The Effects of Covid-19 On the Brain’s Dopamine and Serotonin Systems


This could be why 18% of Covid-19 survivors will receive a psychiatric diagnosis, a population-sized study finds.
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In April 2020, a research review with an interesting title was published: “Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.” This review draws on past pandemics and epidemics to infer what might happen following the Covid-19 pandemic, which a wave of psychiatric maladies.

Fast-forward today, we may finally see that wave. A more recent paper published in The Lancet Psychiatry found that 18% of Covid-19 survivors — regardless of hospitalization status — develop psychiatric disorders within 14 to 90 days of infection. Considering the pandemic scale that has exceeded 180 million cases and 3.9 million deaths, 18% is huge.

What the study did and found

Using the TriNetX Analytics Network that stores health data of nearly 70 million patients across 54 healthcare organizations in the U.S., researchers at the University of Oxford identified 62,354 cases of Covid-19. The study controlled for 50 covariates that may influence the results, which include age, sex, race, socioeconomic factors, nicotine dependence, and comorbidities (e.g., kidney, liver, heart and lung diseases, obesity, hypertension, diabetes, cancer, dementia, and rheumatoid arthritis).

After adjusting for covariates, they found 18% of Covid-19 survivors received a psychiatry diagnosis within 14 to 90 days of infection, of whom 5.8% had no history of psychiatric disorder. These 18% and 5.8% rates translate to a 1.5- to 2-times increased rate of recurrent and first-time diagnoses, respectively, compared to groups with a non-Covid health event — such as influenza, other respiratory infections, skin infections, gallstones, kidney stones, and bone fracture. Anxiety disorders, mood disorders, and insomnia were the most common diagnoses.

Even in Covid-19 cases that do not require hospital care, the risk of psychiatric aftermath remains 1.5–2-times higher. “The elevated risk of psychiatric sequelae after Covid-19 diagnosis compared with control health events could not be readily explained by differences in illness severity,” the authors wrote, although a modest dose-dependent relationship seems to exist. However, I would keep an open mind until further studies replicate the findings that even mild or asymptomatic Covid-19 would affect a person’s mental health.

“People have been worried that Covid-19 survivors will be at greater risk of mental health problems, and our findings … show this to be likely,” Paul Harrison, a professor of psychiatry at the University of Oxford who directed the study, stated.

The study also found that a history of psychiatric disorder led to a 1.6-times increased risk of positive Covid-19 diagnosis. Indeed, pre-existing psychiatric disorders do count as comorbidities that up the risk of more severe Covid-19. “Having a psychiatric disorder should be added to the list of risk factors for Covid-19,” said the study’s lead author, Max Taquet, Ph.D., a psychiatry researcher.

As with any study, results must be interpreted in light of the study's caveats. For one, despite already accounting for 50 covariates, the authors admitted that overlooked covariate may still be present. The geographical limitation to the U.S. only is also another drawback. Specifics about the psychiatric diagnoses were also lacking, such as severity or diagnostic criteria, which is a serious limitation that may undermine the study.

James C. Coyne, a health psychology professor at the University Medical Center Groningen, critiqued that the pandemic’s front liners may not have made diagnoses as accurately as a psychiatrist. A structured psychiatric interview, he said, usually takes 30 to 90 minutes, which is overly time-consuming at a massive scale. Thus, in this study, the diagnosed depression and anxiety cases may not be as severe as to qualify as major depression or anxiety disorders.
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Biomolecular underpinnings

Let’s assume Covid-19 survivors indeed have a 1.5–2-times increased rate of future psychiatric diagnoses than survivors of other health events (e.g., influenza, gallstones, skin infection, etc.). Why is Covid-19 more strongly linked to psychiatry than other health events?

Part I: ACE2/DDC pathway

ACE2 is the receptor SARS-CoV-2 (that causes Covid-19) uses to enter cells. ACE2 co-expresses and co-regulates with dopa decarboxylase (DDC), an enzyme that makes serotonin and dopamine — neurochemicals involved in depression and anxiety. Upon cell infection, SARS-CoV-2 engulfs the ACE2 receptor, which lowers ACE2 expression on the cell. This decreases DDC expression as well, halting the production of dopamine and serotonin.

“Hence, a SARS-CoV-2- induced defective expression of ACE2 might be paralleled by a DDC dysfunction, with consequent potentially altered neurotransmitters’ levels in Covid‐19 patients,” stated a paper published last month in the European Journal of Psychiatry.

Recall that SARS-CoV-2 lowers ACE2 expression. The normal function of ACE2 is to convert angiotensin II to angiotensin 1–7. Therefore, if ACE2 decreases, angiotensin II would increase. And the problem is that angiotensin II promotes depression and anxiety as angiotensin II initiates a cascade of reactions leading to inflammation and oxidative stress in the brain.

Part II: TRP/KYN pathway

The tryptophan/kynurenine (TRP/KYN) pathway is one of the best-studied pathways in depression and anxiety. As tryptophan crosses the blood-brain barrier to turn into serotonin, the TRP/KYN pathway strongly influences the brain’s serotonin levels.

This pathway starts when pro-inflammatory cytokines activate an enzyme called indoleamine 2,3-dioxygenase (IDO-1). IDO-1 degrades TRP into KYN to suppress inflammation. As TRP is lost, serotonin production is compromised. And since IDO-1 is present in many organs, including the brain, systemic inflammation would lead to a system-wide decrease in serotonin levels.

“All of these pathways raise the possibility of patients affected by severe Covid-19 with prolonged exposure to inflammation, may have long-term neurological sequels,” wrote a research review published this month in The Neuroscientist that highlights the TRP/KYN pathway in Covid-depression.
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Short abstract

Covid-19 survivors are at 2- and 1.5-times increased rate of recurrent and first-time psychiatric diagnoses, respectively, compared to survivors of non-Covid health events (e.g., influenza, skin infections, gallstones, etc.). Indeed, 18% of Covid-19 survivors had psychiatric aftermath — most commonly anxiety, depression, and insomnia — of which 5.8% were first-time diagnoses. The propensity to target the ACE2 receptor — in addition to cytokine storm induction— may be why SARS-CoV-2 is a greater risk factor for psychiatric aftermath than other health events.

Yet there’s the critique that diagnoses made by the Lancet study may not be as accurate as a psychiatrist's. The study may have diagnosed depression and anxiety that may not qualify as severe major depression or anxiety disorders. Thus, there may not be a wave of serious psychiatric disorders, but a mental health one. Indeed, coupled with income loss, bereavement, and social isolation, mental health crises may be at an all-time high.

This article was previously published in Microbial Instincts with minor modifications.

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MSc Biology student | 5x first-author academic papers | 100+ articles on coronavirus | Freelance medical writer


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