Effectiveness and Safety of Electroacupuncture for Depression: A Systematic Review and Meta-Analysis

Purpose The purpose of this systematic review and meta-analysis was to comprehensively evaluate the efficacy and safety of electroacupuncture as an effective adjunctive therapy for patients with depression. Methods Randomized controlled trials (RCTs) about the treatment of depression by electroacupuncture therapy from inception to September 2021 were searched and collected in eight databases. HAMD, SDS, and Adverse Reactions were used as outcome indicators. The quality of relevant articles was evaluated using the Cochrane Collaboration's risk of bias tool. The quality of evidence for each outcome was assessed through the Grading of Recommendations Assessment and the Development and Evaluation approach. Stata 15.0 software was used for data analysis. Results A total of 16 depression-related RCTs were included in this meta-analysis. For the main outcome, electroacupuncture significantly reduced HAMD scores (I2:0.0%, SMD: −2.28% (95% CI−3.16 to −1.39)), and the quality of evidence was moderate. The improvement effect of electroacupuncture plus antidepressants was better than that of western drugs in patients with depression (I2:26.2%, SMD: −1.18% (95% CI−1.42 to −0.94)), and the quality of evidence was moderate. Electroacupuncture significantly reduced HAMD scores without significant heterogeneity (I2:0.0%, SMD: −3.76% (95%CI−5.78−1.73)). Studies with very low quality of evidence found that electroacupuncture was as effective as antidepressants in reducing SDS scores (I2:36.4%, WMD: −1.15% (95%CI−2.93–0.63)), and electroacupuncture was found to be more effective than sham electroacupuncture stimulation as well. Moderate quality evidence showed no statistical difference between electroacupuncture plus antidepressants/electroacupuncture and antidepressants (I2:0%, RR:1.05% (95%CI 0.73 to 1.53)). Conclusions Our meta-analysis shows that electroacupuncture reduces HAMD scores. It is suggested to use electroacupuncture plus antidepressants to improve the curative effect and effectively reduce drug side effects.


Introduction
Depression is a common emotional disorder syndrome, mainly characterized by significant and persistent low spirits. Loss of interest, attention difficulties, feelings of guilt, loss of appetite, even suicidal thoughts, and other cognitive, behavioral, and social dysfunction are the main clinical manifestations of depression [1]. A persistent state of depression can cause serious harm to individuals and society. According to the World Health Organization, more than 300 million people are living with depression all around the world. A study showed that major depression is the most common mood disorder in China, with a lifetime prevalence of 3.4% and a 12-month prevalence of 2.1% [2]. At the same time, a meta-analysis has shown that depression treatment brings tremendous socioeconomic pressure [3], and depression is also ranked as the single largest contributor to nonfatal health loss [4]. e treatment of depression mainly includes psychotherapy, complementary and alternative medicine (CAM), exercise, and pharmacotherapy. However, due to the accelerated pace of modern life, drugs are often used as the treatment of choice. e second-generation antidepressants (SGAs) (selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and selective serotonin norepinephrine reuptake inhibitors) are the main drugs used to alleviate depression in clinical practice [5]. But studies [6] have shown that the drug has serious adverse reactions, even neuroleptic malignant syndrome (NMS), and a lack of safety for pregnant women and the elderly [7]. erefore, it is urgent to find an effective and reliable alternative therapy to treat depression.
Acupuncture, as an intervention of traditional Chinese medicine, is widely used to treat neuropsychiatric diseases [8]. Studies have shown that acupuncture can regulate the limbic-paralimbic-neocortical network (LPNN), thus helping to improve the life and sleep quality of patients with depression [9]. Also, it has been recommended as a complementary alternative therapy in the United States [10]. Electroacupuncture (EA), a part of traditional acupuncture, is a combination of acupuncture and electrical stimulation that objectively controls the amount of stimulation. rough research, Sun et al. [11] proved that electroacupuncture is as effective as anti-depressants in the treatment of depression. Although some studies have provided partial evidence for EA in the treatment of depression [12], there is still a lack of high-quality RCTs to confirm the effectiveness and safety of EA for depression on the whole. erefore, we included clinical studies related to EA treatment of depression with a Jadad score greater than or equal to 4. e primary outcome was the HAMD scale, and the secondary outcome was the SDS scale. At the same time, the safety of EA therapy in patients with depression is evaluated to report a more advanced objective validation of available data.

Study Registration.
e SRs-MAs research was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. It was registered at INPLASY's International Prospective Register of Systematic Reviews (INPLASY202210068).

Types of Study.
is study included all RCTs that have published Chinese or English articles about electroacupuncture for depression. At the same time, nonrandomized controlled trials, quasi-randomized controlled trials, conference papers, retrospective studies, medical record reports, protocols, reviews, article abstracts, and metaanalyses were excluded.

Types of Participants.
All patients included in this study were diagnosed with depression according to [10] (ICD-10), the Diagnostic and Statistical Manual [1] (DSM-V, May 2013), or the Criteria for Classification and Diagnosis of Mental Diseases approved by the Chinese Psychiatric Science Committee [13].

Criteria for Intervention.
Studies of EA for depression were included. Whether EA was used alone as an intervention or in combination with other treatments (western medicine, moxibustion, transcranial electrical stimulation, and so on) can be included.

Criteria for Comparison.
e control group was either treated with traditional western medicine, placebo, sham acupuncture, EA, or waited for treatment (with no intervention during the study). Psychological therapies (behavioral therapy, cognitive behavioral therapy, psychological counseling, etc.) were excluded from the intervention of the control group because of their strong subjectivity.

Outcome.
e Hamilton Depression Rating Scale for Depression (HAMD17/24) was considered as the primary outcome index of this study, while the self-rating depression scale (SDS) and adverse reactions that occurred during treatment were regarded as secondary outcome indexes. Adverse reactions and follow-up data were statistically analyzed to evaluate the safety of electroacupuncture for depression treatment.

Search Strategy.
e following eight databases will be searched from inception to 10th September 2021: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), VIP Database, and WanFang Database. We followed key search terms and their potential combinations on PubMed: (1) clinical condition: depression, depressive disorders, depress, Journal Pre-proof "affective disorder, affective symptoms; (2) acupuncture terms: electroacupuncture, Electric acupuncture, EA, Electroacupuncture therapy, Electroacupuncture therapy, Electric acupuncture therapy; (3) study type: randomized controlled trial. We used "and" and "or" to connect the search terms. Search strategies are shown in Table 1.

Study Selection and Data Extraction.
In this study, two reviewers (ZZ and XGX) searched the above databases in no particular language. After preliminary screening according to the titles and abstracts of the articles, duplicate references were deleted using Endnote. After fulltext reading, the remaining articles that could be included in this study were identified, and then information extraction was carried out. Two reviewers (ZZ and XGX) independently extracted data from the included trials, mainly including the data extraction table name, author, name of the magazine, published literature, diagnostic criteria, number, time of intervention, treatment, and outcome indicators, adverse events, and other aspects. ese data were recorded by Office 2019. If the information is incomplete, we will contact the authors by phone or e-mail to acquire more information. When disagreements arise in the research, they are resolved through discussion or consultation with a third reviewer (LFR) until consensus is reached. Evidence-Based Complementary and Alternative Medicine 2.5. Risk of Bias and Quality Assessment. Two reviewers (HLY and TH) independently assessed the risk of bias in the final included studies using the risk of bias assessment tool developed by the Cochrane Collaboration [14]. is standard included six items of selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases, and each standard was divided into "low" bias risk, "high" bias risk, and "unclear" bias risk. Two independent researchers (HFY and LYL) evaluated the legal quality by the Jadad scale [15]. Any ambiguity in the evaluation process was resolved by LFR. Only high-quality studies with Jadad scores greater than or equal to 4 were included in this study.
After the Cochrane Collaboration's Bias Risk Tool and Jadad score were completed, we graded the quality of evidence for each study.
e Grading of Recommendations Assessment, Development, and Evaluations (GRADE) system was used to evaluate the evidence quality of the outcomes [16]. e evaluation of the level of evidence included risk of bias, inconsistency, indirectness, imprecision, and publication bias, and it was divided into four grades: high, moderate, low, and very low.
2.6. Statistical Analysis. Statistical analyses were performed using STATA 15.0 software in our study. After the inclusion information was sorted out, groups were divided according to the type of intervention and control method. If the RCTs set up three matched control groups, they were split and compared in pairs. For the main outcome indicators-HAMD-17/24, we converted the corresponding scores of HAMD-17 into the scores of phase HAMD-24. Meanwhile, we unified the units of each result of different trials according to the international system of units and then imported clinical data into STATA 15.0.
Random-effects models were used to analyze dichotomous and continuous data for risk ratio (RR), standard mean difference (SMD), and 95% confidence intervals (95% CI). Q statistics were used to investigate the heterogeneity between studies, P values <0.10 were considered an indicator of significant heterogeneity. When the heterogeneity test I 2 < 75%, the random effects model was used for data synthesis. If there was considerable heterogeneity in the experiment (I 2 > 75% orP < 0.10), each trial was removed from the population analysis. At the same time, sensitivity analysis was performed to identify studies that significantly affected the population effect. When we included enough trials, the funnel plot was visually examined, and Egger or Begg tests were used to quantitatively evaluate publication bias. e subgroup analysis or meta-regression was not conducted due to a few heterogeneities.

Results on Literature Search and Selection.
We obtained 4884 records from the eight databases through the retrieval strategy in advance and eliminated 2728 duplicate records before preliminary screening. After reading the titles and abstracts, 114 eligible studies were left. Jadad scores were performed on the literature, and 98 trials with Jadad scores of less than 4 points were excluded. Table 2 shows the Jadad score of the included trial (Jadad ≥4). A total of 16 RCTs met the inclusion criteria. Study selection flow chart is shown in Figure 1.

Discussion
Our meta-analysis included 16 high-quality RCTs with EA as the primary intervention, involving 1428 patients with    Evidence-Based Complementary and Alternative Medicine significantly improve the clinical therapeutic effect but also effectively reduce the incidence of adverse drug reactions. e pathogenesis of depression is mainly related to the insufficiency of neurotransmitters such as 5-hydroxytryptamine (5-HT) and noradrenalin (NE) in the brain. Besides, Gammaaminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF), and dopamine (DA) also participate in the pathogenetic process of depression [32,33]. ere is growing evidence that EA has benefits in treating depression. Study [34]   Evidence-Based Complementary and Alternative Medicine other treatment methods on the study and only compared the difference between EA therapy/drugs/sham EA therapy, and excluded the comforting effect of EA. More critically, in addition to focusing on the adverse effects of EA for depression, we also explored the follow-up period to definitively determine the long-term efficacy of EA for depression. Due to the characteristics of EA operation, the deficiency of blindness is the biggest reason for the deviation. In addition, the included study section did not report in detail the calculation of its sample size. Differences in sample size and course of the disease, the selection of acupoints, and EA frequency of studies increase the heterogeneity, which all reduce the level of evidence. ere are some other limitations. All the studies were conducted in China, where acupuncture has a high acceptance as a traditional form of treatment, which may be another source of bias. Besides, this study only regarded electroacupuncture as the only intervention of TCM and neglected to explore the combined use of other treatment methods for better efficacy.
Acupuncture is not the only treatment for depression, but our study demonstrates that EA can significantly improve symptoms of depression. It also reduces the side effects of medication as a safe treatment. However, depression is a chronic and relapsing disease associated with mood, and a large-sample size and long-term follow-up studies are still needed in future studies. It is necessary for us to explore the optimal treatment frequency and acupoint selection of EA therapy to understand its long-term effects for better clinical application. us, EA treatment of depression has greater clinical application space. We hope that more high-quality, large-sample studies will confirm our findings in the future.

Conclusions
In summary, despite the above limitations, the high-quality RCTs we included still suggested that electroacupuncture could reduce HAMD score, and we also suggested that electroacupuncture plus antidepressants should be used to enhance efficacy and effectively reduce drug side effects.
Data Availability e data analyzed in this meta-analysis and systematic review are derived from published articles and can be retrieved from the previous eight databases.

Conflicts of Interest
e authors declare no conflicts of interest regarding the publication of this paper.