Efficacy and Safety of Auricular Acupuncture for Depression: A Randomized Clinical Trial

Daniel Maurício de Oliveira Rodrigues; Paulo Rossi Menezes; Ana Elise Machado Ribeiro Silotto; Artur Heps; Nathália Martins Pereira Sanches; Mariana Cabral Schveitzer; Alexandre Faisal-Cury

doi:10.1001/jamanetworkopen.2023.45138

. 2023 Nov 30;6(11):e2345138. doi: 10.1001/jamanetworkopen.2023.45138

Efficacy and Safety of Auricular Acupuncture for Depression

A Randomized Clinical Trial

Daniel Maurício de Oliveira Rodrigues ^1,^2,³, Paulo Rossi Menezes ¹, Ana Elise Machado Ribeiro Silotto ^1,², Artur Heps ¹, Nathália Martins Pereira Sanches ⁴, Mariana Cabral Schveitzer ⁵, Alexandre Faisal-Cury ^1,^✉

¹Department of Preventive Medicine, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil

²Department of Biological and Health Sciences, University of Southern Santa Catarina, Palhoça, Brazil

³Department of Health Sciences, Cruzeiro do Sul University, São Paulo, Brazil

⁴Institute of Psychiatry of Santa Catarina, São José, Santa Catarina, Brazil

⁵Department of Preventive Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil

Accepted for Publication: October 14, 2023.

Published: November 30, 2023. doi:10.1001/jamanetworkopen.2023.45138

^✉

Corresponding Author: Alexandre Faisal-Cury, MD, PhD, Department of Preventative Medicine, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo 455, Cerqueira César, São Paulo, SP 01246903, Brazil (faisal@usp.br).

Author Contributions: Drs de Oliveira Rodrigues and Faisal-Cury had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rodrigues, Menezes, Silotto, Heps, Sanches, Faisal-Cury.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Rodrigues, Silotto, Heps, Faisal-Cury.

Critical review of the manuscript for important intellectual content: Rodrigues, Menezes, Sanches, Schveitzer, Faisal-Cury.

Statistical analysis: Menezes.

Obtained funding: Rodrigues, Faisal-Cury.

Administrative, technical, or material support: Rodrigues, Silotto, Heps, Sanches.

Supervision: Rodrigues, Menezes, Schveitzer, Faisal-Cury.

Conflict of Interest Disclosures: Dr Rodrigues reported receiving grants from the Education Department of the Government of Santa Catarina, Brazil outside the submitted work. Dr Silotto reported receiving grants from São Paulo Research Foundation (FAPESP) and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) outside the submitted work. Dr Heps reported receiving grants from FAPESP and CAPES outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by FAPESP grant 2018/8117469-5 to Drs Rodrigues, Sanches, and Faisal-Cury.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the undergraduate scholarship holders (research scholarship under Article 171 of the Education Department of the Government of Santa Catarina, Brazil) Isabel Transferetti Pose (University of Southern Santa Catarina), Joana Loudes Lawless (University of Southern Santa Catarina), Gabriela Chaves Reis (University of Southern Santa Catarina), Beatriz Inez Dalsasso (University of Southern Santa Catarina), Juliana Vasconcelos (University of Southern Santa Catarina), Fabiana Tyminski (University of Southern Santa Catarina), and Bruna Caminha Ferreira (University of Southern Santa Catarina) for their recruitment and outreach support. We also thank Maria Eduarda Antunes, BA (University of Southern Santa Catarina) for assistance with data collection; Pedro Henrique de Mesquita Pacheco, BA (Butantan Institute) for statistical analysis; Roberto Ferreira, BA (Albert Einstein Hospital) for data management and data monitoring; and Alexandre Biasi Cavalcanti, MD, PhD (HCor Research Institute) for suggestions on data analysis. These individuals did not receive additional compensation for their support.

^✉

Corresponding author.

PMCID: PMC10690462 PMID: 38032640

This randomized clinical trial analyzes the safety and efficacy of auricular acupuncture as a treatment for depression.

Key Points

Question

Is auricular acupuncture a safe and effective treatment for depression?

Findings

This randomized clinical trial of 74 patients with depression undergoing 6 weeks of auricular acupuncture found no significant differences in adverse event rates between the intervention (specific auricular acupuncture) and control (nonspecific auricular acupuncture) groups, evidencing the intervention’s safety. No significant differences were found in depression recovery (50% reduction in Patient Health Questionnaire–9 score from baseline).

Meaning

These findings suggest that auricular acupuncture is safe for patients with depression, but additional studies with larger samples and longer interventions are needed for confirmation.

Abstract

Importance

Depression is a leading cause of disability worldwide, and there is increasing interest in nonpharmacological treatments. Auricular acupuncture (AA) is a simple, low-cost, and well-tolerated option, but further studies are needed to establish its efficacy and safety.

Objective

To estimate the efficacy and safety of auricular acupuncture as a treatment for depression.

Design, Setting, and Participants

This randomized clinical trial was conducted at 4 university research centers in Brazil, from March to July 2023. Eligible patients were adults aged 18 to 50 years whose score on the Patient Health Questionnaire–9 (PHQ-9) indicated moderate depression (score 10-14) or moderately severe depression (score 15-19). Exclusion criteria included previous application of AA, risk of suicidal ideation, or severe depression (PHQ-9 score >20). An intent-to-treat analysis and modified intent-to-treat analysis were conducted.

Intervention

Participants were randomized into 2 treatment groups, which included specific AA (SA) and nonspecific AA (NSA). Both groups received 12 sessions of AA with semipermanent needles with daily stimulation twice a week over 6 weeks and were followed-up for 3 months. All participants continued with their usual care for ethical reasons. The SA group’s treatment protocol consisted of 6 acupuncture points on the auricular pavilion chosen according to the diagnosis of depression by traditional Chinese medicine (Shenmen, subcortex, heart, lung, liver, and kidney). The NSA group’s acupuncture points were the external ear, the cheek and face area, and 4 nonspecific points in the helix region unassociated with mental health symptoms. A locator device was used to confirm which areas had neuroreactive points.

Main Outcomes and Measures

The primary outcome was a reduction of at least 50% in the PHQ-9 score (ie, depression recovery) at 3 months. Secondary outcomes included depression recovery at 4 and 6 weeks; depression remission (PHQ-9 score < 5) at 4 weeks, 6 weeks, and 3 months); and adverse events.

Results

A total of 304 participants were screened, and 74 participants (62 women [84%]; median [IQR] age, 29 [23-27] years) were included in the intention-to-treat analysis, with 37 participants randomized to each group (SA and NSA). A total of 47 participants (64%) were followed-up through 3 months. The results showed no statistically significant difference in depressive recovery between the groups at 3 months (14 of 24 participants in the SA group [58%] vs 10 of 23 participants in the NSA group [43%]; risk ratio [RR], 1.34; 95% CI, 0.76-2.45; P = .38). The proportions of depression recovery and remission at 4 and 6 weeks based on the PHQ-9 were higher in the SA group (except for depression recovery at 6 weeks) with no statistically significant differences. However, a statistically significant difference was observed in symptom remission at 3 months (11 of 24 participants in the SA group [46%] vs 3 of 23 participants in the NSA group [13%]; RR, 1.99; 95% CI, 1.16-3.34; P = .02) in favor of SA. There were no significant differences in adverse event rates between the groups, evidencing the intervention’s safety. Most participants reported mild pain at the needle application site (33 patients [94%] in the SA group vs 32 patients [91%] in the NSA group). Five participants dropped out of the study due to adverse events.

Conclusions and Relevance

The results of this randomized clinical trial suggest that SA over 6 weeks is safe. Although there was no statistically significant difference between groups for the primary efficacy outcome, patients receiving SA did experience greater symptom remission at 3 months. A larger sample size and longer intervention are needed to further evaluate the efficacy of SA for depression.

Trial Registration

ClinicalTrials.gov Identifier: NCT05855421

Introduction

Depression is one of the leading causes of disability worldwide, affecting more than 300 million people (4.4% of the global population).¹ In 2019, depressive disorders represented the highest proportion of disability-adjusted life-years among mental disorders (37.3%).² In Brazil, the prevalence depression is among of the highest in the world, affecting 5.8% of the Brazilian population and accounting for 10.3% of years of life lost by Brazilians.³ However, less than 10% of those affected by the disease receive appropriate treatment.^1,4 Nonadherence to antidepressant treatment is a concern for health care professionals; adherence to antidepressant therapy ranges from 40% to 90% across different studies, with a mean adherence rate of 65%.⁵

Research has shown that Australians and North Americans prefer integrative treatments for depression.^6,7,8 In this sense, auricular acupuncture (AA), a type of acupuncture in which thin semipermanent needles are inserted into specific points on the auricular pavilion, may be a therapeutic option. AA is easier to implement in clinical settings than body acupuncture owing to its short application time, low technique complexity, relative safety, and daily continuous physiological stimulation.⁹

Several nerves are distributed in the auricular pavilions. The concha area has a rich distribution of the vagus nerve.¹⁰ Anatomical studies have shown that the auricular pavilion is the only place on the human body’s surface with a distribution of the afferent vagus nerve.¹¹ Thus, needle stimulation on the auricular pavilion appears to lead to specific activation in the brain, mainly through the auricular branch of the vagus nerve.^12,13 A systematic review¹⁴ found little evidence of the efficacy of AA for depression. The methodological quality scores showed that most analyzed studies indicated considerable methodological flaws. Additionally, no study in the review¹⁴ used semipermanent needles in the groups. Therefore, this study aims to estimate the efficacy and safety of AA for depression recovery and remission at 4 weeks, 6 weeks, and 3 months.

Methods

Study Design

This randomized clinical trial was approved by the Hospital das Clínicas ethics committee, the University of São Paulo, and the University of Southern Santa Catarina and was monitored by an independent data and safety monitoring board. We followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline and the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA)¹⁵ for the design and reporting of this study. We recruited patients from the community at 4 university research centers in Santa Catarina, Brazil, from March to April 2023. All patients provided written informed consent before participation, and participants did not receive incentives or compensation to be part of the study. The study protocol and statistical analysis plan can be found in Supplement 1.

Participants

The research participants were adults aged 18 to 50 years. Eligible participants were those whose score on the Patient Health Questionnaire–9 (PHQ-9)¹⁶ indicated moderate depression (score of 10-14) or moderately severe depression (score of 15-19). Exclusion criteria included previous application of AA, risk of suicidal ideation, or severe depression (PHQ-9 score ≥20) (eTable 1 in Supplement 2). Demographic characteristics, including gender and race and ethnicity, were collected via self-report on electronic tablets using the REDCap platform. Race and ethnicity categories included Black, White, and multiracial; race and ethnicity were included in this study to align with current research.

Randomization and Blinding

A computer program performed block randomization in a 1:1 ratio, in different block sizes (4, 6, and 8), corresponding to the 2 study groups. The experimental group received specific AA (SA) for depression and usual care, and the control group received nonspecific AA (NSA) and usual care. All participants continued with their usual care for ethical reasons. Participant allocation was concealed and delivered to the acupuncturists in individual opaque sealed envelopes. Participants, evaluators, data managers, and the statistician were blinded to treatment assignment. Neither the study participants nor the investigators had any influence on randomization and allocation concealment, which an independent statistician performed. Participants were informed that there were 2 treatment protocols.

Procedures

The study assessors were trained to approach participants similarly to avoid recruitment biases. The study used a protocol of questions and procedures for all phases: prescreening, screening, data collection, and application of protocols.

Participants with severe depression levels (PHQ score ≥20) or suicidal ideation did not participate in the study and were followed and consulted by a psychiatrist. The sessions of AA application occurred twice weekly, alternating the application on the right and left auricular pavilions, over 6 weeks, totaling 12 sessions, with a duration of 15 minutes each, in reserved rooms. The acupuncturists instructed the participants to stimulate each point manually (de qi stimulation) 3 times a day (morning, afternoon, and evening) for 30 seconds or until the auricular pavilion became red or sensitive to pressure. In this study, the acupuncturists had specific training in the field, with a minimum of 1200 hours in acupuncture and a minimum of 10 years of experience. They received standardized training before the study began.

All participants answered the PHQ-9 questionnaires 4 weeks, 6 weeks, and 3 months after the study initiation and reported adverse events before each AA session (eFigure 1 in Supplement 2). Patients were asked to complete the blinding assessment and treatment efficacy perception assessment and were requested to guess which treatment they received to test the success of blinding after 3 months of the study. More details about AA procedures and outcome assessment can be found in Supplement 1.

SA Treatment

The SA group’s treatment consisted of a protocol of acupuncture points chosen according to the diagnosis of depression by traditional Chinese medicine. All SA participants used 6 preestablished points on the auricular pavilion: Shenmen, subcortex, heart, lung, liver, and kidney^17,18 (eFigure 2 and eTable 2 in Supplement 2). The EL11 device (NKL) was used to find the exact location of the points; the device searches on the skin for areas of lower electrical resistance, indicating more neuroreactive points (ie, true acupuncture points).¹⁹ The size of the semipermanent needle (Complementar) used was 0.2 mm wide and 2.5 mm long. The semipermanent needles were inserted to a depth of 2.5 mm.

NSA Treatment

The existing literature acknowledges the difficulty in establishing protocols to be used as a control because of the high responsiveness and innervation of the auricular pavilion (ie, sham needling is not physiologically inert).^19,20,21 As a control group strategy, our study opted for superficial needling at nonpoints or irrelevant true points, aiming to reach other neural segments. The NSA group points were the external ear, the cheek and face area, and 4 nonspecific points in the helix region (eFigure 3 in Supplement 2), which are points that are not associated with mental health symptoms (eTable 2 in Supplement 2). The EL11 locator device was used to confirm that the sham areas were not neuroreactive points. The size of the needle (Complementar) used in the control group was 0.2 mm wide and 1.0 mm long, aiming for more superficial needling. The semipermanent needles were inserted to a depth of 1.0 mm.

Outcomes

The primary outcome was the proportion of participants who showed improvement of 50% or more in depressive symptoms (ie, depression recovery) between the groups, as assessed by the PHQ-9 at 3 months. Secondary outcomes included the difference in the proportion of participants reaching depression recovery at 4 and 6 weeks; the proportion of participants who achieved a score of less than 5 on the PHQ-9 (indicating depression remission) and differences in depression scores at 4 weeks, 6 weeks, and 3 months; the difference in the proportion of reported adverse events (ie, those arising from the AA technique) and reported adverse effects (ie, the worsening of depression symptoms or the onset of suicidal ideation); and the difference in the proportion of patient blinding to randomization and perception of treatment efficacy (eTable 3 in Supplement 2).

Statistical Analysis

Data analysis in this clinical trial was conducted by an independent hired statistician, blinded to treatment groups. The sample size was designed to detect a 30% difference (experimental group, 60% and control group, 30%) in depression symptom recovery between the 2 groups. A minimum sample of 36 participants per group was estimated, considering the test as 2-tailed, with 80% power and a significance level of P < .05. An additional 10% was added, considering segment losses, totaling 40 participants in each group, for 80 participants.

Initially, a baseline comparison between the SA and NSA groups was performed with median and IQR descriptions for continuous variables and frequencies and percentages for categorical variables. Subsequently, intent-to-treat and modified intent-to-treat analyses were conducted to compare the proportions of depression recovery and remission at different time points in the study using Fisher exact test. The effect size for dichotomous variables was calculated as relative risk.

Scores were subjected to a normality test that rejected the normality hypothesis to verify sample normality. Therefore, nonparametric tests were adopted. The reduction of depression scores over time in both groups was evaluated using the median and IQR. The statistical analysis of these data was conducted using the Wilcoxon-Mann-Whitney U test.

Cochran Q and Friedman analysis of variance tests were also used to verify statistically significant differences in depression scores over time within each group. These tests were followed by post hoc tests to identify significant differences at specific time points. We performed a sensitivity analysis with missing data imputation to evaluate the robustness of the results. Multiple imputation methods were explored, including last observation carried forward, imputation using the generalized estimating equations model, and multiple imputation through the expectation-maximization lag algorithm for categorical variables; the generalized estimating equations model was applied specifically to PHQ-9 depression scores. All analyses were conducted with a significance level of P < .05. Relative and absolute frequency were used to assess treatment safety and identify adverse events. The success of blinding and the perception of treatment efficacy were assessed using Fisher exact test. Statistical analyses were performed using R statistical software version 4.1.0 (R Project for Statistical Computing).

Results

Of the 304 screened volunteers, 230 were excluded for various reasons, resulting in a cohort of 74 participants (62 women [84%]; median [IQR] age, 29 [23-37] years; 5 Black participants [7%]; 61 White participants [82%]; 8 multiracial participants [10%]) comprising the intent-to-treat sample with 37 participants randomized to SA treatment and 37 participants randomized to NSA treatment (Figure 1). At 3 months, 27 patients (36%) were lost to follow-up; a total of 47 patients (64%), including 24 patients in the SA group and 23 participants, in the NSA group, comprised the modified intent-to-treat sample. There was no difference between the study groups in the number of patients lost to follow-up (eTable 4 in Supplement 2). We conducted a comparison of baseline depression scores according to the PHQ-9 among the individuals lost to follow-up (eTable 5 in Supplement 2). The groups were similar regarding demographic characteristics, clinical diagnosis, pharmacological treatments, and health characteristics at the study’s outset, except for race and ethnicity (Table 1).

Table 1. Baseline Demographic and Clinical Characteristics at the Time of Randomization in the Intention-to-Treat Analysis.

Variable	Participants, No. (%) (N = 74)
Variable	SA group (n = 37)	NSA group (n = 37)
Age, median (IQR), y	28 (22-37)	30 (23-36)
Patient Health Questionnaire–9 Score, median (IQR)^a	14.0 (12.0-16.0)	16.0 (14.0-18.0)
Gender
Male	5 (13)	6 (16)
Female	32 (87)	30 (81)
Nonbinary	0	1 (3)
Race and ethnicity
Black	0	5 (14)
Multiracial	2 (5)	6 (16)
White	35 (95)	26 (70)
Income^b
≤3 times the monthly minimum wage	14 (38)	11 (30)
>3 times the monthly minimum wage	23 (62)	26 (70)
Marital status
Single	22 (59)	17 (46)
Not single	15 (41)	20 (54)
Education
Less than high school up to completed high school	10 (27)	10 (27)
Incomplete college education or higher	27 (73)	27 (73)
Weekly working hours, median (IQR) (n = 49)	42 (27-44)	44 (22-44)
Previous diagnosis of depression or other mental illness	16 (43)	16 (43)
Participant used any medication for depression	8 (22)	4 (11)
Participant used medication in the last 3 mo
No	21 (57)	27 (73)
Antidepressant	8 (22)	5 (13)
Tranquilizer or sedative	5 (13)	4 (11)
Anxiolytic	7 (19)	3 (8)
Participant consumes alcoholic beverages	26 (70)	20 (54)
Participant smokes any cigarette
No	35 (95)	35 (96)
Yes	2 (5)	1 (2)
Former smoker	0	1 (2)

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Abbreviations: NSA, nonspecific auricular acupuncture; SA, specific auricular acupuncture.

^{^a}

A score of 10 to 14 indicates moderate depression; 15 to 19, moderately severe depression; and 20 to 25, severe depression.

^{^b}

The monthly minimum wage in Brazil is equivalent to $250 in 2023.

Primary Outcome

Three months after randomization, 14 of the 24 participants (58%) randomized to the SA group had a reduction of at least 50% in the PHQ-9 score compared with 10 of 23 participants (43%) in the NSA group. The result was not statistically significant (risk ratio [RR], 1.34; 95% CI, 0.76-2.45; P = .38) (Table 2).

Table 2. Primary and Secondary Efficacy Outcomes in the Intention-to-Treat Analysis.

Outcomes	Participants, No./Total No. (%)		RR (95% CI)^a	P value^b
Outcomes	SA group	NSA group	RR (95% CI)^a	P value^b
Primary outcome, depression recovery at 3 mo vs baseline (n = 47)^c^,^d	14/24 (58)	10/23 (43)	1.34 (0.76-2.45)	.38
Secondary outcomes
Depression recovery at 4 wk vs baseline (n = 57)	12/28 (43)	9/29 (31)	1.28 (0.74-2.14)	.42
Depression recovery at 6 wk vs baseline (n = 51)	10/26 (38)	10/25 (40)	0.96 (0.53-1.65)	>.99
Symptom remission at 4 wk vs baseline (n = 57)^e	8/28 (28)	5/29 (17)	1.35 (0.72-2.20)	.36
Symptom remission at 6 wk vs baseline (n = 51)	7/26 (27)	5/25 (20)	1.19 (0.61-2.00)	.74
Symptom remission at 3 mo vs baseline (n = 47)	11/24 (46)	3/23 (13)	1.99 (1.16-3.34)	.02

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Abbreviations: NSA, nonspecific auricular acupuncture; RR, risk ratio; SA, specific auricular acupuncture.

^{^a}

Effect size was calculated as RR for dichotomous data.

^{^b}

Statistical significance was calculated with Fisher exact test.

^{^c}

The primary outcome (improvement in depression symptoms) was defined as a reduction of 50% or more from baseline Patient Health Questionnaire-9 (PHQ-9) scores. The number of cases and proportions are based on observed data.

^{^d}

Depressive symptoms measured by PHQ-9 scores range from 0 (least) to 27 (greatest) symptom burden.

^{^e}

Participants who achieved a score less than 5 on the PHQ-9, indicating symptom remission.

Secondary Outcomes

The proportions of patients with depression recovery and remission based on the PHQ-9 at 4 weeks was higher in the SA group, but not at 6 weeks, and there were no statistically significant differences between the groups at 4 or 6 weeks. A statistically significant difference in favor of the SA group was observed in depression remission after 3 months (11 of 24 participants [46%] in the SA group vs 3 of 23 participants in the NSA group [13%]; RR, 1.99; 95% CI, 1.16-3.34; P = .02) (Table 2). The median PHQ-9 scores decreased after 4 weeks, 6 weeks, and 3 months in both groups, with no statistically significant differences. Lower scores were observed in the SA group than in the NSA group (eTable 6 in Supplement 2 and Figure 2).

Figure 2. — The figure shows the median Patient Health Questionnaire-9 (PHQ-9) scores of patients receiving specific auricular acupuncture (SA) and nonspecific auricular acupuncture (NSA) at baseline, 4 weeks, 6 weeks, and 3 months. A score of 10 to 14 indicates moderate depression; 15 to 19, moderately severe depression; and 20 to 25, severe depression. The lines inside the boxes reflect the medians, with the upper and lower ends of the boxes reflecting the IQRs. The error bars reflect the minimum and maximum values. The line plot reflects means.

The modified intent-to-treat analyses showed the similar results as the intention-to-treat analyses. Intragroup analysis was performed using the Cochran Q test, with no statistically significant differences (eTable 7 in Supplement 2). Intragroup analysis was performed using the Friedman analysis of variance test followed by post hoc tests for the differences in PHQ-9 scores at each time point compared with baseline, which revealed statistically significant differences in all evaluations, in both groups, at different assessment points (eTable 8 and eFigure 4 in Supplement 2).

Sensitivity Analyses

The sensitivity analyses revealed that there were no statistically significant differences in depression recovery across the visits (eTable 9 in Supplement 2). These analyses confirmed the statistically significant results in favor of the SA group regarding depression remission after 3 months (eTable 10 in Supplement 2). As for PHQ-9 scores, the generalized estimating equations model demonstrated favorable effect sizes of SA, and the visits had a statistically significant effect on the scores (eTable 11 and 12 in Supplement 2).

Safety

Most participants reported mild pain at the needle application site (33 patients [94%] in the SA group vs 32 patients [91%] in the NSA group). One participant had mild local inflammation in 1 of the auricular points and received appropriate treatment. Regarding adverse events, an increase in depression scores was observed during data collection in 3 participants, and 7 individuals responded positively to question 9 of the PHQ-9, which addresses suicidal ideation. These cases were carefully monitored, and the independent data monitoring and safety committee did not consider these events related to the intervention. No statistically significant difference was found between the groups in the proportion of participants with adverse effects (ie, those arising from AA) and adverse events (ie, worsening of depression symptoms or suicidal ideation). Five participants withdrew from the study as a result of adverse effects. No severe adverse events were reported (Table 3). The study participants did not change their medications or psychotropic medication dosages throughout the data collection.

Table 3. Adverse Effects and Adverse Events Listed by Treatment Group.

Adverse event or adverse effect	Participants, No. (%) (N = 74)
Adverse event or adverse effect	SA group (n = 37)	NSA group (n = 37)
Mild and transient adverse effects
Mild pain	33 (94)	32 (91)
Intense pain	1 (3)	0
Punctate bleeding	3 (9)	2 (6)
Itching in the auricle	11 (31)	14 (40)
Increased appetite	1 (3)	0
Headache	1 (3)	0
Hot flashes	0	1 (3)
Difficulty sleeping	0	2 (6)
Sensitivity to pressure	1 (3)	2 (6)
Facial skin hypersensitivity	0	1 (3)
Moderate adverse effect: local inflammation	1 (3)	0
Moderate adverse events
Worsening of depressive symptoms (4 wk)	0	0
Worsening of depressive symptoms (6 wk)	0	1 (6)
Worsening of depressive symptoms (3 mo)	1 (3)	1 (6)
Emergence of suicidal ideation (4 wk)	0	2 (6)
Emergence of suicidal ideation (6 wk)	0	2 (6)
Emergence of suicidal ideation (3 mo)	2 (6)	2 (6)
Any severe adverse events and adverse effects	0	0
Discontinuation due to adverse effects
Local pain	3 (9)	1 (3)
Local inflammation	1 (3)	0

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Abbreviations: NSA, nonspecific auricular acupuncture; SA, specific auricular acupuncture.

Blinding Quality

For results on the success of blinding, see eTable 13 in Supplement 2. No difference was found between groups in the proportion of patients who guessed correctly what kind of AA they had received and their perception of efficacy in symptom relief after the 3 months.

Discussion

The results of this randomized clinical trial showed no difference in depression recovery between the groups at 3 months. However, depression remission at 3 months was significantly higher in the SA group. In addition, no significant differences were observed in the rates of adverse events and adverse effects, and no severe adverse events were recorded, evidencing practice safety. To our knowledge, this is the first randomized clinical trial on the effectiveness of SA using a semipermanent needle with NSA directed at depression as the comparator group. However, previous studies^{22,23,24,25,26,27,28} using other AA techniques found favorable results in depressive symptoms, but with shorter study duration and different comparators.

These preliminary findings are promising and support the use of SA in depression treatment. The rates of recovery (58%) and remission (46%) from depression in the present study are similar to those observed in meta-analyses of pharmacological treatments^29,30 and superior to those for psychotherapy.³¹ The 33% difference in symptom remission between the groups (ie, 46% remission in the SA group vs 13% in the NSA group) was clinically meaningful; depression remission is crucial for patients, providing better psychosocial functioning and long-term prognosis, not just symptom improvement.³²

The absence of statistically significant differences between the groups for depression recovery can be explained. First, the small sample size resulted in insufficient power and may have underestimated true efficacy. Second, considering the economic cost of time and participant adherence, we provided only 12 sessions over 6 weeks in this study. Therefore, adding AA doses by increasing the treatment duration (eg, 16-18 sessions over 8-12 weeks) may be an effective way to streamline the treatment program. Third, the manual stimulation of the semipermanent needle (known as de qi induction) is a factor that affects the efficacy of AA. To maintain the blinding of the study, the NSA group also used this daily stimulation, which may have contributed to an increased effect size of the technique in this group. Fourth, the study’s follow-up loss (36%) may have impacted the results. However, adherence to depression treatment remains a relevant and common challenge to overcome in clinical trials. A study by Olfson et al³³ found that 36.4% of patients discontinued antidepressant treatment within the first 30 days. A meta-analysis³⁴ reported a 36.4% dropout rate for cognitive behavioral therapy. A study³⁵ on acupuncture in depression treatment observed a dropout rate similar to the present study. This trend of treatment discontinuation seems to be associated with the characteristics of the disease itself (apathy, hopelessness, and lethargy). Regardless of the chosen treatment, patients with depression are likely to discontinue treatment.³⁶

First-line therapy for depression is medication, but several factors interfere with treatment access and adherence, such as system barriers and clinical and individual factors.³⁷ Therefore, it is necessary to offer a wide range of evidence-based therapies to treat depression, aiming at person-centered mental health care.³⁸ AA may be an option for patients who reject medication or psychotherapy because it has fewer adverse effects than pharmacological treatment. A systematic review³⁹ of adverse events associated with AA found that most were transient, mildly intense, and tolerable. No severe adverse events were identified in our study, indicating that AA is a safe treatment.

Besides the technique’s safety, patients in the SA group had increased rates of symptom remission between 6 weeks and 3 months, which may be associated with the delayed effects of AA treatment.⁴⁰ We should underscore that in AA, part of the technique’s effect is attributed to stimulating the auricular branch of the vagus nerve, increasing parasympathetic activity while simultaneously decreasing sympathetic nervous system activity.^41,42 This effect may lead to an improvement in depression-related symptoms.¹³ A systematic review⁴³ concluded that trigeminal nerve stimulation and transcutaneous vagus nerve stimulation improve the treatment of specific neuropsychiatric disorders, such as depression.

An additional hypothesis is that AA may reduce serotonin depletion by inhibiting the hyperactive hypothalamic-pituitary-adrenal axis, which would explain the technique’s prolonged effect at the 3-month follow-up.⁴⁴ Experimental studies confirmed this hypothesis, showing that the antidepressant effect of AA is possibly associated with the normalization of this axis’ hyperactivity.⁴⁵ Additionally, some studies^10,13observed that AA can trigger cardioinhibitory effects similar to vagus nerve stimulation. It is essential to highlight that participants in the NSA group may have also experienced temporary inhibition of this axis due to the perception of having received adequate treatment. However, this effect tends to decrease gradually after the end of the treatment sessions.

This study has strengths. First, the research addressed the selection of AA points, providing a solid foundation for future large-scale studies. In addition, the study included a more extended study period and experienced acupuncturists who used semipermanent needles, which are considered more effective than other stimuli. The control group received needling in nonspecific areas, and blinding measures were implemented for assessors, participants, and the statistician.

Limitations

The present study also has limitations. The predominance of women in the sample precluded the detection of possible gender differences in the results. Using self-report instruments to measure the primary outcome may also introduce bias into the results. Other major limitations include the limited sample size and the relatively high loss of participants during the follow-up period. Additionally, an NSA group with positive results indicates the need to investigate better the mechanisms of action and nonspecific outcomes associated with AA.

Conclusions

The results of this randomized clinical trial suggest that SA over 6 weeks is feasible and safe. Although the differences between SA and NSA groups did not reach statistical significance for the primary outcome, SA did produce greater symptom remission at 3 months. A more extensive sample size study, more protracted intervention, and objective evaluation of the results are necessary to further investigate the efficacy of SA for depression.

Supplement 1.

Study Protocol

Click here for additional data file.^{(564KB, pdf)}

Supplement 2.

eTable 1. Inclusion and Exclusion Criteria

eFigure 1. Data Collection Procedures

eFigure 2. Points Applied in the Auricular Pavilion of the Specific Auricular Acupuncture (SA) Group

eTable 2. Universal Nomenclature, Location, and Indications of the Points Used in the Groups

eFigure 3. Points Applied in the Auricular Pavilion of the Nonspecific Auricular Acupuncture (NSA) Group

eTable 3. Primary and Secondary Outcomes of the Study

eTable 4. Loss to Follow-Up Throughout the Study

eTable 5. Baseline Depression Score Analysis for Participants Who Did Not Complete the Study

eTable 6. Secondary Outcomes of Depression Scores by Intention-to-Treat Analysis

eTable 7. Secondary Efficacy Outcomes in Depression Recovery and Remission by Modified Intent-to-Treat Analysis

eTable 8. Secondary Outcomes of Depression Scores by Modified Intent-to-Treat Analysis

eFigure 4. Median Depression Scores by Modified Intent-to-Treat Analysis

eTable 9. Sensitivity Analysis for Depression Recovery With Missing Data Imputation

eTable 10. Sensitivity Analysis for Symptom Remission With Missing Data Imputation

eTable 11. Sensitivity Analysis for Depression Score With Missing Data Imputation

eTable 12. Adjustment of the Generalized Estimating Equations (GEE) Model

eTable 13. Blinding Assessment and Perception of Treatment Efficacy

Click here for additional data file.^{(412.5KB, pdf)}

Supplement 3.

Data Sharing Statement

Click here for additional data file.^{(16.2KB, pdf)}

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