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Researchers are looking into the potential role played by serotonin in the neurological symptoms of long COVID. Image credit: Jeff Marsh/Stocksy.
  • Long COVID affects around 5–10% of people who became infected with SARS-CoV-2, the virus that causes COVID-19.
  • There are over 200 symptoms that have been identified, and among them are many neurocognitive and psychiatric effects.
  • Researchers have now shown that serotonin levels are lower in people who have long COVID 3–22 months after infection with SARS-CoV-2.
  • This finding suggests that serotonin could be used as a biomarker to help diagnose people with long COVID and better stratify patients in clinical trials.

Long COVID, also known as post COVID-19 syndrome, affects around 5-10% of people who had a SARS-CoV-2 infection, but the risk is higher for people who were hospitalized with COVID-19, and lower for people who received a vaccine.

That long COVID can cause any combination of over 200 symptoms, including neurocognitive effects such as fatigue, memory loss, problems concentrating and “brain fog,” has been recognised since the first long COVID patients started talking about their symptoms in 2020.

As far back as January 2021, some researchers started to coin the term “neuro COVID” to describe the symptoms experienced by this particular cohort of COVID long haulers’ who report symptoms over 12 weeks after the initial infection.

It is not fully understood what causes this symptom, however, and this lack of understanding is partly due to the fact that post-viral syndromes received very little attention from researchers and doctors before the pandemic.

Chief of research and development at the Veterans Affairs St. Louis Health Care System Dr. Ziyad Al-Aly told Medical News Today in an email:

“Unfortunately, prior to the pandemic, we had invested very little in understanding post-viral illnesses. We pretty much ignored this area completely. Consequently, not much is known about the mechanisms of neurologic abnormalities that we see in people with flu and also people with COVID-19.”

This has changed since the COVID-19 pandemic and subsequent emergence of long COVID cases, as researchers have sought to understand the mechanisms underpinning long COVID in order to discover potential biomarkers for diagnostics and treatment targets.

Dr. Al-Aly added that “[t]here are threads of evidence suggesting that inflammation and microglial activation in the brain may be contributing to neurocognitive symptoms in people with long COVID.”

Now, research by a team from Perelman School of Medicine at the University of Pennsylvania has shown that people with long COVID have lower levels of serotonin, and discovered that this is driven by an inflammation pathway mediated by SARS-CoV-2 viral RNA stored in the gut, months after infection.

The research results appear in the journal Cell.

The study authors merged previously published datasets on the biochemical profile of several cohorts of long COVID patients who had experienced symptoms for 3 to 22 months after confirmed infection with SARS-CoV-2.

They placed these patients into 8 different groups based on their clusters of symptoms. For each of these groups, they investigated the biochemical profile of 58 patients considered representative of these symptom clusters, and compared them to the biochemical profile of people while infected with SARS-CoV-2, as well as with the biochemical profile of people who had recovered from COVID-19 with no remaining symptoms.

The researchers discovered that a subset of patients with long COVID had traces of the virus in their stool samples even months after infection, meaning it had remained in the gut.

While serotonin was reduced during the active SARS-CoV-2 infection, serotonin levels during infection did not predict a person’s risk of developing long COVID. However, the researchers discovered a correlation between the number of symptoms of long COVID participants had and lower serotonin levels 4 months later.

Further research in mice showed that the immune reaction caused by these remaining viruses caused inflammation that blocks tryptophan — a building block of a serotonin — uptake in the gut in mice, as well as reducing serotonin storage.

Serotonin is a chemical that allows signalling to occur between nerve cells in the body, and plays a role in mood, sleep, digestion, nausea, healing, blood clotting and sexual desire.

Researchers hypothesized that because reduced signalling in the hippocampus — a part of the brain that is involved in memory formation — has been demonstrated in people with long COVID, memory loss in mice could be due to lower serotonin signalling in this part of the brain.

However, they found that serotonin levels in the brain were normal, but that signalling of nerves outside of the brain, including the vagus nerve, was reduced in these mice, as was memory function.

Lead study author Dr. Christoph Thaiss, an assistant professor of microbiology at Perelman School of Medicine at the University of Pennsylvania told MNT that the findings showed that low serotonin could be used as a biomarker for long COVID.

“Our study suggests that there are a number of possible biomarkers that could be used for the diagnosis or treatment of long COVID, including viral components in stool and reduced levels of serotonin in the blood,” he said.

One question that follows from these findings is whether antidepressants — particularly selective serotonin reuptake inhibitors (SSRIs) — that work by increasing serotonin activity could help treat the neurological symptoms of long COVID.

Dr. Thaiss noted that “at this point, we cannot make any specific recommendations about treatment options, but our findings call for the systematic assessment of interventions targeting serotonin signalling, including SSRIs, in clinical studies”.

The authors of the paper note that low serotonin levels have also been found in patients who had Dengue fever, suggesting that their findings may have wider applications.

According to Dr. Thaiss, the findings of the current study “indicate that some of the key mechanisms we discovered in the context of long COVID are not unique to long-term sequelae caused by SARS-CoV-2 but may extend to other post-viral syndromes.“

“It is thus possible that progress made in long COVID research could help individuals affected by other post-viral syndromes as well,“ he added.

“The symptoms experienced by individuals with Long COVID are indeed similar to those seen in the case of other viruses that can cause long-term symptoms, such as influenza. However, future studies are required to determine whether the precise pathway we describe in the new study — linking viral reservoirs, persistent inflammation, serotonin reduction, vagus nerve dysfunction, and neurocognitive manifestations — is involved in post-flu symptoms.”

– Dr. Christoph Thaiss

Dr. Al-Aly, who was not involved in the research, described it as “meritorious,” noting that “the reality is that long COVID is a complex disease and the neurocognitive and mood abnormalities could be driven by many mechanisms.”

“I think these data present a mechanistic pathway that makes a compelling case for testing SSRIs in trials to determine whether they would ameliorate cognitive outcomes in people with long COVID and ‘brain fog’, the term colloquially used to refer to cognitive abnormalities seen in people with long COVID,” he told us.