Long-Term Consumption of Green Tea Can Reduce the Degree of Depression in Postmenopausal Women by Increasing Estradiol.

Postmenopausal women face a higher risk of depression due to a combination of social and physiological factors. As a beverage rich in a variety of bioactive substances, green tea has significant effects on metabolism, inflammation and endocrine, and may reduce the risk of depression, but few studies have looked at the effects of green tea on postmenopausal women. Therefore, we designed this study to investigate the effects of long-term green tea consumption on inflammation, endocrine and depression levels in postmenopausal women. We investigated a tea-producing village and eventually included 386 postmenopausal women, both in the tea drinking and control groups. The results showed that there were significant differences in the degree of insomnia, degree of depression, BMI, SII and estradiol between the two groups. And, green tea consumption may reduce the risk of depression through the mediating pathway of sleep, SII and estradiol. In summary, long-term green tea consumption can reduce the risk of depression in postmenopausal women by reducing inflammation and increasing estradiol. This kind of living habit deserves further promotion.

Oridonin relieves depressive-like behaviors by inhibiting neuroinflammation and autophagy impairment in rats subjected to chronic unpredictable mild stress.

Major depressive disorder (MDD) is a severe life-threatening disorder with increasing prevalence. However, the mechanistic interplay between depression, neuroinflammation, and autophagy is yet to be demonstrated. This study investigated the effect of Oridonin on CUMS-induced depression, neuroinflammation, and autophagy impairment. Male 4-week-old Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS), some of which were injected with Oridonin, fluoxetine (FLX), or their combination at different durations of CUMS. CUMS significantly increased the levels of cytokines (IL-1ß, IL-18, and caspase-1), reduced autophagy-related protein levels (Beclin-1, p62, Atg5, and LC3B), and caused microglia cells activation. Oridonin prevented and reversed the depressive-like behavior. Furthermore, it has a stronger and longer-lasting antidepressant effect than FLX. And the antidepressant effect of Oridonin in combination with fluoxetine was greater than that of high-dose fluoxetine alone. In addition, Oridonin significantly normalized autophagy-related protein levels, and reduced levels of cytokines by blocking the interaction between NLRP3 and NEK7. Similarly, Oridonin abolished levels of cytokines and reversed autophagy impairment in LPS-activated BV2 cells. All these results supported our hypothesis that Oridonin possesses potent anti-depressive action, which might be mediated via inhibition of neuroinflammation and autophagy impairment by blocking the interaction between NLRP3 and NEK7.

Organized Resting-state Functional Dysconnectivity of the Prefrontal Cortex in Patients with Schizophrenia.

Schizophrenia has prominent functional dysconnectivity, especially in the prefrontal cortex (PFC). However, it is unclear whether in the same group of patients with schizophrenia, PFC functional dysconnectivity appears in an organized manner or is stochastically located in different subregions. By investigating the resting-state functional connectivity (rsFC) of each PFC subregion from the Brainnetome atlas in 40 schizophrenia patients and 40 healthy subjects, we found 24 altered connections in schizophrenia, and the connections were divided into four categories by a clustering analysis: increased connections within the PFC, increased connections between the inferior PFC and the thalamus/striatum, reduced connections between the PFC and the motor control areas, and reduced connections between the orbital PFC and the emotional perception regions. In addition, the four categories of rsFC showed distinct cognitive engagement patterns. Our findings suggest that PFC subregions have specific functional dysconnectivity patterns in schizophrenia and may reflect heterogeneous symptoms and cognitive deficits in schizophrenia.

DNA methylation of the Tacr2 gene in a CUMS model of depression.

Tacr2, the gene encoding the NK2 receptor, belongs to G protein-coupled receptors. Accumulating evidence has indicated that the tachykinin receptors may contribute to the pathophysiology of depression. During the last decade, some studies have shown that Tacr2 activation is involved in the modulation of emotional processes. However, the extent, to which stress impacts Tacr2 expression remains unclear. The molecular mechanisms underlying depression also remain poorly understood. In this study, we subjected adult male Sprague Dawley (SD) rats to chronic unpredictable mild stress (CUMS) to induce a depression-like phenotype. We then measured the body weight and performed the sucrose preference test, forced swimming test (FST) and open field test to detect the effects of stress on anhedonia and activity. Western blotting and real-time PCR were used to study the protein and mRNA expression levels of Tacr2, respectively, in the hypothalamus. To explore DNA methylation of the Tacr2 gene, we used methylated DNA immunoprecipitation sequencing (MeDIP-seq). Additionally, we used the bisulfite sequencing PCR (BSP) to further verify the DNA methylation levels of the Tacr2 receptor gene in rats. We found that the CUMS-sensitive rats exhibited a decrease in body weight and sucrose preference, a decrease in the distance traveled, rearing frequency and velocity in the open field test, and an increase in immobility time in the FST. Compared with the expression in the control rats, Tacr2 protein and mRNA expression in the hypothalamus significantly increased in the CUMS-sensitive rats; however, the DNA methylation levels of the Tacr2 gene were significantly lower than in the control rats. In summary, according to our findings, the stress-induced increase in Tacr2 expression in the hypothalamus correlated with a specific decrease in DNA methylation of the Tacr2 gene. These results may enrich the understanding of the pathological processes of depression and provide insights into therapeutic approaches for its treatment.

WSKY, a traditional Chinese decoction, rescues cognitive impairment associated with NMDA receptor antagonism by enhancing BDNF/ERK/CREB signaling.

Warm­supplementing kidney yang (WSKY) is an herbal prescription that has been used in Traditional Chinese Medicine for the treatment of psychiatric conditions. A previous study by our group found that WSKY significantly improved cognitive function of schizophrenia patients. In the present study, the effects of WSKY on cognitive function and their underlying mechanisms were investigated. WSKY was administered to an MK­801­induced rat model of chronic schizophrenia for 14 days. Memory performance was assessed using the Morris water maze (MWM) test. The expression of brain­derived neurotrophic factor (BDNF), activation of cAMP response element binding protein (pCREB/CREB) and activation of extracellular signal­regulated kinase (pERK/ERK) in the hippocampus was detected using western blot analysis. In the acquisition phase of the MWM test, the escape latency was significantly increased in the MK­801­treated group compared with the normal control group (P<0.01). Treatment with WSKY for 14 days at doses of 100 or 250 mg/kg rescued this cognitive impairment (P<0.05). In the probe test, 250 mg/kg WSKY treatment increased the time spent in the target quadrant (P<0.05) and number of platform crossings (P<0.01). Western blot analysis demonstrated that the levels of BDNF expression in the hippocampus of rats without behavioral tests were elevated following 14 days of WSKY treatment, and the effect of WSKY treatment on hippocampal BDNF expression was presented in an inverted U­shaped dose­response pattern. The pERK1/2 in the hippocampus was significantly enhanced following 100 mg/kg (P<0.01) and 250 mg/kg (P<0.01) WSKY treatment, while only 250 mg/kg WSKY increased the phosphorylation of CREB (P<0.01). The results of the present study indicated that WSKY enhances cognitive performance via the upregulation of BDNF/ERK/CREB signaling, and that WSKY has potential therapeutic implications for cognitive impairment of schizophrenia.

Histone modifications of the Crhr1 gene in a rat model of depression following chronic stress.

Multiple lines of evidence suggest a link between depression and changes in hypothalamic-pituitary-adrenal (HPA)-axis hormone dynamics, including altered regulation of the corticotrophin-releasing hormone (CRH) and its main receptor, corticotrophin-releasing hormone receptor 1 (CRHR1). However, the precise molecular mechanisms underlying depression remain poorly understood. In this study, we employed a model of depression in rats by subjecting animals to 21 days of chronic unpredictable mild stress (CUMS). Real-time PCR and western blotting were used to study the mRNA and protein expression levels of CRHR1 in the hypothalamus. In addition, chromatin immunoprecipitation assays were used to detect histone methylation at the Crhr1 gene promoter; the levels of histone H3 trimethylation at lysines 4 (H3K4) and 9 (H3K9) reflect active transcription and transcriptional repression, respectively. Rats exposed to CUMS exhibited significant reduction in locomotion and sucrose preference. These behavioral alterations were associated with elevated expression levels of CRHR1 mRNA and protein in the hypothalamus of rats in the CUMS group. We also found that the levels of H3K9 trimethylation at the Crhr1 gene promoter in the CUMS group were significantly lower than those in the control group, whereas H3K4 trimethylation levels were the same for both groups. Taken together, our findings suggest that the increase in CRHR1 expression in the hypothalamus of stressed rats correlates with a decrease in the repressive chromatin state caused by reduced H3K9 trimethylation levels. These data are the first in vivo evidence of a role for chromatin modifications in the regulation of Crhr1 gene expression in the hypothalamus, and may provide novel insight into therapeutic approaches to treat depression.

Effect of Warm-Supplementing Kidney Yang (WSKY) added to risperidone on quality of life in patients with schizophrenia: a randomized controlled trial.

OBJECTIVE: To evaluate the quality of life, efficacy and safety of Warm-Supplementing Kidney Yang (WSKY) added to risperidone in patients with schizophrenia. DESIGN: A randomized controlled trial. SETTING: The outpatient and inpatient departments of three hospitals. SUBJECTS: One hundred and twenty patients with clinically diagnosed schizophrenia with predominantly negative symptoms were included in the study. INTERVENTION: All 120 patients were randomly assigned to double-blind treatment with WSKY group (n = 60) or placebo group (n = 60) added to risperidone for eight weeks. MAIN MEASURE: The efficacy measures included the World Health Organization Quality of Life Scale (WHOQOL-100), the Positive and Negative Syndrome Scale (PANSS), the Social Disability Screening Schedule and the Hamilton Rating Scale for Depression. Safety and tolerability were assessed throughout the trial. RESULTS: The scores of quality of life in the WSKY group showed statistically significant improvement at the end-point of treatment compared with those in the placebo group (WSKY, increasing 40.5 (29.4); placebo, increasing 14.4 (27.1); F =24.900, P<0.001), while the scores of social function and depression symptoms also showed statistically significant improvement. The response rates for the WHOQOL-100 total scores were 50.0% for the WSKY group versus 31.7% for placebo group (chi( 2) = 4.172, P=0.041). There were no significant differences in the safety/tolerability measures between the WSKY group and the placebo group during treatment. CONCLUSIONS: The results suggest that WSKY added to risperidone significantly improved the quality of life, social function, depression symptom compared with placebo added to risperidone.

Effects of warm-supplementing kidney yang (WSKY) capsule added on risperidone on cognition in chronic schizophrenic patients: a randomized, double-blind, placebo-controlled, multi-center clinical trial.

OBJECTIVE: To evaluate the effects of warm-supplementing kidney yang (WSKY) capsule added on risperidone on cognition in chronic schizophrenic patients. METHODS: A randomized, double-blind, placebo-controlled, multi-center clinical trial was conducted. All 200 patients who met the DSM-IV diagnostic criteria for schizophrenia were randomly assigned to double-blind treatment with WSKY capsule (n = 100) or placebo (n = 100) added on risperidone for 8 weeks. The primary outcome measure was the cognitive function assessment assessed by the classic form of the Wisconsin Card Sorting Test (WCST) at baseline and week 8. The secondary outcome measures were assessed including the positive and negative symptoms scale (PANSS), the social disability screening schedule (SDSS), and the Hamilton rating scale for depression (HAM-D-17) at baseline, week 2, week 4, and week 8. The extrapyramidal side effects were assessed each week using the abnormal involuntary movement scale (AIMS) and rating scale for extrapyramidal side effects (RSESE), while adverse events were assessed using treatment emergent symptoms scale (TESS) as additional indicators of tolerability throughout the trial. RESULTS: The response rates of the WSKY group for the number of completed categories (CC), errors responses number (ER), perseveringly errors responses number (PER), and conceptual level (CL) of WCST assessment were significantly higher than those of placebo. The reduction in the SDSS score from baseline to endpoint was significantly greater in the WSKY group than those in the placebo. There were no significant differences in the response rates for the correct responses number, perseveringly responses number (PR) of WCST between the treatment groups. The improvements in the WCST indexes, PANSS score, HAM-D-17 score were no significant differences from baseline to endpoint between the two groups at week 8. There were no significant differences in AIMS, RSESE, and TESS compared patients treated with WSKY capsule with those in placebo during treatment. CONCLUSION: WSKY capsule added on risperidone may improve cognitive function, social function of the chronic schizophrenic patients, and the WSKY safely during treatment.

Effectiveness and tolerability of warm-supplementing kidney yang added to risperidone in improving cognitive impairment in patients with schizophrenia: An 8-week, multicenter, randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Certain herbal medicines have been reported to be effective in the treatment of psychiatric conditions, and combination treatment with drugs and herbal medicines has been reported to be useful in enhancing treatment efficacy and reducing recovery time and adverse events (AEs). OBJECTIVE: The purpose of this study was to investigate the effectiveness and tolerability of warm-supplementing kidney yang (WSKY) added to risperidone in improving cognitive impairment and negative symptoms (ie, cognitive function) in patients with schizophrenia. METHODS: This 8-week, multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted in patients who met the clinical classification for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Patients were recruited from 3 centers (including inpatient and outpatient clinics) and were evenly randomized to receive WSKY or placebo added to risperidone for 8 weeks. Primary assessments were conducted at weeks 2, 4, and 8. A clinical response was defined as a ≥50% reduction score (from baseline) on the Positive and Negative Syndrome Scale (PANSS), a ≥30% reduction score (from baseline) on the Scale for the Assessment of Negative Symptoms (SANS), or a ≥50% reduction score (from baseline) on the Hamilton Rating Scale for Depression (HAM-D-17). Cognitive function was assessed using the Wisconsin Card Sorting Test (WCST) at baseline and end point. Extrapyramidal AEs were assessed weekly using the Abnormal Involuntary Movement Scale (AIMS) and the Rating Scale for Extrapyramidal Side Effects (RSESE). AEs were assessed by patient interviews conducted at each clinic visit and also by the Treatment Emergent Symptoms Scale (TESS) scores. RESULTS: One-hundred twenty patients (62 males, 58 females; mean [SD] age, 34.4 [9.4] years; range, 18-45 years; baseline mean [SD] PANSS score, 88.7 [12.3]) were included in this study. Risperidone- and WSKY-treated patients had statistically significant improvements at end point in the number of completed categories (P = 0.019), perseverative responses (P = 0.041), perseverative errors (P = 0.040), and total errors (P = 0.049) on the WCST compared with placebo. The improvements in the PANSS, SANS, and HAM-D-17 scores were not significantly different between the 2 groups at week 8 for observed case and last-observation-carried-forward (LOCF) analyses. The response rates (LOCF) for the PANSS scores in the WSKY and placebo groups were 55.0% and 35.0%, respectively (P = 0.028), while the SANS scores were 63.3% and 45.0% (P = 0.044) and the HAM-D-17 were 35.0% and 45.0% (P = 0.264). There were no significant between-group differences in scores on the AIMS, RSESE, or TESS. CONCLUSIONS: The results of this study suggest that WSKY added to risperidone significantly improved cognitive function in these patients, as measured by the number of completed categories, perseverative responses, perseverative errors, and total errors on the WCST compared with placebo. The response rates in the WSKY group for the PANSS and SANS scores were significantly higher compared with placebo. All treatments were generally well tolerated.

Comparison of the Addition of Siberian Ginseng (Acanthopanax senticosus) Versus Fluoxetine to Lithium for the Treatment of Bipolar Disorder in Adolescents: A Randomized, Double-Blind Trial.

BACKGROUND: Bipolar disorder (BD) is a common, recurrent, and often life-long major psychiatric condition characterized by manic, depressive, and mixed episodes. Without treatment, there is substantial risk for morbidity and mortality, making BD a considerable public health problem. OBJECTIVE: The purpose of this study was to compare the relative effectiveness and tolerability of Acanthopanax senficosus (A senficosus)-an herb that is derived from eleutherosides and polysaccharides found in the plant's root- versus fluoxetine added to lithium in the treatment of BD in adolescents. METHODS: This was a double-blind, 6-week study. The patients were randomized into 2 treatment groups-A senticosus plus lithium (A senticosus group) and fluoxetine plus lithium (fluoxetine group). The patients underwent a baseline assessment using the 17-Item Hamilton Depression Rating Scale (HAMD-17) and the Young Mania Rating Scale (YMRS) during the screening period. Patients were scheduled for clinical visits at the end of weeks 1, 2, 4, and 6. At the end of the 6-week treatment period, each patient's condition was rated as follows: response (indicating an improvement of ≥50% in the HAMD-17 score from baseline); remission (a HAMD-17 score of ⪯7); and switching to mania (a YMRS score >16, and meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition, Text Revision] for a manic episode). At each visit (with the exception of the enrollment visit), the patients were queried as to whether they experienced any health problems since the previous visit, a Treatment Emergent Symptom Scale assessment was completed, and the serum lithium concentration was analyzed. The patients were instructed to report adverse events (AEs) at any time during the study. AEs were also observed by the investigator(s) at clinical visits. RESULTS: Seventy-nine Chinese adolescents were initially enrolled into the study. However, 76 adolescents were assessed for inclusion (45 females, 31 males; mean [SD] age, 15.4 [30.0] years; age range, 12-17 years) in the study. All included patients completed the study. After 6 weeks of treatment, the response rate between the A senticosus and the fluoxetine groups was similar (67.6% vs 71.8%, respectively). The remission rate between both groups was also similar (51.4% vs 48.7%). Analyzed by a general line model, the HAMD-17 scores revealed there was a significant time effect (F = 183.06; P < 0.01), but not a significant group effect (F = 0.99) or group-by-duration of treatment interaction (F = 0.779). Three patients in the fluoxetine group experienced switching to mania compared with no patient in the A senticosus group. AEs reported by patients in the A senticosus group were as follows: nausea, 2 (5.4%); rash, 1 (2.7%); and diarrhea, 1 (2.7%). AEs reported by patients in the fluoxetine group were as follows: nausea, 4 (10.3%); anxiety, 3 (7.7%); insomnia, 3 (7.7%); constipation, 1 (2.6%); and tinnitus, 1 (2.6%). CONCLUSION: Our study found no significant difference in these adolescents with BD treated with lithium plus adjunctive A senticosus or fluoxetine. All treatments were generally well tolerated.

Protective effect of Radix Acanthopanacis Senticosi capsule on colon of rat depression model.

AIM: To investigate the abnormity of rat colon caused by depression and the ameliorative effects of Radix Acanthopanacis Senticosi (RAS) capsule on colon and their mechanisms in rat depression model. METHODS: Chronic stress-induced model of depression of Wistar rats was produced. The experimental animals were randomly divided into model control, 5-aminosalicylic acid (5-ASA) therapy group and three RAS capsule therapy groups. These five groups were intracolonically treated daily (8:00 a.m.) for 2 wk with normal saline, 5-ASA (100 mg/kg) and RAS capsule at the doses of 300, 600 and 900 mg/kg, respectively. A normal control group of rats was also included in the study. Colonic activities of nitric oxide (NO) and superoxide dismutase (SOD), levels of malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) were determined by ultraviolet spectrophotometry. The expression of cyclooxygenase-2 (COX-2) in colonic tissue was detected by immunohistochemistry. RESULTS: Enhanced colon inflammatory response and oxidative stress were observed in the chronic stress-induced rat depression model, which manifested as the significant increase of MDA, iNOS and NO levels, as well as the expressions of COX-2 in the colon tissue, but the colonic SOD activity was significantly decreased compared with the normal control (MDA: 10.34+/-2.77 vs 2.55+/-0.70; iNOS: 1.11+/-0.44 vs 0.25+/-0.16; COX-2: 53.26+/-8.16 vs 4.87+/-1.65; NO: 11.28+/-5.66 vs 4.76+/-1.55; SOD: 53.39+/-11.15 vs 84.45+/-22.31; P < 0.01). However, these parameters were significantly ameliorated in rats treated locally with RAS capsule at the doses of 300, 600 and 900 mg/kg (iNOS: 0.65+/-0.31, 0.58+/-0.22 and 0.64+/-0.33; NO: 5.99+/-2.73, 6.87+/-1.96 and 6.50+/-1.58; MDA: 2.92+/-0.75, 3.19+/-1.08 and 3.26+/-1.24; SOD: 70.81+/-12.36, 73.30+/-15.30 and 69.09+/-11.03, respectively). The expressions of COX-2 in the colon were significantly ameliorated (28.83+/-9.48 and 27.04+/-9.56, respectively) when RAS capsule was administered at the doses of 600 and 900 mg/kg. CONCLUSION: Administration of RAS capsule intracolonically may have significant therapeutic effects on the colon of rat depression model, which are probably due to its antioxidative action and inhibition of arachidonic acid metabolism.