Long overdue and sorely needed, research into chronic fatigue syndrome has picked up speed since the pandemic illuminated the lasting and debilitating effects of long COVID.

The possible causes of chronic fatigue syndrome, otherwise known as myalgic encephalomyelitis (ME) or ME/CFS, remain elusive despite this new research effort, although they are slowly coming into focus. Past viral infections triggering an overactive immune system and malfunctioning mitochondria depleting cells of energy are possible explanations for how chronic fatigue syndrome develops.

Now a new study based on mice suggests that some drugs used to treat depression, which commonly accompanies ME/CFS, could also ignite the condition.

Based on clinical clues, Jin‑Seok Lee, a ME/CFS researcher at Daejeon University in South Korea, and colleagues hypothesized that a spillover of serotonin could lead to ME/CFS.

Known to play a role in governing moods, declining levels of the neurotransmitter serotonin have long been thought to cause depression. Although that theory is now disputed, treatments that target serotonin pathways – such as selective serotonin reuptake inhibitors (SSRI) – are some of the most commonly prescribed antidepressants.

By blocking receptors that bind and remove serotonin from the signalling pathway, the medication artificially maintains a higher level of the mood messenger.

According to several decades-old studies, some patients with ME/CFS appear to have fewer serotonin transporters than healthy volunteers, and may also have receptors that only weakly bind serotonin.

Lee and colleagues thought that if such people had coincidentally been treated with serotonin-based treatments for depression before they developed ME/CFS, they may have had excessive levels of serotonin in their brain. This could have triggered ME/CFS by throwing off a feedback mechanism designed to keep a lid on the immune system and inflammation.

"However, no animal-derived evidence verifying the 'hyper-serotonergic hypothesis' has been reported yet," the researchers explain in their published paper.

Symptoms of ME/CFS include unrelenting chronic fatigue that doesn't ease with sleep, post-exertional malaise (PEM), memory and concentration problems, and a triggering or worsening of symptoms when sitting upright, called orthostatic intolerance. Body pain and depression are also common.

It should be noted that for some people with chronic fatigue syndrome, taking antidepressants to manage their mental health can improve some symptoms when coupled with cognitive behavioral therapy. But there is little evidence to support using antidepressants to treat ME/CFS, and they may cause further fatigue, so it remains controversial.

Lee and colleagues tested whether antidepressants such as SSRIs could trigger the onset of ME/CFS-like symptoms in a series of eight experiments based on mice.

Both female and male mice were injected with either fluoxetine, an SSRI otherwise known by its brand name Prozac, or saline (noting that the animals received a dose of fluoxetine two to five times higher than what is used in clinical practice).

After four weeks, animals treated with fluoxetine had higher levels of serotonin in two parts of the brain, the hypothalamus and dorsal raphe nucleus.

They also developed behaviors that resembled the main symptoms of ME/CFS seen in humans, including unrefreshing sleep, PEM and orthostatic intolerance, but not cognitive impairment. These behaviors disappeared six weeks after the drug was stopped.

Mice whose serotonin receptors were depleted via viral knockout also showed ME/CFS symptoms, further confirming the mechanism. Another experiment showed inhibiting serotonin production could alleviate their symptoms.

"Our study provides the first translational [animal] evidence for the involvement of serotonergic hyperactivity in the pathophysiology of ME/CFS," Lee and colleagues conclude, adding that high levels of serotonin could also be used to distinguish ME/CFS from other similar disorders such as fibromyalgia.

In the scheme of research though, animal experiments are only the first step on a long pathway to clinical studies and trials involving patients. So we'll have to wait to see how this new avenue of research into the link between serotonin levels and ME/CFS unfolds.

One small clinical trial found in 2014 that treating ME/CFS patients with a drug that depletes a precursor to serotonin had no measurable effect on fatigue severity, concentration and mood states, compared to placebo. But with just five patients in that trial, much larger studies are obviously needed.

The research has been published in the Journal of Translational Medicine.