Electroacupuncture plus moxibustion therapy for patients with major depressive disorder: study protocol for a randomized controlled trial
Kim et al. Trials
Electroacupuncture plus moxibustion therapy for patients with major depressive disorder: study protocol for a randomized controlled trial
Mikyung Kim 1
Eun-Ji Choi 0
Sung-Phil Kim 1
Jung-Eun Kim 1
Hyo-Ju Park 1
Ae-Ran Kim 1
Bok-Nam Seo 1
O-Jin Kwon 1
Jung Hyo Cho 2
Sun-Yong Chung 0
Joo-Hee Kim 1
0 Department of Neuropsychiatry, College of Korean Medicine, Kyung Hee University , 892 Dongnam-ro, Gangdong-gu, Seoul , Republic of Korea
1 Clinical Research Division, Korea Institute of Oriental Medicine , 1672 Yuseongdae-ro, Yuseong-gu, Daejeon , Republic of Korea
2 Department of Internal Medicine, College of Traditional Korean Medicine, Daejeon University , 176-9, Daeheung-ro, Jung-gu, Daejeon , Republic of Korea
Background: Major depressive disorder (MDD) is one of the most prevalent mental health disorders and has a significant societal economic burden. Antidepressants and cognitive behavioral therapy are two primary interventions for the standardized treatment of MDD. However, their weaknesses, such as a low response rate, a high risk of adverse events from medication, and the high cost of cognitive behavioral therapy, have resulted in a need for complementary and alternative medicine (CAM). Among the various therapeutic interventions in CAM, electroacupuncture and moxibustion have been widely used to treat various mental illnesses, including MDD. The aim of this study is to evaluate the feasibility of conducting a full-scale randomized controlled trial to investigate the efficacy and safety of electroacupuncture plus moxibustion therapy for MDD. Methods/design: We will include patients between the ages of 19 to 65 years with MDD. A total of 30 participants will be recruited, and they will be randomly allocated into two groups at a 1:1 ratio. Patients in the treatment and control groups will, respectively, receive real and sham electroacupuncture/moxibustion treatments, for a total of 20 sessions over 8 weeks. The primary outcome will be the Hamilton Rating Scale for Depression, and the secondary outcomes will be Beck's Depression Inventory, the Insomnia Severity Index, the State-Trait Anxiety Inventory, the EuroQol 5-Dimension Index, the Measure Yourself Medical Outcome Profile version 2, and electroencephalography. Adverse events will be monitored at each visit to assess safety. All outcomes will be assessed and analyzed by researchers blinded to the treatment allocation. Discussion: This is a two-armed, parallel-design, patient-assessor blinded, multicenter, randomized, sham-controlled pilot clinical trial. Data will be analyzed before and after treatment and during a 4-week follow-up. The results of the trial will provide a basis for further studies assessing the efficacy and safety of electroacupuncture plus moxibustion treatment for MDD. Trial registration: Korean Clinical Trial Registry, CRIS-KCT0001810. Registered on 5 February 2016 (retrospectively registered; date of enrollment of the first participant to the trial: 2 December 2015).
Electroacupuncture; Moxibustion; Depression; Major depressive disorder; Randomized controlled trial
Major depressive disorder (MDD) is one of the most
prevalent mental health disorders  and is
characterized by a depressed mood, feelings of tiredness, anxiety,
poor concentration, disturbed sleep, decreased appetite,
and loss of interest in pleasure . The lifetime
prevalence of MDD is estimated to be 8–12% worldwide .
This common psychiatric disorder diminishes quality of
life and work productivity, which leads to a significant
societal economic burden . MDD is the fourth leading
cause of disease burden worldwide, and it is predicted to
be the second leading cause by 2020 . In Korea, the
lifetime prevalence of MDD was 6.7% as of 2011, which
is lower than global estimates . However, this figure is
a 67% increase over estimates from 10 years prior (4%),
reflecting the general upward trend in MDD . MDD
is also a societal burden to South Korea, with the
socioeconomic cost of the disorder increasing by 41.5% from
2007 to 2011 .
The etiology and mechanisms of MDD are
complicated and treatment is not simple . Pharmacological
therapy and cognitive behavioral therapy are considered
two primary methods of standard treatment for MDD
. Although these two modalities have similar effects,
pharmacological therapy is more commonly prescribed
. The high cost of cognitive behavioral therapy is a
main reason that patients avoid this treatment .
Pharmacological therapy, however, also has challenges,
such as a low response rate (40%) and a high failure rate
of remission achievement (70%) during initial treatment
as well as a high risk of adverse drug reactions .
Because of these limitations, both patients and clinicians
have sought other therapeutic options, such as
complementary and alternative medicine (CAM) . Patients
with neuropsychiatric symptoms tend to use CAM more
often and also tend to spend more money on it [10, 11].
In South Korea, there is another critical reason that
leads people to prefer CAM. According to a survey,
patients are unwilling to visit psychiatric clinics because of
social prejudices and the decline in private health
insurance . Patients instead pursue therapies, such as
CAM, because of these sociocultural issues .
A variety of therapeutic interventions are available in
CAM. Acupuncture, electroacupuncture and
moxibustion are some of the most representative
nonpharmacologic therapies, particularly in traditional medicine in
East Asia, including South Korea, China, and Japan.
China has provided more abundant data than any other
country in this field, and according to a report by Woo
et al.  on the current state of Chinese studies in this
area, acupuncture, electroacupuncture, herbal treatment
plus acupuncture, and acupuncture plus moxibustion
are frequently referred therapeutic modalities for the
treatment of MDD.
The mechanisms underlying the therapeutic effect of
acupuncture in MDD involve regulation of the
hypothalamic-pituitary-adrenal (HPA) axis and
stimulation of the prefrontal-limbic system [14, 15]. Systematic
reviews and meta-analyses of clinical evidence on this
issue, however, have shown that the currently available
evidence is insufficient to firmly conclude the
effectiveness of acupuncture for MDD [8, 16–18].
A few studies conducted in China have shown the
usefulness of acupuncture as an adjunct to antidepressants
such as selective serotonin reuptake inhibitors [19–22].
A British research team also demonstrated that standard
care plus acupuncture was more effective than standard
care alone in improving depression . Another study
compared the effect of real and sham acupuncture for
patients with MDD taking medication . The results
indicated that acupuncture outperformed the sham
device in attenuating anxiety and mitigating the adverse
effects of antidepressants, but the overall therapeutic
response rates between the two groups were not
significantly different . It has been reported that
electroacupuncture, whether alone  or combined with
medication [20, 25], outperforms antidepressant
monotherapy in improving depressive conditions.
Some studies have indicated that acupuncture plus
moxibustion therapy is superior to sham acupuncture
 or to a wait list control . Another study
argued that combined therapy compared favorably with
acupuncture alone for MDD patients taking
antidepressants . Although only a few studies regarding
the effect of electroacupuncture plus moxibustion
have been published, their results indicate that this
combined therapy may be a potential intervention for
MDD. Based on the current state of knowledge
described above, the present pilot clinical trial was
designed to provide a foundation for further studies to
confirm the utility of electroacupuncture interventions
for patients with MDD.
The aims of this study are to explore the efficacy and
safety of electroacupuncture plus moxibustion therapy
for MDD and to create a foundation for evaluating the
feasibility of using these treatments in a full-scale
randomized controlled trial (RCT).
This is a two-armed, parallel-design, patient-assessor
blinded, multicenter, randomized, sham-controlled pilot
clinical trial. Two clinical research centers in South
Korea will conduct the trial: Daejeon Oriental Hospital
of Daejeon University and Kyung Hee University Oriental
Hospital at Gangdong.
To recruit participants, flyers, daily local newspapers,
and advertisement boards at research centers will be
utilized. Potential candidates will visit the research
centers for screening assessment and to sign informed
consent for trial participation after being informed about
the aim and details of the study. Eligible participants will
be randomly allocated at a 1:1 ratio to one of two arms:
electroacupuncture plus moxibustion (treatment group)
or sham acupuncture with mock electrical stimulation
plus sham moxibustion (control group). Participants
will receive treatment for 8 weeks and then visit the
research centers twice during a 4-week follow-up
period (Fig. 1).
1. Between 19 and 65 years of age
2. Fulfillment of Diagnostic and Statistical Manual of
Mental Disorders, version 4 (DSM-IV) diagnostic
criteria for either first-onset or recurrent MDD with
at least one major depressive episode in the 30 days
prior to the date of screening
3. A Hamilton Rating Scale for Depression (HAM-D) score of between 7 and 24 points
4. Willingness to participate in the trial and provide written consent Subjects meeting any of the following criteria will be excluded:
1. Patients at a high risk of attempting suicide (a
score of more than 2 points on the third question
(Suicide) of the HAM-D and a greater than
moderate risk of suicide on the Screening for
Depression and Thoughts of Suicide Scale)
2. Patients with fundamental communication problems
due to severely unstable mental disorders
3. Women who are pregnant, lactating, or planning to become pregnant
4. Patients considered by researchers to be inappropriate for participation due to severely abnormal/unstable laboratory test results or vital signs
5. Diagnosis of unregulated hormone disorders that
can affect mood (e.g., uncontrolled dysthyroidism)
6. Excessive exposure to major stressful life events
within 1 year prior to the date of screening (≤200
points on the Social Readjustment of Rating Scale)
7. People who have undergone any of the following
treatments within the specified period before the
date of screening:
7a. psychotropic drugs, such as antidepressant,
antianxiety, mood stabilizing, or antipsychotic
7b. nonpsychopharmacological drugs with
7c. psychotherapy (including cognitive behavioral
7d. electroshock therapy or transcranial magnetic
7e. any type of therapeutic intervention of
traditional Korean medicine to attenuate MDD
8. Subjects who have acute inflammation at the planned acupuncture site on the body
Fig. 1 Flow chart of the trial
9. Participants with bleeding disorders or those
currently taking anticoagulants
10. Patients with a medical history of severe head
injury, hemorrhagic or ischemic stroke, or other
diseases related to severe physical disability
Randomization, allocation concealment and blinding
An independent statistician will generate a randomization
schedule using SAS (Version 9.4, SAS institute. Inc., Cary,
NC, USA). Fifteen subjects will be assigned to each group
through the gender-stratified block randomization
method. The randomization list will be sealed in
sequentially numbered and gender-marked opaque envelopes,
delivered to each research center, and stored in a
doublelocked cabinet. After a candidate participant who meets
the eligibility criteria signs an Informed Consent Form,
the practitioner will open the corresponding envelope.
After the practitioner checks the group allocation for the
subject, the envelope will be stored again in a separate,
double-locked cabinet. Allocation concealment will be
maintained throughout the trial.
It is impossible to blind the practitioners; therefore,
they will be excluded from the assessment procedure.
All other researchers, such as assessors and data
analysts, will be blinded to the group allocation. To confirm
that participant blinding was achieved, after both the
first and final treatments, assessors will use a “blinding
test” questionnaire to ask participants which type of
therapy, real or sham, they thought they had been given.
The intervention treatment period includes 20 sessions
over 8 weeks. The participants will visit the research
center three times a week through the first 4 weeks and
then twice a week through the last 4 weeks. Licensed
Korean medical doctors who have at least 4 years of
clinical experience will perform the intervention.
Detailed information on acupuncture and moxibustion is
provided in Additional file 1 and Table 1.
For the treatment group, disposable, sterilized, filiform
needles (Dong-Bang Acupuncture Inc., Seoul, Korea,
diameter 0.25 mm, length 40 mm) will be inserted into
the skin at the following acupoints: GV20, EX-HN3,
GV24, CV17, and bilaterally at LI4 and PC6  (Fig. 2).
Practitioners can include up to two additional bilateral
acupoints using the outcome of pattern identification
based on the theory of traditional Korean medicine. The
acupuncture needles will be manipulated to achieve deqi
and retained for 20 min. During the retaining period,
electrical stimulation and moxibustion will be performed
simultaneously. An electric acupuncture device (ES-160,
Ito Co. Ltd., Tokyo, Japan) will be connected to the
GV20 and EX-HN3 acupoints and deliver stimulation
with a 10-Hz frequency. Electrical stimulation will be
delivered at an intensity that the participant can notice
but will still feel comfortable with. For moxibustion, a
cylinder-shaped, indirect moxibustion device, Mox-A
Jook Youm (GuoKu Industrial, Gimpo, Korea, diameter
40 mm, height 50 mm) will be used. The practitioner
will ignite two moxibustions. Moxibustions that give off
smoke and a scent will be applied to CV12 and CV4
acupoints (Fig. 2).
The control group will receive sham acupuncture
using a Park sham placebo device (PSD, Dong-Bang
AcuPrime Ltd., Exeter, UK)  on 10 specific
nonacupoints (bilateral upper limb 1: topmost point in the
middle section of the biceps brachii muscle belly, bilateral
upper limb 2: 1.5 cm above upper limb 1 point, bilateral
lower limb 1: 1.5 cm above the depression at the
midpoint of the upper border of the patella, bilateral lower
limb 2: area one third of the way above the medial part
of the tibia, bilateral lower limb 3: 1.5 cm above lower
limb 2) (Fig. 3). Unlike the real acupuncture needle, the
tip of the PSD needle is too blunt to penetrate the skin.
The same electric acupuncture device used for the
treatment group will be applied for mock
electroacupuncture. The electrosimulator will be connected to the PSD
needles attached to nonacupoints on both legs (lower
limb 2). Electric current will not be delivered, but the
device will make the same beeping sounds and create
the same light signals as it does for the treatment group
. For the sham moxibustion, a hole at the base of the
moxibustion will be plugged with Styrofoam to block
the channel that transfers heat (Fig. 3). Except for the
plugged base, the smoke, scent, and appearance of the
sham moxibustion will be the same as that of the real
moxibustion. Sham moxibustion will be applied to two
nonacupoints on the abdomen (9 cm lateral to the
umbilicus) (Fig. 4). These interventions will be performed
for the same number of sessions over the same period as
the treatment group .
All participants in both groups will receive a brochure
with information about MDD.
Prohibited and permitted concomitant treatment
Participants will be prohibited from receiving any MDD
treatment outside of the interventions of this trial during
the 8-week treatment period. If a patient must start
medication for MDD due to relapse during the
treatment period, they will be withdrawn from the trial. All
new treatments started after the beginning of the trial
and concomitant medications to treat medical
conditions unrelated to MDD will be recorded on the Case
Report Form (CRF).
Table 1 Schedule for treatment and outcome measurements
S screening period, T treatment period, BMI Body Mass Index, SRRS Social Readjustment of Rating Scale, SDTS Screening for Depression and Thoughts of Suicide,
HAM-D Hamilton Rating Scale for Depression, BDI Beck’s Depression Inventory, EQ-5D EuroQol-5 Dimension Index, ISI Insomnia Severity Index, STAI State-Trait
Anxiety Inventory, MYMOP2 Measure Yourself Medical Outcome Profile version 2, EEG electroencephalography
aComplete blood count and differential count, blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, total bilirubin, albumin,
erythrocyte sedimentation rate, thyroid-stimulating hormone, free thyroxine, human chorionic gonadotropin urine test (only for women in their childbearing years)
The primary outcome measurement of this study is
the mean change of total scores in the HAM-D from
baseline to the end of the treatment period (week 9).
Since its development in the 1960s, the HAM-D has
been considered a standard scale to assess MDD severity.
The range of the HAM-D score is 0 to 52, with 0–6
indicating normal, 7–17 indicating mild, 18–24 indicating
moderate, and 25 or more indicating severe MDD. We
will use the validated Korean version of the HAM-D .
Secondary outcome measurements include the average
change in the HAM-D (from baseline to weeks 5 and
13). The same version of the HAM-D used for the
primary outcome measurement will be applied again.
In addition, Beck’s Depression Inventory (BDI), the
Insomnia Severity Index (ISI), the State-Trait Anxiety
Inventory (STAI), the EuroQol-5 Dimension Index
(EQ-5D), the Measure Yourself Medical Outcome Profile
version 2 (MYMOP2), and electroencephalography (EEG)
will be measured as secondary outcomes.
BDI is a multidimensional questionnaire used to assess
the severity of the clinical symptoms of MDD. It
includes 21 questions to evaluate patients’ cognitive,
emotional, and physiological aspects, and the score can
range from 0 to 63 points. A higher score indicates a
more severe condition .
The ISI is an assessment tool designed to diagnose
insomnia and evaluate its severity. The range of the score
is 0 to 28, with 0–7 points indicating no clinically
significant insomnia, 8–14 indicating subthreshold insomnia,
15–21 indicating moderate insomnia, and 22–28
indicating severe insomnia .
The STAI is a questionnaire developed by Spielberger
et al. in the 1970s. It includes two subscales to assess state
anxiety and trait anxiety. Each subscale has 20 items .
The EQ-5D is an instrument developed by the EuroQoL
group to measure quality of life in terms of health
conditions. It includes five items and uses a Visual Analogue
Scale to assess overall health conditions .
Fig. 2 Acupoints for treatment group
The MYMOP2 is a patient-generated questionnaire. It
is optimized to evaluate changes over time for specific
health problems specified by patients themselves. The
MYMOP2 asks patients to identify their most important
symptoms or complaints and rate the severity of the
problems. It also asks how they feel about their general
wellbeing, how long they have suffered from the
problematic symptoms, and whether they take any drugs to
attenuate those symptoms .
EEG is a method of measuring the electrical activity of
the brain by recording the current of electricity captured
on the scalp. EEG will be measured for 5 min in a quiet
room with the patient sitting on a comfortable chair,
and any physical motion will be minimized. Electrodes
will be attached at two sites (F3, F4) out of the
10–20site system of the scalp to evaluate the balance of
prefrontal alpha waves from the right and left hemispheres.
Previous EEG studies have confirmed that a
characteristic, asymmetric pattern of resting frontal activity can be
observed in people with MDD that is unlike
measurements made in the non-MDD population [38, 39].
Pattern identification is a method to identify and
categorize the pattern of clinical signs and symptoms of
patients based on the theory of traditional Korean
medicine. In this study, the result of pattern identification will
be the basis of the choice for optional acupoints. We will
also explore whether there is any difference in the
tendency between the patterns.
Fig. 3 A front view (a, b) and a bottom view (c, d) of real (a, c) and
sham moxibustion (b, d). Nevertheless, the hole at the base of sham
moxibustion is plugged with Styrofoam to block the channel that
transfers heat (d), the front view of the real and sham moxibustion
The purpose of this pilot clinical trial is to explore the
efficacy and safety of electroacupuncture plus
moxibustion therapy for the treatment of MDD. Based on
previous literature  (mean difference 4.34, standard
deviation 3.75) and assuming a dropout rate of 20%, 15
participants will be assigned to each group.
Statistical analyses will be performed by an independent
statistician blinded to group allocation.
Intention-totreat analysis will be primarily applied in addition to
per-protocol analysis. A two-sided test will be used with
a significance level of 0.05. Multiple imputation will be
adopted when datasets are incomplete.
Sociodemographic information will be presented as
the mean ± standard deviation or the frequency (%), and
data will be analyzed using Student’s t test or the
chisquare test. The Wilcoxon rank sum test or Fisher’s
exact test will be performed when data are not normally
distributed. Analysis of covariance (ANCOVA) will be
conducted to compare the mean differences in HAM-D
scores between the two groups by substituting each
group for factors, points acquired at baseline for
covariates, and points assessed at week 9 for dependent
variables. RM ANOVA will be performed to analyze the
mean change in HAM-D score from baseline to the end
of the trial. A paired t test or Wilcoxon signed rank test
will be applied to compare the average changes between
scores assessed before and after treatment. The mean
differences of other secondary outcome measurements,
such as the BDI, ISI, STAI, EQ-5D, and MYMOP2, will
be analyzed following the same methodology as that
used in the primary outcome measurement.
Data handling and safety monitoring
Data collection procedures will be conducted in
compliance with the approved protocol. Any adverse event that
occurs during the study period will be recorded on the
CRF, and its severity and causality will be assessed.
Spontaneous reports by patients; simple interviews by
researchers at every visit; and laboratory tests, including
a complete blood count, differential count, and renal
and liver function tests, will be used to identify and
evaluate adverse events.
Data and safety will be monitored regularly to control
the quality of the trial. The monitoring will confirm
whether the record of the CRF is accurate when
compared with the source document, and the practical
procedures of the research will follow the approved
This is a two-armed, parallel-design, patient-assessor
blinded, multicenter, randomized, sham-controlled pilot
clinical trial designed to explore the efficacy and safety
of electroacupuncture plus moxibustion therapy for the
treatment of patients with MDD. Electroacupuncture
and moxibustion have been commonly used to treat
various psychiatric conditions, including MDD .
These treatments exert antidepressive activity by
regulating the HPA axis , affecting the hippocampus, and
influencing dopaminergic and/or serotonergic systems
[41, 42]. However, there is little scientific evidence
supporting the effectiveness of this combined therapy for
MDD. The results of the present study will help to
create a foundation for a full-scale RCT to confirm the
efficacy and safety of electroacupuncture plus moxibustion
therapy for the treatment of MDD patients.
In this study, random allocation will be performed
with stratification by gender. Women are more prone to
MDD than men [1, 43], with the lifetime incidence of
MDD being twice as high in women compared to men
[1, 5]. This gender difference is important both for
responsiveness to antidepressants as well as for
vulnerability to [44, 45], which led to us to stratify participants by
In this trial, EEG was added as an objective outcome
to the subjective questionnaires. Previous EEG studies
have demonstrated that the brain waves of subjects with
MDD differ significantly from those without MDD.
There are distinguishable patterns in resting EEG waves
Fig. 4 Nonacupoints for control group
between MDD and non-MDD subjects, and activation of
the prefrontal alpha waves is more prominent in the left
hemisphere than in the right in patients with MDD
[38, 39]. The EEG records obtained in this study will
be analyzed with a focus on the balance of prefrontal
alpha waves between the right and left hemispheres.
As sham interventions for real acupuncture and
moxibustion, a mock electrostimulation using a Park sham
placebo device and a modified moxibustion to block the
heat channel will be applied at nonacupoints unrelated
to depression in this study. There may be concerns that
the participants may be aware as to which type of
treatment they have received because of the difference of
numbers and sites of the points used in each group, even
though the appearances of therapeutic tools are
identical. The development of appropriate sham interventions
for acupuncture or moxibustion has been one of the
greatest challenges for researchers in this area. There
have been several types of sham interventions suggested
until now. It is one of the most commonly used types
of sham interventions to apply acupuncture needles
with a blunt edge and insulated moxibustion at
nonacupoints [16–18, 31, 46–48]. No one can say for sure
that it is a perfect and faultless method as a sham
intervention for acupuncture and moxibustion study.
However, to date it is one of the best options that we
can choose [48–50].
In this trial, no one is allowed to see the scene of
intervention aside from the operator. The participants,
therefore, cannot notice anything about the difference of the
numbers of sites of the points between groups.
Moreover, the blinding test to investigate whether the
participants have really noticed the types of
interventions that they have received or not will be performed
after completing the first and last treatment during the
study. The results of the blinding test as well as the
efficacy and safety outcomes will be reported.
Additional file 1: Details of the planned acupuncture and moxibustion
treatment based on Standards for Reporting Interventions in Clinical
Trials of Acupuncture (STRICTA) Checklist. (DOCX 22 kb)
BDI: Beck’s Depression Inventory; CAM: Complementary and alternative
medicine; CRF: Case Report Form; EEG: Electroencephalography;
EQ5D: EuroQol-5 Dimension Index; HAM-D: Hamilton Rating Scale for
Depression; HPA axis: Hypothalamic-pituitary-adrenal axis; IRB: Institutional
Review Board; ISI: Insomnia Severity Index; MDD: Major depressive disorder;
MYMOP2: Measure Yourself Medical Outcome Profile version 2; PSD: Park
sham placebo device; RCT: Randomized controlled trial; STAI: State-trait
The authors appreciate all of the collaborators and participants of the study.
EJC, SPK, JEK, HJP, ARK, BNS, JHC, SYC, and JHK designed and drafted the
study protocol. MK wrote the manuscript. OJK created the statistical design
of the trial. JHC provided technical advice and made critical revisions. SYC
and JHK participated in the trial design as principal investigators. All authors
read and approved the final manuscript.
Consent for publication
Ethical approval and consent to participate
The study protocol was approved by the Institutional Review Boards (IRBs) of
the participating research centers: Daejeon Oriental Hospital of Daejeon
University (djomc-132-1) and Kyung Hee University Oriental Hospital at
Gangdong (KHNMCOH 2015-09-001-003). The study procedures will follow
the protocol approved by the IRBs, and only patients who provide written
consent will be included in this study. This trial is registered with the Clinical
Research Information Service of South Korea (CRIS-KCT0001810).
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