Does decreased autophagy and dysregulation of LC3A in astrocytes play a role in major depressive disorder?

Astrocytic dysfunction contributes to the molecular pathogenesis of major depressive disorder (MDD). However, the astrocytic subtype that mainly contributes to MDD etiology and whether dysregulated autophagy in astrocytes is associated with MDD remain unknown. Using a single-nucleus RNA sequencing (snRNA-seq) atlas, three astrocyte subtypes were identified in MDD, while C2 State-1Q astrocytes showed aberrant changes in both cell proportion and most differentially expressed genes compared with other subtypes. Moreover, autophagy pathways were commonly inhibited in astrocytes in the prefrontal cortices (PFCs) of patients with MDD, especially in C2 State-1Q astrocytes. Furthermore, by integrating snRNA-seq and bulk transcriptomic data, we found significant reductions in LC3A expression levels in the PFC region of CUMS-induced depressed mice, as well as in postmortem PFC tissues and peripheral blood samples from patients with MDD. These results were further validated by qPCR using whole-blood samples from patients with MDD and healthy controls. Finally, LC3A expression in the whole blood of patients with MDD was negatively associated with the severity of depressive symptoms. Overall, our results underscore autophagy inhibition in PFC astrocytes as a common molecular characteristic in MDD and might reveal a novel potential diagnostic marker LC3A.

Does the timing of intake matter? Association between caffeine intake and depression: Evidence from the National Health and Nutrition Examination Survey.

BACKGROUND: Recent research suggests that caffeine intake is associated with a reduced risk of depression. However, the relationship between caffeine intake during different periods of the day and depression is still unclear. METHODS: This cross-sectional study analyzed noninstitutionalized adults from the National Health and Nutrition Examination Survey, with a weighted representation of approximately 218 million US adults. Covariate-adjusted sample-weighted regressions were used to examine associations between caffeine intake and depression in different periods. RESULTS: Caffeine intake during non-early morning periods (outside of 5:00-8:00 AM) is associated with a high prevalence of depression (unadjusted OR: 1.08, 95%CI: 1.05-1.11; adjusted OR: 1.03, 95 % CI: 1.00-1.06). Participants who consumed caffeine in the early morning (5:00-8:00 AM) had a lower prevalence of depression compared to participants who did not consume caffeine in the early morning (unadjusted OR: 0.75, 95%CI: 0.67-0.85; adjusted OR: 0.86, 95 % CI: 0.75-0.99). LIMITATIONS: Cross-sectional study could not determine the temporal association; patients with depression in this study were not clinically diagnosed with Major Depressive Disorder. CONCLUSIONS: Among US adults, early morning caffeine consumers had a lower prevalence of depression than non-consumers; caffeine intake during non-early morning periods is associated with a high prevalence of depression. Our results may suggest the importance of caffeine intake time for depression.

Effects of olanzapine on anhedonia in schizophrenia: mediated by complement factor H.

Background: Anhedonia is a trans-diagnostic symptom in schizophrenia and MDD. Our recent work indicated that increased plasma level of complement factor H (CFH) is associated with anhedonia in major depressive disorder. This study hypothesized that CFH is likely to be a biomarker of anhedonia in schizophrenia. Methods: A 12-week prospective study is performed to observe the effects of olanzapine on anhedonia and CFH. We used the Chinese version of Snaith-Hamilton Pleasure Scale (SHAPS) to evaluate anhedonic phenotype in patients with schizophrenia. Plasma levels of C-reactive protein (CRP), C3, C4 and CFH were measured. Results: Of the recruited 152 samples, patients with anhedonia were found in 99/152 (65.13%). Patients with anhedonia had notably higher PANSS negative subscores, SHAPS total score and higher level of plasma CFH than those without anhedonia (Ps<0.05). Stepwise multivariate linear regression analysis showed that increasing level of plasma CFH was a risk factor for SHAPS total score (ß = 0.18, p = 0.03). Of the 99 patients with anhedonia, 74 completed the 12-week follow-up. We observed significantly reduced scores of PANSS, SHAPS and decreased plasma CFH level, when the patients completed this study. The change of SHAPS total score is positively correlated with the level of CFH decrease (p = 0.02). Conclusion: Our results implied that plasma CFH levels may be a biomarker for anhedonia in schizophrenia, and the effect of olanzapine on treating anhedonia is through decreasing plasma CFH levels.

miR-124 Exacerbates depressive-like behavior by targeting Ezh2 to induce autophagy.

On the basis of our previous research, miR-124 and autophagy have been shown to be associated with depression and antidepressant treatment, respectively. However, whether miR-124 is involved in depressive-like behavior and antidepressant efficacy through regulating autophagy remains poorly understood. The chronic unpredictable mild stress (CUMS) depression model in mice was established, and then intraperitoneal fluoxetine injections (10 mg/kg) were administered for a duration of 4 weeks. The behavioral changes induced by CUMS were evaluated by the tail suspension test, open field test, sucrose preference test, and elevated plus maze test. Quantitative real-time PCR was used to detect expression levels of miR-124 and its three precursor genes in hippocampus of mice. Western blotting was used to detect the expressions of Ezh2 and autophagy proteins (P62, Atg3, Atg7, LC3-I, and LC3- II) in hippocampus of mice. Depression-like behaviors were successfully induced in CUMS models and reversed by SSRI treatments. The expression levels of miR-124 and its precursor gene ( miR-124-3 ) were significantly increased in the hippocampus of CUMS mice, while the expression levels were significantly decreased after 4 weeks of fluoxetine treatment. The mRNA and protein expressions of Ezh2, a validated target of miR-124, were decreased in the hippocampus of CUMS mice, and the fluoxetine treatment could reverse the expressions. A correlation analysis suggested that miR-124 had a significant negative correlation with Ezh2 mRNA expression. The protein levels of LC3-II/I, P62, and Atg7, which were found to be regulated by Ezh2, were increased in the hippocampus of CUMS mice and decreased after fluoxetine treatment. We speculated that autophagy was enhanced in the CUMS model of depression and might be mediated by miR-124 targeting Ezh2.

Mindfulness-based intervention improves residual negative symptoms and cognitive impairment in schizophrenia: a randomized controlled follow-up study.

BACKGROUND: Residual negative symptoms and cognitive impairment are common for chronic schizophrenia patients. The aim of this study was to investigate the efficacy of a mindfulness-based intervention (MBI) on negative and cognitive symptoms of schizophrenia patients with residual negative symptoms. METHODS: In this 6-week, randomized, single-blind, controlled study, a total of 100 schizophrenia patients with residual negative symptoms were randomly assigned to the MBI or control group. The 6-week MBI group and the control group with general rehabilitation programs maintained their original antipsychotic treatments. The scores for the Positive and Negative Syndrome Scale (PANSS), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and the Symptom Checklist 90 (SCL-90) were recorded at baseline and week 6 to assess psychotic symptoms, cognitive performance, and emotional state, respectively. RESULTS: Compared with general rehabilitation programs, MBI alleviated the PANSS-negative subscore, general psychopathology subscore, and PANSS total score in schizophrenia patients with residual negative symptoms (F = 33.77, pBonferroni < 0.001; F = 42.01, pBonferroni < 0.001; F = 52.41, pBonferroni < 0.001, respectively). Furthermore, MBI improved RBANS total score and immediate memory subscore (F = 8.80, pBonferroni = 0.024; F = 11.37, pBonferroni = 0.006), as well as SCL-90 total score in schizophrenia patients with residual negative symptoms (F = 18.39, pBonferroni < 0.001). CONCLUSIONS: Our results demonstrate that MBI helps schizophrenia patients with residual negative symptoms improve clinical symptoms including negative symptom, general psychopathology symptom, and cognitive impairment. TRIAL REGISTRATION: ChiCTR2100043803.

NLRP3 Influences Cognitive Function in Schizophrenia in Han Chinese.

It has been proposed that immune abnormalities may be implicated with pathophysiology of schizophrenia. The nod-like receptor pyrin domain-contraining protein 3 (NLRP3) can trigger immune-inflammatory cascade reactions. In this study, we intended to identify the role of gene encoding NLRP3 (NLRP3) in susceptibility to schizophrenia and its clinical features. For the NLRP3 mRNA expression analysis, 53 drug-naïve patients with first-episode schizophrenia and 56 healthy controls were enrolled. For the genetic study, a total of 823 schizophrenia patients and 859 controls were recruited. Among them, 239 drug-naïve patients with first-episode schizophrenia were enrolled for clinical evaluation. There is no significant difference in NLRP3 mRNA levels between patients with schizophrenia and healthy controls (p = 0.07). We did not observe any significant differences in allele and genotype frequencies of rs10754558 polymorphism between the schizophrenia and control groups. We noticed significant differences in the scores of RBANS attention and total scores between the patients with different genotypes of rs10754558 polymorphism (p = 0.001 and p < 0.01, respectively). Further eQTL analysis presented a significant association between the rs10754558 polymorphism and NLRP3 in frontal cortex (p = 0.0028, p = 0.028 after Bonferroni correction). Although our findings did not support NLRP3 confer susceptibility to schizophrenia, NLRP3 may be a risk factor for cognitive impairment, especially attention deficit in this disorder.

Sex differences between serum total bilirubin levels and cognition in patients with schizophrenia.

BACKGROUND: Cognitive deficits are common in patients with schizophrenia (SCZ). Abnormal serum total bilirubin (TBIL) levels have been involved in cognitive deficits associated with neuropsychiatric diseases such as mild cognitive impairment and subcortical ischemic vascular disease. However, this relationship has not yet been fully investigated in patients with SCZ. Therefore, the aim of this study was to investigate the association between the serum TBIL concentration and cognitive deficits in SCZ patients and to determine whether a sex difference exists in the association. METHODS: A total of 455 participants were eligible and included in this cross-sectional study. Cognition was evaluated using the Montreal Cognitive Assessment. Serum TBIL concentration was measured with an automatic biochemistry analyzer according to the routine protocol in the hospital medical laboratory. RESULTS: Serum TBIL levels were lower in the cognition impairment group than in the cognition normal group in male patients. In contrast, serum TBIL levels tended to be increased in the cognition impairment group in female patients, although the difference was not significant. Further stepwise multiple regression analysis stratified by sex showed that serum TBIL was independently and positively associated with cognitive function in male patients but not in female patients. Moreover, the association between serum TBIL level and cognitive function was also identified by the propensity score matching (PSM) method in male patients, but not in female patients. CONCLUSION: These findings suggest that lower serum TBIL levels may be associated with cognitive impairment in male SCZ patients.

Signatures of 4 autophagy-related genes as diagnostic markers of MDD and their correlation with immune infiltration.

BACKGROUND: Major depressive disorder (MDD) is a debilitating mental illness and one of the primary causes of suicide. This study attempted to develop and validate a multigene joint signature for diagnosing MDD based on autophagy-related genes (ARGs) and to explore their biological role in MDD. METHODS: We downloaded data from the Gene Expression Omnibus (GEO) database and retrieved ARGs from the Human Autophagy Database. The limma package in R software was used to identify differentially expressed genes (DEGs). We used CIBERSORT to analyze differences in the immune microenvironment between MDD patients and controls. Finally, we examined the correlation between diagnostic markers and infiltrating immune cells to better understand the molecular immune mechanism. RESULTS: In this study, we identified 20 differentially expressed ARGs in MDD compared to controls. A signature of 4 autophagy-related genes (GPR18, PDK4, NRG1 and EPHB2) was obtained. ROC analysis showed that our model has good diagnostic performance (AUC=0.779, 95% CI=0.709-0.848). Bioinformatics analysis validated that GPR18 may represent a new candidate gene for MDD. Correlation analysis revealed that GPR18 was positively correlated with regulatory T cells (Treg), CD8+ T cells, naive B cells, and memory B cells and negatively correlated with M0 macrophages and neutrophils in MDD. LIMITATIONS: This was a second mining of previously published data sets. Independent studies are warranted to validate and improve the clinical utility of the identified signature. CONCLUSIONS: We identified a novel four-ARG gene signature that has good diagnostic performance and identified an association between ARG genes and the immune microenvironment in MDD.

Omega-3 fatty acids ameliorate cognitive dysfunction in schizophrenia patients with metabolic syndrome.

Our previous study showed that metabolic abnormalities reduced the levels of brain-derived neurotrophic factor (BDNF) and deteriorated cognitive performance in patients with schizophrenia. Inflammation may play a key role in this process. Omega-3 fatty acids have been documented to ameliorate inflammation. Therefore, we hypothesized that omega-3 fatty acids may be of value in enhancing BDNF levels and improving cognitive function in patients with schizophrenia with metabolic syndrome (MetS). We recruited 80 patients with both schizophrenia and MetS who received long-term olanzapine monotherapy. The enzyme-linked immunosorbent assay was used to measure the plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The patients were randomly assigned to the OMG-3 group (n = 40) or the placebo group (n = 40). Of the 80 patients who consented to the study, 72 completed this 12-week RCT. The primary outcome was the changes from baseline to 12 weeks in clinical characteristics and the levels of BDNF, CRP, IL-6 and TNF-α. There was a significant correlation between omega-3 fatty acid treatment and enhanced delayed memory factor in the RBANS assessment (Fgroup×time = 6.82; df = 1, 66; P = 0.01) when the patients completed this study. Along with cognitive improvement, omega-3 fatty acids enhanced BDNF (Fgroup×time = 4.93; df = 1, 66; P = 0.03) and reduced CRP (Fgroup×time = 17.11; df = 1, 66; P < 0.01), IL-6 (Fgroup×time = 9.71; df = 1, 66; P < 0.004) and TNF-α (Fgroup×time = 6.71; df = 1, 66; P = 0.012) levels after 12 weeks of treatment. The changes in BDNF levels are negatively correlated with the changes in TNF-α levels (r = -0.37, P = 0.03) but not with the changes in CRP and IL-6 levels. Our findings provide suggestive evidence that omega-3 fatty acids have beneficial effects on cognitive function in patients with MetS, which is paralleled by enhanced BDNF levels.

Baseline Serum Levels of Beclin-1, but Not Inflammatory Factors, May Predict Antidepressant Treatment Response in Chinese Han Patients With MDD: A Preliminary Study.

Currently, the choice of medical treatment for major depressive disorder (MDD) is primarily based on a trial-and-error process. Thus, identification of individual factors capable of predicting treatment response is of great clinical relevance. Recent work points towards beclin-1 and inflammatory factors as potential biomarkers of antidepressant treatment response. The primary aim of the study was to investigate whether pre-treatment serum levels of beclin-1 and inflammatory factors could predict antidepressant treatment response in Chinese Han patients with MDD. Forty patients with MDD were treated with either a selective serotonin reuptake inhibitor (SSRI) (paroxetine in 20 cases) or a serotonin-norepinephrine reuptake inhibitor (SNRI) (duloxetine in 13 cases and venlafaxine in 7 cases). Depression scores and serum levels of beclin-1 were measured at the baseline and after 8 weeks of antidepressant treatment. Serum C-reactive protein (CRP), interleukin (IL)-1B, and IL-6 levels were determined using enzyme-linked immunosorbent assay kits at the baseline. Twenty-seven patients were identified as treatment responders, whereas 13 were identified as non-responders after 8 weeks of antidepressant treatment. Baseline serum beclin-1 levels were significantly higher in non-responders than in responders (p = 0.001), whereas no differences were found in baseline serum CRP, IL-1B, or IL-6 levels between responders and non-responders. There were no significant correlations between baseline levels of beclin-1 and baseline IL-1ß, IL-6, and CRP levels-neither in the total sample nor in responder and non-responder groups. Moreover, logistic regression models and a random forest model showed that baseline serum beclin-1, but not inflammatory factors, was an independent and the most important predictor for antidepressant treatment response. Furthermore, serum beclin-1 levels were significantly increased in responders (p = 0.027) but not in non-responders after 8 weeks of treatment (p = 0.221). Baseline serum beclin-1 levels may be a predictive biomarker of antidepressant response in patients with MDD. Moreover, beclin-1 may be involved in the therapeutic effect of antidepressant drugs.

Effects of omega-3 fatty acids on metabolic syndrome in patients with schizophrenia: a 12-week randomized placebo-controlled trial.

RATIONALE: Individuals with schizophrenia are at increased risk of developing metabolic syndrome (MetS) due to their lifestyle and antipsychotic treatment. Our previous study showed that patients with both schizophrenia and MetS present an increased expression and production of tumor necrosis factor-alpha (TNF-alpha). Omega-3 fatty acids have a documented role in suppressing TNF-alpha; therefore, we hypothesized that they may be of value in relieving inflammation and improving metabolic disturbance in patients with both schizophrenia and MetS. OBJECTIVES: This study employed a randomized placebo-controlled trial to investigate the effects of omega-3 fatty acids on MetS in patients with schizophrenia. METHODS: We recruited 80 patients with both schizophrenia and MetS who received long-term olanzapine monotherapy. The patients were randomly assigned to the OMG-3 group (n = 40) or the placebo group (n = 40). RESULTS: Patients with both schizophrenia and MetS had significantly higher levels of TNF-alpha than the control subjects (Z = - 4.37, P < 0.01). There was a significant correlation between omega-3 fatty acid treatment and reduced triglyceride (TG) levels (Fgroup × time = 13.42; df = 1, 66; P < 0.01) when the patients completed this study. Along with metabolic improvement, omega-3 fatty acids decreased TNF-alpha levels after 12 weeks of treatment (Fgroup × time = 6.71; df = 1, 66; P = 0.012). We also found that the extent of TNF-alpha decrease was significantly correlated with that of TG decrease (r = 0.38, P = 0.001). CONCLUSIONS: Our findings provide suggestive evidence that omega-3 fatty acids have beneficial effects on TG metabolism in patients with both schizophrenia and MetS that parallel decreased inflammation levels.