T cell activation and deficits in T regulatory cells are associated with major depressive disorder and severity of depression.

Major depressive disorder (MDD) is associated with T cell activation, but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP (glycoprotein A repetitions predominant)-bearing CD25+ FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1 cell, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+ FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+ CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+ CD71+, CD3+ CD40L+, CD4+ CD71+, CD4+ CD40L+, CD4+ HLADR+, and CD8+ HLADR+ T cells, increased CD3+ CD71+, CD4+ CD71+ and CD4+ HLADR+ expression, and lowered CD25+ FoxP3 expression and CD25+ FoxP+ CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30 and 40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+ CD40L+). In conclusion, increased T helper and cytotoxic cell activation along with decreased Treg homeostatic defenses are important parts of MDD that lead to enhanced immune responses and, as a result, neuroimmunotoxicity.

Higher Seasonal Variation of Systemic Inflammation in Bipolar Disorder.

Seasonal rhythms affect the immune system. Evidence supports the involvement of immuno-inflammatory mechanisms in bipolar disorder (BD), with the neutrophil to lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII; platelets × neutrophils/lymphocytes) consistently reported to be higher in patients with BD than in HC, but seasonal rhythms of innate and adaptive immunity have never been studied. We retrospectively studied NLR and SII in 824 participants divided into three groups: 321 consecutively admitted inpatients affected by a major depressive episode in course of BD, and 255 consecutively admitted inpatients affected by obsessive-compulsive disorder (OCD; positive psychiatric control), and 248 healthy controls (HC). Patients with BD showed markedly higher markers of systemic inflammation in autumn and winter, but not in spring and summer, in respect to both HC and patients with OCD, thus suggesting a specific effect of season on inflammatory markers in BD, independent of a shared hospital setting and drug treatment. Given that systemic inflammation is emerging as a new marker and as target for treatment in depressive disorders, we suggest that seasonal rhythms should be considered for tailoring antidepressant immuno-modulatory treatments in a precision medicine approach.

Identification of novel endoplasmic reticulum-related genes and their association with immune cell infiltration in major depressive disorder.

BACKGROUND: Several lines of evidence point to an interaction between genetic predisposition and environmental factors in the onset of major depressive disorder (MDD). This study is aimed to investigate the pathogenesis of MDD by identifying key biomarkers, associated immune infiltration using bioinformatic analysis and human postmortem sample. METHODS: The Gene Expression Omnibus (GEO) database of GSE98793 was adopted to identify hub genes linked to endoplasmic reticulum (ER) stress-related genes (ERGs) in MDD. Another GEO database of GSE76826 was employed to validate the novel target associated with ERGs and immune infiltration in MDD. Moreover, human postmortem sample from MDD patients was utilized to confirm the differential expression analysis of hub genes. RESULTS: We discovered 12 ER stress-related differentially expressed genes (ERDEGs). A LASSO Cox regression analysis helped construct a diagnostic model for these ERDEGs, incorporating immune infiltration analysis revealed that three hub genes (ERLIN1, SEC61B, and USP13) show the significant and consistent expression differences between the two groups. Western blot analysis of postmortem brain samples indicated notably higher expression levels of ERLIN1 and SEC61B in the MDD group, with USP13 also tending to increase compared to control group. LIMITATIONS: The utilization of the MDD gene chip in this analysis was sourced from the GEO database, which possesses a restricted number of pertinent gene chip samples. CONCLUSIONS: These findings indicate that ERDEGs especially including ERLIN1, SEC61B, and USP13 associated the infiltration of immune cells may be potential diagnostic indicators for MDD.

Childhood trauma and LPS-stimulated inflammation in adulthood: Results from the Netherlands Study of Depression and Anxiety

BACKGROUND: Childhood trauma (CT) is robustly associated with psychiatric disorders including major depressive and anxiety disorders across the life span. The innate immune system may play a role in the relation between CT and stress-related psychopathology. However, whether CT influences the innate production capacity of cytokine levels following ex vivo stimulation by lipopolysaccharide (LPS), is currently unknown. METHODS: Using data from the Netherlands Study of Depression and Anxiety (NESDA, n=1237), we examined whether CT (emotional neglect, emotional, physical, and sexual abuse before the age of 16), assessed by the Childhood Trauma Interview, was associated with levels in supernatants of interferon (IFN)γ, interleukin-2 (IL-2), IL-4, IL-6, IL-8, IL-10, IL-18, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1ß, matrix metalloproteinase-2 (MMP-2), TNFα and TNFß after ex vivo stimulation with LPS. Cytokines were analysed individually and cumulatively (overall inflammation index and number of cytokines in high-risk quartile (HRQ)) using linear regression analyses. RESULTS: After adjustment for demographic, lifestyle, and health-related covariates, total CT severity was associated with the overall inflammation index (ß = 0.085, PFDR = 0.011), the number of cytokines in HRQ (ß = 0.063, PFDR = 0.036), and individual markers of IL-2 (ß = 0.067, PFDR = 0.036), IL-6 (ß = 0.091 PFDR = 0.011), IL-8 (ß = 0.085 PFDR = 0.011), IL-10 (ß = 0.094 PFDR = 0.011), MCP-1 (ß = 0.081 PFDR = 0.011), MIP-1α (ß = 0.061 PFDR = 0.047), MIP1-ß (ß = 0.077 PFDR = 0.016), MMP-2 (ß = 0.070 PFDR = 0.027), and TNFß (ß = 0.078 PFDR = 0.016). Associations were strongest for individuals with severe CT, reporting multiple types or higher frequencies of trauma. Half of the findings persisted after adjustment for psychiatric status. The findings were consistent across different CT types. CONCLUSION: Childhood Trauma is associated with increased LPS-stimulated cytokine levels, with evidence for a dose-response relationship. Our results highlight a dysregulated innate immune system capacity in adults with CT, which could contribute to an increased vulnerability for psychopathology and somatic disorders across the lifespan.

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.

The Immune Profile of Major Dysmood Disorder: Proof of Concept and Mechanism Using the Precision Nomothetic Psychiatry Approach.

Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class, namely major dysmood disorder (MDMD), a new pathway phenotype, namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMD's features and IRS, CIRS, macrophages (M1), T helper (Th)1, Th2, Th17, T regulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 µg/mL of PHA and 25 µg/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity, and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS/CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase-triggered STAT protein phosphorylation, TLR/NF-κB, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMD's heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers.

Augmented T-cell mitochondrial reactive oxygen species in adults with major depressive disorder.

The prevalence of major depressive disorder (MDD) is highest in young adulthood, an effect that has been magnified by the COVID-19 pandemic. Importantly, individuals with MDD are at a greater risk of developing cardiovascular disease (CVD). Accumulating evidence supports immune system dysregulation as a major contributor to the elevated CVD risk in older adults with MDD; however, whether this is present in young adults with MDD without comorbid disease remains unclear. Interestingly, recent data suggest augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) as a potent driver of immune dysregulation in animal models of psychiatric disease. With this background in mind, we tested the hypothesis that young adults with MDD would have augmented T-cell mitoROS and circulating proinflammatory cytokines compared with healthy young adults without MDD (HA). Whole blood was drawn from 14 young adults with MDD (age: 23 ± 2 yr) and 11 HA (age: 22 ± 1 yr). T-cell mitoROS (MitoSOX red; total: CD3+, T-helper: CD4+, T cytotoxic: CD8+) and serum cytokines were assessed by flow cytometry. Total T-cell mitoROS was significantly greater in adults with MDD compared with HA [median: 14,089 arbitrary units (AU); median: 1,362 AU, P = 0.01]. Likewise, both T-helper and T-cytotoxic cell mitoROS were significantly greater in adults with MDD compared with HA (both: P < 0.05). There were no differences in circulating cytokines between groups (all cytokines: P > 0.05). Collectively, these findings suggest that elevated T-cell mitoROS may represent an early marker of immune system dysregulation in young, otherwise healthy, adults with MDD.NEW & NOTEWORTHY To our knowledge, we provide the first evidence of augmented T-cell mitochondrial reactive oxygen species (T-cell mitoROS) in young, otherwise healthy adults with MDD. Although the elevated T-cell mitoROS did not correspond to a proinflammatory profile, these findings suggest that elevated T-cell mitoROS may be an early marker of immune system dysregulation in young adults with MDD.

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.

Inflammatory Process and Immune System in Major Depressive Disorder.

Major depressive disorder (MDD) is one of the most common psychiatric illnesses in the general population. In mental disorders, the activation of inflammatory pathways in the brain is a major producer of excitotoxicity and an inducer of oxidative stress. The occurrence of these 2 events is partly responsible for the neuronal damage inherent in patients with mental disorders. In the case of MDD, the release of hormone and increase in pro-inflammatory cytokines in plasma and indicators of oxidative stress have been identified as consequences of this event. The most important affectations in patients with MDD are changes in their cognitive and executive functions due to brain inflammation. Hence, these biomarkers can serve as diagnostic and severity classification tools and treatment. In this work, we described the communication pathway between the immune and neuroendocrine systems in MDD and suggested possible therapeutic options for the disease.

Intracellular calcium and inflammatory markers, mediated by purinergic stimulation, are differentially regulated in monocytes of patients with major depressive disorder.

The P2X7 receptor (P2X7R) is a ligand-gated ion channel that is being recognized as a major player in neuropsychiatric disorders such as Major Depressive Disorder (MDD). P2X7R activation is triggered by high extracellular ATP concentrations, leading to channel opening and inducing an increase in cytosolic calcium concentration ([Ca2+]c), that activates the inflammatory pathway. Those receptors are expressed not only in CNS cells but also in peripheral blood cells, where they are activated in response to inflammatory molecules such as bacterial lipopolysaccharide (LPS). LPS induced-tissue damage promotes an elevation of extracellular ATP, triggering the NRLP3-inflammasome assembly and activation that, sequentially, induces caspase-1 cleavage and IL-1ß processing and secretion. In this context, we attempt to understand the role of P2X7R in [Ca2+]c homeostasis regulation, inflammasome expression and its pharmacological modulation in MDD. For this purpose, monocytes were isolated from peripheral blood of MDD patients and [Ca2+]c was monitored with the intracellular probe Fura-2. Our results point out to P2X7R as the responsible of the Ca2+ imbalance, as well as TNF-α-dependent activation of caspase-1 in MDD patients. In addition, P2X7R blockade with its specific antagonist, JNJ-47965567, reduces the Ca2+ entry upon Bz-ATP exposure. Altogether, our results point that MDD patients have both, Ca2+ homeostasis alteration and an inflammatory status, which promote an independent-inflammasome activation of caspase-1. Therefore, we propose the pharmacological modulation of P2X7R as a therapeutic approach against MDD symptoms.

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.

Major Depressive Disorder Enhances Th2 and Th17 Cytokines in Patients Suffering from Allergic Rhinitis and Asthma.

INTRODUCTION: Major depressive disorder (MDD) can impact the severity of allergic rhinitis (AR) and asthma (AA). Here, we evaluated the cytokine production by T-cells from AR and AA patients with or without MDD. The effect of serotonin on the in vitro T-cell response was also evaluated. METHODS: The cytokines produced by activated T-cells were measured by Luminex and flow cytometry. In some cell cultures, serotonin was added. RESULTS: MDD not only enhanced the production of Th2- and Th17-related cytokines, but also, the levels of interleukin (IL)-5 and IL-17 were directly correlated with the severity of depression and anxiety symptoms. As compared with AR, the levels of IL-17 were higher and the release of IL-10 was lower in activated T-cell cultures from AA patients, mainly those with MDD. In AA/MDD patients, the severity of anxiety symptoms and lung disease was directly correlated with Th17-like and hybrid Th2/Th17 cells, but inversely correlated with IL-10-secreting CD4+ T-cells. Finally, the addition of serotonin reduced the production of Th2- and Th17-related cytokines, but elevated IL-10 secretion in cell cultures from both AR and AA patients. CONCLUSIONS: Our findings suggest that not only the occurrence of MDD but also the severity of anxiety symptoms, may adversely affect the outcome of allergic reactions by favoring the production of cytokines implicated in the pathogenesis of AR and AA, a phenomenon that was attenuated by serotonin.

Highlighting Immune System and Stress in Major Depressive Disorder, Parkinson's, and Alzheimer's Diseases, with a Connection with Serotonin.

There is recognition that both stress and immune responses are important factors in a variety of neurological disorders. Moreover, there is an important role of several neurotransmitters that connect these factors to several neurological diseases, with a special focus in this paper on serotonin. Accordingly, it is known that imbalances in stressors can promote a variety of neuropsychiatric or neurodegenerative pathologies. Here, we discuss some facts that link major depressive disorder, Alzheimer's, and Parkinson's to the stress and immune responses, as well as the connection between these responses and serotonergic signaling. These are important topics of investigation which may lead to new or better treatments, improving the life quality of patients that suffer from these conditions.

Translational evidence for the Inflammatory Response System (IRS)/Compensatory Immune Response System (CIRS) and neuroprogression theory of major depression.

Major depressive disorder (MDD) is a common, severe and disabling neuropsychiatric disorder with a heterogenous etiology. Among the most widely recognized etiological models, immunopathogenesis is a predominant one. Numerous studies have demonstrated aberrant levels of inflammatory markers in the peripheral blood, cerebrospinal fluid (CSF) and brain of patients with MDD. Multiple studies including meta-analyses have reported increased peripheral levels of acute phase proteins, and pro-inflammatory cytokines, particularly IL-1ß, TNF-α, and IL-6 in MDD. Postmortem brain studies similarly demonstrated upregulated expressions of these pro-inflammatory cytokines. This along with evidence of monocytic, lymphocytic and microglial activation, suggest an activated inflammatory response system (IRS) in MDD. A few studies show increased levels of anti-inflammatory cytokines or defective inflammatory pathways and a deficit in T cell maturation and responses in MDD patients. This suggests the presence of a Compensatory Immune Response System (CIRS), which can counterbalance the effects of IRS in major depression. More recently, simultaneously increased levels of both the pro-and anti-inflammatory cytokines are reported in the brain of MDD patients; this indicates activity of both the IRS and CIRS in MDD. The IRS and CIRS are the evolutionarily conserved and integral elements of an overarching system. The relevance of a dysregulated IRS-CIRS system in the neurobiological construct of MDD is just beginning to be understood. Speculation is rife that the disrupted IRS-CIRS elements might determine the onset, episodes, neuroprogressive processes, treatment response as well as recovery of patients with MDD. Notably, the signatures of an activated IRS-CIRS might emerge as potential biomarkers of MDD. Herein, an attempt has been made to highlight the biology and pathobiological relevance of IRS-CIRS activation in MDD and provide an insight into the role of these components in pharmacological therapy.

Shared metabolic and neuroimmune mechanisms underlying Type 2 Diabetes Mellitus and Major Depressive Disorder.

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease with symptoms that go beyond the domain of glucose metabolism. In fact, research has shown that T2DM is accompanied by neurodegeneration and neuroinflammation. Interestingly, Major Depressive Disorder (MDD), a mood disorder characterized mainly by depressed mood and anhedonia is a key feature of T2DM. A body of evidence demonstrates that there are many shared neuroimmune mechanisms underlying the pathophysiology of T2DM and MDD. Therefore, here we review the state-of-art regarding the underlying factors common to both T2DM and MDD. Furthermore, we briefly discuss how depressive symptoms in diabetic patients could be tackled by using novel therapeutic approaches uncovered by these shared mechanisms. Understanding the comorbidity of depression in diabetic patients is essential to fully address T2DM pathophysiology and treatment.

On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?

Many patients with major depressive disorder (MDD) are reported to have higher levels of multiple inflammatory cytokines including interleukin 6 (IL-6). Recent studies both pre-clinical and clinical have advocated for the functional role of IL-6 in development of MDD and suggested a great potential for targeting this cytokine to open new avenues in pharmacotherapy of depression. The purpose of the present narrative review was to provide an integrated account of how IL-6 may contribute to development of depression. All peer-reviewed journal articles published before July 2020 for each area discussed were searched by WOS, PubMed, MEDLINE, Scopus, Google Scholar, for original research, review articles, and book chapters. Publications between 1980 and July 2020 were included. Alterations in IL-6 levels, both within the periphery and the brain, most probably contribute to depression symptomatology in numerous ways. As IL-6 acts on multiple differing target tissues throughout the body, dysregulation of this particular cytokine can precipitate a multitude of events relevant to depression and blocking its effects can prevent further escalation of inflammatory responses, and potentially pave the way for opening new avenues in diagnosis, treatment, and prevention of this debilitating disorder.

The role of anthranilic acid in the increase of depressive symptoms and major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a and oral ribavirin.

Background: Tryptophan metabolism via the kynurenine pathway is considered the link between the immune and endocrine systems. Dysregulation of serotonergic transmission can stem from the direct influence of interferon-α on the activity of serotonergic receptors 5-HT1A and 5-HT2A, and from its indirect effect on tryptophan metabolism. Induction of the kynurenine pathway increases the concentration of neurotoxic kynurenine metabolites, and the activity of kynurenine derivatives is linked to the onset of depression. The aim of our study was to evaluate the relationships between depressive symptoms and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, indolamine 2,3-dioxygenase (IDO) activity and tryptophan availability to the brain. Methods: The study followed a prospective longitudinal cohort design. We evaluated 101 patients with chronic hepatitis C who were treated with pegylated interferon-α2a, and 40 controls who were awaiting treatment. We evaluated the relationships between total score on the Montgomery-Åsberg Depression Rating Scale and kynurenine, tryptophan, anthranilic acid and kynurenic acid concentrations, IDO activity and tryptophan availability to the brain. A logistic regression model was adapted for the diagnosis of major depressive disorder at each time point, taking into account changes in parameters of the kynurenine pathway between a given time point and the baseline measurement. Results: Of the treated patients, 44% fulfilled the criteria for major depressive disorder at least once during the 24 weeks of treatment. Anthranilic acid concentrations were significantly increased compared to baseline for all time points except week 2. Tryptophan availability showed a significant decrease (ß = -0.09, p = 0.01) only in week 12 of treatment. Over time, kynurenine, tryptophan and anthranilic acid concentrations, as well as IDO activity and tryptophan availability to the brain, were significantly associated with total score on the Montgomery-Åsberg Depression Rating Scale. A logistic regression model revealed that participants with decreased tryptophan availability to the brain at 12 weeks of treatment and participants with increased anthranilic acid concentrations at week 24 of treatment were at increased risk for diagnosis of major depressive disorder (odds ratios 2.92 and 3.59, respectively). Limitations: This study had an open-label design in a population receiving naturalistic treatment. Conclusion: The present study provides the first direct evidence of the role of anthranilic acid in the pathogenesis of inflammation-induced major depressive disorder during treatment for hepatitis C with pegylated interferon-α2a.

Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine.

The spleen is a large immune organ that plays a key role in the immune system. The precise molecular mechanisms underlying the relationship between the spleen and stress-related psychiatric disorders are unknown. Here we investigated the role of spleen in stress-related psychiatric disorders. FACS analysis was applied to determine the contribution of the spleen to susceptibility and resilience in mice that were subjected to chronic social defeat stress (CSDS). We found a notable increase in splenic volume and weight in CSDS-susceptible mice compared to control (no CSDS) mice and CSDS-resilient mice. The number of granulocytes, but not of T cells and B cells, in the spleen of susceptible mice was higher than in the spleen of both control and resilient mice. Interestingly, NKG2D (natural killer group 2, member D) expression in the spleen of CSDS-susceptible mice was higher than that in control mice and CSDS-resilient mice. In addition, NKG2D expression in the spleen of patients with depression was higher than that in controls. Both increased splenic weight and increased splenic NKG2D expression in CSDS-susceptible mice were ameliorated after a subsequent administration of (R)-ketamine. The present findings indicate a novel role of splenic NKG2D in stress susceptibility versus resilience in mice subjected to CSDS. Furthermore, abnormalities in splenic functions in CSDS-susceptible mice were ameliorated after subsequent injection of (R)-ketamine. Thus, the brain-spleen axis might, at least in part, contribute to the pathogenesis of stress-related psychiatric disorders such as depression.

Inflammatory cytokines derived from peripheral blood contribute to the modified electroconvulsive therapy-induced cognitive deficits in major depressive disorder.

Little is known about the pathophysiology of memory deficits in patients with major depressive disorder (MDD) treated with modified electroconvulsive therapy (MECT). This study examined the profiles of cytokines, the memory function, and their association in MECT-treated MDD patients. Forty first-episode, drug-free MDD patients and 40 healthy controls were recruited. MECT was started with antidepressant treatment at a stable initial dose. The Wechsler Memory Scale (WMS) and Hamilton Rating Scale for Depression 17 (HRSD-17) were used to assess the cognitive function. MDD patients were divided into the memory impairment group (WMS < 50) and the non-memory impairment group (WMS ≥ 50) based on the total WMS scores after MECT. The levels of NOD-like receptor 3 (NLRP3) inflammasome, interleukin-18 (IL-18) and nuclear factor kappa-B (NF-κB) in the serum were measured. MDD patients showed significantly higher levels of NLRP3 inflammasome, IL-18 and NF-κB than that in the controls prior to MECT, and the levels also significantly increased after MECT. In MDD patients, the serum levels of these inflammatory cytokines were negatively associated with the total WMS scores and likely contributed to the scores independently. The receiver operating characteristic curve showed that the serum levels of these inflammatory cytokines may predict the cognitive impairment risk in MDD patients receiving MECT. Abnormal levels of NLRP3 inflammasome, IL-18 and NF-κB reflecting the disturbed balance of pro-inflammatory and anti-inflammatory mechanisms likely contribute to the MECT-induced cognitive deficits in MDD patients.