Clinical Efficacy of Integrated Acupuncture and Moxibustion Therapy Combined with Drugs in the Treatment of Acute Depressive Disorder: Protocol for a Pragmatic Randomized Controlled Trial

Introduction

Depressive disorder is a common and disabling mental disorder characterized by persistent low mood, loss of interest, and impaired psychosocial functioning, and it may be associated with suicidal behavior.¹ The disorder imposes a substantial burden on affected individuals, families, healthcare systems, and society.² During the acute phase, patients often experience marked symptom burden and functional impairment. Therefore, the primary goal of acute-phase treatment is to achieve symptom remission and restore baseline functioning as early as possible.³ For adults in the acute phase of moderate-to-severe major depressive disorder, the American College of Physicians recommends either cognitive behavioral therapy or a second-generation antidepressant as initial treatment.³ Selective serotonin reuptake inhibitors are widely used in this setting, and escitalopram oxalate has established efficacy and acceptability for acute treatment.^3,4 However, antidepressant monotherapy may not provide sufficiently rapid improvement for all patients, and tolerability remains an important consideration in treatment selection. In addition, antidepressant benefits are generally expected within 4 weeks and require early review for symptom change and side effects, which may limit the ability of pharmacotherapy alone to meet acute-phase treatment goals.⁵ These limitations have prompted growing interest in adjunctive non-pharmacological interventions during the acute phase. Repetitive transcranial magnetic stimulation (rTMS) is one such option with evidence-based support for depression.⁶ Meta-analytic evidence suggests that rTMS combined with escitalopram can further improve depressive symptoms and is generally well tolerated.⁷ Nevertheless, the need for repeated treatment sessions may reduce its feasibility for some patients in routine practice.^6,7 Therefore, additional adjunctive strategies that are safe, acceptable, and feasible in real-world settings warrant further evaluation.

Acupuncture has been increasingly investigated as an adjunctive treatment for depression. Systematic reviews and meta-analyses suggest that acupuncture combined with antidepressants may improve depressive symptoms, reduce antidepressant-related adverse reactions, and may be associated with earlier clinical benefit;⁸ however, the certainty of the available evidence is low to moderate, and many included studies are methodologically limited.^8,9 Moxibustion, which involves thermal stimulation produced by burning moxa at specific body sites, is often used together with acupuncture in traditional Chinese medicine.¹⁰ Although moxibustion has also been studied in depressive conditions, current clinical evidence remains limited and is derived mainly from specific populations such as post-stroke depression.¹¹ Therefore, the effectiveness and safety of integrative acupuncture and moxibustion during the acute phase of moderate depressive disorder warrant further rigorous evaluation.^8,9,11

This open-label, pragmatic clinical trial conducted in a real-world setting will evaluate the early clinical benefits of integrating iAM with pharmacological treatment in patients with moderate depressive disorder during the acute phase. Specifically, the trial will compare escitalopram plus iAM with escitalopram alone and escitalopram plus rTMS in terms of depressive symptoms, associated clinical outcomes, and safety. The findings are expected to provide clinical evidence on the effectiveness, safety, and feasibility of iAM as an adjunctive treatment for moderate depressive disorder in routine practice. The study will test the following hypotheses: (1) compared with escitalopram alone, escitalopram plus iAM will result in greater early improvement in depressive symptoms during the acute phase; and (2) escitalopram plus iAM will demonstrate effectiveness and safety comparable to those of escitalopram plus rTMS.

Materials and Methods

Trial Design and Setting

This single-center, interventional, open-label, randomized, pragmatic clinical trial will enroll 300 adult patients with a moderate depressive episode. The participants will be randomized in a 1:1:1 ratio to receive escitalopram oxalate alone (standard treatment group), escitalopram oxalate plus repetitive transcranial magnetic stimulation (rTMS group), or escitalopram oxalate plus integrative acupuncture and moxibustion (iAM group), with 100 participants in each group. All participants will receive escitalopram oxalate for 6 weeks. The initial dose will be 5 mg/day for the first 3 days and will be increased by 5 mg every 3 days, as clinically indicated, to a maximum dose of 20 mg/day. rTMS will be given five times per week for 3 consecutive weeks. iAM treatment will be given three times per week for 6 consecutive weeks. The study flowchart is shown in Figure 1.

Figure 1 Study flowchart.

This study was approved by the Ethics Committee of the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (approval #BF2024-176-01). The study was registered with the International Traditional Medicine Clinical Trial Registry (http://itmctr.ccebtcm.org.cn): ITMCTR2024000380.

Recruitment and Consent

Potential participants will be recruited through clinic-based screening and advertisements from the Acupuncture and Moxibustion Clinic (including inpatient wards), Psychosomatic Clinic, Insomnia Clinic, and general outpatient clinics, through paper or electronic posters, WeChat, and the hospital’s official WeChat account. Eligible individuals will be screened by study clinicians. Those who meet the eligibility criteria and provide written informed consent will complete baseline assessments before randomization (Table 1). Study-related assessments and interventions will be provided at no additional cost.

Table 1 Participant Timeline

Inclusion Criteria

The participants in the study must fulfill the following criteria: (1) diagnosis confirmed by at least two psychiatrists after psychiatric interview and clinical evaluation; (2) fulfillment of the ICD-10 diagnostic criteria for a moderate depressive episode; (3) Hamilton Depression Rating Scale 17 (HAMD-17) score >17 and ≤24 points; (4) age 18–65 years; (5) ability to understand the study procedures and comply with treatment and assessment arrangements; and (6) provision of written informed consent and voluntary participation in the study.

Exclusion Criteria

Those meeting the following criteria will be excluded from the study: (1) assessment by a specialist physician of suicidal tendencies or behavior; (2) previously diagnosed with major depressive disorder, bipolar disorder, schizophrenia, or other major mental disorders; (3) severe anxiety state, Hamilton Anxiety Scale (HAMA) score >23 points; (4) liver and kidney dysfunction, tumors, or serious underlying diseases of the circulatory, digestive, endocrine, respiratory, or other systems; (5) history of epileptic seizures or family history, organic brain diseases, or severe physical illnesses; (6) women preparing for pregnancy or pregnant or lactating women; (7) current use of antidepressant medication within the previous 6 weeks, receipt of rTMS or transcranial direct current stimulation within the previous 3 months, or participation in another clinical trial; (8) contraindications for rTMS, such as titanium mesh, steel plate, stent, pacemaker, etc, for patients with implanted metal objects in the body; (9) alcoholic or drug abusers; (10) allergy to alcohol or adhesive tape, skin lesions at the treatment site, coagulation dysfunction, or severe scar diathesis.

Randomization and Blinding

A computer program was used to create a randomized allocation plan, which was subsequently transformed into cards by research assistants not involved in implementing or assessing the intervention. These cards were placed in opaque envelopes and encoded. The intervention operator sequentially opens the envelopes and performs the interventions according to the grouping information contained in the envelopes. This study employs an open-label design, ie, without blinding for the participants and the investigators performing the interventions. The investigators involved in the outcome assessments or statistical analysis are blinded.

Interventions

Standard Treatment Group

According to the 2020 version of the “Guidelines for the Diagnosis and Treatment of Mental Disorders”, all participants will be administered escitalopram oxalate tablets (National Medicine Permission Number: H20080788; Manufacturer: Sichuan Kelun Pharmaceutical Co., Ltd.) as the standard treatment. A daily oral dose of 5 mg will be prescribed for the initial 3 days, followed by an increase of 5 mg every 3 days until an effective dose of 20 mg is achieved. This effective dose will be maintained until the 6^th week of treatment.

rTMS Group (Standard Treatment Combined with rTMS)

Participants in the rTMS group will receive adjunctive rTMS in addition to standard pharmacotherapy. rTMS will be administered once daily, 5 days per week, for 3 consecutive weeks, resulting in 15 treatment sessions and a total of 45,000 stimulation pulses.

A Magneuro60 device (Nanjing Vishee Medical Technology Co., Ltd., Nanjing, China) equipped with a figure-of-eight coil will be used. The resting motor threshold (rMT) will be determined over the primary motor cortex corresponding to the first dorsal interosseous muscle. Stimulation will then be delivered to the left dorsolateral prefrontal cortex at 110% of the rMT using a 10-Hz protocol comprising 75 trains of 4 seconds each, with a 26-second intertrain interval. Each session will last 37.5 minutes and deliver 3000 pulses.

iAM Group (Standard Treatment Plus iAM Treatment)

Participants in the iAM group will receive adjunctive integrative acupuncture and moxibustion (iAM) in addition to standard pharmacotherapy. iAM will be administered three sessions per week for 6 weeks, with an interval of more than 24 hours between sessions, for a total of 18 sessions. Sterile disposable acupuncture needles (0.25 × 25 mm and 0.25×40 mm; Hwato Suzhou Medical Instruments, Suzhou, China) will be used.

iAM is an integrated intervention consisting of manual acupuncture, moxibustion, and intradermal ear acupuncture. The selection and location of acupoints are based on the WHO Standard Acupuncture Point Locations.^12,13

For body acupuncture, the main acupoints will include GV20, GV29, ST8, CV15, CV12, CV10, CV6, CV4, LR3, LI4, and SP6. Participants will be treated in the supine position, and needling will be performed in the following order: limbs, head, and abdomen. Needles of 0.25×25 mm will be used for the head acupoints, and needles of 0.25×40 mm for the abdominal acupoints. After routine skin disinfection, LI4, LR3, and SP6 will be inserted first using a rapid insertion technique to a depth of approximately 0.5–0.8 cun, with manipulation to elicit deqi. GV20, GV29, and ST8 will then be inserted obliquely at approximately 30° to the skin to a depth of 0.3–0.5 cun. CV12, CV10, CV6, and CV4 will be inserted vertically to a depth of approximately 0.8–1.0 cun, with appropriate manipulation to obtain deqi. Infrared lamps will be positioned above the abdomen and feet to maintain warmth, and the needles will be retained for 30 minutes.

Moxibustion will involve the following specific acupoints. BL13, BL17, BL19, and KI1 will be grouped together, while BL42, BL46, BL48, and Kl1 form another group. These two groups will be used alternately. During the procedure, acupoints will first be selected, and Wanhua oil will be evenly applied. Next, moxa cones [2 mm in diameter and 3 mm in height (2×3 mm)] will be placed using a joss stick. If the participant experiences unbearable burning pain, the moxa cones will be removed promptly, and their use will be limited to two times for each acupoint.

Intradermal ear acupuncture will be applied to two alternating sets of auricular points: CO15, CO12, and CO10; and P1, P4, and P5. After routine disinfection, the needles will be inserted and fixed using tweezers.

Follow-Up

Considering the real-world study setting, depressive disorder may have a prolonged or recurrent course. This study focuses on the acute treatment phase. After completion of the 6-week intervention period, participants who achieve a clinical response will continue their original standard treatment and undergo follow-up assessments at weeks 9 and 12. Participants who do not achieve a clinical response at week 6 will be referred to a psychiatrist for treatment adjustment according to clinical need and will not undergo protocol-specified follow-up assessments.

Outcome Measures and Study Procedures

Primary Outcome

The outcome assessors will conduct the HAMD-17 within 24 hours before the first treatment (baseline) and then at weeks 1, 2, 3, 4, 5, and 6. For participants who achieve a clinical response at week 6, follow-up assessments will also be conducted at weeks 9 and 12.

Secondary Outcome

Secondary outcomes will include liver and kidney function tests (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], creatinine [Cr], and blood urea nitrogen [BUN]), and the Stanford Expectations of Treatment Scale (SETS).¹⁴ These assessments will be performed within 24 hours before the first treatment and again at week 6.

Additional secondary outcome measures will include the Beck Depression Inventory-II (BDI-II),¹⁵ the Generalized Anxiety Disorder Scale (GAD-7),¹⁶ the Hamilton Anxiety Scale (HAMA),¹⁷ the Insomnia Severity Index (ISI),¹⁸ and the 36-item Short-Form Health Survey (SF-36). These scales will be completed at baseline and at weeks 1, 2, 3, 4, 5, and 6. For participants who achieve a clinical response at week 6, follow-up assessments will also be conducted at weeks 9 and 12.

Effectiveness Endpoint

Treatment effectiveness will be evaluated using the following criteria: (1) response, defined as a reduction of >50% from baseline in the HAMD-17 score; and (2) remission, defined as a HAMD-17 score ≤7. Given that this study focuses on the 6-week acute treatment phase of moderate depressive disorder, response at week 6 will serve as the primary effectiveness endpoint, and remission at week 6 will serve as a secondary effectiveness endpoint. In addition, longitudinal changes in HAMD-17 scores across the acute treatment phase will be used to characterize early clinical improvement.

Safety Outcomes and Adverse Events

Clinical deterioration will be monitored throughout the study and defined as self-harm, suicidal ideation or behavior, or worsening depressive symptoms with a HAMD-17 score >24. Before trial initiation, participants will be informed of potential adverse events related to the study interventions. For iAM, these may include bleeding, skin irritation, dizziness, pallor, local hematoma, and fainting. Adverse events will be actively assessed at each treatment visit through participant self-report and investigator inquiry, documented in the case report form, and classified according to severity and their possible relationship to the intervention. Participants experiencing clinically significant adverse events will receive prompt medical evaluation and appropriate management. Decisions regarding study continuation after an adverse event will be made according to participant preference and investigator judgment. Participant compliance and treatment-related side effects will also be recorded throughout the study.

Baseline Variables

Baseline variables will include age, sex, duration of illness, educational level, occupation, medical history, and baseline HAMD-17 score.

Data Management

All study data will be stored on password-protected computers and encrypted hard drives accessible only to authorized study personnel and data monitors.

Data Availability Statement

De-identified study data will be available from the corresponding author on reasonable request after publication, subject to ethical and privacy restrictions. Study records will be retained for at least 5 years after publication. Personal identifiers will be kept confidential.

Quality Control

The study protocol was reviewed by experts in acupuncture, psychiatry, statistics, rehabilitation, and research methodology. An independent clinical research assistant will monitor trial documents and study conduct to ensure adherence to the protocol and standard operating procedures. iAM will be delivered by experienced acupuncturists, and all study personnel will receive standardized training before trial initiation.

Sample Size

The sample size was calculated for the primary comparison between the iAM group and the standard treatment group with respect to the week-6 response rate. Based on previous evidence, the 6-week response rate in the standard treatment group was assumed to be 40%. Assuming a response rate of 60% in the iAM group, with a two-sided α of 0.05 and 80% power, 81 participants are required per group. Allowing for an anticipated dropout rate of 20%, 100 participants will be enrolled in each group. Therefore, a total of 300 participants will be randomized in a 1:1:1 ratio.

Statistical Analysis

The full analysis set (FAS) will include all participants who receive at least one study treatment and have at least one post-baseline effectiveness assessment. The per-protocol set (PPS) will include participants who complete the study without major protocol deviations. The safety set (SS) will include all participants who received at least one study treatment and had at least one safety assessment. The primary outcome will be analyzed in the FAS, with the PPS used for sensitivity analysis. Safety will be analyzed in the SS.

The data will be analyzed using SPSS, version 21.0 or later (IBM, Armonk, NY, USA). Continuous outcomes measured repeatedly over time will be analyzed using an appropriate repeated-measures approach, with treatment group, time, and group-by-time interaction included in the model. Between-group comparisons at week 6 will be reported with corresponding effect estimates and 95% confidence intervals. Categorical data will be presented using n (%) and analyzed using the chi-squared test or Fisher’s exact test. Response and remission rates at week 6 will be compared between groups as secondary analyses. The significance level will be set at 5% (two-tailed), with a p-value <0.05 indicating statistical significance.

Ethical Approval and Dissemination

This study protocol adheres to the principles outlined in the Declaration of Helsinki and has received approval from the Ethics Committee of the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Approval No. BF2024-176-01). Written informed consent will be obtained from all participants before any study procedures are performed. The study findings will be published in peer-reviewed journals and disseminated through academic conferences and other appropriate public channels.

Discussion

Although acupuncture has been increasingly studied as an adjunctive treatment for depression, the available evidence remains limited by variable methodological quality and insufficient certainty. Systematic reviews suggest that acupuncture combined with antidepressants may improve depressive symptoms and reduce treatment-related adverse effects; however, these findings should be interpreted cautiously because the overall quality of evidence is low to moderate.^8,9 In addition, most published studies have evaluated acupuncture alone or other acupuncture-based modalities rather than integrative acupuncture and moxibustion (iAM), and few have focused specifically on the acute treatment phase. Reports of randomized controlled trials in this field have also been limited by suboptimal reporting quality.¹⁹ Therefore, further well-designed pragmatic trials are needed to evaluate the effectiveness and safety of iAM for moderate depressive disorder during the acute phase.

This trial has several features that may enhance its clinical relevance. It adopts a pragmatic, open-label, randomized design in a real-world setting, which may better reflect routine clinical practice than highly restrictive explanatory trials. Acupuncture delivery in clinical trials may differ from its use in everyday clinical settings.²⁰ By comparing escitalopram alone, escitalopram plus rTMS, and escitalopram plus iAM, this study is expected to provide clinically relevant evidence regarding the effectiveness, safety, and feasibility of iAM as an adjunctive treatment for moderate depressive disorder during the acute phase.

Several limitations should also be acknowledged. First, recruitment is limited to a single center in one geographic region, which may affect the generalizability of the findings. Second, the open-label design may introduce performance and expectation bias, although randomized allocation and blinded outcome assessment are intended to reduce this risk. Third, the sample size was calculated primarily for the comparison between iAM plus standard treatment and standard treatment alone; therefore, comparisons involving the rTMS group should be interpreted with appropriate caution. Future multicenter studies with broader populations and longer follow-up are warranted to confirm the findings and further evaluate the role of iAM in acute-phase depression management.

Conclusion

This pragmatic randomized trial will evaluate whether integrative acupuncture and moxibustion combined with escitalopram is a feasible, safe, and potentially effective adjunctive treatment for moderate depressive disorder during the acute phase. The study is expected to provide clinically relevant evidence for routine practice and to inform future multicenter confirmatory studies.