Efficacy and Safety of Auricular Acupuncture in Depression During the Covid 19 Pandemic: a Multicenter Triple-blinded Randomized Clinical Trial
Phase: NA
Conditions: Depressive Symptoms, Depression, Anxiety, Insomnia, Quality of Life
Sponsor: Universidade do Sul de Santa Catarina

 
 
FACULTY OF MEDICINE - UNIVERSITY OF SÃO PAULO 
UNIVERSITY OF SOUTHERN SANTA CATARINA 
CRUZEIRO DO SUL UNIVERSITY 
CITY OF SÃO PAULO UNIVERSITY 
 
 
 
 
 
 
 
 
EFFICACY AND SAFETY OF AURICULAR ACUPUNCTURE IN DEPRESSION: A 
MULTICENTER RANDOMIZED CLINICAL TRIAL 
 
  
 
 
 
 
 
 
 
Dr. Alexandre Faisal Cury (FM-USP) 
Dr. Paulo Rossi Menezes (FM-USP) 
Drd. Daniel Maurício de Oliveira Rodrigues (FM-USP; UNISUL; UNICSUL; UNICID) 
MScd. Ana Elise Machado Ribeiro Silotto (FM-USP) 
MScd. Artur Heps (FM-USP) 
 
 
 
 
 
 
 
 
São Paulo  
2023

 
 
 
ABSTRACT  
 
Depression, often under-diagnosed and under-treated, is the leading cause of 
disability worldwide and contributes significantly to the global burden of diseases. 
There is a growing demand for non-medicated forms of treatment for depression. In 
this sense, auricular acupuncture is considered a simple, low cost technique, well 
tolerated by patients. The Unified Health System (Sistema Único de Saúde –SUS)  
had this practice incorporated in 2006, but it lacks studies to verify its efficacy and 
safety. The main objective of this study is to evaluate the efficacy of auricular 
acupuncture to reduce depressive symptoms by comparing it to usual care and non-
specific auricular acupuncture. It is a randomized clinical trial, blinded to the 
evaluator, participant and statistician. The study sample will be composed of 280 
university students, divided equally into two groups: Experimental group - GE 
(auricular acupuncture) and Control group - GC (non-specific auricular acupuncture). 
The GE and GC participants will undergo 12 sessions of auricular acupuncture, 2 
times a week. The primary outcome of the study will be the proportion of participants 
who present improvement of 50% or more in their symptoms, evaluated by PHQ-9, 
three months after inclusion. The secondary outcomes will be: improvement of 50% 
or more in their symptoms, after six months; quality of life (SF-36), sleep quality 
(PSQI), anxiety (STAI), change in the use of antidepressant medication, events and 
adverse effects, levels of Brain-derived neurotrophic factor (BDNF), Interleukin 1β, 
Interleukin-6 and TNF-α in blood plasma. The data will be analyzed aiming at treating 
according to the principles of CONSORT. A semi-structured interview will be applied 
to a sub-sample. These qualitative data will be analyzed using the Content Analysis 
method. The study will begin after approval by CEP-FMUSP.  
 
 
 
 
 
 
 
 

 
 
 
INTRODUCTION 
 
DEPRESSION AS A PUBLIC HEALTH PROBLEM  
 
Depression is one of the most significant public health problems in the world. It 
is a severe mental disorder that has an episodic, recurrent, or persistent course over 
time and causes functional impairment in behavioral, social, family, educational, and 
occupational domains (HENDRICK et al., 1998). Several explanatory models have 
been developed to justify the syndrome, which can be psychogenic, organic, or both 
(BECK; ALFORD, 2011). 
According to the World Health Organization (WHO), depression is the leading 
disabling factor worldwide. More than 300 million people (4.4% of the world's 
population) currently live with depression, an increase of over 18% between 2005 
and 2015. Depression is more common among women (5.1%) than men (3.6%). The 
prevalence also varies according to age, income, WHO macroregions, countries, 
among other variables. Globally, depressive disorders are the leading cause of years 
lived with disability (7.8% of all years lost). In the worst-case scenario, depression 
can lead to suicide. Approximately 800,000 people die from this cause annually, and 
it is the second leading cause of death among adolescents and young adults (15 to 
29 years). Despite high prevalence rates, less than 10% of those affected by the 
disease receive adequate treatment (WORLD HEALTH ORGANIZATION, 2017a, b). 
In the United States of America, 8.1% of adults had depression between 2013 
and 2016, almost twice as prevalent among women (10.4%) compared to men 
(5.5%). About 80% of adults reported difficulties with social activities due to 
depression symptoms (BRODY; PRATT; HUGHES, 2018). Another study with 
American women found a prevalence of 4.8% for major depressive disorder and 
4.3% for mild depression, with only 32.4% of women with major depressive disorder 
and 20.0% with mild depression using antidepressants (GUO et al., 2018). In Brazil, 
the prevalence is one of the highest in the world: 5.8% of the Brazilian population 
suffers from depression, and 10.3% of the years of life lost by Brazilians are due to 
this disease (WORLD HEALTH ORGANIZATION, 2017a, b). 
Depression is the most prevalent health disorder in the university environment: 
university students are at greater risk related to the pathology (NATIONAL 

 
 
 
INSTITUTE OF MENTAL HEALTH, 2018). Regarding the prevalence of depression, 
a systematic review identified twenty-four articles on the prevalence of depression in 
university students. However, the results suggest that most articles have 
methodological flaws. The reported prevalence rates ranged from 10% to 85%, with a 
weighted average prevalence of 30.6%. The results suggest that university students 
have much higher rates of depression than those found in the general population 
(IBRAHIM et al., 2013). 
According to the DSM-V (2014) (Diagnostic and Statistical Manual of Mental 
Disorders), there are several categories of depressive disorders, with the difference 
between them being the relationship between the frequency and severity of 
symptoms. Major Depressive Disorder (MDD), for example, is characterized by one 
or more depressive symptoms, a duration of two weeks with a depressed mood or 
loss of interest, and at least four additional symptoms of depression: significant 
weight loss or gain without dieting; insomnia or hypersomnia; psychomotor agitation 
or retardation; fatigue and loss of energy; feelings of worthlessness or excessive or 
inappropriate guilt; diminished ability to think or concentrate or indecisiveness; 
recurrent thoughts of death (not just fear of dying); recurrent suicidal ideation without 
a specific plan, or a suicide attempt or a specific plan for committing suicide 
(AMERICAN PSYCHIATRIC ASSOCIATION, 2014). 
There are various theories about the etiology of depression. One of the main 
neurobiological hypotheses states that the decrease in the expression of brain-
derived neurotrophic factor (BDNF) contributes to depression. This hypothesis is 
supported by consistent findings of low levels of BDNF in the serum of depressed 
patients, compared to levels detected in non-depressed patients. Meta-analyses 
have confirmed abnormally low concentrations of BDNF in depressed patients and its 
normalization by antidepressant treatment. These findings appear to reflect 
peripheral manifestations, consistent with the neurotrophin hypothesis: depression is 
a consequence of altered BDNF expression in the brain (MOLENDIJK et al., 2014; 
BUS et al., 2015). 
In the pathophysiology of depression, in addition to BDNF, it has increasingly 
been confirmed in recent years that the inflammatory immune system, especially the 
release of signaling molecules (cytokines), could influence many of the 
neurochemical changes induced by stress and contribute to the development of 

 
 
 
depression, interacting with the neuroendocrine system and specific pathways 
related to mood (IRWIN; MILLER, 2007). According to recent studies, alterations in 
the levels of pro-inflammatory cytokines (Interleukin 1β, Interleukin-6, and TNF-α) are 
associated with an increased risk of depression, both in animal models and in 
patients with depression (RAISON; CAPURON; MILER, 2006; SIMON et al., 2008). 
The different types of depression are treated with specific medications, called 
psychopharmacological drugs. Their use is based on the already established 
alteration of neurochemical neurotransmitters. It is with such support that scholars 
explain the nature of the disease and the action of antidepressant medications 
(BARLOW; DURAND, 2008). Medications are the primary treatment for major 
depressive disorder, which explains why there is currently a wide variety of these 
products available. There is also another biological treatment that affects brain 
chemistry, known as electroconvulsive therapy (ECT) (AMERICAN PSYCHIATRIC 
ASSOCIATION, 2008). 
Some healthcare professionals recommend psychotherapeutic interventions 
as a complementary treatment to psychopharmaceuticals, which may encompass 
different methods such as psychotherapy, psychodynamic therapy, interpersonal 
therapy, behavioral therapy, cognitive-behavioral therapy, group therapy, couples 
therapy, and family therapy, as well as interventions in lifestyle changes (SOUZA, 
1999), creating new habits such as in nutrition, exercise practices, and therapeutic 
treatments from other eastern or western therapeutic systems, known as integrative 
and complementary practices in Brazil. 
 
INTEGRATIVE AND COMPLEMENTARY PRACTICES AS A PUBLIC POLICY 
 
Over the last three decades, significant discussions have been taking place in 
academic, political, and technical groups associated with the healthcare sector 
regarding the inclusion of other complex models of healthcare attention that are non-
biomedical, referred to by the World Health Organization (WHO) as Traditional 
Medicine (TM) and Integrative and Complementary Medicine (ICM). These complex 
systems are widely used in both developed and developing countries, in both public 
and private settings. As such, the WHO established that member countries should 
implement therapeutic treatments composed of TM and ICM not belonging to the 

 
 
 
biomedical model in healthcare systems (LUZ, 2005; WORLD HEALTH 
ORGANIZATION, 2013). 
In this scenario, a significant event in Brazil was the creation, in 2006, of the 
National Policy on Integrative and Complementary Practices (PNPIC), to respond to 
the aspirations and demand for diverse forms of healthcare. The Integrative and 
Complementary Practices (ICP) regulated and implemented in the Brazilian Unified 
Health System (SUS) by this policy were Traditional Chinese Medicine/Acupuncture, 
Homeopathy, Medicinal Plants/Phytotherapy, and Social Thermalism/Crenotherapy. 
Later in 2006, Anthroposophic Medicine was also included as an ICP in the SUS 
through the approval and publication of Ministerial Ordinance No. 1600 (BRASIL, 
2006). 
In 2017, Ordinance 849 incorporated fourteen new practices in the PNPIC: art 
therapy, ayurveda, biodanza, circle dance, meditation, music therapy, naturopathy, 
osteopathy, chiropractic, reflexology, reiki, shantala, integrative community therapy, 
and yoga. Data from the National Registry of Health Establishments (CNES) 
demonstrate that 7,700 establishments offer some ICP, which is present in 1,708 
Brazilian municipalities, covering all twenty-seven states and the Federal District, 
also present in all capitals. In the service network, they are mostly present in primary 
care (78%).  
According to data from the 2nd cycle of the National Program for Improving 
Access and Quality of Primary Care (PMAQ-AB), 5,600 family health teams, out of 
the 30,000 evaluated, offer ICP services, and auricular acupuncture is offered in 908 
teams, being the sixth most used ICP in the SUS. In 2016, according to e-SUS data, 
over two million ICP consultations were recorded in Basic Health Units (UBS), with 
770,000 Traditional Chinese Medicine consultations, which includes various 
techniques, notably auricular acupuncture and acupuncture (BRASIL, 2017). In 
recent decades, there has been a significant increase in the use of Complementary 
and Integrative Practices (CIP) worldwide.  
The growing demand for CIP has gained prominence in the health sector due 
to its differentiated approach, which seeks to understand the individual through a 
multidimensional, amplified, and singular perspective of the life-health-disease 
process, with the aim of improving the quality of life and well-being and promoting the 

 
 
 
recovery and maintenance of the population's health (BRASIL, 2006; SABBAG et al., 
2017; WORLD HEALTH ORGANIZATION, 2014).  
Other factors that encourage the use of such practices include attentive 
listening, the establishment of a therapeutic bond, the individual's co-responsibility for 
their health, and the awakening of autonomy and empowerment (SABBAG et al., 
2017). 
In addition to these aspects, numerous studies demonstrate the effectiveness, 
safety, and mechanisms of action of CIP (WORLD HEALTH ORGANIZATION, 2013). 
The Cochrane, an independent, non-profit international organization that aims to 
gather the best evidence to support decision-making, has a reference center for CIP 
at the University of Maryland since 1996, producing the best evidence through 
systematic reviews and meta-analyses. Among the most commonly used and 
researched practices are those of Traditional Chinese Medicine (COCHRANE 
COMPLEMENTARY MEDICINE, 2018). 
The history of Traditional Chinese Medicine (TCM) dates back 2,000 years. 
Various practices are used in TCM, in addition to acupuncture, a technique that is 
well-known in the West. Treatments include Chinese diet therapy and herbal therapy, 
Tai Chi Chuan, Lian Gong, cupping therapy, moxibustion, massage therapy, and 
auricular acupuncture (WORLD HEALTH ORGANIZATION, 2010). 
The practice of auricular acupuncture, an ancient therapy, is according to Dal 
Mas (2004), the art of balancing the body through reflex points distributed in the 
auricular pavilion. Similar to reflexology, it is believed that the human body and all its 
organs and limbs are projected onto the ear, with each region corresponding to a 
specific point. Furthermore, it is believed that stimulation of specific points can 
produce systemic effects or effects on corresponding reflex regions.  
 
 
 
 
 
 
 
 

 
 
 
EXPECTED RESULTS 
 
The present study provides a better understanding of the efficacy and safety of 
auricular acupuncture in the treatment of depression, such as: efficacy in remission 
of depression symptoms in the short and medium term, safety related to adverse 
events and effects, changes in quality of life, sleep quality, and anxiety, and possible 
mechanisms of action related to biological markers. 
In terms of benefits, the research procedures in the recruitment phase will 
identify patients with depression and possibly at risk of suicide - who, otherwise, 
would not have been identified - ensuring specialized care for severe depression or 
suicidal ideation. It is intended to prove the effects of a technique that has been used 
for millennia: if the technique's effects are positive, it could provide well-being to 
people suffering from depression and similar disorders. 
This study will test a simple, low-cost, non-pharmacological, and easy-to-apply 
intervention for the treatment of depression. Therefore, it has the potential to 
generate great gains in public health, in terms of improving access to complementary 
treatments and reducing the treatment gap for depressive disorders. The knowledge 
gained may be crucial in influencing the agenda of collective and mental health 
policies in Brazil. 
Finally, this research will provide training for researchers and the publication of 
papers in scientific journals and international conferences, involving students with 
scientific 
initiation 
projects, 
undergraduate 
and 
postgraduate 
thesis, 
and 
dissertations. It will also contribute to the integration of teaching, research, and 
extension through the topics addressed in the project, which should be discussed in 
undergraduate and postgraduate courses and extension projects, as well as 
academic-institutional exchange between universities. 
 
 
 
 
 
 
 

 
 
 
RESEARCH JUSTIFICATION 
 
A search in the databases Pubmed, Medline, Lilacs, Ibecs, Cumed, Scielo, 
and Cochrane found 32 articles with the keywords in English, Spanish, and 
Portuguese: "ear acupuncture" or "acupuncture auricular" or "auriculotherapy" and 
"depression" or "brain-derived neurotrophic factor" or "Interleukin" or "IC-6" or "IC-1β" 
or "TNFα". Studies with animals, literature reviews, qualitative studies, case studies, 
or studies unrelated to the topic were excluded, leaving only three studies on 
depression. There is a predominance of scientific articles from China, with 
heterogeneity in data collection. The target audience of the studies were 90 women 
with breast cancer, 90 addicted men, and 24 obese women. Auricular acupuncture 
had significant results in depression scores in all three studies, but the studies had a 
low sample size and high risk of biases (XIAOAI; BEI; JING, 2015; SET; CAYIR; 
PIRIM, 2014; LIANG, et al., 2014). 
Other studies have related the effects of auricular acupuncture in different 
situations and psychological outcomes: improvement in anxiety before dental 
treatment (KARTS et al., 2007); Generalized Anxiety Disorders, Decreased Anxiety in 
Pre-Hospital Transport (KOBER et al., 2003); improvement in sleep quality in 
individuals with post-traumatic stress disorder (HING, et al., 2015); improvement in 
stress in nurses (KUREBAYASHI; SILVA, 2014); improvement in stress, cortisol 
levels, and sleep quality in middle-aged women (CHA; PARK; SOK, 2017). However, 
no study has used auricular acupuncture to evaluate levels of BDNF, Interleukin 1β, 
Interleukin-6, and TNF-α in blood plasma with symptoms of depression. 
Auricular acupuncture is one of the most widely disseminated complementary 
and alternative medicine practices today, as it is believed to yield rapid and effective 
results, with few reports of adverse reactions or contraindications. Research has 
shown that Australians and Americans report a preference for complementary and 
alternative medicine practices for depression (KESSLER et al., 2000; JORM et al., 
1997; JORM, et al., 2000). 
Another advantage of auricular acupuncture is its application in psychiatric 
patients. The patient does not need to undress and can remain seated, similar to 
psychotherapy. This allows the patient to maintain eye contact with the therapist 

 
 
 
without being in an inferior and passive position, such as lying down without clothes 
(GEIB et al., 2015). 
Despite reports of safety in practice, acupuncture and auricular acupuncture 
practices are not entirely free of adverse events. White (2001) reported an incidence 
of 684 adverse events per 10,000 consultations. The majority were minor events, 
such as bleeding, needle pain, or worsening of symptoms. In another prospective 
study, MacPherson et al. (2001) demonstrated that no serious adverse events were 
reported after 34,407 acupuncture treatments. This is important evidence for public 
health, as acupuncture practitioners perform approximately two million treatments per 
year in the UK. Comparing this rate of adverse events with the use of routinely 
prescribed medications in primary care suggests that acupuncture is a relatively safe 
form of treatment. 
Several mechanisms may explain the therapeutic effects of acupuncture in 
depression. Strong evidence produced in the last thirty years has demonstrated that 
acupuncture acts on various neurotransmitters, predominantly the endogenous 
opioid 
mechanism, 
catecholamines, 
and 
serotonin, 
norepinephrine, 
and 
approximately 20 to 30 other neuropeptides (LEUNG et al., 2014). In addition, 
acupuncture has produced structural and functional changes demonstrated in 
magnetic resonance imaging and electroencephalography in areas of the anterior 
cingulate cortex, amygdala, hippocampus, hypothalamus, cerebellum, and other 
limbic structures (HUANG, et al., 2012; LIU et al., 2009). Dysfunctions in these brain 
areas have been linked to depressive disorders (HAMILTON et al., 2015). 
Despite published studies on the mechanism of action of the technique, most 
studies on the efficacy and safety of different acupuncture modalities in depression 
have a high risk of bias. A systematic review by Cochrane on the subject (SMITH et 
al., 2018) concluded that most of the 64 studies had biases due to the low 
methodological quality of published clinical trials. Most of the articles included in this 
review used other acupuncture modalities (manual acupuncture, electroacupuncture, 
and laser acupuncture), or combined with auricular acupuncture: only one study 
using auricular acupuncture alone was analyzed in this review (XIAOAI; BEI; JING, 
2015). 
Therefore, based on the clinical experience of professionals in the field and 
the good acceptance of patients, auricular acupuncture has become a widely used 

 
 
 
practice, also because it is economically accessible and easy to apply. However, 
there are few clinical studies with this technique, and most of these published studies 
have many biases, compromising the interpretation of the results. Thus, the purpose 
of this study is to evaluate the efficacy and safety of auricular acupuncture in 
depression. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
OBJECTIVES 
 
GENERAL OBJECTIVE 
 
The primary objective is to estimate the effectiveness of auricular acupuncture 
in reducing depressive symptoms compared to usual care and non-specific auricular 
acupuncture, three months after participant inclusion. 
 
SPECIFIC OBJECTIVES 
 
a) To estimate the effectiveness of auricular acupuncture in reducing 
symptoms six months after participant inclusion; 
b) To estimate the effectiveness of auricular acupuncture in quality of life, 
anxiety and insomnia symptoms, and antidepressant medication use before and after 
the intervention, three months after participant inclusion; 
c) To evaluate occasional events and adverse effects of the use of auricular 
acupuncture technique in the treatment of depression; 
d) To evaluate levels of BDNF, Interleukin 1β, Interleukin-6, and TNF-α in the 
blood plasma before and after the use of auricular acupuncture; 
e) To analyze the perception of the influence of auricular acupuncture on 
depression, quality of life, anxiety, insomnia, and medication use. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
PATIENTS AND METHODS 
 
This research is classified as a quantitative study according to its nature, 
experimental according to the procedures, and explanatory according to the 
objectives (GIL, 2012). This study is characterized as a randomized, participant-
blinded, assessor-blinded, and statistical analysis-blinded clinical trial. The 
Consolidated Standards of Reporting Trials (CONSORT) and its extension for 
acupuncture, Standards for Reporting Interventions in Clinical Trials Acupuncture 
(STRICTA), will be used for the implementation of this research. This clinical trial will 
be registered on the Clinicaltrials platform. 
According to Stux and Birch (2005), in the design of clinical trials in auricular 
acupuncture and acupuncture, several aspects should be considered: the most 
appropriate points for the situation, number of points, number and frequency of 
sessions, techniques and materials applied to each point, appropriate instruments, 
use of other interventions, experience and training of the professional, establishment 
of the control group and the sham auricular acupuncture, and the placebo effect. In 
addition to the difficulties of conducting a double-blind clinical trial, since complete 
blinding by the participant in PIC studies is challenging. Based on these 
considerations, the decision-making for the design will be based on preliminary 
studies and published guidelines. 
 
RESEARCH SUBJECTS 
 
The research subjects will be adults between 18 and 50 years old. The 
research will be advertised on university bulletin boards and invitation letters will be 
sent by email. The sample will be composed of individuals who reach the minimum 
scores and meet the inclusion and exclusion criteria of the study. Participants who 
agree to participate in the study will be required to sign an informed consent form 
(ICF). Afterward, a questionnaire with demographic, socioeconomic, health, and 
behavioral variables  will be applied to determine if they are eligible to participate in 
the study based on the inclusion and exclusion criteria, and to identify individuals with 
depression symptoms using the Patient Health Questionnaire - PHQ-9. Participants 
who obtain moderate depression scores will be selected. The sample will be 

 
 
 
composed of individuals who reach the minimum scores and meet the inclusion and 
exclusion criteria of the study. The ICF and all questionnaires will be administered 
through the REDCap platform to ensure the management of participant data 
according to the General Data Protection Law (GDPL). 
 
RANDOMIZATION AND BLINDING 
 
For the randomization process, a computer program will be used to perform 
the randomization in a 1:1 ratio for the two study groups: experimental group 
(auricular acupuncture - specific points for depression and usual care) and control 
group (auricular acupuncture - non-specific points and usual care). The allocation of 
participants will be concealed, meaning it will be done by a computer-generated 
random sequence, delivered in an opaque and sealed envelope, containing a letter 
informing the group to which the participant will be assigned. 
Participants will be blinded to the group assignment of auricular acupuncture 
(specific and non-specific points for depression). They will be informed that there are 
two treatment protocols: an individualized auricular acupuncture based on Traditional 
Chinese Medicine diagnosis (experimental group) and a fixed point protocol for this 
study (control group - non-specific auricular points). 
The evaluators of the study will be blinded to the groups. The auricular 
acupuncture applicators will not know the results of the participants' questionnaire 
scores. Finally, the statistician will also be blinded to the participants' origin when 
preparing the results reports. 
 
SAMPLE SIZE 
 
The sample size will be designed to detect a difference of 20% (experimental 
group 60% and control group 40%) in the recovery of depressive symptoms (PHQ-9 
<10) between the arms. The minimum sample size is estimated to be 107 
participants per group, considering the test as two-tailed, with 80% power and a 
significance level of 5%. An additional 30% will be added to account for possible 
dropouts, totaling 140 in each group, for a total of 280 participants. For secondary 
outcomes related to biological markers, a new randomization stage will be carried 

 
 
 
out. This procedure aims to respect ethical principles related to non-maleficence, as 
well as the financial aspect of the proposal. The sample size for differences in means 
of biological markers was stipulated according to the standardized effect size 
magnitude indicated for comparisons between effect magnitudes of different 
variables. A standardized effect size magnitude of 0.7 will be used, considering α 
(bilateral) = 0.05 and β = 0.20. A minimum sample size of 34 participants per group is 
estimated (BROWNER; NEWMAN; HULLEY, 2008). For qualitative data, 20 
participants will be randomly selected from each group. 
 
ELIGIBILITY 
 
The eligibility of the study will be assessed in a pre-screening process in the 
classrooms of the University. The inclusion and exclusion criteria of the study are as 
follows. 
 
Inclusion Criteria 
 
• Age between 18 and 50 years old; 
• Obtaining minimum scores on the PHQ-9 for moderate depression; 
• Availability of time for the sessions. 
 
Exclusion Criteria 
 
• Utilization of complementary therapies for at least 3 months; 
• Risk of suicidal ideation assessed through the "Suicide-Risk Assessment 
Protocol" (S-RAP); 
• Severe depression assessed through the PHQ-9 scores; 
• Application of auricular acupuncture for depression previously; 
• Pregnancy; 
• Menopause; 
• Allergy to metals and micropore; 

 
 
 
• Lobes of the auricular pavilions inaccessible due to mutilation, cartilage 
deformation, perforation by wearing earrings or other artifacts that make it impossible 
to apply the auricular technique in the specific point. 
 
STUDY SITE 
 
The research will be conducted at the Clinical Schools of the University of 
Southern Santa Catarina (UNISUL), Cruzeiro do Sul University (UNICSUL), and 
Cidade de São Paulo University (UNICID). 
 
PRIMARY OUTCOME: 
 
The primary outcome will be the proportion of participants who show 
improvement of 50% or more in depressive symptoms, as evaluated by the PHQ-9, 
three months after inclusion. A follow-up score at 3 months demonstrating 50% 
improvement from baseline is considered successful or remission of symptoms. 
 
SECONDARY OUTCOMES: 
 
The study's secondary outcomes will be included to enrich the understanding 
of the primary outcome through a series of exploratory analyses, although the study 
was not designed to answer these scientific questions: 
The proportion of participants who show improvement of 50% or more in 
depressive symptoms, in each treatment group, as evaluated by the PHQ-9, six 
months after inclusion; 
Serum levels of BDNF, Interleukin 1β, Interleukin-6, and TNF-α, assessed at 
the beginning and end of auricular acupuncture applications (end of the sixth week of 
application); 
Quality of life levels evaluated by the SF-36, sleep quality (PSQI), anxiety 
(IDATE) at the beginning, end of the sixth week of auricular acupuncture application, 
three and six months after inclusion; 
Adverse events measured by the PHQ-9 and adverse effects; 
Changes in medication (antidepressants, anxiolytics). 

 
 
 
 
MATERIALS: 
 
The materials used in the research will be: Patient Health Questionnaire - 
PHQ-9; Short Form Health Survey Questionnaire (SF 36); adverse effects 
questionnaire; Safety Monitoring Instrument S-RAP; Material for blood collection, 
disposable and semi-permanent auricular acupuncture needles, micropore, 70° 
alcohol, cotton, tweezers, electronic auricular point locator. 
 
DATA COLLECTION INSTRUMENTS 
 
Blood Collection 
 
BDNF, Interleukin-1β, Interleukin-6, and TNF-α will be analyzed through blood 
plasma in the first and last session (twelfth), collected in the morning. The study 
participant will remain seated for 30 minutes before collection. Blood (4ml) will be 
collected in tubes with the anticoagulant EDTA, and after 15 minutes, the tube will be 
placed on ice and subsequently centrifuged for 20 minutes at a rotation of 3,000 rpm 
and a temperature of 8°C. The plasma will be separated, and 300 microliters will be 
pipetted into eppendorf and stored at a temperature of -80°C for later analysis of 
plasma levels. The markers will be evaluated by the ELISA method. 
 
Evaluation of Depression Levels 
 
The Patient Health Questionnaire - PHQ-9 (SANTOS et al., 2013) will be used 
to assess depression levels. It is a self-assessment instrument used worldwide. The 
PHQ-9 is a brief, validated instrument widely used in clinical research and sensitive 
to changes over time (LOWE et al., 2004; ELL et al., 2007). 
The PHQ-9 consists of nine questions that evaluate the presence of each 
major depression symptom according to the DSM-IV. The frequency of each 
symptom in the last two weeks is evaluated on a Likert scale of 0 to 3 points, 
corresponding to the answers "not at all," "several days," "more than half the days," 
and "nearly every day," respectively. The questionnaire also includes a tenth 

 
 
 
question that assesses the interference of these symptoms in the performance of 
daily activities, such as working and studying (SANTOS et al., 2013). 
The distribution of scores ranges from 0 to 27 points, classified according to 
diagnostic levels of depression: absence of depression (0-4), mild symptoms (5-9), 
moderate symptoms (10-19), and severe symptoms (20-27) (LOWE et al., 2004; 
KROENKE; SPITZER; WILLIAMS, 2001). A PHQ-9 score of <10 is considered 
"recovered," since scores ≥ 10 are considered for a depression treatment plan. 
 
Evaluation of Adverse Events and Effects 
 
In this study, adverse events include: a) worsening of depressive symptoms, 
measured by the PHQ-9; b) appearance of suicidal ideation or self-injury, as 
evaluated by the S-RAP. 
Interviewers may identify severely depressed or suicidal individuals during 
data collection, and specific actions to deal with these situations are included in the 
protocol. The PHQ-9 and S-RAP scores obtained will be analyzed by the research 
supervisor immediately after the evaluators collect the information. After identifying a 
participant at risk at any time during the study, a consultation with a psychiatrist 
researcher from the study will be scheduled for treatment of these symptoms, as well 
as an indication to seek treatment at the Psychology and Naturology School Clinic at 
the University. 
Any worsening of depressive symptoms may not be related to the study itself. 
Considering that the proposed intervention is to reduce depressive symptoms, it is 
very unlikely to be associated with an increase in depression. According to a 
systematic review of clinical studies involving acupuncture and auricular acupuncture 
in depression, included studies confirm safety for depression treatment (SMITH et al., 
2018). However, it is possible that depression may increase despite the intervention, 
and that is why routine evaluation of depressive symptoms and suicidal ideation 
throughout the intervention is necessary. This is related to the safety and monitoring 
plan to avoid inadvertent worsening of their conditions. 
For the evaluation of adverse effects of auricular acupuncture, a questionnaire 
developed specifically for this study will be used in all sessions by the auricular 
acupuncture practitioners. 

 
 
 
Quality of Life Assessment 
 
The Short Form Health Survey Questionnaire (SF-36) is a generic measure of 
quality of life that is highly sensitive to individual improvement. It consists of 36 items, 
of which 35 are grouped into eight dimensions (physical functioning, pain, physical 
role functioning, emotional role functioning, social role functioning, mental health, 
vitality, and general health perceptions), while the last item evaluates changes in 
health over time in order to examine the participant's perception of their own health 
status. The higher the score, the better the individual's quality of life. Therefore, 
changes in quality of life can be assessed by a higher or lower score on the 
questionnaire resulting from certain treatments and assistance programs for groups 
of individuals with various health conditions. For each dimension, SF-36 items are 
coded, grouped, and transformed into a scale from zero (worst health state) to 100 
(best health state). The questionnaire has been translated into Portuguese and 
adapted to the Brazilian culture (CICONELLI et al., 1997). 
 
Sleep Quality Assessment 
 
The Pittsburgh Sleep Quality Index (PSQI) questionnaire will be used to 
evaluate the levels of sleep disturbances. The Portuguese-translated version of the 
questionnaire, without changes from the original version, will be utilized and validated 
by Bertolazi et al. (2011). The questionnaire contains 19 questions about sleep 
quality and disturbances over the last month, assessing seven components of sleep: 
subjective quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances, 
use of sleep medications, and daytime dysfunction. The score for each component 
ranges from 0 to 3, with a maximum score of 21 points (BERTOLAZI et al., 2011). 
The score ranges from 0 to 3, with 0 indicating "no difficulty" and 3 indicating "severe 
difficulty." The scores will be added to form a global value ranging from 0 to 21. 
Scores of 0-4 indicate good sleep quality, scores of 5-10 indicate poor quality, and 
scores above 10 indicate possible sleep disorders (LOURENÇO et al., 2012). 
 
Anxiety Assessment 
 

 
 
 
The IDATE questionnaire is an instrument for classifying individuals according 
to their level of anxiety. It has two stages, the State Anxiety and Trait Anxiety. 
Classification is based on the score, which ranges from 20 to 34 (low), 35 to 45 
(moderate); 50 to 64 (high) and 65 to 80 (very high). The questionnaire was translate 
and validated for use in Brazil (BIAGGIO; NATALÍCIO; SPIELBERGER, 1977).  
 
Participant Perception 
 
Qualitative data will be collected through a semi-structured interview, which 
will be recorded and fully transcribed. For data analysis, the thematic content 
analysis technique systematized by Minayo (2014) will be used. For the qualitative 
data, 20 participants from each group will be randomly selected for analysis. 
 
VARIABLES 
 
There may be differences in the results among the participants of the study 
due to factors such as: 
 
Independent variable 
 
a) Experimental group (specific auricular acupuncture and usual care), control 
group (non-specific auricular acupuncture and usual care). 
 
Dependent variables 
 
a) Depression levels; 
b) BDNF levels; 
c) Interleukin-1β levels; 
d) Interleukin-6 levels; 
e) TNF-α levels; 
f) Quality of life levels; 
g) Sleep quality levels; 
h) Anxiety levels; 

 
 
 
i) Adverse effects; 
j) Change in medication; 
k) Participant perception. 
 
Control variables 
 
a) Medication; 
b) Usual care. 
 
PROCEDURES 
 
The implementation of the present project will take place after approval by the 
Ethics and Research Committee of the School of Medicine at USP and related 
committees, subject to the availability of participants and researchers. Initially, 
potential participants will be instructed about the research objectives, as well as the 
respective ethical implications, through the Informed Consent Form. Then, a 
questionnaire will be administered to collect demographic, socioeconomic, health, 
and behavioral variables to determine eligibility according to inclusion and exclusion 
criteria. The PHQ-9 will be used to identify participants with symptoms of depression, 
and the SF-26 will be used to evaluate quality of life, sleep quality (PSQI), and 
anxiety levels (IDATE). All these instruments will be administered via tablets by 
researchers through the REDCap platform. 
Study assessors will be trained to approach participants in the exact same 
manner to avoid recruitment biases. The study will have a protocol of questions to be 
used in all phases: pre-screening, screening, data collection, and protocol 
application. After randomization, blood collection will occur for all participants in the 
morning. Participants with severe depression (PHQ≥20) or suicidal ideation will not 
be included in the study and will be followed up by a psychiatrist researcher from the 
study and referred to the university's Psychology and Naturology clinic for treatment. 
Auricular acupuncture sessions will take place twice a week for 15 minutes in 
a private and confidential consultation room reserved for the research, subject to the 
availability of participants and researchers, for 6 weeks. The experimental group will 
consist of a protocol of points chosen according to the diagnosis of depression by 

 
 
 
TCM. Six pre-established points will be used in all participants: Shen men, Sub-
cortex, Heart, Lung, Liver, and Kidney (FOCKS, 2005; XIAOAI; BEI; JING, 2015; 
LIANG, et al., 2014). 
International literature recognizes the difficulty in establishing protocols to be 
used as a control due to the high responsiveness and innervation of the auricular 
pavilion (PRADO, 2014). Therefore, the control group (auricular acupuncture - non-
specific points) was chosen based on a previous protocol. The external ear and 
cheek/face area points (PRADO, 2014), and four non-specific points in the helix 
region (ZHONG, et al., 2016) will be used. 
The first application will be performed on the right auricular pavilion of the 
participants, and subsequent sessions will alternate ears with each application. 
Participants will be instructed to keep the needles in and to stimulate the points 
manually for 30 seconds, three times a day (morning, afternoon, and night), every 
day. The research applicators will remove the needles applied in the previous 
session and apply them to the same points on the other auricular pavilion, ensuring 
constant stimulation of the free nerve endings. The research applicators will instruct 
the participants to manually stimulate each point for 30 seconds, three times a day 
(morning, afternoon, and night), every day. 
All participants will respond to the PHQ-9, SF-36, and S-RAP questionnaires 
again in the fourth and sixth week of the study, after three and six months from the 
beginning of the study. Blood collections will take place at the beginning of the study 
and at the end of the application of the protocols so that analyses and comparisons 
of the participants' symptom evolution can be made. 
In the final evaluation (6 months), each participant from the experimental 
(auricular acupuncture) and control group (non-specific auricular acupuncture) will be 
asked about which group they believed they were participating in, to evaluate the 
influence of this bias and whether the protocol applicator informed them of their 
group allocation. If it is found that the participant was not blinded or had access to 
other therapies, they will be classified as non-responders and excluded from the final 
analysis. 
To ensure the blinding of evaluators, the protocol applicators will remove the 
needles from the participants' auricular pavilions prior to the data collection 
interviews. In addition to this procedure, study participants will be instructed not to 

 
 
 
provide information about auricular acupuncture to the evaluators, thus avoiding 
unmasking the intervention. Evaluators will also be trained to avoid this bias. 
The study protocol applicators will not be aware of the participants' levels of 
depression, quality of life, sleep quality, and anxiety. During the application, 
communication with participants will be limited to the necessary explanations about 
the study to avoid possible biases through suggestive observations. These 
researchers will be trained to avoid this type of interference. Professionals with 
specific training in the area and a minimum of three years of experience will be 
selected. 
At the end of the research, control group participants will be invited to receive 
the same care protocol as the auricular acupuncture group if this protocol proves to 
be effective, without any cost to them, ensuring ethical principles of justice and 
equity. 
This study will follow the criteria of good clinical practice according to the "The 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use" of the International Conference on 
Harmonisation 
(ICH), 
including 
independent 
regular 
monitoring 
and 
the 
establishment of an independent data monitoring and safety committee. In addition to 
these guidelines, the ethical principles advocated in the Helsinki Declaration and 
National Health Council resolutions related to research ethics, especially CNS 
Resolution 466/2012, will be followed. 
 
Human resources 
 
The research will involve the participation of eight researchers: research 
supervisor (responsible for the training of evaluators and applicators and for 
monitoring events and adverse effects); research assistant (responsible for 
participant follow-up, scheduling, and follow-up); two evaluators (responsible for 
instrument application and blood collection); two applicators (responsible for protocol 
application); psychiatrist (responsible for the follow-up of participants at risk or with 
severe depression); statistician (responsible for randomization, allocation, and data 
analysis). 
 

 
 
 
ADHERENCE AND FOLLOW-UP 
 
Participants who do not return after the data collection instrument evaluations 
will be considered non-adherent to the study. Two non-consecutive absences during 
treatment sessions will be permitted, as the literature recommends weekly 
applications of auricular acupuncture (DAL MAS, 2004). Participants who do not 
return for evaluations will be considered lost to follow-up. 
To ensure study retention, researchers will involve course coordinators and 
instructors to support the implementation of the study during class periods and the 
release of university students for data collection and auricular acupuncture protocols. 
 
DATA ANALYSIS 
 
The study data will be analyzed using Stata 14 software. The data analysis will 
be performed according to the CONSORT guidelines, primary analysis with intention-
to-treat, emphasizing 
confidence intervals for between-group comparisons. 
Descriptive statistics will be used to determine any imbalances between the groups 
at baseline. A similar analysis, adjusting for baseline PHQ-9 scores and any 
observed imbalances between groups of possible predictor variables, will also be 
performed. Other secondary analyses will compare individuals according to the 
intervention received, accounting for any selection after random allocation. These 
analyses using mean comparisons will employ instrumental variable regression 
models. We will perform an exploratory subgroup analysis to investigate who benefits 
most from this intervention, but these analyses will be interpreted with caution 
because statistical power will be limited for interaction effects. 
 
ETHICAL CONSIDERATIONS 
 
For this research, the recommendations of Resolution n° 466/12 of the 
National Health Council (CNS) are adopted, as the study involves the participation of 
human subjects. Participants will be provided with one of two copies of the Informed 
Consent Form to ensure compliance with the ethical principles outlined in Resolution 
n° 466/12. 

 
 
 
 
In addition, this research project ensures the confidentiality and anonymity of 
the participants, the return of research results to subjects and society, and access to 
research results by the public. The researchers declare no conflicts of interest related 
to the study's outcomes. The research project will be submitted to the Research 
Ethics Committee (CEP) of the University of Sao Paulo School of Medicine for 
evaluation. Once approved by the CEP, data collection will begin. Data will be 
collected only after approval and will be stored for five years before being discarded. 
Participants with severe depression or suicidal ideation will not participate in 
the study due to the severity of their symptoms. These participants will be 
accompanied and medicated by a psychiatrist and researcher from the study 
according to their needs, in addition to being referred to the Psychology Clinic for 
psychological treatment and the Naturology Clinic at the University for 
complementary treatment. 
If the treatment group's effects are clinically significant when compared to 
control groups I and II, the researchers will make the auricular acupuncture protocol 
available to interested participants. 
 
On the risk-benefit balance: 
 
Understanding that, according to Resolution CNS 466/12, all research with 
human beings involves risks of varying types and degrees, this research foresees 
minimal risks, but we will anticipate some circumstances in which they may appear. 
During the recruitment phase, the screening process using the PHQ-9 
questionnaire may be disturbing to some participants. The nature of the questions 
may induce certain emotional feelings, including sadness or crying. Others may worry 
about the PHQ-9 results, which suggest the presence of depressive symptoms or the 
need for other specialized care. We will train all research evaluators in ways to 
minimize these feelings and how to handle these situations. 
From screening to any follow-up contacts, researchers may encounter 
severely depressed, suicidal, or otherwise severely mentally ill individuals. These 
participants will be excluded from the study analysis and referred to a psychiatrist 
who will take necessary measures according to each case. 

 
 
 
Some participants may be concerned about the confidentiality of their data, 
particularly in relation to the possible exposure of opinions that could be 
embarrassing to peers. To minimize risks such as this, precautions will be taken to 
maintain confidentiality and anonymity. 
The other minimal risks relate to minor discomforts associated with auricular 
acupuncture, such as painful sensations at the auricular point and the possible 
emergence of some other physical or emotional reaction resulting from the 
technique, or some physical discomfort with blood collection. Although researchers 
may not be able to identify other risks, if they are identifiable, they will be controlled. 
In terms of benefits, the research procedures during the recruitment phase will 
identify patients with depression and possibly at risk for suicide who would not have 
been identified otherwise, ensuring specialized care for severe depression or suicidal 
ideation or a millenary treatment for participants in the experimental group. It is 
intended to prove the effects of a technique that has been used for millennia, and if 
the effects are positive, this technique could provide well-being to people suffering 
from depression and similar disorders. 
This study will test a simple, inexpensive, non-pharmaceutical, and easy-to-
apply intervention for depression. Therefore, it has the potential to generate 
significant gains in public health in terms of improving access to complementary 
treatments and reducing the treatment gap for depressive disorders. The knowledge 
acquired may be essential in influencing the agenda of collective and mental health 
policies in Brazil. 
Furthermore, the study results will be made available to participants by email 
or in the manner the participant chooses, after completion of the study. 
Thus, this research is justified in its risk-benefit balance, as the potential 
benefits outweigh the possible risks. Since auricular acupuncture is widely used 
worldwide, considered a technique that is easy to apply, low-cost, and with minimal 
side effects. 
 
On the process of free and informed consent: 
 
In order to ensure proper respect and human dignity, this study provides for a 
process of free and informed consent. Therefore, the participants will be contacted by 

 
 
 
the researchers, either in person or by telephone, to invite them to participate in the 
research. The best time, condition, and location suitable for the participant's privacy, 
as determined by the participant, will be identified. Sufficient time will be provided for 
reading, understanding, and reflection. The informed consent form will be drafted in a 
clear and accessible language for the participants, which must be read and 
understood before granting their free and informed consent. Only after signing the 
informed consent form will the questionnaires be provided. The completed 
questionnaires will be placed in a paper envelope, and only the researchers of this 
study will have access to the data. 
 
On the Informed Consent Form: 
 
All recommendations of Resolution CNS 466/12 will be followed in drafting this 
form. It will be prepared in duplicate, with both copies signed by the researchers and 
participants, and the participant will retain the 2nd copy with the respective protocol 
number. The informed consent form will also include contact information for the 
researchers, CEP-USP, and participating centers. 

 
 
 
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