Tag: depression

Discriminating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and comorbid conditions using metabolomics in UK Biobank

Abstract:

Background: Diagnosing complex illnesses like Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is complicated due to the diverse symptomology and presence of comorbid conditions. ME/CFS patients often present with multiple health issues, therefore, incorporating comorbidities into research can provide a more accurate understanding of the condition’s symptomatology and severity, to better reflect real-life patient experiences.

Methods: We performed association studies and machine learning on 1194 ME/CFS individuals with blood plasma nuclear magnetic resonance (NMR) metabolomics profiles, and seven exclusive comorbid cohorts: hypertension (n = 13,559), depression (n = 2522), asthma (n = 6406), irritable bowel syndrome (n = 859), hay fever (n = 3025), hypothyroidism (n = 1226), migraine (n = 1551) and a non-diseased control group (n = 53,009).

Results: We present a lipoprotein perspective on ME/CFS pathophysiology, highlighting gender-specific differences and identifying overlapping associations with comorbid conditions, specifically surface lipids, and ketone bodies from 168 significant individual biomarker associations. Additionally, we searched for, trained, and optimised a machine learning algorithm, resulting in a predictive model using 19 baseline characteristics and nine NMR biomarkers which could identify ME/CFS with an AUC of 0.83 and recall of 0.70. A multi-variable score was subsequently derived from the same 28 features, which exhibited ~2.5 times greater association than the top individual biomarker.

Conclusions: This study provides an end-to-end analytical workflow that explores the potential clinical utility that association scores may have for ME/CFS and other difficult to diagnose conditions.

Source: Huang K, G C de Sá A, Thomas N, Phair RD, Gooley PR, Ascher DB, Armstrong CW. Discriminating Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and comorbid conditions using metabolomics in UK Biobank. Commun Med (Lond). 2024 Nov 26;4(1):248. doi: 10.1038/s43856-024-00669-7. PMID: 39592839; PMCID: PMC11599898.  https://pmc.ncbi.nlm.nih.gov/articles/PMC11599898/ (Full text)

Depressive and anxiety symptoms in current, previous, and no history of ME/CFS: NHIS 2022 analysis

Abstract:

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is associated with anxiety and depressive symptoms. Psychological symptoms are predisposing factors for, as well as symptoms of, ME/CFS. Recovery from ME/CFS is poorly understood and heterogenous, and it is unclear how psychological symptoms may change with recovery. The aim of this study was to examine the associations of depressive and anxious symptoms among individuals with current, previous, and no history of ME/CFS.

Methods: National Health Interview Survey 2022 data were analyzed to assess ME/CFS status, as well as anxiety and depression burden. Adults (unweighted N = 27,651) in the United States reported sociodemographic and health behavior characteristics, with 453 adults reporting current ME/CFS, while 119 reported previous ME/CFS. Sample weights and variance estimation variables were implemented. Multivariable linear regression models were used to analyze the associations between ME/CFS status and anxiety and depression severity after adjusting for sociodemographic and health behavior variables.

Results: Participants were on average 48.1 years of age, and most identified as female (51.3%), white (76.6%), and not Hispanic or Latine (82.8%). Current and previous ME/CFS were associated with anxiety and depressive symptoms compared to individuals with no history of ME/CFS. Clinically significant levels of anxiety and depressive symptoms were substantial for individuals with current (37.6%; 49.0%) and previous (26.5%; 33.4%) ME/CFS compared to individuals with no history of ME/CFS (6.1%; 6.7%).

Conclusion: ME/CFS, regardless of current presence, was related to significantly greater anxiety and depressive symptom burden.

Source: Sirotiak Z, Adamowicz JL, Thomas EBK. Depressive and anxiety symptoms in current, previous, and no history of ME/CFS: NHIS 2022 analysis. Qual Life Res. 2024 Nov 23. doi: 10.1007/s11136-024-03854-2. Epub ahead of print. PMID: 39579271. https://link.springer.com/article/10.1007/s11136-024-03854-2 (Full text)

Psychological outcomes of COVID-19 survivors at sixth months after diagnose: the role of kynurenine pathway metabolites in depression, anxiety, and stress

Abstract:

Coronavirus disease 2019 (COVID-19) has resulted in long-term psychiatric symptoms because of the immunologic response to the virus itself as well as fundamental life changes related to the pandemic. This immune response leads to altered tryptophan (TRP)-kynurenine (KYN) pathway (TKP) metabolism, which plays an essential role in the pathophysiology of mental illnesses. We aimed to define TKP changes as a potential underlying mechanism of psychiatric disorders in post-COVID-19 patients.

We measured plasma levels of several TKP markers, including KYN, TRP, kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), as well as the TRP/KYN, KYNA/3-HK, and KYNA/QUIN ratios, in 90 post-COVID-19 patients (on the first day of hospitalization) and 59 healthy controls (on the first admission to the Check-Up Center). An online questionnaire that included the Depression, Anxiety and Stress Scale-21 (DASS-21) was used 6 months after the initial assessment in both groups.

A total of 32.2% of participants with COVID-19 showed depressive symptoms, 21.1% exhibited anxiety, and 33.3% had signs of stress at follow-up, while 6.6% of healthy controls exhibited depressive and anxiety symptoms and 18.6% had signs of stress. TRP and 3-HK were negative predictors of anxiety and stress, but KYN positively predicted anxiety and stress. Moreover, TRP negatively predicted depression, while KYNA/3-HK was a negative predictor of anxiety.

The correlation between depression, anxiety, and stress and TKP activation in COVID-19 could provide prospective biomarkers, especially the reduction in TRP and 3HK levels and the increase in KYN. Our results suggest that the alteration of TKP is not only a potential biomarker of viral infection-related long-term psychiatric disorders but also that the therapy targets future viral infections related to depression and anxiety.

Source: Kucukkarapinar M, Yay-Pence A, Yildiz Y, Buyukkoruk M, Yaz-Aydin G, Deveci-Bulut TS, Gulbahar O, Senol E, Candansayar S. Psychological outcomes of COVID-19 survivors at sixth months after diagnose: the role of kynurenine pathway metabolites in depression, anxiety, and stress. J Neural Transm (Vienna). 2022 Aug;129(8):1077-1089. doi: 10.1007/s00702-022-02525-1. Epub 2022 Jul 7. PMID: 35796878; PMCID: PMC9261222. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261222/ (Full text)

Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition

Abstract:

With an estimated 65 million individuals affected by post-COVID-19 condition (also known as long COVID), non-invasive biomarkers are direly needed to guide clinical management. To address this pressing need, we used blood transcriptomics in a general practice-based case-control study. Individuals with long COVID were diagnosed according to WHO criteria, and validated clinical scales were used to quantify patient-reported outcomes.

Whole blood samples were collected from 48 individuals with long COVID and 12 control individuals matched for age, sex, time since acute COVID-19, severity, vaccination status, and comorbidities (appendix 1 p 2). Digital transcriptomic analysis was performed using the nCounter (Nanostring Technologies, Seattle, WA, USA) platform, as described for critical COVID-19.

Consequently, 212 genes were identified to be differentially expressed between individuals with long COVID and controls (figure A), of which 70 remained significant after adjustment for false discovery rate correction (appendix 1). Several viral RNAs were upregulated: nucleocapsid, ORF7a, ORF3a, Mpro (a nirmatrelvir plus ritonavir [Paxlovid] target), and antisense ORF1ab RNA. Specifically, the upregulation of antisense ORF1ab RNA suggests ongoing viral replication. SARS-CoV-2-related host RNAs (ACE2/TMPRSS2 receptors, DPP4/FURIN proteases) and RNAs prototypical for memory B-cells and platelets were also upregulated (figure A).

Multivariable logistic regression identified antisense SARS-CoV-2 and FYN RNA concentrations as independent predictors of long COVID (corrected for age and sex; appendix 1 p 2). Receiver operating characteristic curve analysis showed significant discrimination (area under curve [AUC] 0·94, 95% CI 0·86–1·00) between individuals with long COVID (n=48) and controls (n=12), with 93·8% sensitivity and 91·7% specificity (figure B).

Single biomarkers antisense SARS-CoV-2 (AUC 0·78, 0·65–0·90) and FYN RNA (AUC 0·89, 0·79–0·99) were significant predictors with lower sensitivity (52·1% and 72·9%, respectively) but similar specificity (91·7% and 100%, respectively; figure B). Upon summarising transcriptomic results into biological pathways, we found significantly decreased immunometabolism in individuals with long COVID, which was negatively correlated with the blood viral load (appendix 1 p 3).

A qualitative analysis of individual SARS-CoV-2 transcript positivity revealed significant differences between individuals with long COVID and controls for antisense (65% vs 25%), ORF7a (60% vs 25%), and nucleocapsid (50% vs 8%) RNAs (figure C). Similarly, the SARS-CoV-2 transcript positivity with respect to the total blood viral load was also significantly different (60% vs 8%).

By use of multivariable logistic regression, we found that age and sex were not associated with the distinction between a low and high viral RNA load status. Conversely, the number of comorbidities (odds ratio [OR] 1·61, 95% CI 1·14–2·49) and COVID vaccine doses (OR 0·36, 0·14–0·79) emerged as independent predictors of distinguishing between low and high viral RNA load status (appendix 2).

We found that viral and immune parameters, such as the antisense Orf1ab RNA concentrations and immunometabolism score, were also linked to the patient-reported anxiety or depression score. Individuals classified as having severe anxiety or depression (with a score of 4 and 5) displayed significantly higher antisense RNA concentrations and lower immunometabolism scores (p<0·05) than those categorised as mild (with scores of 1–3; figure D).

In conclusion, the associations among persistent viral RNA, immunometabolism, and patient-reported outcomes provide mechanistic insights for addressing the challenges posed by long COVID.

Source: Menezes SM, Jamoulle M, Carletto MP, Moens L, Meyts I, Maes P, Van Weyenbergh J. Blood transcriptomic analyses reveal persistent SARS-CoV-2 RNA and candidate biomarkers in post-COVID-19 condition. Lancet Microbe. 2024 Apr 24:S2666-5247(24)00055-7. doi: 10.1016/S2666-5247(24)00055-7. Epub ahead of print. PMID: 38677304. https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00055-7/fulltext (Full text)

Impact of sleep disruption on cognitive function in patients with postacute sequelae of SARS-CoV-2 infection: initial findings from a Neuro-COVID-19 clinic

Abstract:

Introduction: Fatigue, brain fog, and sleep disturbance are among the most common symptoms of postacute sequelae of SARS-CoV-2 infection (PASC). We sought to determine the impact of sleep disruption on cognition and quality of life in patients with neurologic manifestations of PASC (Neuro-PASC).
Methods: Thirty-nine patients were recruited from Neuro-COVID-19 clinic. Mean age was 48.1 years, 71.8% were female, and 82% were never hospitalized for COVID-19. Patients were evaluated via clinical assessment, quality-of-life measures in domains of cognitive function, fatigue, sleep disturbance, anxiety, and depression, NIH Toolbox cognitive tests, and 7 days of wrist actigraphy.
Results: The median number of neurologic symptoms attributed to PASC was 6, with brain fog being the most common in 89.7%. Regarding non-neurologic symptoms, 94.9% complained of fatigue and 74.4% of insomnia. Patients reported significant impairment in all quality-of-life domains and performed worse in a task of attention compared to a normative US population. Actigraphy showed Neuro-PASC patients had lower sleep efficiency, longer sleep latency (both p < 0.001), and later sleep midpoint (p = 0.039) compared to 71 age-matched healthy controls with no PASC history. Self-reported cognitive symptoms correlated with the severity of fatigue (p < 0.001), anxiety (p = 0.05), and depression (p < 0.01). Objective evidence of sleep disruption measured by wakefulness after sleep onset, sleep efficiency, and latency were associated with decreased performance in attention and processing speed.
Conclusion: Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep disruption on the cognitive function and quality of life of patients with PASC.

Source: Kathryn J Reid, Louis T Ingram, Millenia Jimenez, Zachary S Orban, Sabra M Abbott, Daniela Grimaldi, Kristen L Knutson, Phyllis C Zee, Igor J Koralnik, Mathew B Maas, Impact of sleep disruption on cognitive function in patients with postacute sequelae of SARS-CoV-2 infection: initial findings from a Neuro-COVID-19 clinic, SLEEP Advances, Volume 5, Issue 1, 2024, zpae002, https://doi.org/10.1093/sleepadvances/zpae002 https://academic.oup.com/sleepadvances/article/5/1/zpae002/7517273 (Full text)

Identifying the mental health burden in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients in Switzerland: A pilot study

Highlights:

  • First time study on mental health and well-being among ME/CFS patients in Switzerland.
  • High level (68.5%) of stigmatization reported due to ME/CFS.
  • Overall, ME/CFS led to a third of the patients and to half of the male patients to have suicidal thoughts.
  • ME/CFS led to secondary depression in 14.8% of the patients.
  • Lack of disease recognition and adequate patient support.

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic disease of significant public health and clinical importance. It affects multiple systems in the body and has neuro-immunological characteristics. The disease is characterized by a prominent symptom called post-exertional malaise (PEM), as well as abnormalities in the immune-inflammatory pathways, mitochondrial dysfunctions and disturbances in neuroendocrine pathways. The purpose of this study was to evaluate the impact of ME/CFS on the mental health and secondary psychosocial manifestations of patients, as well as their coping mechanisms.

Method: In 2021, a descriptive cross-sectional study was conducted in Switzerland. A self-administered paper questionnaire survey was used to gather data from 169 individuals diagnosed with ME/CFS.

Results: The majority of the patients (90.5%) reported a lack of understanding of their disease, resulting in patients avoiding talking about the disease due to disbelief, trivialization and avoidance of negative reactions. They felt most supported by close family members (67.1%). Two thirds of the patients (68.5%) experienced stigmatization. ME/CFS had a negative impact on mental health in most patients (88.2%), leading to sadness (71%), hopelessness for relief (66.9%), suicidal thoughts (39.3%) and secondary depression (14.8%). Half of the male patients experienced at least one suicidal thought since clinical onset. Factors significantly associated with depression were the lack of cure, disabilities associated with ME/CFS, social isolation and the fact that life was not worth anymore with ME/CFS. The three main factors contributing to suicidal thoughts were (i) being told the disease was only psychosomatic (89.5%), (ii) being at the end of one’s strength (80.7%) and (iii) not feeling being understood by others (80.7%).

Conclusion: This study provided first time significant insights into the mental and psychological well-being of ME/CFS patients in Switzerland. The findings highlight the substantial experiences of stigmatization, secondary depression and suicidal thoughts compared to other chronic diseases, calling for an urgent need in Switzerland to improve ME/CFS patient’s medical, psychological and social support, in order to alleviate the severe mental health burden associated with this overlooked somatic disease.

Source: Rahel Susanne König, Daniel Henry Paris, Marc Sollberger, Rea Tschopp.  Identifying the mental health burden in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients in Switzerland: A pilot study, HELIYON (2024), doi: https:// doi.org/10.1016/j.heliyon.2024.e27031. https://www.sciencedirect.com/science/article/pii/S2405844024030627 (Full text)

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) 

Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease

Abstract:

Importance: While the understanding of inflammation in the pathogenesis of many neurological diseases is now accepted, this special commentary addresses the need to study chronic inflammation in the propagation of cognitive Fog, Asthenia, and Depression Related to Inflammation which we name Brain FADE syndrome. Patients with Brain FADE syndrome fall in the void between neurology and psychiatry because the depression, fatigue, and fog seen in these patients are not idiopathic, but instead due to organic, inflammation involved in neurological disease initiation.

Observations: A review of randomized clinical trials in stroke, multiple sclerosis, Parkinson’s disease, COVID, traumatic brain injury, and Alzheimer’s disease reveal a paucity of studies with any component of Brain FADE syndrome as a primary endpoint. Furthermore, despite the relatively well-accepted notion that inflammation is a critical driving factor in these disease pathologies, none have connected chronic inflammation to depression, fatigue, or fog despite over half of the patients suffering from them.

Conclusions and relevance: Brain FADE Syndrome is important and prevalent in the neurological diseases we examined. Classical “psychiatric medications” are insufficient to address Brain FADE Syndrome and a novel approach that utilizes sequential targeting of innate and adaptive immune responses should be studied.

Source: Khalid A. Hanafy, Tudor G. Jovin. Brain FADE syndrome: the final common pathway of chronic inflammation in neurological disease. Front. Immunol., 17 January 2024, Sec. Inflammation, Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1332776 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1332776/full (Full text)

Microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19

Abstract:

Although some studies have shown neuroimaging and neuropsychological alterations in post-COVID-19 patients, fewer combined neuroimaging and neuropsychology evaluations of individuals who presented a mild acute infection. Here we investigated cognitive dysfunction and brain changes in a group of mildly infected individuals.

We conducted a cross-sectional study of 97 consecutive subjects (median age of 41 years) without current or history of psychiatric symptoms (including anxiety and depression) after a mild infection, with a median of 79 days (and mean of 97 days) after diagnosis of COVID-19. We performed semi-structured interviews, neurological examinations, 3T-MRI scans, and neuropsychological assessments. For MRI analyses, we included a group of non-infected 77 controls. The MRI study included white matter (WM) investigation with diffusion tensor images (DTI) and functional connectivity with resting-state functional MRI (RS-fMRI).

The patients reported memory loss (36%), fatigue (31%) and headache (29%). The quantitative analyses confirmed symptoms of fatigue (83% of participants), excessive somnolence (35%), impaired phonemic verbal fluency (21%), impaired verbal categorical fluency (13%) and impaired logical memory immediate recall (16%). The WM analyses with DTI revealed higher axial diffusivity values in post-infected patients compared to controls.

Compared to controls, there were no significant differences in the functional connectivity of the posterior cingulum cortex. There were no significant correlations between neuropsychological scores and neuroimaging features (including DTI and RS-fMRI).

Our results suggest persistent cognitive impairment and subtle white matter abnormalities in individuals mildly infected without anxiety or depression symptoms. The longitudinal analyses will clarify whether these alterations are temporary or permanent.

Source: Scardua-Silva, L., Amorim da Costa, B., Karmann Aventurato, Í. et al. Microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19. Sci Rep 14, 1758 (2024). https://doi.org/10.1038/s41598-024-52005-7  https://www.nature.com/articles/s41598-024-52005-7 (Full text)

Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome

Introduction: A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed.

Methods: We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).

Results: Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.

Conclusion: Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.

Source: Saito Suguru, Shahbaz Shima, Luo Xian, Osman Mohammed, Redmond Desiree, Cohen Tervaert Jan Willem, Li Liang, Elahi Shokrollah. Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome. Frontiers in Immunology, Vol 15, 2024. DOI=10.3389/fimmu.2024.1341843  https://www.frontiersin.org/articles/10.3389/fimmu.2024.1341843/full (Full text)