The Baihe Dihuang Decoction(BDD) is a representative traditional Chinese medicine formula that has been used to treat depression. This study employed metabolomics and network pharmacology to investigate the mechanism of BDD in the treatment of depression. Fifty male Sprague-Dawley(SD) rats were randomly assigned to the normal control group, model group, fluoxetine group, and high-and low-dose BDD groups. A rat model of depression was established through chronic unpredictable mild stress(CUMS), and the behavioral changes were detected by forced swimming test and open field test. Metabolomics technology was used to analyze the metabolic profiles of serum and hippocampal tissue to screen differential metabolites and related metabolic pathways. Additionally, network pharmacology and molecular docking techniques were used to investigate the key targets and core active ingredients of BDD in improving metabolic abnormalities of depression. A "component-target-metabolite-pathway" regulatory network was constructed. BDD could significantly improve depressive-like behavior in CUMS rats and regulate 12 differential metabolites in serum and 27 differential metabolites in the hippocampus, involving tryptophan metabolism, phenylalanine, tyrosine, and tryptophan biosynthesis, alanine, aspartate, and glutamate metabolism, tyrosine metabolism, and purine metabolism. Verbascoside, isorbascoside, and regaloside B were the key active ingredients for improving metabolic abnormalities in depression. Epidermal growth factor receptor(EGFR), protooncogene tyrosine-protein kinase(SRC), glycogen synthase kinase 3β(GSK3β), and androgen receptor(AR) were the key core targets for improving metabolic abnormalities of depression. This study offered a preliminary insight into the mechanism of BDD in alleviating metabolic abnormalities of depression through network regulation, providing valuable guidance for its clinical use and subsequent research.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Rats, Sprague-Dawley ; Rats ; Metabolomics ; Depression/genetics* ; Antidepressive Agents/chemistry* ; Network Pharmacology ; Hippocampus/drug effects* ; Humans ; Molecular Docking Simulation ; Behavior, Animal/drug effects* ; Disease Models, Animal

To explore the anti-depression effect of Suanzaoren Decoction(SZRD), the regulatory effects on endogenous metabolites in the liver of rats with depression induced by chronic unpredictable mild stress(CUMS) were analyzed by using LC-MS metabolomics. The rats were randomly divided into normal control group, model group, low-dose SZRD group, high-dose SZRD group, and positive drug group. The CUMS depression model was replicated by applying a variety of stimuli, such as fasting and water deprivation, ice water swimming, hot water swimming, day and night reversal, tail clamping, and restraint for rats. Modeling and treatment were conducted for 56 days. The behavioral indexes of rats in each group, including body weight, open field test, sucrose preference test, and tail suspension test, were observed. Plasma samples and liver tissue samples were collected, and the contents of 5-hydroxytryptamine(5-HT), dopamine(DA), and norepinephrine(NE) in plasma were measured using enzyme-linked immunosorbent assay(ELISA). Meanwhile, the regulatory effects of SZRD on the liver metabolic profile of CUMS model rats were analyzed by the LC-MS metabolomics method. The results show that SZRD can significantly improve the depression-like behavior of CUMS model rats and increase the neurotransmitter levels of 5-HT, DA, and NE in plasma. A total of 24 different metabolites in the rats' liver are identified using the LC-MS metabolomics method, and SZRD can reverse 13 of these metabolites. Metabolic pathway analysis indicates that nine metabolic pathways are found to be significantly associated with depression, and in the low-dose SZRD group, four pathways can be regulated, including pentose phosphate pathway, purine metabolism, inositol phosphate metabolism, and sphingolipid metabolism. In the high-dose SZRD group, two metabolic pathways can be regulated, including sphingolipid metabolism and glycerol glycerophospholipid metabolism. Sphingolipid metabolism is a metabolic pathway that can be regulated by SZRD at different doses, so it is speculated that it may be the primary pathway through which SZRD can alleviate metabolic disturbances in the liver of CUMS model rats.
Animals ; Rats ; Drugs, Chinese Herbal/administration & dosage* ; Metabolomics ; Depression/metabolism* ; Male ; Liver/drug effects* ; Rats, Sprague-Dawley ; Antidepressive Agents/administration & dosage* ; Serotonin/blood* ; Humans ; Disease Models, Animal ; Behavior, Animal/drug effects*

Based on serum metabolomics and gut microbiota technology, this study explores the effects and mechanisms of the water extract of Ziziphi Spinosae Semen(SZRW) and the petroleum ether extract of Ziziphi Spinosae Semen(SZRO) in improving depressive-like behaviors induced by sleep deprivation. A modified multi-platform water environment method was employed to establish a rat model of sleep deprivation. Depressive-like behaviors in rats were assessed through the sucrose preference test and forced swim test. The expression of barrier proteins, such as Occludin, in the colon was determined by immunofluorescence. UPLC-Q-Orbitrap MS was utilized to analyze the serum metabolic profiles of sleep-deprived rats, screen for differential metabolites, and analyze metabolic pathways. The diversity of the gut microbiota was detected using 16S rRNA gene sequencing. Spearman correlation coefficient analysis was conducted to assess the correlation between differential metabolites and gut microbiota. The results indicated that SZRO significantly increased the sucrose preference index and decreased the immobility time in the forced swim test in rats. A total of 34 differential metabolites were identified through serum metabolomics. SZRW and SZRO shared five metabolic pathways, including phenylalanine metabolism. SZRW uniquely featured taurine and hypotaurine metabolism, while SZRO uniquely featured linoleic acid metabolism and tyrosine metabolism. Correlation analysis revealed that SZRW could upregulate the abundance of Bilophila, promoting the production of indole-3-propionic acid and subsequently upregulating the expression levels of intestinal tight junction proteins such as ZO-1, Occludin, and Claudin-1. SZRO could indirectly influence metabolic pathways such as arginine metabolism and linoleic acid metabolism by upregulating the abundance of gut microbiota such as Coprococcus and Eubacterium species. Both SZRW and SZRO can regulate endogenous metabolism, including amino acids, energy, and lipids, alter the gut microbiota microecology, and improve depressive-like behaviors. SZRO demonstrated superior effects in regulating metabolic pathways and gut microbiota structure compared to SZRW. The findings of this study provide a scientific basis for elucidating the pharmacodynamic material basis of Ziziphi Spinosae Semen.
Animals ; Rats ; Gastrointestinal Microbiome/drug effects* ; Male ; Metabolomics ; Drugs, Chinese Herbal/administration & dosage* ; Depression/blood* ; Rats, Sprague-Dawley ; Sleep Deprivation/complications* ; Ziziphus/chemistry* ; Antidepressive Agents/administration & dosage* ; Behavior, Animal/drug effects* ; Humans

In this study, serum metabolomics techniques and molecular biology methods were used to investigate the intervention effect of kaji-ichigoside F1 on chronic unpredictable mild stress(CUMS) depression mouse model and its mechanism. The CUMS depression mouse model was constructed, and the mice were divided into blank group, model group, escitalopram(ESC, 10 mg·kg~(-1)) group, and low-dose, medium-dose, and high-dose kaji-ichigoside F1 groups(1, 2, and 4 mg·kg~(-1)). CUMS modeling was performed on all mice except the blank group, and the cycle was four weeks. At the end of modelling, ESC and kaji-ichigoside F1 were administered by gavage once a day for 28 days. After the end of the administration, behavioral testing(sucrose preference test, open field test, forced swimming test, and tail suspension test) was conducted to evaluate the improvement of depression symptoms of different doses of kaji-ichigoside F1 on CUMS depression mouse model. The morphology of neurons and the number of Nissl bodies in the hippocampus were observed by Nissl staining. Metabolomics technique was used to analyze the changes in serum differential metabolites in mice. Protein expression levels of P2X7 purinergic receptor(P2X7R), adenosine A1 receptor(A1R), and adenosine receptor A2A(A2AR) in mouse hippocampus were detected by Western blot. The results showed that compared with that in the blank group, the body weight of mice in the model group was significantly decreased, and the sucrose preference rate was significantly decreased. The immobility time was significantly increased in the forced swimming and tail suspension tests, and the total moving distance was significantly decreased in the open field test. The number of Nissl bodies was significantly decreased, and the depression-like behavior and the number of Nissl bodies in the hippocampus of mice were significantly improved after administration of kaji-ichigoside F1. In the metabonomics analysis, the purine metabolism of serum after kaji-ichigoside F1 administration was involved in the metabolic passage of depression, and Western blot analysis verified the expression of P2X7R, A1R, and A2AR proteins in purine metabolic pathways. The results show that kaji-ichigoside F1 significantly decreases the expression of P2X7R and A2AR proteins in the hippocampus of CUMS model mice and increases the expression level of A1R proteins. It is suggested that kaji-ichigoside F1 may play an antidepressant role by regulating the expression of P2X7R, A1R, and A2AR proteins in the purine metabolism pathway.
Animals ; Mice ; Antidepressive Agents/administration & dosage* ; Metabolomics ; Depression/genetics* ; Male ; Drugs, Chinese Herbal/administration & dosage* ; Disease Models, Animal ; Hippocampus/metabolism* ; Behavior, Animal/drug effects* ; Humans

OBJECTIVES: Whether vortioxetine has a utility as an adjuvant drug in the treatment of bipolar depression remains controversial. This study aimed to validate the efficacy and safety of vortioxetine in bipolar depression. METHODS: Patients with bipolar Ⅱ depression were enrolled in this prospective, two-center, randomized, 12-week pilot trial. The main indicator for assessing treatment effectiveness was a Montgomery-Asberg Depression Rating Scale (MADRS) of ≥50%. All eligible patients initially received four weeks of lurasidone monotherapy. Patients who responded well continued to receive this kind of monotherapy. However, no-response patients were randomly assigned to either valproate or vortioxetine treatment for eight weeks. By comprehensively comparing the results of MADRS over a period of 4‍‒‍12 weeks, a systematic analysis was conducted to determine whether vortioxetine could be used as an adjuvant drug for treating bipolar depression. RESULTS: Thirty-seven patients responded to lurasidone monotherapy, and 60 patients were randomly assigned to the valproate or vortioxetine group for eight weeks. After two weeks of combined valproate or vortioxetine treatment, the MADRS score in the vortioxetine group was significantly lower than that in the valproate group. There was no difference in the MADRS scores between the two groups at 8 and 12 weeks. The incidence of side effects did not significantly differ between the valproate and vortioxetine groups. Importantly, three patients in the vortioxetine group appeared to switch to mania or hypomania. CONCLUSIONS This study suggested that lurasidone combination with vortioxetine might have potential benefits to bipolar II depression in the early stage, while disease progression should be monitored closely for the risk of switching to mania.
Humans ; Bipolar Disorder/drug therapy* ; Vortioxetine/therapeutic use* ; Male ; Female ; Middle Aged ; Adult ; Valproic Acid/administration & dosage* ; Lurasidone Hydrochloride/administration & dosage* ; Prospective Studies ; Treatment Outcome ; Pilot Projects ; Drug Therapy, Combination ; Sulfides/therapeutic use* ; Antidepressive Agents/therapeutic use*

Of the different phases of bipolar disorder, bipolar depression is more prevailing and is more difficult to treat. However, there is a deficit in systemic research on the pharmacological treatment of acute bipolar depression. Therefore, consensuses on the pharmacological treatment strategies of acute bipolar depression has yet to be made. Currently, there are only three drugs approved by the Food and Drug Administration for acute bipolar depression : quetiapine, olanzapine-fluoxetine complex, and lurasidone. In clinical practice, other drugs such as mood stabilizers (lamotrigine, lithium, valproate) and/or the other atypical antipsychotics (aripiprazole, risperidone, ziprasidone) are frequently prescribed. There remains controversy on the use of antidepressants in bipolar depression. Here, we summarized the evidence of current pharmacological treatment options and reviewed treatment guidelines of acute bipolar depression from recently published studies.
Antidepressive Agents ; Antipsychotic Agents ; Bipolar Disorder* ; Consensus ; Lithium ; Lurasidone Hydrochloride ; Quetiapine Fumarate ; Risperidone ; United States Food and Drug Administration

Less than one third of patients who suffer from major depressive disorder (MDD) report remission following antidepressant treatments requiring more diverse treatment approaches. Augmentation of second generation antipsychotics (SGAs) has been increasingly recognized as an important treatment option. The authors have previously provided a comprehensive review of SGAs for the treatment of MDD in 2013. Since then, numerous additional clinical trials have been conducted to investigate diverse issues regarding the utility of SGAs in MDD. Moreover, a new SGA, brexpiprazole, was recently approved by the Food and Drug Administration in July 2015 for the treatment of MDD as an augmentation agent to antidepressants. Thus, the aim of this study was to provide a concise update of all the available SGAs for the treatment of MDD, in particular on the additional clinical trials which have been published since 2013.
Antidepressive Agents ; Antipsychotic Agents ; Depressive Disorder ; Depressive Disorder, Major ; Depressive Disorder, Treatment-Resistant ; Humans ; United States Food and Drug Administration

Sini Powder (SP), a traditional Chinese herbal formula, has long been used to treat depression in patients, although the underlying mechanisms remain to be elucidated. In the present study, we found that rats treated with SP extract for 7 days showed a significant increase in swimming time and reduction in immobility time in forced swimming test in a dose-dependent manner, without changes in locomotion. These effects could be attributed to SP's modulation of the hypothalamus-pituitary-adrenal axis, because a single pretreatment of SP extract could rescue increased serum corticosterone and plasma adrenocorticotropin levels induced by acute elevated platform stress. A single pretreatment of SP extract could also elevate the mRNA expression of hippocampal glucocorticoid receptors. In conclusion, our results suggest that SP extract may act as an anti-stress medication to produce antidepressant-like effects.
Adrenocorticotropic Hormone ; blood ; Animals ; Antidepressive Agents ; administration & dosage ; Corticosterone ; blood ; Depression ; drug therapy ; genetics ; metabolism ; physiopathology ; Drugs, Chinese Herbal ; administration & dosage ; Hippocampus ; drug effects ; Humans ; Male ; Pituitary-Adrenal System ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Glucocorticoid ; genetics ; metabolism

As regulating the function of the liver and spleen of the famous traditional formula, Sini San is widely used in the treatment of various diseases caused by liver depression and Qi stagnation, and its efficacy is significant clinically. Recently it is discovered that Sini San is effective in the treatment of nervous system diseases such as depression. Furthermore, there is a lot of literature about the effect of Sini San on the molecular mechanism of antidepressant. However, the anti-depression mechanism of Sini San is not very clear, in our present study, based on the auxiliary mechanism elucidation system for Chinese medicine and network pharmacology system to construct the chemical ingredients of the target interactions and disease-related protein of the interaction network. Results show that there are 263 chemical ingredients and 19 corresponding targets of depression in Sini San network. Sini San can anti-depressant effect through G-protein coupled receptor protein signaling pathway, cAMP system, neurological system process and neurotransmitter secretion, inflammatory response, neuroendocrine, metal ion transport and so on. These studies provided valuable clues for the mechanism and treatment of anti-depressant.
Animals ; Antidepressive Agents ; administration & dosage ; chemistry ; Databases, Factual ; Depression ; drug therapy ; genetics ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Gene Regulatory Networks ; drug effects ; Humans ; Signal Transduction

OBJECTIVETo observe the differences in onset time and the overall efficacy of the acupuncture therapy of dredging Governor Vessel and regulating mentality combined with fluoxetine and the fluoxetine for post-stroke depression(PSD).

METHODSSixty-three patients were randomly divided into an acupuncture intervention of dredging Governor Vessel and regulating mentality group(acupuncture and medication group, 33 cases) and a control group (medication group, 30 cases). In the medication group, 20 mg fluoxetine was used by oral administration, once a day at 7:00 in the morning, continuously for 4 weeks. In the acupuncture and medication group, based on the oral administration of fluoxetine, the acupuncture intervention of dredging Governor Vessel and regulating mentality was applied mainly at Baihui(GV 20), Fengfu(GV 16), Shenting(GV 24), Shuigou(GV 26), Dazhui(GV 14) and Shendao(GV 11), once a day, 6 times a week, continuously for 4 weeks. Twenty-four items in Hamilton Depression Scale(HAMD), modified Edinburgh Scandinavia Stroke Scale(MESSS) and activity of daily life scale(ADL, Barthel index, BI) were used before and after 2-week and 4-week treatment. The efficacy was compared between the two groups.

RESULTSAfter 2-week treatment, the HAMD score and the MESSS score in the acupuncture and medication group were obviously decreased and the BI score was apparently increased(all P<0. 01). In the medication group, however, the score of every scale was not statistically different from that before treatment(P'>0. 05). After 4-week treatment, HAMD scores and MESSS scores in the two groups were obviously decreased and the BI scores I were apparently increased(all P<0. 01). After 2-week and 4-week treatment, the HAMD scores and the MESSS scores in the acupuncture and medication group were lower than those in the medication group and the BI scores were higher than those in the medication group(P<0. 01, P<0. 05). The total effective rate of anti-depression (97. 0%, 32/33) the total effective rate of nerve function impairment(90. 9%, 30/33) and the total effective rate of daily life activity(97. 0% 32/33) in the acupuncture and medication group were better than 80. 0% (24/30), 80. 0%(24/30), 83. 3%(25/30) in the medication group(all P<0. 05).

CONCLUSIONThe acupuncture therapy of dredging Governor Vessel and regulating mentality could reduce the onset time of anti-depression medicine treatment of PSD and enhance the overall efficacy. Therefore, it enhances the clinical compliance.

Acupuncture Therapy ; Adult ; Aged ; Antidepressive Agents ; administration & dosage ; Combined Modality Therapy ; Depression ; drug therapy ; etiology ; therapy ; Female ; Humans ; Male ; Meridians ; Middle Aged ; Stroke ; complications ; psychology