Tag: serotonin

Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome

Abstract:

Background: Fatigue of unknown origin is a hallmark symptom in chronic fatigue syndrome (CFS) and is also found in 20% of hypothyroidism patients despite appropriate levothyroxine treatment. Here, we suggest that in these disorders, peripheral serotonin levels are low, and elevating them to normal range with L-carnitine is accompanied with reduced fatigue.

Methods: We conducted a retrospective analysis of follow-up clinical data (CFS N=12; hypothyroidism with fatigue N=40) where serum serotonin and fatigue levels were compared before vs. after 7 weeks of oral L-carnitine supplementation.

Results: After L-carnitine, serotonin increased (8-fold in CFS, Sig. = 0.002, 6-fold in hypothyroidism, Sig. < 0.001) whereas fatigue decreased (2-fold in both CFS and hypothyroidism, Sig. = 0.002 for CFS, Sig. < 0.001 for hypothyroidism). There was a negative correlation between serotonin level and fatigue (for CFS, rho = -0.49 before and -0.67 after L-carnitine; for hypothyroidism, rho = -0.24 before and -0.83 after L-carnitine).

Conclusions: These findings suggest a new link between low peripheral serotonin, L-carnitine, and fatigue.

Source: Tommi Raij, Kari Raij. Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome. Front. Endocrinol. Sec. Neuroendocrine Science, Volume 15 – 2024 | doi: 10.3389/fendo.2024.1358404 https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1358404/abstract

SSRI Use During Acute COVID-19 Infection Associated with Lower Risk of Long COVID Among Patients with Depression

Abstract:

Background Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a poorly understood condition with symptoms across a range of biological domains that often have debilitating consequences. Some have recently suggested that lingering SARS-CoV-2 virus in the gut may impede serotonin production and that low serotonin may drive many Long COVID symptoms across a range of biological systems. Therefore, selective serotonin reuptake inhibitors (SSRIs), which increase synaptic serotonin availability, may prevent or treat Long COVID. SSRIs are commonly prescribed for depression, therefore restricting a study sample to only include patients with depression can reduce the concern of confounding by indication.

Methods In an observational sample of electronic health records from patients in the National COVID Cohort Collaborative (N3C) with a COVID-19 diagnosis between September 1, 2021, and December 1, 2022, and pre-existing major depressive disorder, the leading indication for SSRI use, we evaluated the relationship between SSRI use at the time of COVID-19 infection and subsequent 12-month risk of Long COVID (defined by ICD-10 code U09.9). We defined SSRI use as a prescription for SSRI medication beginning at least 30 days before COVID-19 infection and not ending before COVID-19 infection. To minimize bias, we estimated the causal associations of interest using a nonparametric approach, targeted maximum likelihood estimation, to aggressively adjust for high-dimensional covariates.

Results We analyzed a sample (n = 506,903) of patients with a diagnosis of major depressive disorder before COVID-19 diagnosis, where 124,928 (25%) were using an SSRI. We found that SSRI users had a significantly lower risk of Long COVID compared to nonusers (adjusted causal relative risk 0.90, 95% CI (0.86, 0.94)).

Conclusion These findings suggest that SSRI use during COVID-19 infection may be protective against Long COVID, supporting the hypothesis that serotonin may be a key mechanistic biomarker of Long COVID.

Source: Zachary Butzin-Dozier, Yunwen Ji, Sarang Deshpande, Eric Hurwitz, Jeremy Coyle, Junming (Seraphina) Shi, Andrew Mertens, Mark J. van der Laan, John M. Colford Jr., Rena C. Patel, Alan E. Hubbard, the National COVID Cohort Collaborative (N3C) Consortium. SSRI Use During Acute COVID-19 Infection Associated with Lower Risk of Long COVID Among Patients with Depression. medRxiv 2024.02.05.24302352; doi: https://doi.org/10.1101/2024.02.05.24302352 https://www.medrxiv.org/content/10.1101/2024.02.05.24302352v1.full-text (Full text) 

Assessing the effect of selective serotonin reuptake inhibitors in the prevention of post-acute sequelae of COVID-19

Abstract:

Background: Post-acute sequelae of COVID-19 (PASC) produce significant morbidity, prompting evaluation of interventions that might lower risk. Selective serotonin reuptake inhibitors (SSRIs) potentially could modulate risk of PASC via their central, hypothesized immunomodulatory, and/or antiplatelet properties although clinical trial data are lacking.

Materials and methods: This retrospective study was conducted leveraging real-world clinical data within the National COVID Cohort Collaborative (N3C) to evaluate whether SSRIs with agonist activity at the sigma-1 receptor (S1R) lower the risk of PASC, since agonism at this receptor may serve as a mechanism by which SSRIs attenuate an inflammatory response. Additionally, determine whether the potential benefit could be traced to S1R agonism. Presumed PASC was defined based on a computable PASC phenotype trained on the U09.9 ICD-10 diagnosis code.

Results: Of the 17,908 patients identified, 1521 were exposed at baseline to a S1R agonist SSRI, 1803 to a non-S1R agonist SSRI, and 14,584 to neither. Using inverse probability weighting and Poisson regression, relative risk (RR) of PASC was assessed. A 29% reduction in the RR of PASC (0.704 [95% CI, 0.58-0.85]; P = 4 ×10-4) was seen among patients who received an S1R agonist SSRI compared to SSRI unexposed patients and a 21% reduction in the RR of PASC was seen among those receiving an SSRI without S1R agonist activity (0.79 [95% CI, 0.67 – 0.93]; P = 0.005).Thus, SSRIs with and without reported agonist activity at the S1R were associated with a significant decrease in the risk of PASC.

Source: Sidky H, Hansen KA, Girvin AT, Hotaling N, Michael SG, Gersing K, Sahner DK; N3C consortium. Assessing the effect of selective serotonin reuptake inhibitors in the prevention of post-acute sequelae of COVID-19. Comput Struct Biotechnol J. 2024 Jan 9;24:115-125. doi: 10.1016/j.csbj.2023.12.045. PMID: 38318198; PMCID: PMC10839808. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10839808/ (Full text)

Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology

Abstract:

Objectives: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a significant medical challenge, with no indisputable pathophysiological mechanism identified to date.

Methods: Based on clinical clues, we hypothesized that 5-hydroxytryptamine (5-HT) hyperactivation is implicated in the pathogenic causes of ME/CFS and the associated symptoms. We experimentally evaluated this hypothesis in a series of mouse models.

Results: High-dose selective serotonin reuptake inhibitor (SSRI) treatment induced intra- and extracellular serotonin spillover in the dorsal raphe nuclei of mice. This condition resulted in severe fatigue (rota-rod, fatigue rotating wheel and home-cage activity tests) and ME/CFS-associated symptoms (nest building, plantar and open field test), along with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis response to exercise challenge. These ME/CFS-like features induced by excess serotonin were additionally verified using both a 5-HT synthesis inhibitor and viral vector for Htr1a (5-HT1A receptor) gene knockdown.

Conclusions: Our findings support the involvement of 5-HTergic hyperactivity in the pathophysiology of ME/CFS. This ME/CFS-mimicking animal model would be useful for understanding ME/CFS biology and its therapeutic approaches.

Source: Lee JS, Kang JY, Park SY, Hwang SJ, Bae SJ, Son CG. Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology. J Transl Med. 2024 Jan 8;22(1):34. doi: 10.1186/s12967-023-04808-x. PMID: 38191373. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04808-x (Full text)

Serotonin reduction in post-acute sequelae of viral infection

Highlights:

  • Long COVID is associated with reduced circulating serotonin levels
  • Serotonin depletion is driven by viral RNA-induced type I interferons (IFNs)
  • IFNs reduce serotonin through diminished tryptophan uptake and hypercoagulability
  • Peripheral serotonin deficiency impairs cognition via reduced vagal signaling

Summary:

Post-acute sequelae of COVID-19 (PASC, “Long COVID”) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction.
Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
Source: Wong et al., Serotonin reduction in post-acute sequelae of viral infection, Cell (2023), https://doi.org/
10.1016/j.cell.2023.09.013 https://www.cell.com/cell/fulltext/S0092-8674(23)01034-6 (Full text)

Links between Serotonin Levels and Stress: Cortisol, Candida A./Mycetes, Omega 3/6 Ratio and Dysbiosis (Skatole/Indoxyl Sulfate) Role in Chronic Fatigue Syndrome (CFS) and Depression

Abstract:

Intestinal microbiota attracts daily attention of a growing number of study which have attempted to link gut dysbiosIs with a variety of disease states: irritable bowel syndrome (IBS), inflamed bowel disease (IBD), Crohn’s disease (CD), leaky gut syndrome (LGS), food intolerance, diabetes, metabolic syndrome, cancer, etc.

In our study we analyzed how intestinal dysbiosis may be related to chronic fatigue syndrome (CFS) and depression through the exchange of information through the gut-brain axis (GBA).

We studied 33 subjects, 13 males and 20 females, who reported CFS or/and depression: we investigated their salivary cortisol levels, blood serotonin, omega 3/6 ratio, intestinal dysbiosis (calculated on the urinary levels of indoxyl sulfate and skatole), and we looked for the presence of Candida a. or mycetes in the stool; the data accumulated with this research show a correlation between the presence of Candida a./miceti, indoxyl sulfate urine values beyond the physiological and low serotonin levels.

In addition, data analysis showed that the EPA/DHA values also show pro-inflammatory levels in case of dysbiosis and low serotonina levels. The relationship, however, with cortisol levels requires further research although this study showed a statistically significant positive correlation between these values, measured at specific times, and serotonin levels.

Aims: We investigated the relationship between stress (evaluated through the measurement of salivary cortisol levels) and gastrointestinal efficiency measured as a function of intestinal fermentative and putrefactive dysbiosis, evaluating the levels of urinary indoxyl sulfate in the first case (a possible correlation with the presence of Candida spp or Mycetes in the subjects feces was investigated), urinary skatole levels in the second one, in patients with chronic fatigue syndrome (SFC) and depression.

In these patients we also have studied omega 3/6 ratio, and finally we have analized the impact that the alteration of these parameters can have on the serotonin levels.

This research attemps to highlight the contact points, in some cases not so obvious, among these topics, contact points that, although they give us interesting indications, show the need to be further deepened by analyzing a larger amount of data.

Source: Orlandoni, D.; Di Fede, G.; Mantovani, M.; Nava, C.R.; Tomasi, M.; Fusi, P. Links between Serotonin Levels and Stress: Cortisol, Candida A./Mycetes, Omega 3/6 Ratio and Dysbiosis (Skatole/Indoxyl Sulfate) Role in Chronic Fatigue Syndrome (CFS) and Depression. Preprints 2023, 2023090253. https://doi.org/10.20944/preprints202309.0253.v1 https://www.preprints.org/manuscript/202309.0253/v1 (Full text available as PDF file)

Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia

Abstract:

Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them.

Through accelerometry objective parameters, physical activity/sedentarism levels in relation to fatigue are studied, as well as whether perceived levels of stress, anxiety, and pain correspond to objective biomarkers, all of these with respect to a reference group (RG) of women without FM.

FM patients have a worse psychological state and perceived quality of life than those with RG. These perceived outcomes are consistent with impaired objective levels of a sedentary lifestyle, higher systemic levels of cortisol and noradrenaline, and lower levels of serotonin.

However, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS.

In conclusion, while perceived health parameters do not detect differences, when objective neuroimmunoendocrine parameters related to stress, inflammation, pain, and fatigue are used, people with CFS could be overdiagnosed with FM. This reinforces the need for objective biomarker assessment of these patients for better diagnostic discrimination between both syndromes.

Source: Otero E, Gálvez I, Ortega E, Hinchado MD. Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia. Biomedicines. 2023; 11(5):1488. https://doi.org/10.3390/biomedicines11051488 https://www.mdpi.com/2227-9059/11/5/1488 (Full text)

An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome

Abstract:

Chronic fatigue syndrome (CFS) is one of the most intractable diseases and is characterized by severe central fatigue that impairs even daily activity. To date, the pathophysiological mechanisms are uncertain and no therapies exist. Therefore, a proper animal model reflecting the clinical features of CFS is urgently required.

We compared two CFS animal models most commonly used, by injection with lipopolysaccharide (LPS from Escherichia coli O111:B4) or polyinosinic: polycytidylic acid (poly I:C), along with bilateral adrenalectomy (ADX) as another possible model. Both LPS- and poly I:C-injected mice dominantly showed depressive behaviors, while ADX led to fatigue-like performances with high pain sensitivity.

In brain tissues, LPS injection notably activated microglia and the 5-hydroxytryptamine (HT)1A receptor in the prefrontal cortex and hippocampus. Poly I:C-injection also remarkably activated the 5-HT transporter and 5-HT1A receptor with a reduction in serotonin levels in the brain. ADX particularly activated astrocytes and transforming growth factor beta (TGF-β) 1 in all brain regions.

Our results revealed that LPS and poly I:C animal models approximate depressive disorder more closely than CFS. We suggest that ADX is a possible method for establishing a mouse model of CFS reflecting clinical features, especially in neuroendocrine system.

Source: Lee JS, Jeon YJ, Park SY, Son CG. An Adrenalectomy Mouse Model Reflecting Clinical Features for Chronic Fatigue Syndrome. Biomolecules. 2020 Jan 1;10(1). pii: E71. doi: 10.3390/biom10010071. https://www.mdpi.com/2218-273X/10/1/71 (Full article)

Maintenance of Chronic Fatigue Syndrome (CFS) in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A > G Genotype

Abstract:

Earlier studies have shown that genetic variability in the SLC6A4 gene encoding the serotonin transporter (5-HTT) may be important for the re-uptake of serotonin (5-HT) in the central nervous system. In the present study we investigated how the 5-HTT genotype i.e. the short (S) versus long (L) 5-HTTLPR allele and the SNP rs25531 A > G affect the physical and psychosocial functioning in patients with chronic fatigue syndrome (CFS).

All 120 patients were recruited from The Department of Paediatrics at Oslo University Hospital, Norway, a national referral center for young CFS patients (12-18 years). Main outcomes were number of steps per day obtained by an accelerometer and disability scored by the Functional Disability Inventory (FDI).

Patients with the 5-HTT SS or SLG genotype had a significantly lower number of steps per day than patients with the 5-HTT LALG, SLA or LALA genotype. Patients with the 5-HTT SS or SLG genotype also had a significantly higher FDI score than patients with the 5-HTT LALG, SLA or LALA genotype.

Thus, CFS patients with the 5-HTT SS or SLG genotype had worse 30 weeks outcome than CFS patients with the 5-HTT LALG, SLA or LALA genotype. The present study suggests that the 5-HTT genotype may be a factor that contributes to maintenance of CFS.

 

Source: Meyer B, Nguyen CB, Moen A, Fagermoen E, Sulheim D, Nilsen H, Wyller VB, Gjerstad J. Maintenance of Chronic Fatigue Syndrome (CFS) in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A > G Genotype. PLoS One. 2015 Oct 16;10(10):e0140883. doi: 10.1371/journal.pone.0140883. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608737/ (Full article)