Dr. Maura Boldrini

With more than a year of observing the wide-ranging impact of COVID-19 on multiple organ systems, psychiatrists have acquired a growing knowledge base of short- and long-term neuropsychiatric symptoms and long-term brain sequelae. Maura Boldrini, MD, PhD, Director of the Human Neurobiology Laboratory in the Department of Psychiatry at Columbia University Irving Medical Center and the New York State Psychiatric Institute, conducts research focused on understanding the underlying mechanisms of behavioral and cognitive changes associated with brain disease. Dr. Boldrini was recently asked by JAMA Psychiatry to provide a review of current thinking about the ramifications of COVID-19 from a psychiatric perspective.

“There have been more than 130 million COVID cases worldwide, so it’s more important than ever to understand how this disease may affect the brain and behavior,” says Dr. Boldrini, who as a member of Columbia’s psychiatry consult service, has cared for COVID-19 patients with new-onset delusions, hallucinations, anxiety, and depression. “While isolation, financial burden, and increased drug use due to the pandemic may cause anxiety and depression, we also think that biological changes such as inflammation are linked to behavior and may provide another explanation for how infectious diseases can affect mental health.”

Among the symptoms reported in the literature are loss of sense of smell, cognitive and attention deficits, new-onset anxiety, depression, psychosis, seizures, and suicidal behavior that can present before, during, and after respiratory symptoms. Notably, these symptoms are unrelated to respiratory insufficiency, which suggests brain damage occurs independently.

“In psychiatry, we have been interested in understanding the role of neuroinflammation in psychosis, depression, and other mental health conditions,” says Dr. Boldrini. “Previously, our group has found increased inflammation in the brains of people who die by suicide and we are now investigating if COVID-19-related inflammation can trigger suicidal thinking and other psychiatric effects.”

The severe cytokine storm that can accompany COVID-19 infection is associated with increased serum levels of proinflammatory cytokines, which, once they cross the blood-brain barrier, activate microglia and astrocytes. This launches a cascade of events that could possibly induce altered learning, memory difficulties, neuroplasticity, hallucinations, and nightmares.

In their review, published in the March 26, 2021 issue of JAMA Psychiatry, Dr. Boldrini and her co-authors suggest that COVID’s effects on the brain may be caused by small blood clots and inflammation that potentiate each other. “Based on what we know about COVID so far, systemic inflammation may unleash chemicals that trigger symptoms such as hallucinations, anxiety, depression, and suicidal thinking, depending on which part of the brain is affected,” notes Dr. Boldrini. “We don’t think that the virus is directly invading the neurons or other cells in the brain.”

Evidence suggests that a small amount of virus may be able to enter the brainstem and cerebellum via the circumventricular organs – midline structures around the third and fourth ventricles. “These openings in the blood-brain barrier allow us to sense and respond to toxins,” says Dr. Boldrini. “In fact, the little amount of virus that’s been detected in the brain has been found in regions located near the circumventricular organs.”

Dr. Boldrini and her colleagues are now examining the electronic health records of deceased COVID patients who had neuropsychiatric symptoms. “In my lab, we’re analyzing the brain tissue in greater detail to look for cells and molecules that may be involved in these pathogenic pathways. We’re measuring the amount of microglia, neuronal damage, and inflammatory markers that are present in the brains of these patients. If we find that inflammation is causing psychiatric symptoms in COVID patients, we would look to approaches that could modulate the inflammatory markers to slow down a persistent inflammatory response and prevent brain damage.”

“Psychiatric researchers play an important role in helping to uncover the biological effects of COVID on the brain,” adds Dr. Boldrini. “If we don’t do this work, we could be dealing with a mental health pandemic long after the COVID-19 pandemic is over.”