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fpsyt-13-1012606 January 3, 2023 Time: 10:41 # 1
TYPE Systematic Review
PUBLISHED 06 January 2023
DOI 10.3389/fpsyt.2022.1012606
OPEN ACCESS
EDITED BY
Yogesh Dwivedi,
The University of Alabama
at Birmingham, United States
REVIEWED BY
Hao Wen,
Sun Yat-sen University, China
Xinjing Yang,
Shenzhen University, China
*CORRESPONDENCE
Liming Lu
lulimingleon@126.com
Yong Huang
nanfanglihuang@163.com
†These authors have contributed
equally to this work and share first
authorship
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This article was submitted to
Mood Disorders,
a section of the journal
Frontiers in Psychiatry
RECEIVED 05 August 2022
ACCEPTED 13 December 2022
PUBLISHED 06 January 2023
CITATION
Zhang Z, Cai X, Liang Y, Zhang R,
Liu X, Lu L and Huang Y (2023)
Electroacupuncture as a rapid-onset
and safer complementary therapy
for depression: A systematic review
and meta-analysis.
Front. Psychiatry 13:1012606.
doi: 10.3389/fpsyt.2022.1012606
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practice. No use, distribution or
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not comply with these terms.
Electroacupuncture as a
rapid-onset and safer
complementary therapy for
depression: A systematic review
and meta-analysis
Zhinan Zhang1†, Xiaowen Cai1†, Yuying Liang1, Rui Zhang1,
Xinyu Liu1, Liming Lu2*and Yong Huang1*
1School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong,
China, 2Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese
Medicine, Guangzhou, Guangdong, China
Background: Electroacupuncture (EA) is a promising therapy for depression.
However, a comprehensive review of EA for depression is needed.
Methods: We conducted a systematic review and meta-analysis in
accordance with the Preferred Reporting Items for Systematic Reviews and
Meta-analyses (PRISMA 2020) guidelines to evaluate the efficacy and safety
of EA for depression. Potentially relevant trials and reviews were searched in
MEDLINE, EMBASE, PsycINFO, and CENTRAL from inception to March 2022.
EA alone and combined with other therapy were eligible for inclusion. The
severity of depression during and after treatment and the number of adverse
events were assessed as outcomes. Risk of bias (ROB) evaluation, subgroup
analysis, sensitivity analysis, reporting bias assessment, and GRADE system
evaluation were also conducted.
Results: Thirty-four trials were included. The overall ROB was medium.
Low-quality evidence showed that the efficacy of EA was not less than
that of antidepressants [EA + selective serotonin reuptake inhibitors (SSRIs)
and tricyclic antidepressants (TCAs)] and manual acupuncture (MA). EA and
EA + SSRIs had better efficacy than SSRIs alone in decreasing the severity
of depression during the early treatment. Moderate-quality evidence also
showed that EA and EA + SSRIs were safer than SSRIs alone. Sensitivity analysis
was mostly not feasible. Major publication bias was unlikely.
Conclusion: These results indicate that the efficacy of EA is not less than that
of antidepressants and MA. Moreover, EA and EA + SSRI treatments show a
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Zhang et al. 10.3389/fpsyt.2022.1012606
more rapid onset and greater safety than SSRIs. More high-quality trials are
needed for further confirmation.
Systematic review registration: [www.crd.york.ac.uk/prospero/display_
record.php?RecordID=329143], identifier [CRD42022329143].
KEYWORDS
rapid-onset, safety, electroacupuncture, depression, meta-analysis
1. Introduction
Depression, an emerging concern in modern communities
(1), is a mood disorder characterized by a constantly low mood
and may be accompanied by sadness or irritability, sleeping
disorders, appetite loss, libido disorders, constipation, and low
self-esteem (2). More importantly, depression is the leading
cause of suicide and has been linked to disability and other
disease burdens (3).
The mechanisms underlying the therapeutic effects of
EA are still not fully understood. Efforts have been made
to explore these mechanisms (4), and possible mechanisms
include reduction of inflammation (5), regulation of endocrine
activity (6), increasing neurotransmitters (7), and increasing
synaptic plasticity (8). Although the mechanism of action
of EA is not clear, a multitarget mode of activity seems to
be a reasonable explanation. Nevertheless, mechanism studies
Abbreviations: 5-HT, 5-hydroxytryptamine; ACC, anterior cingulate
cortex; AE, adverse event; BDI, Beck Depression Inventory; BI,
Barthel Daily Living Index; BMI, Body Mass Index; CCMD, Chinese
Classification and Diagnostic Criteria of Mental Disorders; CGI,
Clinical Global Impression Scale; CGIS, Clinical Global Impressions
Scale; CIs, confidence intervals; CTRS, Credibility of Treatment
Rating Scale; DSM, Diagnostic and Statistical Manual of Mental
Disorders; EA, electroacupuncture; ECG, electrocardiograph; EEG,
electroencephalogram; EPDS, Edinburgh Postpartum Depression Scale;
ESS, Epworth Sleepiness Scale; GAS, Global Assessment Scale; GDNF,
glial cell-derived neurotrophic factor; HADS, Hospital Anxiety and
Depression Scale; HAMA, Hamilton Anxiety Rating Scale; HAMD,
Hamilton Depression Rating the Scale; ICD, International Classification
of Diseases; IFG, inferior frontal gyrus; MA, manual acupuncture; MADRS,
Montgomery–Asberg Depression Rating Scale; MD, mean difference;
MFI, Multidimensional Fatigue Inventory; MMPI, Minnesota Multiphasic
Personality Inventory; NARI, noradrenaline reuptake inhibitor; NIHSS,
National Institutes of Health Stroke Scale; PCOS, polycystic ovary
syndrome; PCOSQ, Polycystic Ovary Syndrome Quality of Life Scale;
PRISMA 2020, preferred reporting items for systematic reviews and
meta-analyses; PSD, post stroke depression; PSQI, Pittsburgh Sleep
Quality Index; RCTs, randomized controlled trials; ROB, risk of bias; RR,
relative risk; SA, sleep awake times; SAS, Self-Rating Anxiety Scale; SCL-
90, Symptom Checklist-90; SDS, Self-Rating Depression Scale; SDSS,
social disability screening schedule; SE, sleep efficiency; SERS, Side
Effects Rating Scale; SF-36, 36-item Short Form Health Survey; SF-
36, Short Form Health Survey; SNRI, serotonin-norepinephrine reuptake
inhibitor; SSI, Somatic Symptom Inventory; SSRI, selective serotonin
reuptake inhibitor; TESS, Treatment Emergent Symptoms Scale; TST, total
sleep time; WHOQOL, World Health Organization Quality of Life.
can provide fundamental research evidence for the efficacy of
EA in depression.
The first-line medicines for depression include SNRIs,
selective NARIs, and SSRIs, which block the reuptake of
neurotransmitters and increase their concentration in the
synaptic cleft (9). SSRIs are the most commonly used
medications for depression (10). However, these medications
have some concerning limitations. About 1/3rd of the patients
do not respond to medications (11). Moreover, the onset
of their therapeutic effects may require more than 1 week
(12). Therefore, alternative rapid-acting therapeutic agents are
required for clinical practice (13).
Electroacupuncture (EA) involves the passage of a small
electric current between pairs of acupuncture needles (14).
For years, more and more RCTs examined the effectiveness
and safety of EA in depression, which provided some
evidence indicating that EA may serve as an alternative for
antidepressants. However, the efficacy and safety of EA in
depression remains debatable. A review in 2018 exploring the
overall efficacy of acupuncture (both EA and MA) on depression
found weak evidence suggesting that the efficacy and safety
of acupuncture was no less than that of antidepressants, and
that acupuncture combined with antidepressants may have
better efficacy than antidepressants alone (15). Some reviews
focusing on EA for specific subtype of depression, such as
PSD (16) postpartum depression (17,18) found EA had similar
efficacy to other therapy and better safety. But most of these
reviews did not carry subgroups comparison and the evidence
grade was low mainly due to lack of included studies. On the
other hand, these reviews are outdated. After their publication,
several RCTs data came up providing newer and higher-quality
evidence for systematic review and meta-analysis. We also found
week evidence indicating that EA had rapid-onset efficacy for
depression in 2016 (19,20). Considering the possible rapid-
onset efficacy of EA, we notice that it lacks of review updating
the comparison of the efficacy of EA and other therapies in
different time point, such as early period of the treatment.
Therefore, a comprehensive review exploring the efficacy of EA
on depression in different phase of treatment with latest RCTs
updated data is required to support the effectiveness and safety
of EA for depression.
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Considering the increasing need for alternative therapeutic
modalities for depression, and possible rapid-onset efficacy of
EA, it may be a promising method for treating depression. Some
RCTs have been published since the latest comprehensive
review in 2018 (15). Moreover, the last reviews only
included 14 eligible trials and more RCTs are needed
to improve the evidence level and focused on subtype
of depression. Therefore, in this review, we planned to
conduct a meta-analysis to evaluate and update the efficacy
of EA for depression in different time points and safety
by including data from the latest trials to explore the
rapid-onset efficacy and safety of EA as complementary
therapy for depression.
2. Materials and methods
The study was conducted in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-analyses
(PRISMA 2020) guidelines (21). This review has been registered
on PROSPERO (CRD420223291431).
2.1. Criteria for considering studies for
this review
2.1.1. Types of studies
We sought to include parallel-group randomized trials,
irrespective of their publication status and language of
publication. Cluster-randomized trials, controlled before-and-
after studies, case reports, cohort studies, and other non-
randomized studies were excluded.
2.1.2. Types of participants
We included trials with and without sex and age restrictions.
Patients should have been diagnosed with depression or
developed clinical symptoms of depression using the following
criteria: the DSM; the RDC; the International Statistical
Classification of Diseases and Related Health Problems (ICD);
the CCMD; If necessary, the definitions of trial authors. Trials
on patients with comorbidities were also included as long as
depression was the main focus of the study. All treatment
settings were eligible for inclusion.
2.1.3. Types of interventions
2.1.3.1. Experimental interventions
Studies evaluating EA and combinations of EA with other
eligible therapies (e.g., EA + antidepressants, EA + psychological
therapies) were eligible for inclusion.
1www.crd.york.ac.uk/prospero/display_record.php?RecordID=329143
2.1.3.2. Comparator interventions
The eligible comparator interventions for inclusion
were waitlist control; treatment as usual; placebo; sham
acupuncture; MA; antidepressant medication; psychological
therapies (cognitive-behavioral therapy, behavioral therapy,
and psychotherapy, counseling); physical therapies; and
combinations of two or more eligible therapies.
2.1.4. Types of outcome measures
Depression severity scores rated as continuous data were
eligible. When the trial adopted two or more scales, the
hierarchy of outcome measures was as follows:
(1) Hamilton Depression Rating Scale (HAMD) (17- or 24-
item versions) (22).
(2) Beck Depression Inventory (BDI) (23).
(3) Self-rating depression scale (SDS) (24).
(4) World Health Organization Quality of Life (WHOQOL)
depression score (25).
(5) Short Form Health Survey (SF-36) depression score (26).
(6) Depression scores of other quality of life measures.
(7) Other depression scales.
The total number of adverse events was also eligible as an
outcome to assess the safety of the interventions.
In our preliminary searching, we found that 6-weeks-
treatment with measurement of every 2 weeks is the mostly-used
paradigm. Therefore, weeks 2, 4, and 6 were chose to represent
early, middle, and later phase time points.
The time points for outcome measurement were as
follows:
(1) At the end of the treatment (right after the last
time of treatment).
(2) At the end of week 2 during treatment.
(3) At the end of week 4 during treatment.
(4) At the end of week 6 during treatment.
(5) At the end of follow-up (If a study provided several follow-
ups, we adopt the last data).
2.2. Search methods for identification
of studies
MEDLINE, EMBASE, and PsycINFO were searched using
the OVID database, and CENTRAL was searched using the
Cochrane Library. To identify potentially relevant articles, we
searched the databases for articles published from database
inception to March 2022 with no restrictions on language.
In brief, the key search terms were (electroacupuncture∗)
and (depression∗or depressive disorder∗or depressive
disorder, major∗). The search themes were adapted to each
electronic database (Supplementary material). Relevant
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references of reviewed articles and the included studies
were also searched.
2.3. Data collection and analysis
2.3.1. Selection of studies
All of the retrieved trial records were reviewed by two
authors (YL and XL) independently, with an extra author
(LL) serving as a referee for differences in assessments by the
two authors. After the duplicated records were removed, the
two authors screened the title and abstract of the remaining
article records to determine their eligibility. The full text of the
remaining article records was reviewed and read for inclusion.
We also recorded this process in the study flow diagram.
2.3.2. Data extraction and management
After the trials were included, trial characteristics (methods,
participants, interventions, and outcomes) and data (depression
severity) were extracted and recorded by two authors (YL and
XL). Besides, we contacted corresponding authors to ask for
additional trial data if the published data were inadequate. We
planned to conduct the following comparisons:
(1) EA vs. antidepressants.
(2) EA + antidepressants vs. antidepressants.
(3) EA vs. MA.
(4) EA + antidepressants vs. MA + antidepressants.
(5) EA vs. psychological therapies.
(6) EA + psychological therapies vs. psychological therapies.
(7) EA vs. physical therapies.
(8) EA + physical therapies vs. physical therapies.
(9) EA vs. control (waitlist control; treatment as usual; no
treatment; placebo; sham acupuncture).
2.4. Assessment of the risk of bias in
the included studies
Using the ROB 2.0 tools (new ROB evaluate method with
reducing subjectivity bias of the reviewer by using standardized
system and algorithm to generated ROB grades) (27), two review
authors (YL and XL) independently assessed the ROB of every
included trial in accordance with the criteria outlined in the
Cochrane Handbook for Systematic Reviews of Interventions
(28). An extra author (LL) served as a referee to address
any differences in the assessments by the two reviewers.
The ROB 2.0 assessment included the following six domains,
and each domain was rated as low risk, some concerns, or
high risk:
(1) Randomization process.
(2) Deviations from intended interventions.
(3) Missing outcome data.
(4) Measurement of outcomes.
(5) Selection of the reported result.
(6) Overall.
2.5. Measures of treatment effect
The data were pooled using Review Manager software
(version 5.4). Continuous data were presented in terms
of mean difference (MD) with 95% CIs and dichotomous
data in terms of RR with 95% CIs. We also pooled the
data obtained using different methods (e.g., HAMD and
SDS) to measure the severity of depression due to their
conceptual similarity.
2.6. Unit of analysis issues
When trials contained more than two EA groups (e.g., EA at
acupoint A vs. EA at acupoint B vs. no treatment control), we
combined data from both groups.
2.7. Dealing with missing data
When we encountered trials for which only the abstract
was available, the data were presented as different values at
different time points without other data to calculate the original
mean difference. We also contacted the corresponding authors
of the trials through email for more information on the trial
characteristics and data details.
2.8. Assessment of heterogeneity
Heterogeneity was assessed using the I2statistic and
P-values through chi-square test. When P<0.05, the criteria
for heterogeneity defined by I2ranges were as follows:
(1) I2less than 40%: low heterogeneity.
(2) 30% <I2<60%: potentially moderate heterogeneity.
(3) 50% <I2<90%: potentially substantial heterogeneity.
(4) 75% <I2<100%: considerable heterogeneity.
2.9. Assessment of reporting biases
Reporting bias was assessed using a funnel plot. If 10 or
more trials were included in a meta-analysis, we examined the
funnel plot of the analysis. Generally, if the funnel plot shows
a symmetric inverted funnel shape, publication bias is unlikely.
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In contrast, an asymmetric funnel plot on visual assessment
indicated major reporting biases.
2.10. Data synthesis
When the I2value is 50% or less, we used a fixed-effects
model to pool the meta-analysis; for I2values greater than 50%,
we used a random-effects model to pool the meta-analysis (29).
2.11. Subgroup analysis and
investigation of heterogeneity
Considering the differences in EA and medication protocols
among the trials, we planned to conduct subgroup analyses
based on different EA characteristics (acupoints, current
frequency, waveform, and retaining time), antidepressant
medication characteristics (classes, dosage, and duration), and
therapy protocols. We also planned to conduct subgroup
analyses of different time points (at the end of week 2, 4, and
6 of treatment).
2.12. Sensitivity analysis
We planned to conduct sensitivity analysis by pooling the
data after excluding trials that met the following criteria:
(1) High overall ROB.
(2) High ROB in more than two domains.
(3) Dropout rate >20%.
2.13. Evidence tables
The quality evaluation of outcome measures in the meta-
analysis was presented in the GRADE system. The GRADE
system included six domains: study design, ROB, inconsistency,
indirectness, imprecision, and other considerations. On the
basis of the domain assessment, the certainty of each meta-
analysis was graded as high, moderate, low, and very low.
3. Results
3.1. Description of studies
3.1.1. Results of the search
A total of 7,080 article records were retrieved [electronic
searches: 7,054 records; other resources: 26 records (30–63)].
After excluding 2,057 duplicates, two independent authors
FIGURE 1
Study flow diagram.
screened and read the remaining article records with an extra
author serving as a referee for differences in assessments. The
remaining 5,023 records were screened on the basis of their
titles and abstracts, and 4,816 records were excluded in this step.
The full text of the remaining 207 article records was reviewed,
of which 173 were excluded. A total of 34 article records were
included in qualitative synthesis, of which 32 were included in
quantitative synthesis (meta-analysis) (Figure 1).
3.1.2. Included studies
In the 34 trials included, the number of participants ranged
from 20 (34) to 477 (63), with a total of 2,988 participants and a
median of 88 participants.
The diagnoses in these trials were primary depression
(26 trials), post-stroke depression [4 trials, (30,33,36,
42)], postpartum depression [1 trial, (34)], post-schizophrenic
depression [1 trial, (44)], PCOS with depression [1 trial, (62)],
and depression with insomnia [1 trial, (60)]. With regard to
the diagnostic criteria for depression, 12 trials adopted the
DSM-III, IV, or V, seven adopted the Chinese Classification
and Diagnostic Criteria of Mental Disorders (CCMD)-unknown
version or 3, and seven adopted the ICD-9 or 10. Three trials
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adopted combinations of two criteria (36,46,52). Three trials
recruited participants based on HAMD or SDS scores (42,58,
62). Two used criteria reported in books or conferences (33,47).
The average age of the patients ranged from 30.5 to 72 years.
Two trials recruited only female patients (34,62), and 32
included patients with no sex restriction. Thirty-two trials were
conducted in China and three in Hong Kong (34,35,59).
With regard to interventions, 19 trials adopted 2-arm designs
and 15 adopted 3-arm designs. The number of acupoints used
in each trial ranged from 2 to 18. GV20, GV29, SP6, PC6,
and HT7 were the top five acupoints used. The antidepressant
medications used in these trials included SSRIs (23 trials) and
tricyclic antidepressants (TCAs; five trials). Six trials did not
specify the actual classes of antidepressant medication used.
Twenty trials lasted 6 weeks, four trials lasted 8 weeks, four trials
lasted 4 weeks, two trials lasted 5 weeks, one trial lasted 10 days,
one trial lasted 3 weeks, and two trials lasted more than 8 weeks.
Follow-up assessments were described in 10 trials.
All trials assessed the severity of depression at baseline. Most
trials adopted HAMD (31 trials), while two trials used the SDS
as the primary outcome (54,62), and one trial used checklist 90
(31) (Table 1 and Supplementary Table 1).
3.1.3. Risk of bias in included studies
Two independent authors evaluated the ROB of the included
trials. For the randomization process, 22 trials were rated as
showing some concerns in ROB, while the rest were rated as
showing low ROB. For deviations from intended interventions,
six trials were rated as showing high ROB, five were rated as
showing some concerns in ROB, and the rest were rated as
showing low ROB. For missing outcome data, all trials were
rated as showing low ROB. For measurement of the outcome,
one trial was rated as showing some concerns in ROB, while
the rest were rated as showing low ROB. For selection of the
reported result, 20 trials were rated as showing some concerns
in ROB, and the rest were rated as showing low ROB. Overall,
six trials were rated as showing high ROB, 20 as showing some
concerns in ROB, and the rest were rated as showing low ROB
(Figure 2).
In summary, the overall ROB and the ROBs for the
randomization process, deviations from intended interventions,
and selection of the reported result were medium, while the
ROBs for missing outcome data and measurement of the
outcome were low (Figure 3).
3.2. Effects of interventions
3.2.1. EA vs. antidepressants
3.2.1.1. Severity of depression at the end of treatment
At the end of treatment, very-low-quality evidence
(Table 2.1) showed that the overall depression severity of EA
was similar to that of antidepressants [MD, 0.51; 95% CI, −0.83
to 1.86; 16 trials, 1,083 participants; Tau2= 5.17; Chi2= 65.28,
df = 15 (P<0.00001); I2= 77%]. In comparisons with different
antidepressants, the depression severity of EA was almost
similar to that of SSRIs [MD, 1.34; 95% CI, −0.02 to 2.69;
11 trials, 705 participants; Tau2= 3.47; Chi2= 37.00, df = 10
(P<0.0001); I2= 73%] and similar to that of TCAs [MD, −1.66;
95% CI, −4.95 to 1.64; 5 trials, 378 participants; Tau2= 10.21;
Chi2= 17.22, df = 4 (P= 0.002); I2= 77%] (Figure 4A).
3.2.1.2. Severity of depression at the end of week 2
during treatment
At the end of week 2 during treatment, very-low-quality
evidence (Table 2.1) showed that EA had less overall depression
severity to antidepressants [MD, 3.31; 95% CI, 0.90 to 5.73;
6 trials, 396 participants; Tau2= 8.21; Chi2= 58.37, df = 5
(P<0.00001); I2= 91%]. As for specific antidepressants, all
included trials used SSRIs (Figure 4B).
3.2.1.3. Severity of depression at the end of week 4
during treatment
At the end of week 4 during treatment, very-low-quality
evidence (Table 2.1) showed that EA had similar overall
depression severity as antidepressants [MD, 1.63; 95% CI, −0.02
to 3.29; 8 trials, 498 participants; Tau2= 4.41; Chi2= 39.30, df = 7
(P<0.00001); I2= 82%]. As for specific antidepressants, EA
was superior to SSRIs [MD, 2.50; 95% CI, 1.33 to 3.66; 7 trials,
468 participants; Tau2= 1.53; Chi2= 16.88, df = 6 (P= 0.010);
I2= 64%]. Comparison with TCAs could not be performed due
to insufficient data (Figure 4C).
3.2.1.4. Severity of depression at the end of week 6
during treatment
At the end of week 6 during treatment, low-quality evidence
(Table 2.1) showed that EA had similar overall depression
severity as antidepressants [MD, 0.93; 95% CI, −0.39 to 2.25;
10 trials, 749 participants; Tau2= 2.60; Chi2= 23.71, df = 9
(P= 0.005); I2= 62%]. As for specific antidepressants, EA was
barely superior to SSRIs [MD, 1.43; 95% CI, −0.04 to 2.89;
7 trials, 448 participants; Tau2= 2.20; Chi2= 14.95, df = 6
(P= 0.02); I2= 60%] and similar to TCAs [MD, −0.47; 95% CI,
−3.43 to 2.49; 3 trials, 301 participants; Tau2= 4.32; Chi2= 5.80,
df=2(P= 0.06); I2= 66%] (Figure 4D).
3.2.1.5. Adverse events
Overall moderate-quality evidence showed (Table 2.1) that
EA was associated with a lower adverse event rate than
antidepressants [RR, 7.39; 95% CI, 2.91 to 18.76; 6 trials, 607
participants; Chi2= 5.20, df = 5 (P= 0.39); I2= 4%]. In
comparisons with specific antidepressants, EA showed a lower
adverse event rate than SSRIs [RR, 7.76; 95% CI, 2.92 to 20.60; 5
trials, 366 participants; Chi2= 5.08, df = 4 (P= 0.28); I2= 21%].
Comparison with TCAs could not be performed because of
insufficient data (Figure 4E).
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TABLE 1 Characteristics of the included trials.
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
1 (30) Parallel-arm
RCT;
Single-
center;
Single-blind
(patients)
China PSD. Stroke:
Guidelines for the
diagnosis and
treatment of acute
ischemic stroke.
Depression:
DSM-V.
EA 67.8 ±
10.91
20/13 4 weeks 3 times a week. 0 week;
2 weeks;
4 weeks;
8 weeks
(follow-up).
HAMD-24;
SDS;
NIHSS;
BI;
Depression scale
of traditional
Chinese
medicine;
AEs.
12.30%
Non-invasive
acupuncture
control
66.7 ±
11.42
18/14 4 weeks 3 times a week.
2 (31) RCT;
Multi-center
China Primary
unipolar
depression.
ICD-10. Paroxetine 35.37 ±
11.37
14/21 6 weeks Sid. 0 week;
2 weeks;
4 weeks;
6 weeks;
10 weeks
(follow-up).
SCL-90. 9.52%
MA +
Paroxetine
32.11 ±
9.38
14/21 6 weeks Paroxetine: Sid;
MA: every other
day, 3 times a
week.
EA + Paroxetine 31.89 ±
8.81
15/20 6 weeks Paroxetine: Sid;
EA: every other
day, 3 times a
week.
3 (32) RCT;
Single-
center
China Liver-qi
stagnation and
spleen
deficiency in
the elderly
with
post-stroke
depression.
Stroke:
Diagnostic efficacy
evaluation criteria
for stroke;
Diagnostic essentials
of various
cerebrovascular
diseases.
Depression:
Diagnostic efficacy
standard of TCM
disease and
syndrome;
CCMD.
Stomach
acupuncture
(manual
manipulation)
72 ±8 8/11 6 weeks Once every
other day for 21
times.
0 week;
2 weeks;
4 weeks;
6 weeks.
HAMD-/;
SDS;
SDSS;
AEs.
0%
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
EA 69 ±7 9/10 6 weeks Once every
other day for 21
times.
Basic treatment
control
69 ±6 10/9 6 weeks Sid.
4 (33) RCT;
Single-
center
China PSD Diagnostic criteria of
4th National
Conference on
cerebrovascular
disease;
Diagnostic criteria
for Post Stroke
Mood Disorders in
Neurorehabilitation
(CT/MRI).
EA 54–78 20/16 8 weeks 5 times a week. 0 week;
8 weeks;
6 months
(follow-up).
HAMD-/;
AEs.
0%
Fluoxetine 58–72 18/18 8 weeks Sid.
5 (34) RCT;
Multi-
center;
Single-blind
(patients
and
assessors)
Hong Kong
SAR, China
Postpartum
depression
DSM-IV. EA 35.3 ±
4.7
0/20 4 weeks Twice a week, at
least 2 days
apart.
0 week;
2 weeks;
4 weeks;
8 weeks
(follow-up).
HAMD-17;
EPDS;
HADS;
CGI;
Sheehan
Disability Scale;
CTRS;
AEs.
30%;
Small
sample size
and high
dropout
rate.
Non-invasive
acupuncture
control
34.4 ±
2.2
4 weeks Twice a week, at
least 2 days
apart.
6 (35) RCT;
Single-
center;
Single-blind
(patients
and
assessors)
Hong Kong
SAR, China
Depression
with insomnia
DSM-IV. EA +
antidepressants
48.8 ±
9.9
14/46 4 weeks Antidepressants:
/;
EA: 3 times a
week.
0 week;
1 week;
5 weeks.
SE;
ISI;
PSQI;
HAMD-17;
HAMA;
HADS;
SSI;
Sheehan
Disability Scale;
MFI;
ESS;
SF-36;
AEs.
10.67%
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
Sham acupoints
acupuncture +
antidepressants
50.9 ±
9.5
14/46 4 weeks Antidepressants:
/;
Sham
acupoints
acupuncture: 3
times a week.
Non-invasive
acupuncture +
antidepressants
47.4 ±
9.5
3/27 4 weeks Antidepressants:
/;
Non-invasive
acupuncture: 3
times a week.
7 (36) RCT;
Single-
center
China PSD Stroke:
Diagnostic criteria
revised at the 4th
National Conference
on cerebrovascular
disease (1995);
Stroke diagnosis by
CT or MRI.
Depression:
CCMD-3;
DSM-IV.
EA 58.4 ±
9.6
25/13 4 weeks Once a day, 10
times as a
course of
treatment, a
total of 3
courses of
treatment.
0 day;
4 weeks
(30 days).
HAMD-/;
SDS;
Serum 5-HT.
/
MA 59.21 ±
7.56
23/13 4 weeks Once a day, 10
times as a
course of
treatment, a
total of 3
courses of
treatment.
Fluoxetine 56.61 ±
8.21
19/15 4 weeks Sid.
8 (37) RCT;
Single-
center
China Depression CCMD-3;
Diagnostic efficacy
standard of TCM
diseases.
Fluoxetine 39.47 ±
11.20
8/17 6 weeks Sid. 0 week;
1 week;
2 weeks;
3 weeks;
4 weeks;
5 weeks;
6 weeks.
HAMD-/;
SDS;
TESS;
AEs.
6.67%
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
EA 40.42 ±
10.71
9/16 6 weeks Once a day, 5
times a week,
2 days off for
the next week of
treatment.
Fluoxetine + EA 38.17 ±
11.31
8/17 6 weeks Fluoxetine: Sid;
EA: once a day,
5 times a week,
2 days off for
the next week of
treatment.
9 (38) RCT;
Single-
center;
Blind
method
used
(assessors)
China Depression ICD-10. Fluoxetine 35 ±8 6/49 6 weeks Sid. 0 week;
6 weeks.
HAMD-17;
MRI;
AEs.
6.67%
EA + fluoxetine 6 weeks Fluoxetine: Sid;
EA: once a day,
5 times a week,
2 days off for
the next week of
treatment.
10 (39) RCT;
Single-
center
China First episode
mild to
moderate
depression
DSM-V. MA 39.0
(35.0,
46.5)
statistical
meaning
unknown
8/17 6 weeks Every other day,
3 times a week.
0 week;
6 weeks;
6 months
(follow-up)
HAMD-/;
SDS.
10%
EA 37.0
(32.0,
41.5)
statistical
meaning
unknown
8/17 6 weeks Every other day,
3 times a week.
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
11 (40) RCT;
Single-
center;
Blind
method
used
(investigators,
assessors,
data
collectors,
and
statisticians)
China Comorbidity
of anxiety and
depression
(CAD)
CCMD-3. rTMS 40.3 ±
13.0
13/32 10 days Once a day, 10
times in total.
0 day;
5 days;
10 days.
HAMD-/;
HAMA.
23.5%
EA + rTMS 35.4 ±
9.1
13/27 10 days Once a day, 10
times in total.
12 (41) RCT;
Single-
center
China Depression CCMD-3. EA 49.19 ±
13.46
15/17 6 weeks Once a day. 0 week;
6 weeks.
HAMD-24;
Onset time;
Effective time.
/
Fluoxetine/
paroxetine
47.00 ±
13.08
10/14 6 weeks Sid.
13 (42) RCT;
Single-
center
China PSD Diagnostic essentials
of various
cerebrovascular
diseases revised at
the fourth national
cerebrovascular
disease academic
conference in 1996.
Fluoxetine 66.42 ±
6.25
5/5 8 weeks Sid. 0 week;
2 weeks;
4 weeks;
8 weeks.
HAMD-17;
SPECT.
0%
EA 62.56 ±
6.85
4/7 8 weeks Once a day,
5 days a week.
14 (43) RCT;
Single-
center;
Blind
method
used
(assessors
and
statisticians)
China Moderate
depression
DSM-IV. Antidepressants 38.75 ±
11.45
11/19 8 weeks Antidepressants:
/;
0 week;
4 weeks;
8 weeks;
12 weeks
(follow-up).
HAMD-24;
Urinary
metabolites.
11.67%
EA +
antidepressants
40.3 ±
10.99
11/19 8 weeks Antidepressants:
/;
EA: once every
other day, 3
times a week.
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
15 (44) RCT;
Single-
center
China Post
schizophrenic
depression
ICD-10. EA + sertraline 29.6 ±
11.2
16/14 6 weeks Sertraline: Sid;
EA: once every
other day, 3
times a week.
0 week;
1 week;
2 weeks;
4 weeks;
6 weeks.
GAS;
HAMD-17;
AEs.
8.33%
Sertraline 29.2 ±
10.5
17/13 6 weeks Sid.
16 (45) RCT;
Single-
center
China Depression DSM-III. EA 39 15/12 5 weeks Once a day
except Sunday.
0 week;
1 week;
2 weeks;
3 weeks;
4 weeks;
5 weeks.
HAMD-24;
CGI;
SERS (Asberg).
0%
Amitriptyline 35 6/14 5 weeks Tid.
17 (46) RCT;
Multi-
center;
Single-blind
(medication
placebo)
China Depression National diagnostic
criteria for manic
depressive disorder;
CCMD;
ICD-9.
EA + placebo 32
(mini-
mum–
maxi-
mum:
17–64)
109/132 6 weeks Placebo: /;
EA: once a day.
0 week;
1 week;
2 weeks;
3 weeks;
4 weeks;
5 weeks;
6 weeks.
HAMD-/;
CGI;
SERS (Asberg);
AEs;
Biochemical test;
Electrophysiological
examination.
6.50%
Amitriptyline 6 weeks /.
18 (47) RCT;
Multi-center
China Depressive
psychosis
Criteria presented at
the Huangshan
Symposium on
manic-depression;
Handbook of
epidemiological
investigation mental
illness in China.
EA 36 32/22 5 weeks Once a day. 0 week;
1 week;
2 weeks;
3 weeks;
4 weeks;
5 weeks;
6 weeks.
HAMD-24;
CGI;
SERS (Asberg).
/
Amitriptyline 19/28 5 weeks Tid.
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
19 (48) Parallel
RCT;
Multi-
center;
Blind
method
used
(statisticians)
China Mild or
moderate
depression
ICD-10. Paroxetine 40.52 ±
14.21
19/10 6 weeks Sid. 0 week;
1 week;
2 weeks;
4 weeks;
6 weeks.
HAMD-17;
SERS;
CGI;
AEs.
3.64%
EA 46.27 ±
13.13
17/9 6 weeks Once every
other day, 3
times a week.
20 (49) RCT;
Multi-
center;
Blind
method
used
(statisticians)
China Depression ICD-10. Paroxetine 35.58 ±
10.62
31/34 6 weeks Sid. 0 week;
1 week;
2 weeks;
4 weeks;
6 weeks.
HAMD-17;
SDS;
SERS;
AEs.
2.05%
EA + paroxetine 34.03 ±
10.60
28/34 6 weeks Paroxetine: Sid;
EA: once every
other day, 3
times a week.
EA 33.2 ±
9.0
36.58 ±
10.9
23/41 6 weeks Once every
other day, 3
times a week.
21 (50) RCT;
Single-
center;
Single-blind
(patients
and
assessors)
China Depression DSM-IV. Sham acupoints
acupuncture +
fluoxetine
33.9 ±
12.4
81 (sex not
covered in
the original
text)
6 weeks Fluoxetine: Sid;
Sham
acupoints
acupuncture:
every weekend.
0 week;
6 weeks.
HAMD-24;
Serum G
protein.
/
EA + placebo 30.8 ±
10.9
6 weeks Placebo: Sid;
EA: every
weekday.
Sham acupoints
acupuncture +
placebo
30.5 ±
12.0
6 weeks Placebo: Sid;
Sham
acupoints
acupuncture:
every weekday.
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
22 (51) RCT;
Single-
center;
Single-blind
(patients
and
assessors)
China Depression DSM-IV. EA + placebo 30 ±11 13/19 6 weeks Placebo: Sid;
EA: 3 times a
week.
0 week;
1 week;
2 weeks;
3 weeks;
4 weeks;
5 weeks;
6 weeks.
Serum cytokine;
HAMD-24 (21
in the article);
CGI.
12.63%
Sham acupoints
acupuncture +
fluoxetine
34 ±13 13/18 6 weeks Fluoxetine: Sid;
Sham
acupoints
acupuncture: 3
times a week.
Sham acupoints
acupuncture +
placebo
30 ±12 13/19 6 weeks Placebo: Sid;
Sham
acupoints
acupuncture: 3
times a week.
23 (52) RCT;
Multi-center
China Depression CCMD-3;
DSM-IV.
EA1 35.9 ±
14.5
13/15 6 weeks Once a day,
5 days a week,
2 days off on
weekends.
0 week;
2 weeks;
4 weeks;
6 weeks.
HAMD-24;
Serum IL-1β,
IL-6, and
TNF-α.
6.67%
EA2 41.1 ±
11.5
5/23 6 weeks Once a day,
5 days a week,
2 days off on
weekends.
Fluoxetine 39.1 ±
13.2
3/25 6 weeks Sid.
24 (53) RCT;
Single-
center;
Blind
method
used
(assessors of
GDNF)
China Depression DSM-IV. EA1 43.10 ±
13.86
8/12 6 weeks Once a day, 5
times a week.
0 week;
2 weeks;
4 weeks;
6 weeks.
HAMD-24;
Serum GDNF.
18.67%
EA2 42.56 ±
10.70
3/13 6 weeks Once a day, 5
times a week.
Fluoxetine 40.72 ±
12.80
3/22 6 weeks Sid.
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
25 (54) RCT;
Single-
center;
Non-blind
China Depression DSM-IV. EA 48.10 ±
13.40
7/17 24 weeks 3 times a week. 0 week;
24 weeks.
MMPI;
SDS;
SAS;
MADRS;
AEs.
20%
Paroxetine 47.10 ±
10.60
8/16 24 weeks Sid.
26 (55) Parallel
RCT;
Multi-center
China Mild or
moderate
depression
ICD-10. Paroxetine 48 ±9 6/11 6 weeks Sid. 0 week;
1 week;
2 weeks;
4 weeks;
6 weeks;
10 weeks
(follow-up).
HAMD-17;
SERS;
WHOQOL-Bref;
AEs.
12.50%
MA +
paroxetine
45 ±12 10/22 6 weeks Paroxetine: Sid;
MA: once every
other day, 3
times a week.
EA + paroxetine 47 ±11 3/20 6 weeks Paroxetine: Sid;
EA: once every
other day, 3
times a week.
27 (56) RCT;
Single-
center (part
of multi-
center)
China Depression CCMD-3. SSRIs 47.42 ±
8.89
11/19 6 weeks / 0 week;
1 week;
2 weeks;
4 weeks;
6 weeks.
HAMD-17. 0%
MA + SSRIs 48.01 ±
8.16
10/15 6 weeks SSRIs: /;
MA: once every
other day, 3
times a week.
EA + SSRIs 47.54 ±
8.03
7/13 6 weeks SSRIs: /;
EA: once every
other day, 3
times a week.
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
28 (57) RCT;
Single-
center;
Blind
method
used
(assessors)
China Depression CCMD. EA 38 ±5 10/9 30 times (possibly
6 weeks)
Once a day. 0 week;
1 week;
2 weeks;
3 weeks;
4 weeks;
5 weeks;
6 weeks.
HAMD-/;
CGIS.
0%
Amitriptyline 36 ±8 3/8 6 weeks Tid.
29 (58) RCT;
Single-
center
China Mental
depression
Clinical criteria for
diagnosis of manic
depression.
EA 22–57 17/24 6 weeks 6 times a week,
followed by 1
day off;
0 week;
1 week;
2 weeks;
3 weeks;
4 weeks;
5 weeks;
6 weeks.
HAMD-24;
EEG.
0%
Amitriptyline 6 weeks /.
30 (59) Parallel
RCT;
Single-
center;
Single-blind
(patients
and
assessors)
Hong Kong
SAR, China
Depression DSM-IV;
With insomnia
complaint.
EA +
antidepressants
47.5 ±
8.5
6/20 3 weeks Antidepressants:
/;
EA: 3 times a
week.
0 week;
1 week;
4 weeks
(follow-up).
ISI;
PSQI;
Sleep diary;
Actigraphy
measures;
HAMD-17;
AEs.
9%
Sham acupoint
acupuncture +
antidepressants
46.7 ±
9.7
7/19 3 weeks Antidepressants:
/;
Sham
acupoints
acupuncture: 3
times a week.
Non-invasive
acupuncture +
antidepressants
50.1 ±
9.1
3/23 3 weeks Antidepressants:
/;
Non-invasive
acupuncture: 3
times a week.
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
31 (60) RCT;
Single-
center;
Single-blind
(patients
and
assessors)
China Depression
with insomnia
DSM-IV. EA +
antidepressants
47.30 ±
14.89
11/19 8 weeks Antidepressants:
/;
EA: 3 times a
week.
0 week;
4 weeks;
8 weeks;
12 weeks
(follow-up).
PSQI;
SE;
TST;
SA;
HAMD-17;
SDS;
HAMA;
AEs.
14.44%
Sham acupoint
acupuncture +
antidepressants
49.80 ±
15.13
10/20 8 weeks Antidepressants:
/;
Sham
acupoints
acupuncture: 3
times a week.
Non-invasive
acupuncture +
antidepressants
46.77 ±
15.57
11/19 8 weeks Antidepressants:
/;
Non-invasive
acupuncture: 3
times a week.
32 (61) RCT;
Single-
center
China Depression CCMD-3. Paroxetine 37.1 ±
10.2
9/11 6 weeks Sid. 0 week;
1 week;
2 weeks;
4 weeks;
6 weeks.
HAMD-17;
TESS;
Routine blood,
urine test;
ECG.
0%
EA + paroxetine 36.6 +
9.7
12/10 6 weeks Paroxetine: Sid;
EA: once a day,
6 times a week.
33 (62) RCT;
Single-
center
China PCOS with
mild
anxiety/depression
Rotterdam PCOS
diagnostic criteria;
With mild
anxiety/depression.
Lifestyle
intervention
28 ±3 0/40 4 months 1 month is a
course of
treatment, a
total of 4
courses of
treatment.
0 month;
4 months
(16 weeks).
BMI;
SAS;
SDS;
PCOSQ;
Hairiness score;
Serum sex
hormone;
AEs.
13.04%
(Continued)
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TABLE 1 (Continued)
No. References Methods Location Diagnosis Method of
diagnosis
Group Age
(yr)
Sex
(male/
female)
Intervention
duration
Frequency
of
treatment
Time
points for
assessment
Outcomes Dropout
rate and
others
EA + lifestyle
intervention
29 ±2 4 months Lifestyle
intervention: at
least 3 times a
day; 1 month is
a course of
treatment, a
total of 4
courses of
treatment;
EA: once every
other day, 3
times a week.
34 (63) RCT;
Multi-
center;
Single-blind
(assessors)
China Depression ICD-10. SSRIs 41.76 ±
12.85
57/99 6 weeks Sid. 0 week;
1 week;
2 weeks;
4 weeks;
6 weeks;
10 weeks
(follow-up).
HAMD-17;
SDS;
CGI;
SERS;
AEs.
20%
MA + SSRIs 41.42 ±
12.53
56/105 6 weeks SSRIs: Sid;
MA: 3 times a
week.
EA + SSRIs 41.18 ±
12.00
52/108 6 weeks SSRIs: Sid;
EA: 3 times a
week.
/, not covered in the original text; 5-HT,5-hydroxytryptamine; AE, adverse event; BI, Barthel Daily Living Index; BMI, body mass index; CCMD, Chinese Classification and Diagnostic Criteria of Mental Disorders; CGI, Clinical Global Impression Scale; CGIS,
Clinical Global Impressions Scale; CTRS, Credibility of Treatment Rating Scale; DSM, Diagnostic and Statistical Manual of Mental Disorders; EA, electroacupuncture; ECG, electrocardiograph; EEG, electroencephalogram; EPDS, Edinburgh Postpartum
Depression Scale; ESS, Epworth Sleepiness Scale; GAS, Global Assessment Scale; GDNF, glial cell-derived neurotrophic factor; HADS, Hospital Anxiety and Depression Scale; HAMA, Hamilton Anxiety Rating Scale; HAMD, Hamilton Depression Rating
the Scale; ICD, International Classification of Diseases; MA, manual acupuncture; MADRS, Montgomery–Asberg Depression Rating Scale; MFI, multidimensional fatigue inventory; MMPI, Minnesota Multiphasic Personality Inventory; NIHSS, National
Institutes of Health Stroke Scale; PCOS, polycystic ovary syndrome; PSD, post stroke depression; PCOSQ, Polycystic Ovary Syndrome Quality of Life scale; PSQI, Pittsburgh Sleep Quality Index; RCTs, randomized controlled trials; SA, sleep awake times;
SAS, Self-Rating Anxiety Scale; SCL-90, Symptom Checklist-90; SDS, Self-Rating Depression Scale; SDSS, Social Disability Screening Schedule; SE, sleep efficiency; SERS, Side Effects Rating Scale; SF-36, 36-item Short Form Health Survey; SSI, Somatic
Symptom Inventory; TESS, Treatment Emergent Symptoms Scale; TCM, Traditional Chinese Medicine; TST, total sleep time; WHOQOL-BREF, World Health Organization Quality of Life.
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Zhang et al. 10.3389/fpsyt.2022.1012606
FIGURE 3
Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.
3.2.2. EA + antidepressants vs. antidepressants
3.2.2.1. Severity of depression at the end of treatment
At the end of treatment, low-quality evidence
(Table 2.2) showed that the overall depression severity of
EA + antidepressants was less than that of antidepressants alone
[MD, 2.99; 95% CI, 1.30 to 4.68; 14 trials, 1198 participants;
Tau2= 9.06; Chi2= 209.18, df = 13 (P<0.00001); I2= 94%].
In comparisons with different antidepressants, EA + SSRIs
was superior to SSRIs [MD, 2.14; 95% CI, 0.78 to 3.49; 9
trials, 799 participants; Tau2= 3.15; Chi2= 53.35, df = 8
(P<0.00001); I2= 85%]; however, comparisons with other
antidepressants were not possible because of insufficient data
(Figure 5A).
3.2.2.2. Severity of depression at the end of week 2
during treatment
At the end of week 2 during treatment, low-quality evidence
(Table 2.2) showed that the overall depression severity of
EA + antidepressants was less than that of antidepressants [MD,
3.26; 95% CI, 1.06 to 5.46; 7 trials, 421 participants; Tau2= 7.73;
Chi2= 76.72, df = 6 (P<0.00001); I2= 92%], and all trials in
this comparison adopted SSRIs as the antidepressant medication
(Figure 5B).
3.2.2.3. Severity of depression at the end of week 4
during treatment
At the end of week 4 during treatment, low-quality evidence
(Table 2.2) showed that the overall depression severity of
EA + antidepressants was less than that of antidepressants
[MD, 4.47; 95% CI, 2.08 to 6.86; 9 trials, 571 participants;
Tau2= 11.74; Chi2= 119.24, df = 8 (P<0.00001); I2= 93%].
In comparisons with different antidepressants, EA + SSRIs was
superior to SSRIs [MD, 3.42; 95% CI, 1.19 to 5.65; 7 trials, 421
participants; Tau2= 7.70; Chi2= 66.55, df = 6 (P<0.00001);
I2= 91%]. Comparisons with other antidepressants could not
be performed due to insufficient data (Figure 5C).
3.2.2.4. Severity of depression at the end of week 6
during treatment
At the end of week 6 during treatment, very-low-quality
evidence (Table 2.2) showed that the overall depression
severity of EA + antidepressants was less than that of
antidepressants [MD, 1.63; 95% CI, 0.29 to 2.96; 10 trials, 820
participants; Tau2= 3.47; Chi2= 64.26, df = 9 (P<0.00001);
I2= 86%]. In comparisons with different antidepressants,
EA + SSRIs was superior to SSRIs [MD, 2.14; 95% CI, 0.78
to 3.49; 9 trials, 997 participants; Tau2= 3.15; Chi2= 53.35,
df = 8 (P<0.00001); I2= 85%]. Comparisons with other
antidepressants could not be performed due to insufficient data
(Figure 5D).
3.2.2.5. Severity of depression at the end of the
follow-up period
At the end of the follow-up assessments after the trials,
moderate-quality evidence (Table 2.2) showed that the overall
depression severity of EA + antidepressants was less than
that of antidepressants [MD, 5.56; 95% CI, 2.21 to 8.90;
5 trials, 552 participants; Tau2= 13.10; Chi2= 138.60,
df = 4 (P<0.00001); I2= 97%]. However, in comparisons
with different antidepressants, EA + SSRIs was similar to
SSRIs [MD, 1.10; 95% CI, −1.11 to 3.30; 2 trials, 324
participants; Tau2= 2.40; Chi2= 19.86, df = 1 (P<0.00001);
I2= 95%]. Comparisons with other antidepressants could not
be performed due to insufficient data (Figure 5E).
3.2.2.6. Adverse events
Overall high-quality evidence (Table 2.2) showed that
EA + antidepressants almost had a lower adverse event rate
than antidepressants [RR, 1.51; 95% CI, 0.99 to 2.31; 10
trials, 1,056 participants; Chi2= 14.63, df = 9 (P= 0.10);
I2= 38%]. In comparisons with different antidepressants,
EA + antidepressants showed a lower adverse event rate than
SSRIs [RR, 1.86; 95% CI, 1.11 to 3.09; 7 trials, 738 participants;
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TABLE 2.1 GRADE evidence table of the main comparison.
Electroacupuncture (EA) compared to antidepressants for depression.
Certainty assessment Number of patients Effect Certainty Importance
Number
of
studies
Study
design
Risk of
bias
Inconsistency Indirectness Imprecision Other
considerations
EA Anti-
depressants
Relative
(95% CI)
Absolute
(95% CI)
EA vs. antidepressants in severity of depression at the end of treatment
16 Randomized
trials
SeriousaSeriousbNot serious Not serious Publication bias strongly
suspectedc
504 579 – MD 0.51
(–0.83 to 1.86)
⊕###
Very low
Important
EA vs. antidepressants in severity of depression at week 2 during treatment
6 Randomized
trials
Not serious SeriousbNot serious SeriousdPublication bias strongly
suspectedc
180 216 – MD 3.31
(0.9 to 5.73)
⊕###
Very low
Critical
EA vs. antidepressants in severity of depression at week 4 during treatment
8 Randomized
trials
SeriousaSeriousbNot serious Not serious Publication bias strongly
suspectedc
225 273 – MD 1.63
(–0.02 to 3.29)
⊕###
Very low
Critical
EA vs. antidepressants in severity of depression at week 6 during treatment
10 Randomizsed
trials
SeriousaNot serious Not serious Not serious Publication bias strongly
suspectedc
369 380 – MD 0.93
(–0.39 to 2.25)
⊕⊕##
Low
Critical
EA vs. antidepressants in adverse events
6 Randomized
trials
Not serious Not serious Not serious Not serious Publication bias strongly
suspectedc
34/290
(11.7%)
3/317 (0.9%) RR 7.39
(2.91 to 18.76)
–⊕⊕⊕#
Moderate
Critical
CI, confidence interval; MD, mean difference; RR, risk ratio.
aMore than one study had high overall risk of bias.
bConsiderable heterogeneity (I2>75%).
cAll studies are from the same region/country.
dTotal event number less than 400.
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TABLE 2.2 GRADE evidence table of the main comparison.
EA + antidepressants compared to antidepressants for depression.
Certainty assessment Number of patients Effect Certainty Importance
Number
of
studies
Study
design
Risk of
bias
Inconsis-
tency
Indirectness Imprecision Other
considera-
tions
EA + anti-
depressants
antide-
pressants
Relative
(95% CI)
Absolute
(95% CI)
EA + antidepressants vs. antidepressants in severity of depression at the end of treatment
14 Randomized
trials
SeriousaSeriousbNot serious Not serious None 646 552 – MD 2.99
(1.3 to 4.68)
⊕⊕##
Low
IMPORTANT
EA + antidepressants vs. antidepressants in severity of depression at week 2 during treatment
7 Randomized
trials
Not serious SeriousbNot serious Not serious Publication bias
strongly suspectedc
214 207 – MD 3.26
(1.06 to 5.46)
⊕⊕##
Low
CRITICAL
EA + antidepressants vs. antidepressants in severity of depression at week 4 during treatment
9 Randomized
trials
Not serious SeriousbNot serious Not serious Publication bias
strongly suspectedc
304 267 – MD 4.47
(2.08 to 6.86)
⊕⊕##
Low
CRITICAL
EA + antidepressants vs. antidepressants in severity of depression at week 6 during treatment
10 Randomized
trials
SeriousaSeriousbNot serious Not serious Publication bias
strongly suspectedc
414 406 – MD 1.63
(0.29 to 2.96)
⊕###
Very low
CRITICAL
EA + antidepressants vs. antidepressants in severity of depression at the end of follow-up
5 Randomized
trials
Not serious SeriousbNot serious Not serious None 310 242 – MD 5.56
(2.21 to 8.9)
⊕⊕⊕#
Moderate
IMPORTANT
EA + antidepressants vs. antidepressants in adverse events
10 Randomized
trials
Not serious Not serious Not serious Not serious None 54/567 (9.5%) 30/489 (6.1%) RR 1.51
(0.99 to 2.31)
–⊕⊕⊕⊕
High
CRITICAL
CI, confidence interval; MD, mean difference; RR, risk ratio.
aMore than one study had high overall risk of bias.
bConsiderable heterogeneity (I2>75%).
cAll studies are from the same region/country.
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FIGURE 4
Forest plot of comparison: EA vs. antidepressants. (A) Severity of depression at the end of treatment. (B) Severity of depression at week 2 during
treatment. (C) Severity of depression at week 4 during treatment. (D) Severity of depression at week 6 during treatment. (E) Adverse events.
1HAMD; 2SDS.
FIGURE 5
Forest plot of comparison: EA + antidepressants vs. antidepressants. (A) Severity of depression at the end of treatment. (B) Severity of depression
at week 2 during treatment. (C) Severity of depression at week 4 during treatment. (D) Severity of depression at week 6 during treatment.
(E) Severity of depression at end of follow-up. (F) Adverse events. 1HAMD; 3checklist 90 depression score.
Chi2= 9.70, df = 6 (P= 0.14); I2= 38%]. Comparison of
EA + TCAs with other antidepressants could not be performed
due to insufficient data (Figure 5F).
3.2.3. EA vs. MA
3.2.3.1. Severity of depression at the end of treatment
At the end of treatment, very-low-quality evidence
(Supplementary Table 2) showed that EA had similar
depression severity as MA [MD, 2.93; 95% CI, −1.96 to 7.82;
2 trials, 158 participants; Tau2= 16.06; Chi2= 15.94, df = 2
(P= 0.0003); I2= 87%] (Supplementary Figure 1). Only one
trial (32) qualified for the comparison of adverse events, and no
adverse events occurred in either group in this trial.
3.2.4. EA + antidepressants vs.
MA + antidepressants
3.2.4.1. Severity of depression at the end of treatment
At the end of treatment, moderate-quality evidence
(Supplementary Table 3) showed that EA + antidepressants had
similar depression severity as MA + antidepressants [MD, 0.18;
95% CI, −0.11 to 0.46; 4 trials, 464 participants; Chi2= 1.48,
df=3(P= 0.69); I2= 0%] (Supplementary Figure 2A).
3.2.4.2. Severity of depression at the end of week 2
during treatment
At the end of week 2 during treatment, low-quality evidence
(Supplementary Table 3) showed that EA + antidepressants had
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similar depression severity as MA + antidepressants [MD, 0.13;
95% CI, −0.22 to 0.47; 4 trials, 193 participants; Chi2= 1.22,
df=3(P= 0.75); I2= 0%] (Supplementary Figure 2B).
3.2.4.3. Severity of depression at the end of week 4
during treatment
At the end of week 4 during treatment, low-quality evidence
(Supplementary Table 3) showed that EA + antidepressants had
similar depression severity as MA + antidepressants [MD, 0.01;
95% CI, −0.30 to 0.32; 3 trials, 154 participants; Chi2= 0.91,
df=2(P= 0.64); I2= 0%] (Supplementary Figure 2C).
3.2.4.4. Severity of depression at the end of week 6
during treatment
At the end of week 6 during treatment, moderate-
quality evidence (Supplementary Table 3) showed that
EA + antidepressants had similar depression severity as
MA + antidepressants [MD, 0.18; 95% CI, −0.11 to 0.46; 4
trials, 464 participants; Chi2= 1.48, df = 3 (P= 0.69); I2= 0%]
(Supplementary Figure 2D).
3.2.4.5. Adverse events
Overall, moderate-quality evidence (Supplementary
Table 3) showed no difference in the rate of adverse events
between EA + antidepressants and MA + antidepressants [RR,
0.65; 95% CI, 0.30 to 1.37; 3 trials, 446 participants; Chi2= 2.09,
df=2(P= 0.35); I2= 4%]. All the included trials adopted SSRIs
as antidepressants (Supplementary Figure 2E).
3.2.5. EA vs. control
3.2.5.1. Severity of depression at the end of treatment
In general, at the end of treatment, low-quality evidence
(Supplementary Table 4) showed that EA had less depression
severity than control treatment methods [MD, 3.70; 95% CI, 0.38
to 7.01; 5 trials, 241 participants; Tau2= 11.34; Chi2= 20.74,
df=4(P= 0.0004); I2= 81%] (Supplementary Figure 3).
In comparisons with specific control treatment methods, EA
almost showed a superior effect to invasive acupuncture control
[MD, 2.59; 95% CI, −0.09 to 5.26; 2 trials, 117 participants;
Tau2= 0.73; Chi2= 1.23, df = 1 (P= 0.27); I2= 19%]. EA
showed almost similar depression severity as the non-invasive
acupuncture control [MD, 2.76; 95% CI, −5.66 to 11.18; 2 trials,
83 participants; Tau2= 34.33; Chi2= 13.95, df = 1 (P= 0.0002);
Tau2= 34.33; Chi2= 13.95, df = 1 (P= 0.0002); I2= 93%].
Comparisons with the waitlist control could not be performed
due to insufficient data (Supplementary Figure 3).
3.2.6. EA vs. other therapies
Only two trials compared EA with other therapies, which
were lifestyle interventions (62) and rTMS (40). EA + lifestyle
intervention showed less depression severity than lifestyle
intervention alone. One patient reported an adverse event after
EA (62). EA + rTMS also showed less depression severity than
rTMS alone with no adverse events (40).
3.3. Heterogeneity
The overall heterogeneity among the included trials was
substantial. The heterogeneity could be attributed to the
following factors:
(1) The patients’ diagnoses included primary, secondary, and
comorbid depression.
(2) The average age of the patients varied from 30.5 to 72 years.
(3) Two trials only included female patients.
(4) The duration of the interventions varied from
10 days to 24 weeks.
(5) The control medications varied from SSRI and
TCAs to unknown.
(6) The frequency of EA varied from twice a week to
five times a week.
(7) The waveform, frequency, intensity, and voltage of the EA
current varied across trials.
(8) The scale for evaluation varied from HAMD (−17, −24,
unknown version) to SCL-90 depression score.
We planned to conduct subgroup meta-analysis based on
differences in EA characteristics, medications, and therapies.
However, except for the antidepressant medication, we could
not find enough trials to conduct meta-analyses. To minimize
the effects of heterogeneity, a random-effects model was used to
pool the results of all trials if I2>50%.
3.4. Sensitivity analysis
For the sensitivity analysis, we excluded trials with high
overall ROBs. However, sensitivity analysis was not performed
since very few trials (<5) remained in most comparisons. When
trials with high overall ROB, high ROB in more than two
domains, or dropout rate >20% were excluded, comparisons
of EA + antidepressants with antidepressants showed no
significant difference in the severity of depression at the end
of treatment [MD, 5.17; 95% CI, 1.05 to 9.29; 6 trials, 741
participants; Tau2= 25.04; Chi2= 126.74, df = 5 (P<0.00001);
I2= 96%] and the adverse event rate [RR, 0.95; 95% CI, 0.55 to
1.66; 5 trials, 694 participants; Chi2= 3.57, df = 4 (P= 0.47);
I2= 0%]. Other comparisons and subgroup analyses were not
feasible due to the lack of trials.
3.5. Reporting bias
Funnel plots of comparisons with 10 or more trials were
examined. The plots showed a roughly symmetric inverted
funnel shape, indicating that major publication bias was unlikely
(Figure 6).
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FIGURE 6
Funnel plots of comparisons. (A) EA vs. antidepressants in severity of depression at the end of treatment. (B) EA vs. antidepressants in severity of
depression at week 6 during treatment. (C) EA + antidepressants vs. antidepressants in severity of depression at the end of treatment.
(D) EA + antidepressants vs. antidepressants in severity of depression at week 6 during treatment. (E) EA + antidepressants vs. antidepressants in
adverse events.
4. Discussion
A total of 34 trials with 2,988 participants were included,
and the data were pooled to perform systematic review
and meta-analysis. The 34 trials included both outpatients
and inpatients. Although a few trials only included female
patients, patients of both sexes were eligible for most trials.
Most trials were based in mainland China, while some were
conducted in Hong Kong. The treatment acupoints varied
across trials, but almost all trials used GV20 and GV29 as
intervention acupoints. The comparison groups mainly received
antidepressant medication, and none of the studies included
treatment control, sham acupuncture, psychology, and physical
therapy groups. The majority of antidepressant medications
were SSRIs and TCAs. However, some trials did not specify the
category of antidepressant medication.
The quality of evidence was generally moderate. Six of the
34 trials were rated as showing high overall ROB, 20 were
rated as showing some concerns, and eight were rated as low
risk. Blinding-related biases contributed most to the high ROB
(the “deviations from the intended interventions” domain),
which could be mainly attributed to the nature of EA, which
precluded blinding of patients and clinicians administering the
treatment. Efforts were made to minimize the bias attributable
to patients and assessors.
The ROBs for the randomization process and selection
of the reported result were generally medium, mainly
due to flaws in the study design and staff arrangement.
However, the ROBs for missing outcome data and
measurement of the outcome were generally low. We mainly
compared the main effects of EA vs. antidepressants and
EA + antidepressants vs. antidepressants. Comparisons of EA
vs. MA, EA + antidepressants vs. MA + antidepressants, and EA
vs. control interventions were also conducted.
Generally, EA showed greater efficacy than SSRIs in week
2 and 4, but not in week 6. Very weak evidence showed that,
generally, EA had similar efficacy as TCAs. As for safety, EA
showed a lower rate of adverse events than antidepressants,
especially SSRIs.
Moderate-quality evidence indicated that
EA + antidepressants showed better efficacy than
antidepressants alone at the end of treatment, during the
treatment and follow-up. EA + SSRIs contributed the most to
this finding. Moreover, EA + antidepressants, especially SSRIs,
showed a lower adverse event rate than antidepressants alone.
Low-to-moderate-quality evidence also indicated that EA
had similar efficacy and safety as MA alone or in combination
with antidepressants. Very-low-quality of evidence showed
that the efficacies of EA + lifestyle intervention/rTMS were
similar to those of lifestyle intervention/rTMS alone at the end
of the treatment.
Beside reviewing the included trials, we also evaluated
six other published reviews on the effectiveness of EA for
depression. We found three meta-analyses addressing EA for
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depression in 2018. A Cochrane meta-analysis of acupuncture
(including EA) for depression (13 trials of EA) (15) yielded
low-quality evidence indicating that EA and EA + SSRIs reduce
the severity of depression during and at the end of treatment
more than SSRIs alone. The efficacy of EA was also similar to
invasive control and non-invasive electro-control. As for safety,
the findings showed no evidence of an increase in adverse events
with EA. Another meta-analysis of the use of EA for post-stroke
depression (16) also yielded low-quality evidence (18 trials),
indicating that EA and antidepressants have similar efficacy
in decreasing the severity of depression. However, EA caused
fewer adverse events than antidepressants. Another meta-
analysis of acupuncture for postpartum depression included
four trials of EA (17); however, a meta-analysis for EA was
not conducted because of insufficient data and trials. Notably,
the trials included in the latter two studies are mostly from
Chinese databases.
In 2020, one systematic review included two trials evaluating
the endocrine and immune effects of EA in depression (64). Both
studies reported that EA had a positive effect on depression.
In 2021, two related reviews were published. One was an
update of a meta-analysis of EA for post-stroke depression
in 2018 (19 trials) (18), which indicated that in comparison
with antidepressants, EA has a similar effect in improving
depression symptoms and shows better safety in post-stroke
depression patients. Another systematic review focused on
the neuroimaging effects of acupuncture (including EA) in
depression (10 trials of EA) (65). However, that study did not
conduct a meta-analysis of efficacy or neuroimaging data of EA
for depression because of the limited number of trials and the
fact that most of the trials used pre-post designs. Nevertheless,
the study did show that acupuncture affects certain brain regions
such as the precuneus, IFG, and ACC.
This meta-analysis included 34 trials. The quality of the
evidence is slightly higher comparing with previous reviews
due to the greater number of trials. Consistent with the
results of previous reviews, we also found low-to-moderate–
quality evidence indicating that EA and EA + SSRIs had
better efficacy than SSRIs alone in decreasing severity of
depression during the treatment. Moreover, EA and EA + SSRIs
also caused fewer adverse events than SSRIs. As for other
antidepressants, very weak evidence showed that EA and
TCAs had similar efficacy, while data for the comparison of
EA + TCAs and TCAs were inadequate. Moreover, safety data
were insufficient for comparison.
Our findings also yielded low-to-moderate–quality evidence
showing that EA and MA had similar efficacy alone or in
combination with SSRIs. EA + SSRIs and MA + SSRIs seemed
to be equally safe. Moreover, EA had better overall efficacy
than control, and single trials showed that EA + lifestyle
intervention/rTMS was similar to lifestyle intervention/rTMS
alone. Thus, considering the limitations of SSRIs and other
antidepressants, including the lack of response and adverse
reactions (11), EA may serve as a possible alternative therapy
to antidepressants such as SSRIs.
Another limitation of SSRIs is delayed onset of action (12).
Since the pooled data indicated that EA or EA + SSRIs decreased
the severity of depression during and at the end of treatment
more than SSRIs alone during the treatment (2 and 4 weeks),
EA may be used to accelerate the action of SSRIs or serve as
an alternative for SSRIs in the first few weeks until the effects
of SSRIs begin to manifest. Another notable aspect was that
MA exerted similar effects as EA alone or in combination with
SSRIs. Thus, MA may be an alternative for EA under conditions
involving limited equipment.
To our best knowledge, this review presents a
comprehensive assessment of the current evidence of the
efficacy of EA in depression, and is the largest review on
this topic to date. We also compare EA to other therapies
(especially SSRIs antidepressants), in early, middle, and later
phrases of treatment to examine the rapid-onset effect of EA.
We also compared the safety of EA with other therapies. The
results could provide new evidence for the supplementary and
complementary usage of EA for antidepressants. However,
for the efficacy and safety of EA for depression, the quality of
the evidence remained at a low-to-moderate level. Although
this was better than the previous reviews, more high-quality
trials are needed for further confirmation of the current results.
One notable matter regarding the trail quality improvement
for future review is EA protocol for depression. Our review
and other reviews showed substantial heterogeneity between
trials. A major cause of this heterogeneity may be the diversity
of EA intervention protocols. Thus, standardization and
popularization of an EA protocol for depression may be a
precondition for future studies.
Besides, we conducted comparison EA to multiple
treatments using subgroups comparison. This study could also
be done by a network meta-analysis, which could provide more
clear results. Although the method we used emphasizes the
efficacy of EA, we will also learn to use network meta-analysis
in the further research.
Potential biases during the review process may be that non-
English databases were not systematically searched because of
the generally low quality of trials included in the non-English
databases. This may have resulted in exclusion of some eligible
trials. We also tried to contact the corresponding author for data
if vital details were not published. These missing data may have
resulted in biases. Moreover, one of the authors (YH) of this
study was an author of one included trial (31). The reviews and
ROB evaluations were conducted by other authors.
5. Conclusion
These results indicate that the efficacy of EA is no less than
that of antidepressant medication. EA also had similar efficacy
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Zhang et al. 10.3389/fpsyt.2022.1012606
to MA alone or combined with antidepressants. Moreover,
EA + SSRIs was more effective than SSRIs alone throughout
the treatment period. In the early period, EA and EA + SSRIs
showed a more rapid onset of effects than SSRIs alone. Besides,
the safety of EA and EA + SSRIs was superior to that of SSRIs
alone. However, the quality of the evidence was still at a low-to-
moderate level, and more high-quality trials with standardized
EA protocols are needed for further confirmation.
Data availability statement
The original contributions presented in this study are
included in the article/Supplementary material, further
inquiries can be directed to the corresponding authors.
Author contributions
LL: conceptualization and investigation. XC, YL, and RZ:
validation. ZZ: methodology and formal analysis. YL, XL, and
LL: ROB assessment. YL and XL: selecting the articles and
extracting the data. YH: resources, writing – review and editing,
project administration, and funding acquisition. XC and RZ:
data curation. ZZ and XC: writing – original draft preparation.
ZZ and RZ: visualization. LL and YH: supervision. All authors
have read and agreed to the published version of the manuscript.
Funding
This work was supported by the National Natural Science
Foundation of China (grant numbers: 81873359 and 82074519),
the Natural Science Foundation of Guangdong Province
(grant number: 2022A1515011658), the Sanming Project of
Medicine in Shenzhen (grant number: SZZYSM202108013), and
the Student’s Platform for Innovation and Entrepreneurship
Training Program of Southern Medical University of China
(grant number: S202112121164).
Acknowledgments
We thank the South China Research Center for
Acupuncture and Moxibustion for the technical support.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be
found online at: https://www.frontiersin.org/articles/10.3389/
fpsyt.2022.1012606/full#supplementary-material
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