectious neuroinflammatory disorders associated with a variety of different viral illnesses,” says Dr. Samuel Pleasure, a neurology professor at the University of California, San Francisco (UCSF). “Normally we see it in very small numbers, but here we have [COVID-19] infecting tens of millions of people at the same time.” Even rare cases of psychiatric conditions will start to show themselves when the sample group of infected people is so large.

At this stage, there are many questions and more answers than answers. It’s still unclear whether the severity of COVID-19 symptoms plays any factor in the probability of a mental breakdown. “There seem to be clearly cases of neuropsychiatric consequences of COVID that are linked to cases that are not severe,” Pleasure says. “I believe that the quality of the studies at this point are so preliminary, and the ability to really capture these patients to study is really at early stages, so it’s hard to be definitive.” Similarly, Pleasure says, it’s impossible to say whether people suffering from Long COVID—symptoms that last for months after the infection is over—are more susceptible to psychotic symptoms.

There are multiple possible mechanisms at work, any one of which—or a combination—could be contributing to the neuropsychiatric symptoms associated with COVID-19. Pleasure says that direct infected brain tissue would be the easiest. If that’s so, the number of COVID-19 patients who suffer loss of the sense of taste and smell would suggest that the brain’s olfactory bulb may be struck by the virus first.

“There are documented cases where people have done MRIs early in the [COVID-19 disease] process and have seen some local inflammation in the olfactory bulb,” Pleasure says. “That has contributed further to the idea that maybe that’s the portal of entry.” Once that portal has been breached, the brain at large could be exposed.

It is not clear how COVID-19 infects the brain. Pleasure performed lumbar punctures on three teenagers with neuropsychiatric symptoms who were suffering from COVID-19. Wilson was an associate professor of neurology at UCSF. Two cases showed antibodies to neural antigens found in their fluid. This was a puzzle because the patients were suffering from SARS-CoV-2. They should have antibodies against the virus and not their neural tissue. Pleasure points to a Yale University study that showed antibodies against the coronavirus spike protein can cross-react with nerve cell receptors, attacking them.

“There was molecular mimicry between the spike protein and a neural antigen,” he says. “One of the main hypotheses is that if there’s an antibody that targets the virus, then, out of bad luck, you also see damage to the host.” In other words, he says, you start with an immune response adaptive to fighting the virus, and that turns into an autoimmune response.

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That’s just one theory. COVID-19 could also be transmitted to the brain through other methods. Upper respiratory infections can, on occasion, cause the immune system to go awry and develop antibodies against parts of the brain known as NMDA (N-methyl-D-aspartate) receptors, which are the main excitatory receptors that react to neurotransmitters. Dr. Mudasir Firdosi says that a wide-ranging attack on neurotransmitter receptors throughout the brain may cause rapid and serious symptoms. Consulting Psychiatrist in the Kent and Medway NHS and Social Care Partnership TrustAnd a Co-author for the 2021 BMJ Paper.

“[NMDA involvement] presents a very, very florid way to be psychotic,” Firdosi says. Slan is in agreement: “When someone has an abrupt onset of psychosis following a viral illness, NMDA antibodies are frequently invoked,” he says.

The so-called “Neuropsychiatric Syndrome” is another factor in neuropsychiatric symptoms. Cytokine StormThis is often due to infection with SARS/CoV-2. The immune system makes cytokines which are important proteins that aid cell signaling. These proteins can lead to inflammation, which in turn may fight off infection. However, if the cytokine levels get out of control it can cause severe inflammation throughout the body. Brain tissue could also be affected.

“The neurons themselves are not being invaded,” says Slan, “but what happens is that the systemic inflammatory response causes both stress and changes in signaling throughout the body. These types of inflammation can also affect the brain. [psychotic] symptoms.”

The history of COVID-19 and psychotic breaks is another source of proof. This evidence comes from not the current scientific literature. Following the influenza pandemic of 1918 and 1919, there was a spike in what was called encephalitis lethargica, which was essentially a form of early-onset Parkinson’s disease that often didn’t appear for a number of years after the infection—but left patients in what was effectively a state of catatonia.

“That flu virus caused a post-infection inflammation that killed brain cells that in turn led to the Parkinson’s,” says Pleasure. Both the book and film Awakenings, about patients who temporarily recovered consciousness and lucidity after treatment with l-dopa—a precursor of the neurotransmitter dopamine—was based on cases of people suffering from that form of Parkinson’s.

However, unlike other forms of psychosis that can be chronically recurrent, cases related to COVID-19 are unlikely to last. Smith and Slan say that symptoms may respond to antipsychotic medication like Risperdal, risperidone, and Zyprexa (olanzapine). Intravenous immunoglobulin infusions—which reduce the overall load of abnormal cells and inflammatory agents—and steroids, which also reduce inflammation, can be effective as well.

The case against virus-triggered psychosis is not over. Even Slan, who has first-hand experience treating a patient suffering from a seemingly virus-linked psychotic break believes that there is more work to be done—and acknowledges the doubts of the researchers who believe other psychological factors might be at play.

“Given the stress of COVID,” he says, “given the concerns about mortality, seclusion, all of these things represent huge psychosocial stressors, and they have the potential to precipitate oftentimes short-lived psychotic symptoms.”

Of course, even a transitory psychosis is still a psychosis—something no one wants to experience even fleetingly. It is important to prevent infection. “The best way to treat COVID-19 and the risk of psychosis is to prevent it,” says Smith. “Even if neurological complications are rare, getting vaccinated remains the smartest choice.”


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