Circulating myeloid-derived MMP8 in stress susceptibility and depression.

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Significantly elevated phosphatidylethanol levels in recent suicide attempters, but not in depressed controls and healthy volunteers.

INTRODUCTION: Suicide is a complex transdiagnostic phenomenon. It is strongly associated with, but not exclusive to major depressive disorder (MDD). Hazardous alcohol drinking has also been linked to an increased risk of suicidal behaviours, however, it is often underreported. The study aimed to evaluate whether an objective measure of chronic alcohol use, phosphatidylethanol (PEth) could be useful as a biomarker in clinical practice. METHOD: ology. The present case-control multi-centric study recruited 156 participants into three study groups: 52 patients treated for major depressive disorder (MDD), 51 individuals immediately following a suicide attempt (SA), and 53 volunteers. Sociodemographic data, medical history, and laboratory data, including PEth concentrations and C-reactive protein levels, were collected from study participants. RESULTS: PEth concentrations were the highest in suicide attempters (232,54 ± 394,01 ng/ml), followed by patients with MDD (58,39 ± 135,82 ng/ml), and the control group (24,45 ± 70,83 ng/ml) (Kruskall Wallis χ2 = 12.23, df = 2, p = .002). In a multinomial logistic regression model with adjustments, PEth concentration was able to predict belonging to suicide attempters' group, but not to depression group (p = .01). Suicide attempters were also more likely to underreport their recent alcohol consumption. LIMITATIONS: We did not analyze SA methods, psychiatric comorbidity and several other factors that might be associated with PEth levels, such as body mass index, race, and haemoglobin levels. Sample recruited in hospital settings may not be representative of the whole population. The results of this adult-only study cannot be generalized to adolescents. CONCLUSIONS: PEth levels in recent suicide attempters significantly exceeded those of patients with MDD and controls. Suicide attempters also were more likely to underreport their alcohol consumption when questioned about their consuption. PEth might be an interesting biomarker to evaluate individuals at risk of SA.

Elevated BICD2 DNA methylation in blood of major depressive disorder patients and reduction of depressive-like behaviors in hippocampal Bicd2-knockdown mice.

Major depressive disorder (MDD) is a prevalent and devastating mental illness. To date, the diagnosis of MDD is largely dependent on clinical interviews and questionnaires and still lacks a reliable biomarker. DNA methylation has a stable and reversible nature and is likely associated with the course and therapeutic efficacy of complex diseases, which may play an important role in the etiology of a disease. Here, we identified and validated a DNA methylation biomarker for MDD from four independent cohorts of the Chinese Han population. First, we integrated the analysis of the DNA methylation microarray (n = 80) and RNA expression microarray data (n = 40) and identified BICD2 as the top-ranked gene. In the replication phase, we employed the Sequenom MassARRAY method to confirm the DNA hypermethylation change in a large sample size (n = 1,346) and used the methylation-sensitive restriction enzymes and a quantitative PCR approach (MSE-qPCR) and qPCR method to confirm the correlation between DNA hypermethylation and mRNA down-regulation of BICD2 (n = 60). The results were replicated in the peripheral blood of mice with depressive-like behaviors, while in the hippocampus of mice, Bicd2 showed DNA hypomethylation and mRNA/protein up-regulation. Hippocampal Bicd2 knockdown demonstrates antidepressant action in the chronic unpredictable mild stress (CUMS) mouse model of depression, which may be mediated by increased BDNF expression. Our study identified a potential DNA methylation biomarker and investigated its functional implications, which could be exploited to improve the diagnosis and treatment of MDD.

Plasma levels of S100B and neurofilament light chain protein in stress-related mental disorders.

The pathophysiological changes underlying stress-related mental disorders remain unclear. However, research suggests that alterations in astrocytes and neurons may be involved. This study examined potential peripheral markers of such alterations, including S100B and neurofilament light chain (NF-L). We compared plasma levels of S100B and NF-L in patients with chronic stress-induced exhaustion disorder (SED), patients with major depressive disorder (MDD), and healthy controls. We also investigated whether levels of S100B and NF-L correlated with levels of astrocyte-derived extracellular vesicles (EVs that indicate astrocyte activation or apoptosis) and with symptom severity. Only women had measurable levels of S100B. Women with SED had higher plasma levels of S100B than women with MDD (P < 0.001) and healthy controls (P < 0.001). Self-rated symptoms of cognitive failures were positively correlated with levels of S100B (rs = 0.434, P = 0.005) as were depressive symptoms (rs = 0.319, P < 0.001). Plasma levels of astrocyte-derived EVs were correlated with levels of S100B (rs = 0.464, P < 0.001). Plasma levels of NF-L did not differ between the groups and were not correlated with symptom severity or EV levels. Thus, long-term stress without sufficient recovery and SED may be associated with raised plasma levels of S100B, which may be evidence of pathophysiological changes in astrocytes. The findings also support the hypothesis that plasma levels of S100B are associated with cognitive dysfunction.

Major depression favors the expansion of Th17-like cells and decrease the proportion of CD39+Treg cell subsets in response to myelin antigen in multiple sclerosis patients.

BACKGROUND: Mood disorders have been associated with risk of clinical relapses in multiple sclerosis (MS), a demyelinating disease mediated by myelin-specific T cells. OBJECTIVES: We aimed to investigate the impact of major depressive disorder (MDD) and cytokine profile of T-cells in relapsing remitting MS patients. METHODS: For our study, plasma and PBMC were obtained from 60 MS patients (30 with lifetime MDD) in remission phase. The PBMC cultures were stimulated with anti-CD3/anti-CD28 beads or myelin basic protein (MBP), and effector and regulatory T cell phenotypes were determined by flow cytometry. The cytokine levels, both in the plasma or in the supernatants collected from PBMC cultures, were quantified by Luminex. In some experiments, the effect of serotonin (5-HT) was investigated. RESULTS: Here, higher Th17-related cytokine levels in response to anti-CD3/anti-CD28 and MBP were quantified in the plasma and PBMC cultures of the MS/MDD group in comparison with MS patients. Further, elevated frequency of CD4+ and CD8+ T cells capable of producing IL-17, IL-22 and GM-CSF was observed in depressed patients. Interestingly, the percentage of myelin-specific IFN-γ+IL-17+ and IFN-γ+GM-CSF+ CD4+ T cells directly correlated with neurological disabilities. In contrast, the occurrence of MDD reduced the proportion of MBP-specific CD39+Tregs subsets. Notably, the severity of both neurological disorder and depressive symptoms inversely correlated with these Tregs. Finally, the addition of 5-HT downregulated the release of Th17-related cytokines in response to anti-CD3/anti-CD28 and myelin antigen. CONCLUSIONS: In summary, our findings suggested that recurrent major depression, by favoring imbalances of effector Th17 and Treg cell subsets, contributes to MS severity.

Circulating hsa-let-7e-5p and hsa-miR-125a-5p as Possible Biomarkers in the Diagnosis of Major Depression and Bipolar Disorders.

BACKGROUND: Evidence shows that microRNAs (miRNAs) could play a key role in the homeostasis and development of major depressive disorder and bipolar disorder. The present study is aimed at investigating the changes in circulating miRNA expression profiles in a plasma of patients suffering from major depressive disorder (MDD) and bipolar disorder (BD) to distinguish and evaluate these molecules as biomarkers for mood disorders. METHODS: A study enrolled a total of 184 subjects: 74 controls, 84 MDD patients, and 26 BD patients. Small RNA sequencing revealed 11 deregulated circulating miRNAs in MDD and BD plasma, of which expression of 5, hsa-miR-139-3p, miRNAs hsa-let-7e-5p, hsa-let-7f-5p, hsa-miR-125a-5p, and hsa-miR-483-5p, were further verified using qPCR. miRNA gene expression data was evaluated alongside the data from clinical assessment questionnaires. RESULTS: hsa-let-7e-5p and hsa-miR-125a-5p were both confirmed upregulated: 0.75-fold and 0.25-fold, respectively, in the MDD group as well as 1.36-fold and 0.68-fold in the BD group. Receiver operating curve (ROC) analysis showed mediocre diagnostic sensitivity and specificity of both hsa-let-7e-5p and hsa-miR-125a-5p with approximate area under the curve (AOC) of 0.66. ROC analysis of combined miRNA and clinical assessment data showed that hsa-let-7e-5p and hsa-miR-125a-5p testing could improve MDD and BD diagnostic accuracy by approximately 10%. CONCLUSIONS: Circulating hsa-let-7e-5 and hsa-miR-125a-5p could serve as additional peripheral biomarkers for mood disorders; however, suicidal ideation remains the major diagnostic factor for MDD and BD.

C-Reactive Protein as a Biomarker for Major Depressive Disorder?

The etiopathogenesis of depression is not entirely understood. Several studies have investigated the role of inflammation in major depressive disorder. The present work aims to review the literature on the association between C-Reactive Protein (CRP) and depression. A systematic review was performed for the topics of 'CRP' and 'depression' using the PubMed database from inception to December 2021. Fifty-six studies were identified and included in the review. Evidence suggested the presence of dysregulation in the inflammation system in individuals with depression. In most studies, higher blood CRP levels were associated with greater symptom severity, a specific pattern of depressive symptoms, and a worse response to treatment. Moreover, about one-third of depressed patients showed a low-grade inflammatory state, suggesting the presence of a different major depressive disorder (MDD) subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis, which could benefit from monitoring of CRP levels and might potentially respond to anti-inflammatory treatments. This work provides robust evidence about the potential role of CRP and its blood levels in depressive disorders. These findings can be relevant to developing new therapeutic strategies and better understanding if CRP may be considered a valuable biomarker for depression.

Increased serum resistin but not G-CSF levels are associated in the pathophysiology of major depressive disorder: Findings from a case-control study.

BACKGROUND: Many studies have predicted major depressive disorder (MDD) as the leading cause of global health by 2030 due to its high prevalence, disability, and illness. However, the actual pathophysiological mechanism behind depression is unknown. Scientists consider alterations in cytokines might be tools for understanding the pathogenesis and treatment of MDD. Several past studies on several inflammatory cytokine expressions in MDD reveal that an inflammatory process is activated, although the precise causes of that changes in cytokine levels are unclear. Therefore, we aimed to investigate resistin and G-CSF in MDD patients and controls to explore their role in the pathogenesis and development of depression. METHODS: We included 220 participants in this study. Among them, 108 MDD patients and 112 age-sex matched healthy control (HCs). We used DSM-5 to evaluate study participants. Also, we applied the Ham-D rating scale to assess the severity of patients. Serum resistin and G-CSF levels were measured using ELISA kits (BosterBio, USA). RESULTS: The present study observed increased serum resistin levels in MDD patients compared to HCs (13.82 ± 1.24ng/mL and 6.35 ± 0.51ng/mL, p <0.001). However, we did not find such changes for serum G-CSF levels between the groups. Ham-D scores showed a significant correlation with serum resistin levels but not G-CSF levels in the patient group. Furthermore, ROC analysis showed a fairly predictive performance of serum resistin levels in major depression (AUC = 0.746). CONCLUSION: The present study findings suggest higher serum resistin levels are associated with the pathophysiology of MDD. This elevated serum resistin level may serve as an early risk assessment indicator for MDD. However, the role of serum G-CSF in the development of MDD is still unclear despite its neuroprotective and anti-inflammatory effects.

Sex-specific impact of major depressive disorder on 12-year change in glycaemic status: Results from a nationwide cohort study of adults without diabetes in Germany.

AIMS: There is evidence for an increased type 2 diabetes (T2D) risk associated with depression, but its role for diabetes prevention remains unclear. This study aimed to add insight by investigating the impact of major depressive disorder (MDD) on prospective glycaemic changes. METHODS: The study was based on a cohort of n = 1,766 adults without diabetes (776 men, 990 women; 18-65 years of age) who participated in the mental health supplement of the German National Health Interview and Examination Survey (GNHIES98-MHS, 1997-1999) and in a follow-up survey (DEGS1, 2008-2011). Glycaemic status was defined as normoglycaemia [HbA1c < 39 mmol/mol (<5.7%)], prediabetes [39 ≤ HbA1c < 48 mmol/mol (5.7-6.4%)] and diabetes [HbA1c ≥ 48 mmol/mol (≥ 6.5%), diagnosed diabetes, or antidiabetic medication], and glycaemic changes categorized as 'remission', 'stability' and 'progression'. Baseline MDD was assessed via a modified German version of the WHO Composite International Diagnostic Interview. Multivariable logistic regressions were applied to analyse the association of MDD with glycaemic changes and incident T2D, adjusting for socio-demographics, lifestyle conditions, chronic diseases, antidepressant use and mental health care. RESULTS: MDD prevalence was 21.4% for women and 8.9% for men. Among women, MDD was associated with a lower chance for remission (RRR 0.43; 95% CI 0.23, 0.82). Among men, MDD was not significantly related to glycaemic changes. MDD had no significant effect on incident T2D (men: OR 1.58; 0.55, 4.52; women: OR 0.76; 0.37, 1.58). CONCLUSIONS: Findings of the current study highlight the role of depression in T2D prevention, particularly among women.

Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study.

BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

Interaction effect of serum serotonin level and age on the 12-week pharmacotherapeutic response in patients with depressive disorders.

Despite the recognized antidepressant role of serotonin (5-hydroxytryptamine [5-HT]) signaling pathways in the central nervous system, the association between baseline peripheral 5-HT level and the antidepressant treatment response in clinical studies remains debatable. We investigated the interaction effects of baseline serum 5-HT level and age on the 12-week remission in outpatients with depressive disorders who received stepwise antidepressant treatment. Baseline serum serotonin levels were measured and the age of 1094 patients recorded. The patients received initial antidepressant monotherapy; then, patients with an insufficient response or who experienced uncomfortable side effects received alternative treatments every 3 weeks (3, 6, and 9 weeks). Subsequently, 12-week remission, defined as a Hamilton Depression Rating Scale (HAMD) score of ≤ 7, was evaluated. Individual and interaction effects of serum 5-HT level (as a binary [low vs. high, based on the median value of 72.6 ng/mL] or continuous variable) and age (as a binary [< 60 vs. ≥ 60 years] or continuous variable) on the 12-week remission rate were analyzed using logistic regression models after adjusting for relevant covariates. High 5-HT (≥ 72.6 ng/mL) and age ≥ 60 years were associated with the highest 12-week remission rates and a significant multiplicative interaction effect. The interaction effect of the two variables on the 12-week remission rate was significant even when analyzed as a continuous variable. Our study suggests that the association between baseline serum 5-HT level and 12-week antidepressant treatment outcomes differs according to patient age.

The Correlation Between Thyroid Function, Frontal Gray Matter, and Executive Function in Patients With Major Depressive Disorder.

The present study was aimed to investigate the relationships between serum thyroid hormones (THs), frontal gray matter volume, and executive function in selected patients with major depressive disorder (MDD). One hundred and four MDD patients and seventy-five healthy controls (HCs) were subjected to thyroid-stimulating hormone (TSH), free Triiodothyronine (fT3), free Thyroxine (fT4), and executive function tests and underwent structural magnetic resonance imaging (MRI). Voxel-based morphometry (VBM) analysis was performed to compare group differences in the gray matter for the frontal lobe. Furthermore, mediation analysis was used to investigate whether gray matter volumes of the frontal gyrus mediated the relationship between serum THs and executive function in MDD patients. MDD patients exhibited significant gray matter volume reduction in several brain regions, including the left rectus, right middle frontal cortex, and left middle frontal cortex. Serum TSH levels are positively associated with altered regional gray matter volume patterns within MFG and executive function. Importantly, gray matter in the right MFG was a significant mediator between serum TSH levels and executive function. These findings expand our understanding of how thyroid function affects brain structure changes and executive function in MDD patients.

Psychophysiological Effects of Lactobacillus plantarum PS128 in Patients with Major Depressive Disorder: A Preliminary 8-Week Open Trial.

Recent studies have suggested that gut-brain axis may be one of the mechanisms of major depression disorder (MDD). The current study aimed to investigate the effects of Lactobacillus plantarum PS128 (PS128) on psychophysiology in patients with MDD. We recruited 11 patients with MDD and gave them PS128 for 8 weeks. We compared depression symptoms, serum markers of inflammation and gut permeability, and gut microbiota before and after 8-week intervention and also explored the correlations among symptoms, biomarkers, and gut microbiota. After 8-week PS128 intervention, scores of Hamilton Depression Rating Scale-17 and Depression and Somatic symptoms Scale significantly decreased. Serum levels of high sensitivity c-reactive protein, interluekin-6, and tumor necrosis factor-α, zonulin and intestinal fatty acid binding protein, and the composition of gut microbiota did not significantly change after 8-week PS128 intervention. However, we found changes of some genera were correlated with changes of symptoms and biomarkers. In conclusion, this is an open trial with small sample size and has several limitations. The results need to be verified by randomized, double-blind, placebo-controlled trial with larger sample size.

Fat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice.

Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. Suppressing Fto expression in the mouse hippocampus results in depression-like behaviors in adult mice, whereas overexpression of FTO expression leads to rescue of the depression-like phenotype. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampus of Fto knockdown (KD), Fto knockout (cKO), and FTO-overexpressing (OE) mice allows us to identify adrenoceptor beta 2 (Adrb2) mRNA as a target of FTO. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. Our findings suggest that FTO is a regulator of a mechanism underlying depression-like behavior in mice.

Combined rs-fMRI study on brain functional imaging and mechanism of RAGE-DAMPs of depression: Evidence from MDD patients to chronic stress-induced depression models in cynomolgus monkeys and mice.

More and more evidence show that major depressive disorder (MDD) is closely related to inflammation caused by chronic stress, which seriously affects human physical and mental health. However, the inflammatory mechanism of depression and its effect on brain function have not been clarified. Based on resting-state functional magnetic resonance imaging (rs-fMRI), we investigated change of brain functional imaging and the inflammatory mechanism of damage-related molecular patterns (DAMPs)-receptor of advanced glycation protein end product (RAGE) in MDD patients and depressive-like cynomolgus monkeys and mice models induced by chronic stress. The regional homogeneity (ReHo) and functional connectivity (FC) were analyzed using MATLAB and SPM12 software. We detected the expression of DAMPs-RAGE pathway-related proteins and mRNA in MDD peripheral blood and in serum and brain tissue of cynomolgus monkeys and mice. Meanwhile, RAGE gene knockout mice, RAGE inhibitor, and overexpression of AVV9RAGE adeno-associated virus were used to verify that RAGE is a reliable potential biomarker of depression. The results showed that the ReHo value of prefrontal cortex (PFC) in MDD patients and depressive-like cynomolgus monkeys was decreased. Then, the PFC was used as a seed point, the FC of ipsilateral and contralateral PFC were weakened in depressive-like mice. At the same time, qPCR showed that RAGE and HMGB1 mRNA were upregulated and S100ß mRNA was downregulated. The expression of RAGE-related inflammatory protein in PFC of depressive-like monkeys and mice were consistent with that in peripheral blood of MDD patients. Moreover, the results were confirmed in RAGE-/- mice, injection of FPS-ZM1, and overexpression of AAV9RAGE in mice. To sum up, our findings enhance the evidence that chronic stress-PFC-RAGE are associated with depression. These results attempt to establish the links between brain functional imaging, and molecular targets among different species will help to reveal the pathophysiological mechanism of depression from multiple perspectives.

δEPCD: the electrophysiologic coefficient of depressiveness.

Despite research advances, recently identified biological markers for depression are either non-specific or impractical in daily clinical practice. Hence, we aim to identify a novel biomarker: δEPCD, the electrophysiologic coefficient of depressiveness. δEPCD must be sensitive and specific to the vulnerability towards depression. It should also detect the presence of a depressive clinical state and be able to quantify its severity. Moreover, it should be easily accessible and cost-effective. Accordingly, combining high-frequency heart rate variability (HF-HRV), which reflects a reduction in vagal tone, and tryptophan metabolism, which influences serotonin synthesis pathway, may have a good diagnostic and prognostic accuracy in depression. δEPCD is the multiplication of the intrinsic difference between state 0 (rest) and state 1 (exposure to stress) of HF-HRV and the plasma concentration ratio between quinolinic acid and kynurenine. δEPCD theoretically fluctuates between -1000 and 0 where being closer to 0 signifies no vulnerability to depression. Individuals with a score between -16.7 and -167 have a high vulnerability to depression. Finally, individuals with a δEPCD closer to -1000 have the most severe forms of depression. δEPCD is theoretically conceived to be easy to assess and monitor which makes it a candidate for further evaluation of reliability and validity.CLINICAL SIGNIFICANCEDepression is currently diagnosed based on emotional and behavioural symptoms; however there is currently a rising interest in the field of neurobiological markers that could improve diagnostic accuracy.Many current biological approaches are primarily based on single neurobiological markers that are either non-specific or impractical in daily clinical practice.Among other neurological effects, depression may modify the parasympathetic nervous system tone and disturb the tryptophan metabolism.The electrophysiological coefficient of depressiveness δEPCD combines heart rate variability (HRV) and tryptophan metabolism to reflect the intrinsic individual vulnerability towards depression and the inherent severity of an index depressive disorder.δEPCD is the intrinsic difference between state 0 (without stress) and state 1 (exposed to a stressful task) of the high-frequency heart rate variability multiplied by the intrinsic difference between both states, e.g. state 0 and 1, of the plasma concentration ratio of quinolinic acid over kynurenine.

Incident Major Depressive Disorder Predicted by Three Measures of Insulin Resistance: A Dutch Cohort Study.

OBJECTIVE: Major depressive disorder is the leading cause of disability worldwide. Yet, there remain significant challenges in predicting new cases of major depression and devising strategies to prevent the disorder. An important first step in this process is identifying risk factors for the incidence of major depression. There is accumulating biological evidence linking insulin resistance, another highly prevalent condition, and depressive disorders. The objectives of this study were to examine whether three surrogate measures of insulin resistance (high triglyceride-HDL [high-density lipoprotein] ratio; prediabetes, as indicated by fasting plasma glucose level; and high central adiposity, as measured by waist circumference) at the time of study enrollment were associated with an increased rate of incident major depressive disorder over a 9-year follow-up period and to assess whether the new onset of these surrogate measures during the first 2 years after study enrollment was predictive of incident major depressive disorder during the subsequent follow-up period. METHODS: The Netherlands Study of Depression and Anxiety (NESDA) is a multisite longitudinal study of the course and consequences of depressive and anxiety disorders in adults. The study population comprised 601 NESDA participants (18-65 years old) without a lifetime history of depression or anxiety disorders. The study's outcome was incident major depressive disorder, defined using DSM-IV criteria. Exposure measures included triglyceride-HDL ratio, fasting plasma glucose level, and waist circumference. RESULTS: Fourteen percent of the sample developed major depressive disorder during follow-up. Cox proportional hazards models indicated that higher triglyceride-HDL ratio was positively associated with an increased risk for incident major depression (hazard ratio=1.89, 95% CI=1.15, 3.11), as were higher fasting plasma glucose levels (hazard ratio=1.37, 95% CI=1.05, 1.77) and higher waist circumference (hazard ratio=1.11 95% CI=1.01, 1.21). The development of prediabetes in the 2-year period after study enrollment was positively associated with incident major depressive disorder (hazard ratio=2.66, 95% CI=1.13, 6.27). The development of high triglyceride-HDL ratio and high central adiposity (cut-point ≥100 cm) in the same period was not associated with incident major depression. CONCLUSIONS: Three surrogate measures of insulin resistance positively predicted incident major depressive disorder in a 9-year follow-up period among adults with no history of depression or anxiety disorder. In addition, the development of prediabetes between enrollment and the 2-year study visit was positively associated with incident major depressive disorder. These findings may have utility for evaluating the risk for the development of major depression among patients with insulin resistance or metabolic pathology.

Common and disorder-specific upregulation of the inflammatory markers TRAIL and CCL20 in depression and schizophrenia.

Schizophrenia (SZ) and major depressive disorder (MDD) are severe mental disorders, which have been associated with alterations of the peripheral inflammatory network. However, studies for both disorders have not been fully consistent and have focused on few canonical markers with high relevance to the innate immune system, while the role of the adaptive immune system is studied less. Furthermore, it is unclear to what extent inflammatory abnormalities are diagnosis-specific or transdiagnostic. The purpose of this study was to investigate 75 peripheral inflammatory markers including the acute phase protein high-sensitivity C-reactive protein (hsCRP) in patients with MDD (n = 37), SZ (n = 42) and healthy controls (HC) (n = 17), while considering possible confounders and correcting rigorously for multiple testing in group comparisons. We identified C-C chemokine ligand 20 (CCL20) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as the inflammatory markers with significant group differences after controlling for multiple comparisons and adjusting for BMI, sex and smoking as confounders. TRAIL was elevated in both MDD and SZ compared to HC. CCL20 was specifically increased in SZ compared to MDD and HC. There were no significant group differences in hsCRP after correcting for multiple testing. Finally, we observed no significant correlations among CCL20, TRAIL and CRP. TRAIL is a transdiagnostic marker for SZ and MDD, with both markers being independent from CRP and body mass index (BMI). CCL20 may be a novel and specific biomarker of schizophrenia, but an influence of antipsychotic medication cannot be excluded. Identifying novel markers in mental disease bears the potential for future research towards novel treatment strategies by modifying inflammation-related processes.

Potential biomarkers of major depression diagnosis and chronicity.

BACKGROUND: Molecular biomarkers are promising tools to be routinely used in clinical psychiatry. Among psychiatric diseases, major depression disorder (MDD) has gotten attention due to its growing prevalence and morbidity. METHODS: We tested some peripheral molecular parameters such as serum mature Brain-Derived Neurotrophic Factor (mBDNF), plasma C-Reactive Protein (CRP), serum cortisol (SC), and the salivary Cortisol Awakening Response (CAR), as well as the Pittsburgh sleep quality inventory (PSQI), as part of a multibiomarker panel for potential use in MDD diagnosis and evaluation of disease's chronicity using regression models, and ROC curve. RESULTS: For diagnosis model, two groups were analyzed: patients in the first episode of major depression (MD: n = 30) and a healthy control (CG: n = 32). None of those diagnosis models tested had greater power than Hamilton Depression Rating Scale-6. For MDD chronicity, a group of patients with treatment-resistant major depression (TRD: n = 28) was tested across the MD group. The best chronicity model (p < 0.05) that discriminated between MD and TRD included four parameters, namely PSQI, CAR, SC, and mBDNF (AUC ROC = 0.99), with 96% of sensitivity and 93% of specificity. CONCLUSION: These results indicate that changes in specific biomarkers (CAR, SC, mBDNF and PSQI) have potential on the evaluation of MDD chronicity, but not for its diagnosis. Therefore, these findings can contribute for further studies aiming the development of a stronger model to be commercially available and used in psychiatry clinical practice.