Progress of researches on mechanisms of acupuncture for secondary prevention of ischemic stroke. / é’ˆåˆºå‚ä¸Žç¼ºè¡€æ€§è„‘å’ä¸­äºŒçº§é¢„é˜²çš„ç ”ç©¶è¿›å±•.

Ischemic stroke (IS) is one of the main causes inducing death and disability in adults. Because of the high recurrence rate of IS, prevention of recurrence is of great significance to this population, for which the evidence-based and effective secondary prevention strategy is an important means, and acupuncture intervention has a positive effect on its risk factors. In the present article, we reviewed the progress of researches on the mechanisms of acupuncture underlying prevention of IS relapse from the perspective of its main risk factors, namely 1) hypertension (preventing and controlling the adverse effects caused by the imbalance of blood pressure level, vascular and other tissue structures, endocrine factors and central nervous system activities in patients with hypertension after IS), 2) hypercholesterolemia (lowering serum total cholesterol, triglyceride, low-density lipoprotein-cholesterol (LDL-C) and raising high-density lipoprotein cholesterol), 3) diabetes (regulating the secretion function of adipose tissue, activating the insulin signal transduction pathway, protecting the function of pancreatic ß cells, and regulating the central nervous system functions to participate in the secondary prevention of IS), 4) smoking (relieving the symptoms of smoking cessation and reducing the smoker's dependence on smoking by changing the internal environment, lowering the level of blood endorphin and regulating the excitability of central nervous system), 5) sleep apnea syndrome (regulating local muscle function and the excitability of the nervous system, but also affecting some organic changes as reducing tonsil swelling) and 6) obesity (lowering blood glucose and lipid, increasing the ratio of brown/white fat, reducing leptin resistance, and suppressing appetite to induce body weight loss, or directly regulate the changes of fat tissue, etc). Results shows that the acupuncture's regulatory mechanism for IS risk factors is closely related to the neuroendocrine system, and simultaneously involves multiple targets of multiple risk factors. Due to its good efficacy and safety, acupuncture therapy is of great value for clinical promotion as an important intervention for secondary prevention.

Acupuncture as Add-on Therapy to SSRIs Can Improve Outcomes of Treatment for Anxious Depression: Subgroup Analysis of the AcuSDep Trial.

Purpose: Anxious depression (AD) is a common, distinct depression subtype. This exploratory subgroup analysis aimed to explore the effects of acupuncture as an add-on therapy of selective serotonin reuptake inhibitors (SSRIs) for patients with AD or non-anxious depression (NAD). Patients and Methods: Four hundred and sixty-five patients with moderate-to-severe depression from the AcuSDep pragmatic trial were included in analysis. Patients were randomly assigned to receive MA+SSRIs, EA+SSRIs, or SSRIs alone (1:1:1) for six weeks. AD was defined by using dimensional criteria. The measurement instruments included 17-items Hamilton Depression Scale (HAMD-17), Self-Rating Depression Scale (SDS), Clinical Global Impression (CGI), Rating Scale for Side Effects (SERS), and WHO Quality of Life-BREF (WHOQOL-BREF). Comparison between AD and NAD subgroups and comparisons between groups within either AD or NAD subgroups were conducted. Results: Eighty percent of the patients met the criteria for AD. The AD subgroup had poorer clinical manifestations and treatment outcomes compared to those of the NAD subgroup. For AD patients, the HAMD response rate, remission rate, early onset rate, and the score changes on each scale at most measurement points on the two acupuncture groups were significantly better than the SSRIs group. For NAD patients, the HAMD early onset rates of the two acupuncture groups were significantly better than the SSRIs group. Conclusion: For AD subtype patients, either MA or EA add-on SSRIs showed comprehensive improvements, with small-to-medium effect sizes. For NAD subtype patients, both the add-on acupuncture could accelerate the response to SSRIs treatment. The study contributed to the existing literature by providing insights into the potential benefits of acupuncture in combination with SSRIs, especially for patients with AD subtypes. Due to its limited nature as a post hoc subgroup analysis, prospectively designed, high-quality trials are warranted. Clinical Trials Registration: ChiCTR-TRC-08000297.

Acupuncture Ameliorates Depression-Like Behaviors Through Modulating the Neuroinflammation Mediated by TLR4 Signaling Pathway in Rats Exposed to Chronic Restraint Stress.

Recently, emerging evidence has identified that stress-induced activation of neuroinflammation is considered to be one of the most prevalently precipitating factors in the pathogenesis of depression. Data from clinical trials and experimental findings has verified the efficacy and safety of acupuncture in the prevention and treatment of depression. However, the mechanism of the preventive effect of acupuncture for depression has not been fully elucidated. The current study aimed to investigate the preventive effect and mechanism of acupuncture through modulating the neuroinflammation mediated by toll-like receptor 4 (TLR4) signaling pathway in rats exposed to chronic restraint stress (CRS). All rats were subjected to CRS for 21 days, with the exception of rats in control group. One hour before CRS, rats in acupuncture group were exposed to acupuncture at Baihui (GV20) and Yintang (GV29). The depression-like behaviors were evaluated by body weight assessment and sucrose preference test at 0, 7, 14, and 21 days. The expression of activated microglia in hippocampus was detected by immunofluorescence. The expression of key proteins on TLR4 signaling pathway of TLR4, MyD88, TRAF6, NF-κB p65, TNF-α, and mRNA of TLR4 in the hippocampus was detected by western blot and real-time quantitative polymerase chain reaction to investigate the effect of acupuncture on stress-induced activation of neuroinflammation. The present study provided evidence that acupuncture exerted potential preventive effect that might be mediated in part by suppressing the neuroinflammation induced by TLR4 signaling pathway, which may be a promising treatment target to improve current treatments for depression.

[Application of single-arm objective performance criteria/performance goal in acupuncture-moxibustion clinical trials].

Due to various constraints, such as clinical implementation conditions and unique characteristics of acupuncture-moxibustion, some randomized controlled trials (RCTs) of acupuncture-moxibustion still suffer from relatively low quality and limited applicability. The single-arm objective performance criteria/performance goal can be considered as an ideal supplementary and alternative research approach to RCTs. In this paper, the feasibility of applying the single-arm objective performance criteria/performance goal in acupuncture-moxibustion clinical research is explored from the limitations of conducting acupuncture-moxibustion RCTs, the principles, the essential design considerations and key statistical steps. In addition, illustrative examples are provided. The objective is to offer insights into resolving practical difficulties in acupuncture-moxibustion clinical research.

Fire Needling Therapy of Different Frequencies versus External Diclofenac Diethylamine Emulgel for Knee Osteoarthritis: Study Protocol for a Pilot Randomized Controlled Trial.

Purpose: Knee osteoarthritis (KOA) is regarded as one of the leading musculoskeletal diseases. Although the efficacy is under exploration, fire needling therapy is considered an effective alternative for KOA. This trial aims to investigate the effectiveness of different frequencies of fire needling therapy in attenuating pain and promoting function in KOA patients. Methods: This is a study protocol for a pilot, three-arm, single-center, randomized controlled trial. A total of 90 participants with KOA will be recruited and randomly assigned to the high-frequency fire needling group (3 sessions per week, for 6 weeks), the low-frequency fire needling group (1 session per week, for 6 weeks) or the positive control group (Diclofenac Diethylamine Emulgel, 3 times per day, for 6 weeks) in a 1:1:1 ratio. Participants will accomplish the trial at Week 14 after a follow-up evaluation. The response rate will be set as the primary outcome that the proportion of participants obtaining a minimal clinically important difference, which is identified as ≥2 units on the numerical rating scale (NRS) and ≥6 units on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score at Week 6 compared with Week 0. Secondary outcomes are NRS, WOMAC, Brief Pain Inventory, Short-Form Health Survey-12, Timed Up and Go Test, and pain threshold. Discussion: This is the first standardized protocol comparing fire needling therapy and positive control drugs. This trial may provide reliable evidence for the effectiveness of fire needling therapy and dose-effect property of it in KOA. Trial registration: The trial has been registered on Chinese Clinical Trial Registry (Registered number: ChiCTR2100043041), registered on 4 February 2021.

[Overview on the modern development of fire needling device: from tradition to innovation].

The appropriate needle device is crucial for obtaining the curative effect of fire needling therapy. The article introduces the material specification, clinical operation, indications, characteristics and advantages of the contemporary traditional fire needling devices (e.g. He's fire needle and Shi 's fire needle) and the contemporary new-type ones (e.g. fire needling with filiform needle and micro-needle); and determines the innovations of modern fire needling. It is anticipated that the needle specifications, production process and operation standard of fire needling devices should be further unified so as to provide the references for the selection of fire needling devices in treatment based on clinical syndrome differentiation and expand the clinical application of fire needling therapy.

Effects of acupuncture on regulating the hippocampal inflammatory response in rats exposed to post-traumatic stress disorder.

Data from clinical and experimental studies have verified the efficacy and safety of acupuncture in the treatment of post-traumatic stress disorder (PTSD). However, the concrete mechanism has not been well elucidated. The stress-induced activation of inflammatory response is involved in the development and pathogenesis of PTSD. Here, we aimed to investigate the effects of acupuncture on regulating the hippocampal inflammatory response in rats exposed to PTSD. Forty male rats were randomly divided into control, model, acupuncture and sertraline group. Within 1 day after adaptive feeding, all rats were exposed to single prolonged stress (SPS), except for the rats in the control group. Rats in acupuncture group were exposed to acupuncture intervention at the acupoints of Baihui (GV20) and Yintang (GV29), 20 min once per day for 15 days. Rats in sertraline group were exposed to a suspension of sertraline and distilled water (0.2 mg/ml), once per day for 15 days continuously. Body weight and elevated plus maze experiment were detected at different time-points to evaluate the behavioral changes of rats. HE staining method was used to observe the basic pathological morphological changes in hippocampus. Immunofluorescence staining method was used to observe the activation of hippocampal microglia. The content of IL-6 and IL-1ß in serum were detected by ELISA method. Compared with the control group, the body weight of rats in model group significantly decreased on 8 days, and the percentage of time in open arms and open arm entries decreased significantly on 15 days after SPS procedures, which indicated that SPS induced PTSD-like behavior in rats. Acupuncture exerted therapeutic effect. Simultaneously, the result of HE staining confirmed that SPS induced hippocampal morphological changes in SPS rats. Notably, acupuncture reversed the reduction and pathological injury to some extent. The results have also shown that acupuncture intervention effectively reversed the activated microglia of the hippocampus in rats. Moreover, the expression of IL-1ß in serum was significantly decreased by acupuncture intervention. In summary, the present study demonstrated that the role of acupuncture in eliminating PTSD-like behavior might be connected with reversing the pathological process of the inflammatory response mediated by the activation of microglia induced by SPS.

[Innovation, development and application of contemporary fire needling].

Physicians in the past dynasties have improved the theory of fire needling from the aspects of fire needling instruments, clinical efficacy, application scope, operation, precautions, etc., which promoted the clinical application of fire needling. Modern fire needling breaks through the traditional clinical taboos such as heat syndrome, face, forbidden acupoints, and no needle retention. By using modern fire needling with various types, characteristics and functions, multiple needles and multiple methods are used to treat various diseases, which can further exert the therapeutic effect of fire needling and promote the popularization and application of fire needle therapy.

Serum NLRP3 Inflammasome and BDNF: Potential Biomarkers Differentiating Reactive and Endogenous Depression.

Background: The highly heterogeneous pathogenesis of depression and limited response to current antidepressants call for more objective evidence for depression subtypes. Reactive and endogenous depression are two etiologically distinct subtypes associated with different treatment responses. This study aims to explore the potential biomarkers that differentiate reactive and endogenous depressions. Methods: The clinical manifestations and biological indicators of 64 unmedicated mild-to-moderate depression patients (32 reactive depression patients and 32 endogenous depression patients) and 21 healthy subjects were observed. The 24-item Hamilton rating scale for depression (HAMD-24) was used to evaluate the severity of depression. Serum levels of depression-related biological indicators were measured by using the enzyme-linked immunosorbent assay. Results: The NLRP3 level of reactive depression was significantly lower than those of endogenous depression and healthy controls. There was a significant negative correlation between the BDNF level and the HAMD-24 total scores for patients with reactive depression. Conclusion: Our findings suggested the serum NLRP3 and BDNF levels could be potential biomarkers for detecting and evaluating the severity of reactive depression.

Antidepressant effect of electroacupuncture on modulating the expression of c-Fos/AP-1 through the JNK signaling pathway.

The effectiveness and safety of electroacupuncture (EA) for depression have been identified by abundant clinical trials and experimental findings. The c-Jun-NH(2)-terminal kinase (JNK) signaling pathway is considered to be involved in the antidepressant mechanism of EA. However, the antidepressant effect of EA via modulating the expression of c-Fos/activator protein-1 (AP-1) under the condition of JNK inhibition remains unexplored. In this study, we investigated the antidepressant effect and possible mechanism of EA in regulating the expression of c-Fos/AP-1 under the condition of JNK inhibition by SP600125 in rats exposed to chronic unpredictable mild stress (CUMS). The depression-like behaviors were evaluated by the body weight, sucrose preference test (SPT), and open field test (OFT). The expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum of CUMS induced rat model of depression were detected by ELISA. The results indicated that treatment with EA and fluoxetine can reverse the CUMS-induced depression-like behaviors in rats and can up-regulate the expression levels of c-Jun in the hypothalamus, c-Fos in the pituitary gland, and c-Fos and AP-1 in the serum. Of note, the data demonstrated that SP600125, the inhibitor of JNK signaling pathway, can exert synergistic effect with EA in regulating CUMS-induced abnormal activation of the JNK signaling pathway. The antidepressant effect of EA might be mediated by modulating the expression of c-Fos/AP-1.

Psychological Impact of COVID-19 Cases on Medical Staff of Beijing Xiaotangshan Hospital.

PURPOSE: To investigate the psychological impact of cases of coronavirus disease 19 (COVID-19) on medical staff of Beijing Xiaotangshan Hospital. METHODS: The 287 online questionnaires were distributed to medical staff working at Beijing Xiaotangshan Hospital, comprising three main sections and 17 questions: basic information, current departmental position, and the 12-item General Health Questionnaire (GHQ-12). The threshold for emotional distress was defined to be a total score of 4 on the GHQ-12 and above. RESULTS: A total of 255 members of medical staff participating in this study presented an emotional distress rate of 17%. Members who were male, aged 50-59, married with children, positioned as doctors, and in administration were the population with the highest rate of emotional distress. Furthermore, the severity of emotional distress among those under 30 was significantly lower than those aged 30-39 and 50-59. Doctors and other occupations shared a lower level of satisfaction on routine activities compared with nurses, so did staff in the administration compared with those who were working in screening or logistic departments. Besides, males and staff of the confirmation department had more difficulty in concentrating than females and those of the screening department, respectively. CONCLUSION: Medical staff working at Xiaotangshan Hospital underwent relatively low levels of emotional distress thanks to sufficient medical and psychological preparations. However, special attention should be paid to those who were male, married with children, senior, doctors, in administration, and in the confirmation department.

Locations for noninvasive brain stimulation in treating depressive disorders: A combination of meta-analysis and resting-state functional connectivity analysis.

OBJECTIVE: Many noninvasive brain stimulation techniques have been applied to treat depressive disorders. However, the target brain region in most noninvasive brain stimulation studies is the dorsolateral prefrontal cortex. Exploring new stimulation locations may improve the efficacy of noninvasive brain stimulation for depressive disorders. We aimed to explore potential noninvasive brain stimulation locations for depressive disorders through a meta-analysis and a functional connectivity approach. METHODS: We conducted a meta-analysis of 395 functional magnetic resonance imaging studies to identify depressive disorder-associated brain regions as regions of interest. Then, we ran resting-state functional connectivity analysis with three different pipelines in 40 depression patients to find brain surface regions correlated with these regions of interest. The 10-20 system coordinates corresponding to these brain surface regions were considered as potential locations for noninvasive brain stimulation. RESULTS: The 10-20 system coordinates corresponding to the bilateral dorsolateral prefrontal cortex, bilateral inferior frontal gyrus, medial prefrontal cortex, supplementary motor area, bilateral supramarginal gyrus, bilateral primary motor cortex, bilateral operculum, left angular gyrus and right middle temporal gyrus were identified as potential locations for noninvasive brain stimulation in depressive disorders. The coordinates were: posterior to F3, posterior to F4, superior to F3, posterior to F7, anterior to C4, P3, midpoint of F7-T3, posterior to F8, anterior to C3, midpoint of Fz-Cz, midpoint of Fz-Fp1, anterior to T4, midpoint of C3-P3, and anterior to C4. CONCLUSION: Our study identified several potential noninvasive brain stimulation locations for depressive disorders, which may serve as a basis for future clinical investigations.

Subthreshold depression may exist on a spectrum with major depressive disorder: Evidence from gray matter volume and morphological brain network.

BACKGROUND: Subthreshold depression (StD) is a prevalent condition that may increase the risk of incident major depressive disorder (MDD). However, the relationship between StD and MDD remains unclear. METHODS: A total of 153 adult subjects, including 53 drug-naive MDD, 50 StD and 50 healthy control (HC) subjects, underwent a T1-weighted magnetic resonance imaging scan, and the gray matter volume (GMV) alterations among the three groups were quantitatively analyzed using voxel-based morphometry (VBM). Then, to capture the whole-brain connectivity characteristics, we constructed morphological brain networks (MBN) based on the similarity among brain regions of individual VBM images and compared the network connection strengths among the three groups. RESULTS: The StD and MDD subjects had similar patterns of GMV reductions in the orbitofrontal cortex and left temporal gyrus, although the magnitude of the reductions was smaller in StD subjects. Moreover, a total of 21 morphological connections were significantly different among the three groups. For the majority of the different connections (15/21), the connection strength of the StD group took an intermediate position between that of the MDD and HC groups. LIMITATIONS: There is still a lack of a consistent definition of StD, and the age range of the subjects in this study was wide. Meanwhile the mechanisms and biological significance of the MBN remains to be clarified. CONCLUSIONS: These results may support the hypothesis that depression is better expressed as a spectrum and that StD exists on a spectrum with MDD.

Factor analysis of electroacupuncture and selective serotonin reuptake inhibitors for major depressive disorder: an 8-week controlled clinical trial.

BACKGROUND: There is evidence supporting electroacupuncture (EA) for the treatment of major depressive disorder (MDD), but its characteristics have not been well investigated. OBJECTIVE: To investigate the effectiveness and characteristics of EA in MDD. METHODS: 60 subjects were enrolled-35 in the EA group and 25 in the selective serotonin reuptake inhibitor (SSRI) group based on their preferences-in an 8-week non-randomised controlled clinical trial. The 24-item Hamilton depression rating scale (HAMD-24) and clinical global impression (CGI) were adopted for clinical assessment. The Columbia suicide severity rating scale and adverse event form were used to measure safety and tolerability. The characteristics of EA and SSRIs were compared by analysing seven factors of the HAMD-24. RESULTS: There was no significant difference between the two groups in terms of HAMD-24 response rate after intervention (P>0.05). Patients treated with EA demonstrated a significant reduction in CGI scores (P<0.05) with fewer adverse events compared with SSRIs (P<0.01). Although HAMD-24 factor analysis showed both EA and SSRIs could improve factor scores in cognitive impairment, diurnal variation, retardation, sleep disturbance, anxiety/somatisation and feelings of despair, EA showed greater improvement in anxiety/somatisation and feelings of despair than SSRIs (P<0.05). CONCLUSIONS: There was no significant difference between EA and SSRIs in the treatment of MDD with respect to our primary outcome. However, as a potential therapy for MDD, EA appeared to result in greater symptom improvement than SSRI treatment with respect to anxiety/somatisation and feelings of despair. The results of this secondary analysis should be interpreted cautiously given the inherent issues of multiple testing.

[Acupuncture improved depressive behavior by regulating expression of hippocampal apoptosis-related factors in psychological stress-induced depression rats].

OBJECTIVE: To investigate the effect of acupuncture on behavior changes and the expression of reactive oxygen species (ROS), cytochrome C, cysteine-containing aspartate-specific proteases-3 (caspase-3), apoptosis inducing factor (AIF) in the hippocampus of rats exposed to chronic restraint stress (CRS), so as to provide experimental evidence for the prevention and treatment of depression. METHODS: Thirty two male SD rats were equally randomized into control, model, acupuncture and medication (Fluoxetine) groups according to the random number table. The depression model was established by chronic psychological stress stimulation (fasting, water deprivation, chronic restraint combined with solitary raising for 28 days). Manual acupuncture stimulation (2 circles/s) was applied to "Baihui" (GV20), "Yintang" (GV29) and bilateral "Sanyinjiao" (SP6) for 2 min, followed by retaining the needles for 20 min. Rats in the medication group were treated by gavage of Fluoxetine (0.18 mg/mL, 1 mL/100 g body weight). The treatment was conducted once daily for 28 days. The depression-like behavior was evaluated by using open-field test, sucrose preference test, and body weight. The content of ROS of the right hippocampus tissue was detected by using dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay, and the expression levels of cytochrome C, caspase-3 and AIF proteins of hippocampus were determined by using Western blot. RESULTS: After 28 days' stress procedure, the depression rats in the model group showed a significant decrease in the numbers of crossing and rearing of open-field test, sucrose preference index and the body weight compared to the control group (P<0.01). The content of ROS and expression levels of cytochrome C, caspase-3 and AIF in the hippocampus of the model group were significantly increased relevant to the control group (all P<0.01). After the intervention and compared with the model group, the decreased levels of the numbers of crossing and rearing, body weight and sucrose preference index, and the up-regulated levels of content of ROS and expression of cytochrome C, caspase-3 and AIF proteins were all reversed in both acupuncture and medication groups (P<0.01，P<0.05), displaying an anti-depressant effect. The effect of acupuncture was significantly superior to that of medication in up-regulating the numbers of crossing and rearing (P<0.01, P<0.05), and in down-regulating the expression of caspase-3 (P<0.01). No significant differences were found between the medication and acupuncture groups in increasing the body weight and sucrose preference index, and in down-regulating the expression of cytochrome C and AIF proteins (P>0.05). CONCLUSION: Acupuncture intervention can significantly reduce ROS content and expression level of cytochrome C, caspase-3 and AIF proteins in the hippocampus possibly by inhibiting the chronic psychological stress-hippocampal oxidative stress-mitochondrial apoptotic pathway in psychological stress-induced depression rats, which may contribute to its effect in relieving depression.

Can acupuncture combined with SSRIs improve clinical symptoms and quality of life in patients with depression? Secondary outcomes of a pragmatic randomized controlled trial.

OBJECTIVES: To explore the effects of acupuncture (manual acupuncture or electroacupuncture) combined with SSRIs for moderate to severe depression improving major clinical symptoms and life quality of the patients on secondary outcomes. DESIGN: Pragmatic, parallel, randomized controlled trial. SETTING: 6 hospitals in China. INTERVENTIONS: 6 weeks of manual acupuncture (MA)+selective serotonin reuptake inhibitors (SSRIs), electroacupuncture (EA)+SSRIs, and SSRIs alone. MAIN OUTCOME MEASURES: The primary outcome was response rate of 17-item Hamilton Depression Scale (HAMD-17) total score at 6th week. The secondary outcomes reported in this analysis were HAMD-17 factor scores at 1st, 2nd, 4th, 6th, 10th week and WHO Quality of Life-BREF (WHOQOL-BREF) scores at 6th week. RESULTS: 477 patients were randomly assigned into MA + SSRIs (n = 161), EA + SSRIs (n = 160), or SSRIs alone (n = 156) groups. For HAMD-17 (at 6th week), the MA + SSRIs group was significantly better than the SSRIs alone group in retardation factor (p = 0.008), while the EA+SSRIs group was significantly better than the SSRIs alone group in anxiety/somatization factor (p<0.001) and sleep disturbance factor (p = 0.002). For WHOQOL-BREF (at 6th week), the EA + SSRIs group, compared with the SSRIs alone group, produced a more significant improvement in the overall quality of life, general health, physical health, and psychological health (p<0.05). While, the MA + SSRIs group, compared to the SSRIs alone group, showed significant advantage only in psychological health (p = 0.023). CONCLUSIONS: Either MA or EA combined SSRIs treatment could improve symptoms and quality of life for patients with moderate to severe depression. The main limitation of this trial was not using a sham control therefore the placebo effect could not be excluded.

Manual or electroacupuncture as an add-on therapy to SSRIs for depression: A randomized controlled trial.

Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants, however, only around 60% of patients could benefit from them. Acupuncture is supported by insufficient evidence to help with symptom relieving and SSRIs tolerance. This pragmatic randomized controlled trial compared SSRIs alone versus SSRIs together with manual acupuncture (MA) or electroacupuncture (EA) in moderate to severe depressed patients. Patients were randomly allocated to receive MA + SSRIs (161), EA + SSRIs (160), or SSRIs alone (156) for six weeks, and then followed up for another four weeks. The primary outcome was response rate of the 17-item Hamilton Depression Scale (HAMD-17) at 6th week. The secondary outcomes were HAMD-17 (remission rate, early onset rate, total score), Self-Rating Depression Scale (SDS: total score), Clinical Global Impression (CGI), Rating Scale for Side Effects (SERS: total and domain scores), number of patients with adjusted dosage of SSRIs and adverse events (AEs). Both MA + SSRIs and EA + SSRIs were significantly better than SSRIs at 6th week on HAMD-17 response rate (RR = 1.21, 95% CI 1.04, 1.42, P = 0.013; RR = 1.27, 95% CI 1.09, 1.48, P = 0.0014), HAMD-17 early onset rate (P < 0.0001), HAMD-17 and SDS total scores (P < 0.05), CGI (P < 0.01), SERS total score (P < 0.01), number of patients with increased dosage of SSRIs (P < 0.01). For HAMD-17 remission rate, EA + SSRIs was significantly higher than SSRIs (P = 0.0083), while MA + SSRIs showed no significant difference at 6th week (P = 0.092). No unintended acupuncture-related severe AE was observed. This study identified that both MA and EA showed beneficial effects in addition to SSRIs alone in patients with moderate to severe depression, and were well tolerated. Clinical trials registration: ChiCTR-TRC-08000297.

[Effect of Acupuncture Intervention on Depression Behavior and Expression of ERK 1/2 and BDNF in Prefrontal Cortex in Chronic Unpredictable Mild Stress Induced Depression Rats].

OBJECTIVE: To investigate the effect of acupuncture intervention on the depression behavior and expression of extracellular signal-regulated protein kinases (ERK 1/2), p-ERK 1/2 and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of chronic unpredictable mild stress (CUMS) induced depression rats, so as to explore its antidepressant mechanism. METHODS: Sixty-four male SD rats were randomly divided into control, model, acupuncture, Fluoxetine, model ＋ Dimethyl sulfoxide (DMSO), model ＋ PD 98059(an ERK pathway inhibitor), acupuncture ＋ PD 98059 and Fluoxetine ＋ PD 98059 groups (n＝8 rats in each). The CUMS depression model was established by using chronic mild and unpredictable stress methods for 21 days. Manual acupuncture stimulation was applied to "Baihui" (GV 20) and "Yintang" (GV 29) for 10 min before modeling, once daily for 21 days. Fluoxetine hydrochloride suspension (1.8 mg•kg－1•d－1) was given to rats of the Fluoxetine group and Fluo-xetine ＋ PD 98059 group by gavage 30 min before CUMS. PD 98059 (dissolved in DMSO, 10 µL) was administered to rats of model ＋ PD 98059 group, acupuncture ＋ PD 98059 and Fluoxetine ＋ PD 98059 group, and DMSO (10 µL) to rats of model ＋ DMSO group by intracerebroventricular injection 1 h before CUMS. Sucrose consumption test was carried out to evaluate the depressive behavior. Western blot was performed to detect the expression of ERK 1/2, p-ERK 1/2 and BDNF of prefrontal cortex. RESULTS: Compared with the control group, the sucrose consumption and the expression levels of p-ERK 1/2 and BDNF protein in the prefrontal cortex were significantly reduced in the model and model＋DMSO group (P<0. 01). After the intervention, modeling induced decrease of the sucrose consumption, and p-ERK 1/2 and BDNF expression was significantly up-regulated in both acupuncture and Fluoxetine groups (P<0.01, P<0.05), but not in the model＋PD 98059, Fluoxetine ＋PD 98059 and acupuncture＋PD 98059 groups (P>0.05). No significant differences were found among the model＋PD 98059, Fluoxetine ＋PD 98059 and acupuncture＋PD 98059 groups in the sucrose consumption, and ERK 1/2, p-ERK 1/2 and BDNF expression levels (P>0.05), and in the expression levels of ERK 1/2 protein among the 8 groups (P>0.05). CONCLUSION: Acupuncture intervention has an anti-depressive role in CUMS induced depression rats, which may be related to its effects in up-regulating the expression of p-ERK 1/2 and BDNF in the prefrontal cortex tissue.

Antidepressant-Like Effects of Acupuncture-Insights From DNA Methylation and Histone Modifications of Brain-Derived Neurotrophic Factor.

Sensitive and stable biomarkers that facilitate depression detection and monitor the antidepressant efficiency are currently unavailable. Thus, the objective is to investigate the potential of DNA methylation and histone modifications of brain-derived neurotrophic factor (BDNF) in monitoring severity and antidepressive effects of acupuncture. The depression rat model was imitated by social isolation and chronic unpredicted mild stress (CUMS). The expression of serum BDNF was detected by enzyme-linked immunosorbent assay (ELISA), the hippocampal BDNF, acetylation levels in histone H3 lysine 9 (acH3K9), and HDAC2 by Western blot, the hippocampal mRNA of BDNF by RT-polymerase chain reaction (PCR). The DNA methylation patterns of the promoter I of BDNF was detected by MS-PCR. We investigated that the expression of BDNF in serum and hippocampus were significantly downregulated compared with controls. The same trend was found in mRNA of BDNF. Notably, acupuncture reversed the downregulation of BDNF in serum and hippocampus and mRNA of BDNF compared with model group. Acupuncture reversed the CUMS-induced downregulation of hippocampal acH3K9. On the contrary, the CUMS-induced upregulation of hippocampal HDAC2 in model group was significantly reversed by acupuncture. Collectively, the antidepressant effect of acupuncture might be mediated by regulating the DNA methylation and histone modifications of BDNF, which may represent novel biomaker for detection of depression and monitoring severity and antidepressive effects.

The Role of MAPK and Dopaminergic Synapse Signaling Pathways in Antidepressant Effect of Electroacupuncture Pretreatment in Chronic Restraint Stress Rats.

Acupuncture has demonstrated the function in ameliorating depressive-like behaviors via modulating PKA/CREB signaling pathway. To further confirm the antidepressant mechanism of EA on the mitogen-activated protein kinase (MAPK) and dopaminergic synapse signaling pathways, 4 target proteins were detected based on our previous iTRAQ analysis. Rats were randomly divided into control group, model group, and electroacupuncture (EA) group. Except for the control group, all rats were subjected to 28 days of chronic restraint stress (CRS) protocols to induce depression. In the EA group, EA pretreatment at Baihui (GV20) and Yintang (GV29) was performed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes) prior to restraint. The antidepressant-like effect of EA was measured by body weight and open-field test. The protein levels of DAT, Th, Mapt, and Prkc in the hippocampus were examined by using Western blot. The results showed EA could ameliorate the depression-like behaviors and regulate the expression levels of Prkc and Mapt in CRS rats. The effect of EA on DAT and Th expression was minimal. These findings implied that EA pretreatment could alleviate depression through modulating MAPK signaling pathway. The role of EA on dopaminergic synapse signaling pathways needs to be further explored.