Due to their beneficial effect in acute COVID-19, selective serotonin reuptake inhibitors (SSRIs) have also been discussed for the treatment of people who are already suffering from Long COVID. One study so far reported significant improvement with SSRIs in patients with existing Long COVID who are suffering from depression as a consequence of COVID-19. In response to these positive results, a recent study aimed to further investigate SSRIs in Long COVID patients.
What are selective serotonin reuptake inhibitors (SSRIs) and how do they work?
SSRIs are a class of medications primarily used to treat depression and anxiety. They work by increasing the levels of serotonin in the brain.
Serotonin is a neurotransmitter (the body’s chemical messenger that transmits signals between nerve cells) that contributes to feelings of well-being and happiness. SSRIs block the reabsorption (reuptake) of serotonin into neurons, making more serotonin available in the brain, which helps improve mood and reduce anxiety.
Interestingly, SSRIs also have anti-inflammatory effects and can influence our immune system in three main ways:
First, SSRIs can modulate the so-called hypothalamic-pituitary-adrenal (HPA) axis through the activation of serotonin and norepinephrine (another important neurotransmitter). The HPA axis is involved in the release of glucocorticoids, which affect virtually all immune cells.
Second, SSRIs can interact with kynurenine pathway, which is involved in producing an important energy molecule, nicotinamide adenine dinucleotide (NAD+). The kynurenine pathway is overactive in many conditions, including Long COVID, and can influence immune responses.
Finally, some SSRIs have additional characteristics, such as modulating specific molecules that reduce virus replication and reactivation.
Mechanism of action of SSRIs (Lattimore et al.)
A Dutch study investigated SSRIs in 95 patients with Long COVID
In this study, patients who were interested in treatment with an SSRI were included. Their general practitioners were informed by e-mail about the experimental nature of the treatment, the possible response to SSRIs in patients with Long COVID, which SSRIs should be preferred (fluvoxamine, citalopram, escitalopram and fluoxetine), the dosages and potential side effects. Patients were advised to start with a low dose and gradually increase it based on their response and side effects.
The study included 95 patients from the Netherlands with a confirmed SARS-CoV-2 infection who developed Long COVID and were treated with SSRIs. The average age of the patients was 43 years, with almost six times more women than men. All patients completed a questionnaire before SSRI treatment to collect information on Long COVID symptoms, medical history, and medication use. Around one month after starting SSRI treatment, patients completed another questionnaire to report on the specific SSRI used, response to therapy, symptom improvements and side effects.
Before starting SSRIs, patients had Long COVID for an average of 15 months, with most of them experiencing severe symptoms. All patients reported brain fog, fatigue, and post-exertional malaise (PEM). Nearly all patients also had sensory overload, headaches and palpitations, muscle weakness, muscle pain, and spasms.
SSRIs improved symptoms of Long COVID in some patients
Almost two-thirds of patients reported a decrease in symptoms after SSRI treatment; of these, improvement was reasonably good in 26.9% of patients, good in 29.0% and strong in 7.5% (Figure). In terms of specific symptoms, 31.1% reported improved sleep and 72.0% described a decrease in PEM. Four patients noted decreased stomach symptoms, one patient reported disappearance of fever and one patient experienced improved chewing ability.
All 14 patients with dissociative symptoms reported that these had disappeared. Notably, 24 patients who took the SSRI for more than six months reported that the positive outcomes were maintained.
The study further provided strong statistical evidence for the positive effect of SSRI treatment on Long COVID symptoms. More in detail, brain fog and sensory overload decreased the most, by 3.8 and 3.6 points on a scale from 0-10, respectively. Muscle pain decreased by 2.1 and muscle weakness decreased by 1.9 points on a scale from 0-10. Some patients also reported a large decrease in PEM and improvement in tinnitus. Patients with fibromyalgia reported little or no improvement after using an SSRI.
After SARS-CoV2 infection, Long COVID patients experienced a significant decline in functionality, with their scores dropping from 94.2 to 23.5 on average, according to the Bell functionality score.
Following SSRI treatment, the average score increased to 47.2. This improvement indicates a return to full self-care, the ability to shop and walk, and a partial return to work. Among the 36 patients who used an SSRI for two months or less, nearly half reported continued symptom reduction after the measurement period.
Nine patients did not respond to treatment with SSRIs. These patients seemed to have worse initial symptoms and described a more severe disease than the patients who responded to SSRIs. Three of them were hospitalized because of severe pneumonia, pulmonary embolism, and thrombosis.
Most patients initially experienced side effects, but these mainly reduced or disappeared within a few weeks. Around one-third of patients experienced serious side effects, 55% experienced mild and 14% had no side effects. Notably, three-quarters of patients experienced side effects without positive outcomes in the first few weeks of treatment.
Results from a questionnaire on outcomes in 93 patients with Long COVID who were treated with SSRIs. Most patients experienced at least moderate improvements.
Potential mechanisms of action of SSRIs in Long COVID
The study authors proposed several potential mechanisms of action through which SSRIs may improve Long COVID symptoms:
- Dysregulation of the tryptophan system: The tryptophan system breaks down the essential amino acid tryptophan, which is important for serotonin production. This system becomes overactive during Long COVID, resulting in a significant depletion of tryptophan in the blood. This depletion is associated with cognitive impairments in patients with Long COVID and neuronal damage. SSRIs can counteract tryptophan deficiency by making more serotonin available in neurons, which can relieve Long COVID symptoms. Potential treatments that work through the tryptophan system include dietary supplements like resveratrol and nicotine but more research is needed to confirm their benefits.
- Disrupted HPA axis: The HPA axis, which is responsible for stress hormone regulation, can be disrupted in Long COVID patients. This disruption leads to reduced cortisol levels (cortisol, or stress hormone, is a molecule that affects almost every organ and tissue in the body). SSRIs can affect the HPA axis and potentially restore its function, which may improve Long COVID symptoms.
- Disrupted brain stem: The brain stem is a part of our brain that regulates vital functions such as body temperature, sleep, heart rate, breathing, digestion, and sensory activities. The brain stem relies on neurotransmitters such as serotonin, norepinephrine, and dopamine. The SARS-CoV-2 virus can enter brain stem cells through special proteins (receptors). Although SSRIs typically worsen sleep, many patients in the present study reported improved sleep, possibly through the effect of SSRIs on the brain stem and increased production of melatonin (a hormone that plays a role in sleep). Other improvements, such as reduced palpitations, shortness of breath and stomach complaints, also suggest that SSRIs may help restore disrupted neurotransmitter systems in the brain stem.
- Disrupted autonomic nervous system balance: Disorders of the autonomic nervous system (dysautonomia), particularly postural orthostatic tachycardia syndrome, or POTS (increased heart beating upon standing up), are a common symptom of Long COVID. This condition is characterized by patients experiencing palpitations, lightheadedness, and tiredness as if they are stuck in a fight-or-flight response. This response usually releases extra cortisol and glucose to prepare muscles for action. However, in Long COVID patients, cortisol levels are only about half of normal, which leads to muscle weakness because the glucose is not released in the muscle. SSRIs are often used to reduce POTS and palpitations.
- CNS symptoms: Patients with cognitive symptoms such as brain fog and sensory overload respond well to SSRI treatment. SSRIs can improve the cooperation between sensory brain regions and reduce sensory overload. Many Long COVID patients also experience forgetfulness and SSRIs can stimulate serotonin production in the hippocampus, the memory control center in the brain.
- Sigma1 receptor agonists: Some types of SSRIs, also called sigma1 receptor agonists, have shown anti-inflammatory effects during COVID-19 by decreasing pro-inflammatory cytokines (interleukins) in the brain. The sigma1 receptor is important for reducing virus replication and preventing the reactivation of herpes viruses like Epstein-Barr Virus (EBV).
- The positive influence of SSRIs on the circulatory system: Many patients with Long COVID develop microclots, which are small clumps in the blood that prevent the flow of oxygen and nutrients. Platelets are fragments in our blood that form clots and become less functional with serotonin deficiency. By inhibiting serotonin reuptake, SSRIs prolong clotting time and may help dissolve microclots. SSRIs also have an anti-inflammatory effect on endothelial cells, which line all blood vessels, potentially offering cardioprotective effects.
The number of these different mechanistic considerations both shows the potential of SSRIs in Long COVID but also how little is yet known about their effects. SSRIs are strong medications that can have significant side effects and their use should be thoroughly evaluated by a doctor for each person based on their medical history and their current symptoms.
If you have used SSRIs as a treatment for Long COVID, feel free to share your experiences with our community in the Altea Forum.
