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Long Covid

An Update on Long COVID and Psychiatric Symptoms

Inflammation from COVID can result in structural and functional brain changes.

Key points

  • Individuals with long COVID may experience a spectrum of clinical manifestations.
  • The invasive properties of COVID can cause inflammation in the brain and central nervous system.
  • Patients with long COVID can experience psychiatric symptoms.
  • No single treatment is proven effective, but some options are available.

During a 60 Minutes interview in September of 2022, President Biden said, “The Covid-19 pandemic is over in the United States.” While some rejoiced, and others felt a sense of relief, Michelle Williams, Dean of Harvard T.H. Chan School of Public Health, stated, “President Joe Biden’s declaration that the pandemic is over, made during a September 18 television interview, is premature and harmful to the country’s COVID-19 response.”

Yesterday, the CDC website reported over 6,000 hospitalizations and over 1,100 deaths from COVID between May 17 and June 13 of this year. These are not the astronomical numbers reported at the height of the pandemic, but they are not inconsequential. As important as these numbers are, what about those who continue to experience long COVID symptoms?

According to the CDC, long COVID is broadly defined as “signs, symptoms, and conditions that continue or develop after initial COVID-19 infection. A 2022 research study in Experimental and Therapeutic Medicine reported, “individuals with long COVID may experience a spectrum of clinical manifestations, both pulmonary and extrapulmonary, as well as fatigue and malaise.”

Research suggests the neuro-invasive properties of the virus with respect to the brain and central nervous system can lead to inflammation in those systems from an overproduction of inflammatory proteins, such as cytokines, as well as hyperactivation of the immune system. Several lines of evidence indicate that neuropsychiatric disturbances in long COVID patients may be associated with a hyperinflammatory state along with elevated levels of pro-inflammatory cytokines.

In 2020, researchers studied over 400 COVID survivors who sought treatment at an emergency room and found that, overall, over 50 percent scored in the unhealthy range for psychiatric symptoms. This included depression, anxiety, post-traumatic stress disorder, and obsessive-compulsive disorder. Of the patients studied, those more likely to develop these symptoms included women, patients with a pre-existing psychiatric diagnosis, and those who had previously managed their COVID symptoms at home. On follow-up three months later, at least one-third of those studied still experienced psychiatric symptoms in at least one area.

A 2022 review article in the Journal of Psychiatric Research reported current findings in a series of studies that looked at neuropsychiatric complications of long COVID. The neuropsychiatric symptoms in adults resemble chronic fatigue syndrome. The most common complaints include severe incapacitating fatigue, pain, compromised sleep, and cognitive difficulties. Cognitive impairment is more frequently observed in patients who required admission to the ICU. Similar to findings reported in 2020, the main risk factors for depression in these studies included female sex and previous psychiatric history.

Unfortunately, unlike other complaints, psychiatric symptoms were slow to resolve and sometimes lasted over 12 months. The authors reviewed several studies that looked at changes in brain metabolism and anatomy after a COVID infection. One study reported the results of patient PET scans (a technique that measures physiological function by looking at blood flow and metabolism) three weeks after a COVID infection. They found decreased metabolism in several brain areas, and interestingly, “brain fog” was correlated with highly specific areas of decreased metabolism.

In a different study that looked at brain (MRI) images of participants after infection, researchers found the severity of depression that patients reported was correlated with the degree of decreased volume in an area of the brain associated with emotions and behavior. The authors of both studies concluded that brain inflammation during an acute episode of COVID predicted structural and functional changes in survivors’ brains as well as psychiatric complications in those with long COVID.

What are some treatment options?

The treatment of long COVID is dynamic and multidisciplinary, depending on the involved systems and the patient’s relative signs and symptoms. According to an article in the Nepal Journal of Epidemiology, a large proportion of individuals reportedly seek self-care and often resort to polypharmacy to gain relief from the worst symptoms. Although there is no single treatment recommended for patients who experience neuropsychiatric symptoms after COVID, the following options have proved effective in some individuals:

  • Antidepressants: Just as antidepressants are often prescribed for patients with depression, there has also been a preliminary study using antidepressants to treat patients with COVID. The study showed rapid improvement in decreasing reports of depressive symptoms, and in addition, SSRI medications showed promise in decreasing the inflammatory properties of the virus itself. Why are SSRIs effective in treating COVID? They work by increasing the brain’s level of serotonin, a neurotransmitter that helps to improve mood and decrease anxiety. Serotonin also influences the immune system. In patients with COVID, it may help limit the cytokine release process that is partly responsible for worsening the inflammatory component of the illness.
  • ADD Meds: Researchers at Yale University published initial evidence that two drugs used to treat attention deficit disorder can lessen or even eliminate brain fog. Guanfacine was approved by the Food and Drug Administration (FDA) for treating ADHD in 2009, but clinicians have also used it extensively off-label for other brain disorders, such as traumatic brain injury and PTSD. Arman Fesharaki-Zadeh, M.D., Ph.D., assistant professor of psychiatry and neurology, has been treating long COVID patients with a combination of guanfacine and N-acetylcysteine (NAC), an antioxidant also used for the treatment of traumatic brain injury. The combined therapy was successful in relieving brain fog for a small group of individuals. While larger, placebo-controlled clinical trials will be needed to establish these drugs as a bona fide treatment for post-COVID neurocognitive deficits, patients can obtain them now if their doctors wish to prescribe them.
  • Vitamin C Supplementation: Vitamin C has immune-modulating properties and is an antioxidant. One study involving 720 patients found two-thirds of the patients receiving vitamin C supplementation produced marked reductions in fatigue scores as well as improvements in concentration, sleep hygiene, and depression compared to those who did not receive the supplementation.
  • Melatonin: Long COVID is believed to be due to a prolonged and protracted low-grade inflammatory process. Therefore, it has been hypothesized that a pharmacological agent with anti-oxidative effects may be beneficial in the treatment of the syndrome. Melatonin is a drug that activates NRF2, a protein that is believed to increase the formation of antioxidants on a cellular level. In addition, melatonin has beneficial effects on sleep disturbances experienced in some patients with long COVID.
  • Probiotics? A study is currently underway looking at the possible benefits of probiotic supplementation in patients with long COVID symptoms. Some researchers believe the disruption of the natural gut biome during COVID contributes to long-haul symptoms. We know the gut and the brain are intimately connected, so the theory makes sense. Probiotics have few, if any, side effects and are available over the counter, so there is little risk in trying this option.


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