The results of this exploratory questionnaire-based study of the effect of treatment with an SSRI in PCS show that an SSRI contributes significantly to the reduction of PCS symptoms. 63,4% (n = 95) of patients reported a reasonably good to strong decrease in symptoms and an improvement in functioning. This increased quality of life can contribute to social participation. Four patients had developed clinical depression or anxiety disorder during PCS. Treatment with an SSRI also eliminated these disorders. People who had felt despondent due to PCS also felt less gloomy after an SSRI, but all attributed this to the reduction in their PCS symptoms.
An explanation for the skewed gender distribution in this study - also found in other research in PCS - may be that many genes for the immune system lie on the X chromosome so that men are more likely to have severe Covid-19 infections, but women are more likely to have more severe PCS symptoms that last longer.13,28
The high level of education in this study compared to other studies1 can probably be explained by the recruitment of patients through LinkedIn. The overrepresentation of female patients from healthcare and education could be caused by the predominance of female workers in these professions on the front lines of the pandemic. Moreover, they returned to work quickly after their Covid-19 infection which is a risk factor for PCS.1 Many other risk factors for PCS in this study are consistent with the recent review article by Davis et al.,1 such as: asthma, allergies, connective tissue diseases, Epstein-Barr virus etc. A notable addition to the known risk factors is factor V Leiden thrombophilia. In this study, there were two patients with this coagulation disorder, while the prevalence in the general population is only 1:5000.29 Patients with this coagulation disorder have an 80-fold increased risk of thrombosis.
All patients in our group (n = 95) were chronically fatigued during PCS while in a German study5 only 19/42 patients of the PCS study population reported chronic fatigue such as in ME/CFS. An explanation for this difference could be that fatigue in PCS increases with time. While the duration of PCS in the German study was only six months, in our study it averaged 15 months. Also, in this German study, of the other PCS patients without chronic fatigue (23/42), only 15 had a neurological or cognitive impairment. In our study, 100% had a neurological or cognitive impairment. However, neurocognitive symptoms begin only a month to a few months after Covid-19 infection and worsen over time.30
Strength and weakness of the study
No validated questionnaires are yet available for PCS. However, with a new disease, it is important to learn about all symptoms, so we used a questionnaire that included open-ended questions. Thus, we discovered that symptoms can shift over time. Dyspnoea and decrease in smell seem to decrease over time, while fatigue and brainfog seem to increase. Through the open-ended questions we also discovered new symptoms, such as derealization.
Using three different instruments to determine treatment effectiveness is a further strength of this study. There is strong evidence for the reliability of these measures. The Bell score is a widely used instrument in research on (chronic) fatigue, although not validated. Furthermore, the rating of the Open question outcomes was found to be reliable. Importantly, the three effect measures correlated strongly with each other, supporting the reliability of the individual measures.
The main weakness of this study is that it is not a double-blind randomized controlled trial (RCT). Therefore, a placebo effect cannot be ruled out. However, there is evidence that a placebo effect may not fully explain the results. A placebo effect usually occurs shortly after the start of an intervention and diminishes again after a few weeks, unless a positive expectation is given again.31 However, 72 patients (n = 95) still had no response in the first weeks, but instead suffered side effects. The 24 patients who used the SSRI for more than six months reported that the effect was maintained, while they were not asked by us to do so, as we had no treatment relationship with the patients. It is known that 85% of patients who have symptoms two months after Covid-19 infection still have them after one year.1 ME/CFS and dysautonomia are usually lifelong.1 So without treatment with an SSRI, many PCS patients may suffer from these conditions in permanently. Finally, low-cost SSRIs are covered by insurance and there is no cost to the patient, which argues against a placebo effect.32 However, the possibility of a placebo effect can only be completely ruled out by an RCT.
The Bell score for Covid-19/PCS and the Bell score during PCS before starting an SSRI were completed retrospectively by all patients. This may have led to some bias. The complaint of PEM was not part of the 8 complaints in the Score list; patients had to list and score this on their own under "other complaints". This may have led to underreporting of this important symptom. LinkedIn gave an overrepresentation of patients with a higher level of education, but perhaps also of a group of initially healthy people who were fully employed. It is precisely in this group that the impact of PCS as well as the outcomes of an SSRI may be well observed.
Potential explanatory mechanisms of action of SSRIs
SSRIs stimulate serotonin metabolism and - to a lesser extent - noradrenergic metabolism. SSRIs make reuptake of these neurotransmitters less likely at the presynaptic neuron, allowing the neurotransmitters to pass their signal to the postsynaptic neuron for longer.10,33 SSRIs have several potential targets for the treatment of PCS discussed below.
The clinical picture that emerges with a Bell score < 30 during PCS as revealed by the answers to the open-ended questions is striking: agitated patients with palpitations lying limp and exhausted on the couch. Our hypothesis is that in this state, the brainstem exhibits increased arousal and together with the autonomic nervous system (ANS) is in the ‘fight-or-flight’ response. This is a primitive survival mechanism in the face of danger, where the sympathetic ANS dominates. The ‘fight-or-flight’ response involves activation of the HPA axis, so that extra cortisol is released and glucose is released into the muscles for action.34 Instead, on average in PCS patients, measured cortisol levels are only 50% of normal11 and muscles are weak rather than ready to start contracting. It appears that the pattern of this primitive survival mechanism is disrupted.
The following are seven potential explanatory mechanisms related to the study outcomes:
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Disrupted HPA axis
Cortisol levels that were on average halved are an indication that the HPA axis is disrupted.8,11 In comparison, in ME/CFS, the HPA axis is less severely disrupted.7 SSRIs affect the HPA axis.8–10 In ME/CFS, an SSRI works moderately in only one-third of patients.7 SSRIs seem to work better in PCS than in ME/CFS. This may be an indication that SSRIs are (partly) effective in PCS by influencing this hormone axis.9,10 Another indication of this hypothesis is our report of the patient who was given hydrocortisone because PCS caused her only functioning adrenal gland to fail, but who recovered with an SSRI, after which she was able to taper off this medication. In this patient, the SSRI apparently restored not only the HPA axis, but also the disrupted hypothalamic-pituitary-thyroid axis. The question is therefore whether - apart from the HPA axis - more hormonal axes starting from the hypothalamus are disturbed by Covid-19/PCS. Thus, reported changes in the menstrual cycle after Covid-1935 could also result from a disrupted hypothalamic-pituitary-gonadal axis.
2. Disrupted brainstem
The brainstem also appears to be affected in PCS. Hypometabolic areas in the pons were found in a study of three PCS patients15,17 The serotonergic neurons begin in the raphe nuclei in the pons and may exert their influence there.17
Typically, SSRIs worsen sleep quality.36 However, in this study, 29 patients reported in the open-ended question that their sleep improved on the SSRI. This could be explained by the influence of the SSRI on the brainstem. The decrease in palpitations, shortness of breath, gastrointestinal complaints, better temperature regulation (one patient) and the ability to chew better (one patient) also supports the idea that SSRIs may (partially) restore the neurotransmitter systems disrupted in the brainstem.
3. Disrupted ANS balance
The vagus nerve of the (parasympathetic) ANS also originates from the pons. In many patients in this study, an SSRI seems to restore ANS balance: i.e., the sympathetic ANS became less predominant over the parasympathetic ANS. Possibly because of this, after treatment with an SSRI, there were less POTS, palpitations and faster recovery after an activity, i.e., less PEM.
4. Improvement in CNS symptoms
Brainfog and sensory overload responded best to treatment with an SSRI. Dissociative symptoms also disappeared. In sensory overload and dissociation, there is sensory overload due to lack of filtering. The primary unimodal sensory brain regions do not cooperate well with the associative sensory brain regions.37,38 It is known that an SSRI can sometimes help with this.38,39
Many PCS patients struggle with forgetfulness.1 In the hippocampus, the control centre of memory, serotonergic neurons are dominant.40 SSRIs also stimulate the production of serotonin cells in the hippocampus.40 Possibly partly because of this, the patients’ forgetfulness decreased.
5. Dysregulation of the Kynurenine pathway (KP)
In PCS, the catabolic kynurenine pathway (KP) is found to be dysregulated.41 The KP degrades 95% of the essential amino acid tryptophan to produce a vital energy cofactor. This releases three metabolites: kynurenine, quinolinic acid and 3-hydroxyanthranilic acid. The rest of the tryptophan serves as a building block for serotonin and melatonin. During inflammation, the KP is overactive and releases additional metabolites. There appears to be a significant relationship between the level of metabolites in blood and the severity of cognitive impairment in PCS (p < 0.001).42 Overactive KP puts pressure on the production of serotonin and melatonin.42 This deficiency of serotonin in neurons could be (partially) compensated by treatment with an SSRI. To test this mechanism of action, KP metabolites should be measured in patients with PCS both before and during SSRI use.
6. Anti-inflammatory effects of SSRIs
The SSRIs fluvoxamine and fluoxetine have been shown to have anti-inflammatory effects during Covid-19 infection by inhibiting sphingomyelinase acid (ASM).43 Furthermore, an SSRI reduces the pro-inflammatory cytokines Interleukin 2 (IL 2) and IL 17 in the CNS. In this case, the SSRI may be a sigma1 receptor agonist. This opioid receptor is inter alia involved in reducing virus replication and inhibiting reactivation of herpes viruses such as Epstein-Barr Virus (EBV).44 We recommended only SSRIs who are Sigma1 receptor agonists. 22,44 One patient was first given sertraline by the GP, with no response. After switching to citalopram, she did respond reasonable good. In five other patients, family physicians prescribed the sigma1 receptor antagonists sertraline (n = 4) or paroxetine (n = 1). These five patients reported good (n = 2), reasonable good (n = 2) or moderate (n = 1) improvement. There was no evidence in favour of or against a difference in effect measured by the open question depending on whether patients received sigma1 agonists or antagonists (BF = 0.43). If we include the patient who changed from sertraline (no effect) to citalopram (reasonable good effect), no significant difference remains (BF = 0.39) This is only anecdotal evidence that the mechanism via the Sigma1 receptor plays a role in the action of SSRI in PCS. However, the group using a Sigma1 antagonist in this study is too small for a proper statistical analysis.
7. Anticoagulant effect of SSRIs.
Many Covid-19 and PCS patients have microclots indicative of coagulation problems. Platelets are involved in clotting. Platelets transport serotonin, because serotonine has a function in clotting. With serotonin deficiency, platelets become less functional. SSRIs prolong clotting time and could theoretically dissolve microclots.45 The two patients with factor V Leiden thrombophilia responded well and moderately, respectively. This could mean that the anticoagulant effect of SSRIs - assuming that microclots played a role in these patients - might contribute to their response. If it were confirmed that PCS is more common in factor V Leiden thrombophilia, this coagulation disorder should be added to the list of risk factors.
Subgroup with fibromyalgia
Muscle pain and weakness decreased the least in the total group (n = 95). We also see this in the patients with fibromyalgia (n = 5) who reported little or no improvement after using an SSRI.
Non-responders
The group of non-responders (n = 9) were more severely ill with Covid-19 infection than those who did report good response to SSRIs. It is possible that the cascade of severe inflammation caused by Covid-19 in the CNS46 released much histamine. Inhibitory histamine receptors lower serotonin in the CNS, preventing an SSRI from effectively releasing extracellular serotonin.47 By adding Histamine1 and 2 antagonists to treatment, an SSRI could in principle still become effective.47 However, the lack of response to an SSRI may also have been caused by a serious factor: namely, neuropathology similar to Alzheimer’s disease is found in Covid-19 infections. In the CNS β-amyloid aggregations, plaque formations, tauopathy and cell death have been described.48 In these conditions, an SSRI cannot possibly be effective anymore.
When should the SSRI be phased out?
Our hypothesis is that for many PCS symptoms, neurotransmitter systems are not damaged but dysregulated. But after a chronic course of PCS lasting two years, SSRIs cannot be expected to ”reset” these systems in a short time. By comparison, the treatment duration for initial depression is six months to 1 year and for recurrent depression usually at least 3 years.49 In toxic drug-induced depersonalization disorder, sometimes 6 years of treatment is advised (first author’s clinical experience).39 Drug-induced depersonalization disorder is phenomenologically similar to PCS, excluding fatigue and muscle pain. Poor stimulus selection, sensory overload, derealization and brainfog are similar in the two conditions. The preliminary recommendation is to continue treatment with an SSRI for at least 1.5-2 years. More research is needed to support our hypothesis regarding the resetting of neurotransmitter systems by SSRIs. Another possibility could be that SSRIs only suppress symptoms. Contrary to this is the experience of one patient (with a very low Bell score of 20 at the start of SSRI treatment) who discontinued the SSRI after 8 months because he felt completely healthy for 2 months. He continues to do well (four months after discontinuation). However, most patients mention that, despite the good response to the SSRI, they must continue to be cautious their limits.