Predictors of increased affective symptoms and suicidal ideation during the COVID-19 pandemic: results from a large-scale study of 14 271 Thai adults.

BACKGROUND: Increasing data suggest emergent affective symptoms during the COVID-19 pandemic. OBJECTIVES: To study the impact of the COVID-19 pandemic on affective symptoms and suicidal ideation in Thai adults. METHODS: The Collaborative Outcomes Study on Health and Functioning during Infection Times uses non-probability sampling (chain referring and voluntary response sampling) and stratified probability sampling to identify risk factors of mental health problems and potential treatment targets to improve mental health outcomes during pandemics. FINDINGS: Analysing 14 271 adult survey participants across all four waves of the COVID-19 pandemic in Thailand, covering all 77 provinces from 1 June 2020 to 30 April 2022, affective symptoms and suicidality increased during COVID-19 pandemic. Affective symptoms were strongly predicted by pandemic (feelings of isolation, fear of COVID-19, loss of social support, financial loss, lack of protective devices) and non-pandemic (female sex, non-binary individuals, adverse childhood experiences (ACEs), negative life events, student status, multiple mental health and medical conditions, physical pain) risk factors. ACEs, prior mental health conditions and physical pain were the top three risk factors associated with both increased affective symptoms and suicidal ideation during the COVID-19 pandemic. Partial least squares analysis showed that ACEs were the most important risk factor as they impacted most pandemic and non-pandemic risk factors. CLINICAL IMPLICATIONS: Rational policymaking during a pandemic should aim to identify the groups at highest risk (those with ACEs, psychiatric and medical disease, women, non-binary individuals) and implement both immediate and long-term strategies to mitigate the impact of ACEs, while effectively addressing associated psychiatric and medical conditions.

Distress Symptoms of Old Age and Mild Cognitive Impairment are Two Distinct Dimensions in Older Adults Without Major Depression.

Background: Studies in old adults showed bidirectional interconnections between amnestic mild cognitive impairment (aMCI) and affective symptoms and that adverse childhood experiences (ACE) may affect both factors. Nevertheless, these associations may be confined to older adults with clinical depression. Aim: To delineate the relationship between clinical symptoms of aMCI and affective symptoms in older adults without major depression (MDD) or dysfunctions in activities of daily living (ADL). Methods: This case-control study recruited 61 participants with aMCI (diagnosed using Petersen's criteria) and 59 older adults without aMCI and excluded subjects with MDD and ADL dysfunctions. Results: We uncovered 2 distinct dimensions, namely distress symptoms of old age (DSOA), comprising affective symptoms, perceived stress and neuroticism, and mild cognitive dysfunctions, comprising episodic memory test scores, the total Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. A large part of the variance (37.9%) in DSOA scores was explained by ACE, negative life events (health and financial problems), a subjective feeling of cognitive decline, and education (all positively). ACE and NLE have a highly significant impact on the DSOA score and are not associated with aMCI or its severity. Cluster analysis showed that the diagnosis of aMCI is overinclusive because some subjects with DSOA symptoms may be incorrectly classified as aMCI. Conclusion: The clinical impact is that clinicians should carefully screen older adults for DSOA after excluding MDD. DSOA might be misinterpreted as aMCI.

Towards a major methodological shift in depression research by assessing continuous scores of recurrence of illness, lifetime and current suicidal behaviors and phenome features.

BACKGROUND: The binary major depressive disorder (MDD) diagnosis is inadequate and should never be used in research. AIMS: The study's objective is to explicate our novel precision nomothetic strategy for constructing depression models based on adverse childhood experiences (ACEs), lifetime and current phenome, and biomarker (atherogenicity indices) scores. METHODS: This study assessed recurrence of illness (ROI: namely recurrence of depressive episodes and suicidal behaviors, SBs), lifetime and current SBs and the phenome of depression, neuroticism, dysthymia, anxiety disorders, and lipid biomarkers including apolipoprotein (Apo)A, ApoB, free cholesterol and cholesteryl esters, triglycerides, high density lipoprotein cholesterol in 67 normal controls and 66 MDD patients. We computed atherogenic and reverse cholesterol transport indices. RESULTS: We were able to extract one factor from a) the lifetime phenome of depression comprising ROI, and traits such as neuroticism, dysthymia and anxiety disorders, and b) the phenome of the acute phase (based on depression, anxiety and quality of life scores). PLS analysis showed that 55.7 % of the variance in the lifetime + current phenome factor was explained by increased atherogenicity, neglect and sexual abuse, while atherogenicity partially mediated the effects of neglect. Cluster analysis generated a cluster of patients with major dysmood disorder, which was externally validated by increased atherogenicity and characterized by increased scores of all clinical features. CONCLUSIONS: The outcome of depression should not be represented as a binary variable (MDD or not), but rather as multiple dimensional scores based on biomarkers, ROI, subclinical depression traits, and lifetime and current phenome scores including SBs.

Serum proinsulin levels as peripheral blood biomarkers in patients with cognitive impairment.

Insulin has long been associated with dementia. Insulin affecting the clearance of amyloid-ß peptide and phosphorylation of tau in the CNS. Proinsulin is a precursor of insulin and its elevated serum levels are associated with peripheral insulin resistance that may reduce brain insulin levels. Our study aimed to assess differences in serum proinsulin levels between normal and cognitive impairment groups. Prospective recruitment of elderly participants was initiated from October 2019 to September 2023. Patients were divided into "cognitive impairment" and "normal cognition" group. All participants had blood drawn and serum proinsulin was measured at baseline and 12 months. Neurocognitive testing was performed every 6 months. A total of 121 participants were recruited. Seventy-seven were in the normal cognition group and 44 in the cognitive impairment group. The glycemic control and prevalence of diabetes type 2 was similar between groups. Baseline serum proinsulin levels were higher in the cognitively impaired group compared to the normal group at baseline (p = 0.019) and correlated with worse cognitive scores. We identified cognitive status, age, and BMI as potential factors associated with variations in baseline proinsulin levels. Given the complex interplay between insulin and dementia pathogenesis, serum biomarkers related to insulin metabolism may exhibit abnormalities in cognitive impaired patients. Here we present the proinsulin levels in individuals with normal cognitive function versus those with cognitive impairment and found a significant difference. This observation may help identifying non-diabetic patients suitable for treatment with novel AD drugs that related to insulin pathway.

T helper-1 activation via interleukin-16 is a key phenomenon in the acute phase of severe, first-episode major depressive disorder and suicidal behaviors.

BACKGROUND: Immune-inflammatory pathways in major depressive disorder are confined to the major dysmood disorder (MDMD) phenotype (Maes et al., 2022). No studies have addressed the immune profile of first episode MDMD (FE-MDMD). METHODS: This study investigated the immune profiles of 71 patients with the acute phase of first-episode major depressive disorder (FE-MDMD) and 40 healthy controls. We measured 48 cytokines/chemokines/growth factors, classical M1, alternative M2, T helper (Th)-1, Th-2, and Th-17 phenotypes, immune-inflammatory response system (IRS), compensatory immunoregulatory system (CIRS), and neuro-immunotoxicity profiles. RESULTS: FE-MDMD patients show significantly activated M1, M2, Th-1, IRS, CIRS, and neurotoxicity, but not Th-2 or Th-17, profiles compared to controls. FE-MDMD is accompanied by Th-1 polarization, while there are no changes in M1/M2 or IRS/CIRS ratios. The top single indicator of FE-MDMD was by far interleukin (IL)-16, followed at a distance by TRAIL, IL-2R, tumor necrosis factor (TNF)-ß. The severity of depression and anxiety was strongly associated with IRS (positively) and Th-2 (inversely) profiles, whereas suicidal behavior was associated with M1 activation. Around 56-60% of the variance in depression, anxiety, and suicidal behavior scores was explained by IL-16, platelet-derived growth factor (PDGF) (both positively), and IL-1 receptor antagonist (inversely). Increased neurotoxicity is mainly driven by IL-16, TNF-α, TRAIL, IL-6, and chemokine (CCL2, CCL11, CXCL1, CXCL10) signaling. Antidepressant-treated patients show an increased IRS/CIRS ratio as compared with drug-naïve FE-MDMD patients. CONCLUSIONS: FE-MDMD is accompanied by positive regulation of the IRS mainly driven by Th-1 polarization and T cell activation (via binding of IL-16 to CD4), and TNF, chemokine, and growth factor signaling.

The tryptophan catabolite or kynurenine pathway in autism spectrum disorder; a systematic review and meta-analysis.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication and interaction, as well as rigid and unchanging interests and behaviors. Several studies have reported that activated immune-inflammatory and nitro-oxidative pathways are accompanied by depletion of plasma tryptophan (TRP), increased competing amino acid (CAAs) levels, and activation of the TRP catabolite (TRYCAT) pathway. This study aims to systematically review and meta-analyze data on peripheral TRP, CAAs, TRYCAT pathway activity, and individual TRYCATs, including kynurenine (KYN) and kynurenic acid (KA) levels, in the blood and urine of ASD patients. After extensively searching PubMed, Google Scholar, and SciFinder, a total of 25 full-text papers were included in the analysis, with a total of 6653 participants (3557 people with ASD and 3096 healthy controls). Our results indicate that blood TRP and the TRP/CAAs ratio were not significantly different between ASD patients and controls (standardized mean difference, SMD = -0.227, 95% confidence interval, CI: -0.540; 0.085, and SMD = 0.158, 95% CI: -0.042; 0.359), respectively. The KYN/TRP ratio showed no significant difference between ASD and controls (SMD = 0.001, 95% CI: -0.169; 0.171). Blood KYN and KA levels were not significantly changed in ASD. Moreover, there were no significant differences in urine TRP, KYN, and KA levels between ASD and controls. We could not establish increases in neurotoxic TRYCATs in ASD. In conclusion, this study demonstrates no abnormalities in peripheral blood TRP metabolism, indoleamine 2,3-dioxygenase enzyme (IDO) activity, or TRYCAT production in ASD. Reduced TRP availability and elevated neurotoxic TRYCAT levels are not substantial contributors to ASD's pathophysiology.

Reverse cholesterol transport and lipid peroxidation biomarkers in major depression and bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Major depression (MDD) and bipolar disorder (BD) are linked to immune activation, increased oxidative stress, and lower antioxidant defenses. OBJECTIVES: To systematically review and meta-analyze all data concerning biomarkers of reverse cholesterol transport (RCT), lipid-associated antioxidants, lipid peroxidation products, and autoimmune responses to oxidatively modified lipid epitopes in MDD and BD. METHODS: Databases including PubMed, Google scholar and SciFinder were searched to identify eligible studies from inception to January 10th, 2023. Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: The current meta-analysis included 176 studies (60 BD and 116 MDD) and examined 34,051 participants, namely 17,094 with affective disorders and 16,957 healthy controls. Patients with MDD and BD showed a) significantly decreased RCT (mainly lowered high-density lipoprotein cholesterol and paraoxonase 1); b) lowered lipid soluble vitamins (including vitamin A, D, and coenzyme Q10); c) increased lipid peroxidation and aldehyde formation, mainly increased malondialdehyde (MDA), 4-hydroxynonenal, peroxides, and 8-isoprostanes; and d) Immunoglobulin (Ig)G responses to oxidized low-density lipoprotein and IgM responses to MDA. The ratio of all lipid peroxidation biomarkers/all lipid-associated antioxidant defenses was significantly increased in MDD (standardized mean difference or SMD = 0.433; 95% confidence intervals (CI): 0.312; 0.554) and BD (SMD = 0.653; CI: 0.501-0.806). This ratio was significantly greater in BD than MDD (p = 0.027). CONCLUSION: In MDD/BD, lowered RCT, a key antioxidant and anti-inflammatory pathway, may drive increased lipid peroxidation, aldehyde formation, and autoimmune responses to oxidative specific epitopes, which all together cause increased immune-inflammatory responses and neuro-affective toxicity.

Mood Symptoms and Chronic Fatigue Syndrome Due to Relapsing-Remitting Multiple Sclerosis Are Associated with Immune Activation and Aberrations in the Erythron.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune and neuroinflammatory disease of the central nervous system characterized by peripheral activation of immune-inflammatory pathways which culminate in neurotoxicity causing demyelination of central neurons. Nonetheless, the pathophysiology of relapsing-remitting MS (RRMS)-related chronic fatigue, depression, anxiety, cognitive impairments, and autonomic disturbances is not well understood. OBJECTIVES: The current study aims to delineate whether the remitted phase of RRMS is accompanied by activated immune-inflammatory pathways and if the latter, coupled with erythron variables, explain the chronic fatigue and mood symptoms due to RRMS. MATERIAL AND METHODS: We recruited 63 MS patients, 55 in the remitted phase of RRMS and 8 with secondary progressive MS, and 30 healthy controls and assessed erythron variables, and used a bio-plex assay to measure 27 serum cytokines. RESULTS: A significant proportion of the MS patients (46%) displayed activation of the immune-inflammatory response (IRS) and compensatory immune response (CIRS) systems, and T helper (Th)1 and Th17 cytokine profiles. Remitted RRMS patients showed increased chronic fatigue, depression, anxiety, physiosomatic, autonomic, and insomnia scores, which could partly be explained by M1 macrophage, Th1, Th-17, growth factor, and CIRS activation, as well as aberrations in the erythron including lowered hematocrit and hemoglobin levels. CONCLUSIONS: Around 50% of remitted RRMS patients show activation of immune-inflammatory pathways in association with mood and chronic-fatigue-like symptoms. IRS and CIRS activation as well as the aberrations in the erythron are new drug targets to treat chronic fatigue and affective symptoms due to MS.

Exploration of the Gut Microbiome in Thai Patients with Major Depressive Disorder Shows a Specific Bacterial Profile with Depletion of the Ruminococcus Genus as a Putative Biomarker.

Maes et al. (2008) published the first paper demonstrating that major depressive disorder (MDD) is accompanied by abnormalities in the microbiota-gut-brain axis, as evidenced by elevated serum IgM/IgA to lipopolysaccharides (LPS) of Gram-negative bacteria, such as Morganella morganii and Klebsiella Pneumoniae. The latter aberrations, which point to increased gut permeability (leaky gut), are linked to activated neuro-immune and oxidative pathways in MDD. To delineate the profile and composition of the gut microbiome in Thai patients with MDD, we examined fecal samples of 32 MDD patients and 37 controls using 16S rDNA sequencing, analyzed α- (Chao1 and Shannon indices) and ß-diversity (Bray-Curtis dissimilarity), and conducted linear discriminant analysis (LDA) effect size (LEfSe) analysis. Neither α- nor ß-diversity differed significantly between MDD and controls. Rhodospirillaceae, Hungatella, Clostridium bolteae, Hungatella hathewayi, and Clostridium propionicum were significantly enriched in MDD, while Gracillibacteraceae family, Lutispora, and Ruminococcus genus, Ruminococcus callidus, Desulfovibrio piger, Coprococcus comes, and Gemmiger were enriched in controls. Contradictory results have been reported for all these taxa, with the exception of Ruminococcus, which is depleted in six different MDD studies (one study showed increased abundance), many medical disorders that show comorbidities with MDD, and animal MDD models. Our results may suggest a specific profile of compositional gut dysbiosis in Thai MDD patients, with increases in some pathobionts and depletion of some beneficial microbiota. The results suggest that depletion of Ruminococcus may be a more universal biomarker of MDD that may contribute to increased enteral LPS load, LPS translocation, and gut-brain axis abnormalities.

The effects of adverse childhood experiences on depression and suicidal behaviors are partially mediated by neuroticism: A subclinical manifestation of major depression.

Introduction: Neuroticism, a personality trait, can predict major depressive disorder (MDD). The current study aims to determine whether a) neuroticism is a feature of the acute state of MDD, including suicidal behaviors (SB); and b) adverse childhood experiences (ACEs) are associated with neuroticism in MDD. Methods: This study included 133 participants, 67 healthy controls and 66 MDD patients, and assessed the Big 5 Inventory (BFI), ACEs using the ACE Questionnaire, and the phenome of depression using the Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory (BDI), The State-Trait Anxiety Inventory (STAI) and Columbia Suicide Severity Rating Scale (C-SSRS) scores to assess current SB. Results: Neuroticism was significantly higher in MDD than controls, and it explained 64.9% of the variance in the depression phenome (a latent vector extracted from HAM-D, BDI, STAI, and current SB scores). The other BFI domains had much less (extraversion, agreeableness) or no effect (openness, conscientiousness). One latent vector could be extracted from the phenome, lifetime dysthymia, lifetime anxiety disorders and neuroticism scores. Neglect (physical and emotional) and abuse (physical, neglect and sexual) account for approximately 30% of the variance in this latent vector. Partial Least Squares analysis showed that the effects of neglect on the phenome were partially mediated by neuroticism, whereas the effects of abuse were completely mediated by neuroticism. Discussion: Neuroticism (trait) and the MDD phenome (state) are both manifestations of the same latent core, with neuroticism being a subclinical manifestation of MDD.

Paraoxonase 1 status is a major Janus-faced component of mild and moderate acute ischemic stroke and consequent disabilities.

AIMS: This study aims to examine the associations between paraoxonase 1 (PON)1 status and acute ischemic stroke (AIS) and consequent disabilities. METHODS: This study recruited 122 patients with AIS and 40 healthy controls and assessed the Q192R gene variants, arylesterase (AREase) and chloromethyl phenylacetate (CMPAase) activities, and high-density lipoprotein cholesterol (HDLc) in baseline conditions. AREase and CMPAase were measured 3 months later. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin score (mRS) were assessed at baseline and 3 and 6 months later. RESULTS: Reduced CMPAase and increased AREase activities are significantly associated with AIS and mRS and NIHSS scores (baseline and 3 and 6 months later). The best predictor of AIS/disabilities was a decrease in the z-unit-based composite zCMPAase-zAREase score. Serum high density lipoprotein cholsterol (HDLc) was significantly correlated with CMPAase, but not AREase, activity and a lowered zCMPAase + zHDLc score was the second best predictor of AIS/disabilities. Regression analysis showed that 34.7% of the variance in baseline NIHSS was explained by zCMPAase-zAREase and zCMPAase + zHDLc composites, HDLc, and hypertension. Neural network analysis showed that stroke was differentiated from controls with an area under the ROC curve of 0.975 using both new composite scores, PON1 status, hypertension, dyslipidemia, previous stroke as body mass index. The PON1 Q192R genotype has many significant direct and mediated effects on AIS/disabilities, however, its overall effect was not significant. DISCUSSION: PON1 status and the CMPAase-HDLc complex play key roles in AIS and its disabilities at baseline and 3 and 6 months later.

Adverse childhood experiences and reoccurrence of illness impact the gut microbiome, which affects suicidal behaviours and the phenome of major depression: towards enterotypic phenotypes.

The first publication demonstrating that major depressive disorder (MDD) is associated with alterations in the gut microbiota appeared in 2008 (Maes et al., 2008). The purpose of the present study is to delineate a) the microbiome signature of the phenome of depression, including suicidal behaviours (SB) and cognitive deficits; the effects of adverse childhood experiences (ACEs) and recurrence of illness index (ROI) on the microbiome; and the microbiome signature of lowered high-density lipoprotein cholesterol (HDLc). We determined isometric log-ratio abundances or prevalences of gut microbiome phyla, genera, and species by analysing stool samples from 37 healthy Thai controls and 32 MDD patients using 16S rDNA sequencing. Six microbiome taxa accounted for 36% of the variance in the depression phenome, namely Hungatella and Fusicatenibacter (positive associations) and Butyricicoccus, Clostridium, Parabacteroides merdae, and Desulfovibrio piger (inverse association). This profile (labelled enterotype 1) indicates compositional dysbiosis, is strongly predicted by ACE and ROI, and is linked to SB. A second enterotype was developed that predicted a decrease in HDLc and an increase in the atherogenic index of plasma (Bifidobacterium, P. merdae, and Romboutsia were positively associated, while Proteobacteria and Clostridium sensu stricto were negatively associated). Together, enterotypes 1 and 2 explained 40.4% of the variance in the depression phenome, and enterotype 1 in conjunction with HDLc explained 39.9% of the variance in current SB. In conclusion, the microimmuneoxysome is a potential new drug target for the treatment of severe depression and SB and possibly for the prevention of future episodes.

In Mild and Moderate Acute Ischemic Stroke, Increased Lipid Peroxidation and Lowered Antioxidant Defenses Are Strongly Associated with Disabilities and Final Stroke Core Volume.

In acute ischemic stroke (AIS), there are no data on whether oxidative stress biomarkers have effects above and beyond known risk factors and measurements of stroke volume. This study was conducted in 122 mild-moderate AIS patients and 40 controls and assessed the modified ranking scale (mRS) at baseline, and 3 and 6 months later. We measured lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products, paraoxonase 1 (PON1) activities and PON1 Q192R genotypes, high density lipoprotein cholesterol (HDL), sulfhydryl (-SH) groups), and diffusion-weighted imaging (DWI) stroke volume and fluid-attenuated inversion recovery (FLAIR) signal intensity. We found that (a) AIS is characterized by lower chloromethyl acetate CMPAase PON1 activity, HDL and -SH groups and increased LOOH and neurotoxicity (a composite of LOOH, inflammatory markers and glycated hemoglobin); (b) oxidative and antioxidant biomarkers strongly and independently predict mRS scores 3 and 6 months later, DWI stroke volume and FLAIR signal intensity; and (c) the PON1 Q192R variant has multiple effects on stroke outcomes that are mediated by its effects on antioxidant defenses and lipid peroxidation. Lipid peroxidation and lowered -SH and PON1-HDL activity are drug targets to prevent AIS and consequent neurodegenerative processes and increased oxidative reperfusion mediators due to ischemia-reperfusion injury.

Brooding and neuroticism are strongly interrelated manifestations of the phenome of depression.

Introduction: We found that neuroticism may be identified as a subclinical manifestation of the phenome of depression, comprising depressive and anxiety symptoms, and suicidal behaviors. Rumination is positively associated with depression and neuroticism and may mediate the effects of neuroticism on depression. This study aimed to determine whether rumination or its components, including brooding or reflection, mediate the effects of neuroticism on depression or, alternatively, whether both neuroticism and rumination are manifestations of the phenome of depression. Methods: This study recruited 74 depressed subjects and 44 healthy controls. The depression group was split into groups with high versus low brooding scores. We used partial least squares (PLS) to examine mediation effects. Results: We found that brooding and reflection scores are significantly higher in depressed patients than in controls. Patients with higher brooding scores have increased severity of depression, anxiety, insomnia, neuroticism, and current suicidal ideation as compared with patients with lower brooding scores and controls. There is a strong positive association between rumination, and neuroticism, depression, anxiety, and lifetime and current suicidal behaviors. PLS analysis shows that brooding does not mediate the effects of neuroticism on the depression phenome because no discriminant validity could be established between neuroticism and brooding, or between neuroticism and brooding and the depression phenome. We were able to extract one validated latent vector from brooding and neuroticism, insomnia, depression, anxiety, and current suicidal behaviors. Conclusion: Overall, this study supports the theory that rumination and neuroticism are reflective manifestations of the phenome of depression.

The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: A systematic review and meta-analysis.

Background: There is now evidence that affective disorders including major depressive disorder (MDD) and bipolar disorder (BD) are mediated by immune-inflammatory and nitro-oxidative pathways. Activation of these pathways may be associated with activation of the tryptophan catabolite (TRYCAT) pathway by inducing indoleamine 2,3-dioxygenase (IDO, the rate-limiting enzyme) leading to depletion of tryptophan (TRP) and increases in tryptophan catabolites (TRYCATs). Aims: To systematically review and meta-analyze central and peripheral (free and total) TRP levels, its competing amino-acids (CAAs) and TRYCATs in MDD and BD. Methods: This review searched PubMed, Google Scholar and SciFinder and included 121 full-text articles and 15470 individuals, including 8024 MDD/BD patients and 7446 healthy controls. Results: TRP levels (either free and total) and the TRP/CAAs ratio were significantly decreased (p < 0.0001) in MDD/BD as compared with controls with a moderate effect size (standardized mean difference for TRP: SMD = -0.513, 95% confidence interval, CI: -0.611; -0.414; and TRP/CAAs: SMD = -0.558, CI: -0.758; -0.358). Kynurenine (KYN) levels were significantly decreased in patients as compared with controls with a small effect size (p < 0.0001, SMD = -0.213, 95%CI: -0.295; -0.131). These differences were significant in plasma (p < 0.0001, SMD = -0.304, 95%CI: -0.415, -0.194) but not in serum (p = 0.054) or the central nervous system (CNS, p = 0.771). The KYN/TRP ratio, frequently used as an index of IDO activity, and neurotoxicity indices based on downstream TRYCATs were unaltered or even lowered in MDD/BD. Conclusions: Our findings suggest that MDD and BD are accompanied by TRP depletion without IDO and TRYCAT pathway activation. Lowered TRP availability is probably the consequence of lowered serum albumin during the inflammatory response in affective disorders.

Impact of SARS-CoV-2 infection on the profiles and responses of innate immune cells after recovery.

BACKGROUNDS: SARS-CoV-2 infection results in a broad spectrum of clinical outcomes, ranging from asymptomatic to severe symptoms and death. Most COVID-19 pathogenesis is associated with hyperinflammatory conditions driven primarily by myeloid cell lineages. The long-term effects of SARS-CoV-2 infection post recovery include various symptoms. METHODS: We performed a longitudinal study of the innate immune profiles 1 and 3 months after recovery in the Thai cohort by comparing patients with mild, moderate, and severe clinical symptoms using peripheral blood mononuclear cells (n = 62). RESULTS: Significant increases in the frequencies of monocytes compared to controls and NK cells compared to mild and moderate patients were observed in severe patients 1-3 months post recovery. Increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were observed in all recovered patients, even after 3 months. Increased IL-6 and TNFα levels in monocytes were observed 1 month after recovery in response to lipopolysaccharide (LPS) stimulation, while decreased CD86 and HLA-DR levels were observed regardless of stimulation. A multiplex analysis of serum cytokines performed at 1 month revealed that most innate cytokines, except for TNFα, IL4/IL-13 (Th2) and IFNγ (Th1), were elevated in recovered patients in a severity-dependent manner. Finally, the myelopoiesis cytokines G-CSF and GM-CSF were higher in all patient groups. Increased monocytes and IL-6- and TNFα-producing cells were significantly associated with long COVID-19 symptoms. CONCLUSIONS: These results reveal that COVID-19 infection influences the frequencies and functions of innate immune cells for up to 3 months after recovery, which may potentially lead to some of the long COVID symptoms.

The Tryptophan Catabolite or Kynurenine Pathway in a Major Depressive Episode with Melancholia, Psychotic Features and Suicidal Behaviors: A Systematic Review and Meta-Analysis.

Major depressive disorder (MDD) and bipolar disorder (BD) with melancholia and psychotic features and suicidal behaviors are accompanied by activated immune-inflammatory and oxidative pathways, which may stimulate indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of the tryptophan catabolite (TRYCAT) pathway resulting in increased tryptophan degradation and elevated tryptophan catabolites (TRYCTAs). The purpose of the current study is to systematically review and meta-analyze levels of TRP, its competing amino acids (CAAs) and TRYCATs in patients with severe affective disorders. Methods: PubMed, Google Scholar and SciFinder were searched in the present study and we recruited 35 studies to examine 4647 participants including 2332 unipolar (MDD) and bipolar (BD) depressed patients and 2315 healthy controls. Severe patients showed significant lower (p < 0.0001) TRP (standardized mean difference, SMD = -0.517, 95% confidence interval, CI: -0.735; -0.299) and TRP/CAAs (SMD = -0.617, CI: -0.957; -0.277) levels with moderate effect sizes, while no significant difference in CAAs were found. Kynurenine (KYN) levels were unaltered in severe MDD/BD phenotypes, while the KYN/TRP ratio showed a significant increase only in patients with psychotic features (SMD = 0.224, CI: 0.012; 0.436). Quinolinic acid (QA) was significantly increased (SMD = 0.358, CI: 0.015; 0.701) and kynurenic acid (KA) significantly decreased (SMD = -0.260, CI: -0.487; -0.034) in severe MDD/BD. Patients with affective disorders with melancholic and psychotic features and suicidal behaviors showed normal IDO enzyme activity but a lowered availability of plasma/serum TRP to the brain, which is probably due to other processes such as low albumin levels.

The Tryptophan Catabolite or Kynurenine Pathway in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Alzheimer's disease (AD), which is characterized by progressive brain dysfunction and memory loss, is one of the most significant global health concerns for older adults. Neuroinflammation and increased oxidative stress contribute to the pathophysiology of AD, thereby presumably inducing tryptophan (TRP) degradation through the TRP catabolite (TRYCAT) pathway. OBJECTIVE: To delineate the activity of the TRYCAT pathway along with levels of TRP and tryptophan catabolites (TRYCATs) in AD patients. METHODS: We used PubMed, Google Scholar, Web of Science, and SciFinder during the month of January 2022 to gather the pertinent publications. We found 19 eligible articles which involved 738 patients and 665 healthy controls. RESULTS: Our results revealed a significant difference (p = 0.008) in the kynurenine (KYN)/TRP ratio (standardized mean difference, SMD = 0.216, 95% confidence interval, CI: 0.057; 0.376), and a significant decrease in TRP in AD patients (SMD = -0.520, 95% CI: -0.738; -0.302, p < 0.0001). Moreover, we also found a significant increase in the central nervous system (CNS), brain, and cerebrospinal fluid kynurenic acid (KA)/KYN ratio but not in peripheral blood, as well as a significant decrease in plasma KA and xanthurenic acid in the CNS and blood. CONCLUSION: AD is characterized by TRP depletion but not by an overactivity of the TRYCAT pathway. IDO-induced production of neurotoxic TRYCATs is not a key factor in the pathophysiology of AD.

The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both induce indoleamine-2,3-dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of this study was to systematically review and meta-analyze the status of the TRYCAT pathway, including the levels of TRP and kynurenine (KYN) and the activity of IDO, as measured by the ratio of KYN/TRP. METHODS: This systematic review searched PubMed, Google Scholar, and Web of Sciences and included 14 articles that compared TRP and tryptophan catabolites (TRYCATs) in COVID-19 patients versus non-COVID-19 controls, as well as severe/critical versus mild/moderate COVID-19. The analysis was done on a total of 1269 people, including 794 COVID-19 patients and 475 controls. RESULTS: The results show a significant (p < 0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD = 1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD = 1.123, 95% CI: 0.730; 1.516) and significantly lower TRP (SMD = - 1.002, 95%CI: - 1.738; - 0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD = 0.945, 95%CI: 0.629; 1.262) and KYN (SMD = 0.806, 95%CI: 0.462; 1.149) were also significantly (p < 0.0001) higher and TRP lower (SMD = - 0.909, 95% CI: - 1.569; - 0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in kynurenic acid (KA) and the KA/KYN ratio between COVID-19 patients and controls. CONCLUSIONS: Our results indicate increased activity of the IDO enzyme in COVID-19 and severe/critical patients. The TRYCAT pathway is implicated in the pathophysiology and progression of COVID-19 and may signal a worsening outcome of the disease.

Oxidative stress and antioxidant defenses in mild cognitive impairment: A systematic review and meta-analysis.

This study aims to systematically review and meta-analyze the nitro-oxidative stress (O&NS)/antioxidant (ANTIOX) ratio in the peripheral blood of people with mild cognitive impairment (MCI). We searched PubMed, Scopus, Google Scholar, and Web of Science for articles published from inception until July 31, 2021. Forty-six studies on 3.798 MCI individuals and 6.063 healthy controls were included. The O&NS/ANTIOX ratio was significantly higher in MCI than in controls with a Standardized Mean Difference (SMD)= 0.378 (95% CI: 0.250; 0.506). MCI individuals showed increased lipid peroxidation (SMD=0.774, 95%CI: 4.416; 1.132) and O&NS-associated toxicity (SMD=0.621, CI: 0.377; 0.865) and reduced glutathione (GSH) defenses (SMD=0.725, 95%CI: 0.269; 1.182) as compared with controls. MCI was also accompanied by significantly increased homocysteine (SMD=0.320, CI: 0.059; 0.581), but not protein oxidation, and lowered non-vitamin (SMD=0.347, CI: 0.168; 0.527) and vitamin (SMD=0.564, CI: 0.129; 0.999) antioxidant defenses. The results show that MCI is at least in part due to increased neuro-oxidative toxicity and suggest that treatments targeting lipid peroxidation and the GSH system may be used to treat or prevent MCI.