Comparison of effects and brain imaging mechanisms of acupuncture and paroxetine for depressive patients with suicidal ideation: study protocol of a 20-week clinical trial

Comparison of effects and brain imaging mechanisms of acupuncture and paroxetine for depressive patients with suicidal ideation: study protocol of a 20-week clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Comparison of effects and brain imaging mechanisms of acupuncture and paroxetine for depressive patients with suicidal ideation: study protocol of a 20-week clinical trial Qifu Li, Yi Lu, Jinbo Sun, Gaoyangzi Huang, Yi Gong, Bingkui Zhang, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2409325/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Suicide is a devastating and major medical and social problem, and effective management of depression with suicidal ideation (DWSI) is of significant importance in reducing suicide rates. Acupuncture has been less studied in DWSI, and its central mechanisms have not been elucidated. This study aims to carry out a clinical trial using multimodal brain imaging techniques to investigate the mechanism of brain network regulation of DWSI by acupuncture. Method A total of 70 patients with DWSI and 30 healthy subjects will be recruited for this study. This trial will include a 1-week baseline phase, a 12-week treatment phase, and a 8-week follow-up phase. Patients in the acupuncture group will receive 36 sessions of acupuncture, 3 times a week for 12 weeks. Patientsin the paroxetine control group will receive paroxetine 10 mg per day (week 1), 20 mg per day (weeks 2); and 30 mg per day (weeks 3-12). The primary outcomes are the mean change in the Hamilton Depression Rating Scale-24 scores and the Beck scale for suicide ideation. The secondary outcomes include the Depression Self-Rating Scale, Clinical Global ImpressionsScale, Asberg Antidepressant side effect scale and World Health Organization Quality of Life Questionaire abbreviated version. Magnetic resonance imaging data will be collected from each participant at baseline and each patient at the end of treatment. Conclusions This study hypothesised that acupuncture therapy could treat DWSI by restoring the pathological center of suicidal ideation in brain. This study will clarify the mechanism of brain network regulation of DWSI by acupuncture. Trial registration number ChiCTR2200059267, registered on April 7, 2022. suicidal ideation depression acupuncture paroxetine multimodal magnetic resonance imaging central mechanism study protocol Figures Figure 1 Figure 2 Background Suicide is an action to end one’s own life by self-selection and occurs in all areas and throughout the life cycle. According to the World Health Organization (WHO), more than 800,000 people die by suicide each year worldwide, with one suicide occurring every 40 seconds and more than 20 attempted suicides for every death by suicide [1] . There is no single explanation for why someone dies by suicide, which is a complex behavior caused by a combination of personal, social, psychological, cultural, biological and environmental factors, with devastating and profoundly damaging effects on families, friends and communities, and is a major medical and social problem worldwide [1] . The Mental Health Action Plan (2013-2020), directed by WHO, recommends that countries should aim for a 10% reduction in suicide rates [2] . The key to reducing suicide rates lies in effective interventions for patients with suicidal ideation. Depression, especially major depressive disorder (MDD), is the main psychological manifestation preceding suicidal behavior and is an important risk factor for suicide [3] . Effectively treating patients with depression with suicidal ideation (DWSI) is an effective means of reducing the rate of suicide. According to the WHO. [2] Depression affects approximately 322 million people worldwide, with 4.4% of the world’s population suffering from depression in 2015. An European psychiatric study showed that 10.92% of people with psychiatric abnormalities had major depression and 60.39% of them were at risk of suicide [4] . In China, patients with MDD also show a high incidence of suicidal ideation [5, 6] . Effective treatment of patients with DWSI is an effective means of reducing suicide rates and has been a focus of current clinical research. Suicidal ideation is associated with malfunctioning of emotional control due to negative depressive emotions, and the regulation of depressive and ideational emotions in patients with DWSI so that they can normalize their emotional control is the key to treatment [7, 8] . Some studies have used repetitive transcranial magnetic stimulation to treat DWSI showing some efficacy, but no consensus has been reached [9, 10] . There is no published guideline for the treatment of patients with DWSI specifically and the main focus is on the treatment of depression. The current treatment of depression is mainly based on medication and psychotherapy, however only 50%-70% of those who complete the full course of treatment achieve remission, and about 30%-40% of patients with major depression have poor outcomes, and considering side effects and other factors, more and more patients are turning to acupuncture for treatment [11-13] . Studies have shown that acupuncture has better overall clinical efficacy in the treatment of depression, with mild and transient adverse effects, and can enhance emotional control and effectively prevent suicidal ideation [12, 14, 15] . Our team’s previous study also showed that acupuncture significantly reduced the Hamilton Depression Rating Scale (HAMD) and Beck suicidal ideation scores in patients with DWSI [16] . Despite the current lack of high-quality evidence, acupuncture is recommended by many national guidelines for the management and treatment of depression [11, 17] . Because of the widespread use of acupuncture, an increasing number of scholars have begun to focus on the elaboration of its central mechanisms. Studies have shown that acupuncture can modulate the structure and function of depression-related pathological centers [18] . However, the central mechanisms of acupuncture on DWSI are still in the exploration stage. Therefore, this study aims to carry out a clinical trial using multimodal brain imaging techniques to (1) confirm the clinical efficacy of acupuncture versus paroxetine in the treatment of patients with DWSI; (2) reveal the changes in brain structure and function in patients with DWSI, and clarify the correlation between the clinical efficacy of acupuncture and paroxetine on DWSI and the structural and functional changes in brain function; (3) investigate the mechanism of brain network regulation of DWSI by acupuncture. Here, we describe the protocol for this study. Method This trial will be reported in accordance with the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines [19] (Supplementary material) and will follow the Consolidated Standards of Reporting Trials (CONSORT) [20] and the Standards for Reporting Interventions in Clinical Trials of Acupuncture principles (STRICTA) [21] . The protocol was approved by the Ethics Committee of Kunming Psychiatry Hospital (approval no. 2022LLSC01) (Supplementary material) and is registered with the Chinese Clinical Trial Registry (registration no. ChiCTR2200059267). Study design and setting Te research will be carried out in two Yunnan-area hospitals: the Second Affiliated Hospital of Yunnan University of Traditional Chinese Medicine and Kunming Psychiatry Hospital. This non-randomised clinical trial will enroll 72 patients with DWSI and 30 healthy subjects. The study will last 20 weeks. For patients with DWSI, this will be followed by a 12-week treatment period and an 8-week follow-up period. The enrollment schedules, interventions, and assessments are summarised in Table 1. Relevant assessment scales and multimodalMRI scans will be performed at baseline. Clinical outcomes will be evaluated after treatment and during the follow-up. A study flowchart is presented in Figure 1. Recruitment and informed consent All patients with DWSI and healthy subjects will be recruited from outpatient and inpatient psychiatric departments of the Affiliated Hospital of Yunnan University of Traditional Chinese Medicine and Kunming Psychiatry Hospital or the community. Qualified psychiatrists will strictly follow the inclusion and exclusion criteria to determine whether patients are eligible for this study. To promote the recruitment, recruitment advertisements will be designed to recruit patients online or offline (e.g. WeChat public account, website). All participants will be explained the purpose and nature of this study protocol and will be fully informed about the study, including the study procedures, benefits and potential risks. They will voluntarily sign an informed consent form before enrolment. Patients with DWSI will need to be accompanied by their family members at all times during each visit. All participants will be able to withdraw from the study at any time without penalty or loss of benefit, and without giving a reason. The reason for withdrawal will be recorded. Participants 70 patients with DWSI and 30 healthy subjects will be recruited for this study. Inclusion criteria for patients with DWSI are as follows: (1) right handed, Han nationality, length of education ≥ 6 years; (2) aged 35-55 years; (3) meet the diagnostic criteria for DSM-V of depression; (4) Hamilton Depression Scale -24 items(HAND-24)score≥20; (5) Beck Suicidal Ideation Scale rated as positive; (6) suicidal ideation only, no experience of self-injury or suicidal behavior; (7) signed the informed consent form and accompanied by family members throughout the study period. Exclusion criteria were as follows: (1) with bidirectional depression and other psychiatric disorders in the DSM-V diagnosis; (2) a history of self-injurious or suicidal behaviour; (3) severe depression with unstable emotion and abnormal behaviour with difficulty in cooperating with the assessment; (4) serious primary diseases such as cardiovascular system, liver, kidney and hematopoietic system; (5) chronic pain (such as migraine, women with dysmenorrhea); (6) pregnancy, lactation, or plans to become pregnant within 1 year; (7) brain with definite organic lesions or severe asymmetry between the right and left side of the cranial structure; (8) nuclear magnetic contraindications (such as metal implant, vascular stents, cardiac pacemakers, false tooth, claustrophobia, etc.); (9) has received acupuncture treatment within 6 months; (10) has taken antidepressant or other psychotropic drugs within 6 months and with drug dependence; (11) transsexual, homosexuality, abnormal sexual orientation, special fetishes, alcohol addict, etc; (12) participation in a similar study in the last 3 months. Inclusion criteria for healthy subjects are as follows: (1) right handed, Han nationality, length of education ≥ 6 years (2) aged 35-55 years; (3) no history of any neurological or psychiatric disorders and family history of genetic disorders, with a HAMD-17 score <7; (4) no physical abnormalities during the trial period(e.g. flu, fever, etc.); (5) no drugs or alcohol for at least 2 days before participation in the trial, and no stimulant drug use for at least 1 month; (6) signed the informed consent form. Healthy subjects will be excluded if they meet the following criteria: (1) serious primary diseases such as cardiovascular system, brain, liver, kidney, hematopoietic system, mental disease and obvious cognitive dysfunction; (2) chronic pain (such as migraine, women with dysmenorrhea); (3) women during pregnancy and lactation; (4) brain with definite organic lesions or severe asymmetry between the right and left side of the cranial structure; (5) nuclear magnetic contraindications (such as metal implant, vascular stents, cardiac pacemakers, false tooth, claustrophobia, etc.); (6) has received acupuncture treatment within 6 months; (7) transsexual, homosexuality, abnormal sexual orientation, special fetishes, alcohol or drug abuse, etc. Blinding The trial is not randomised and the intervention is chosen according to the patient’s wishes, so it cannot be blinded to the patients and operators. This trial follows the principle of separation of researchers, evaluators, and statistical analysts. Description of intervention Acupuncture group Patients in this group will receive acupuncture treatment [16] . The prescriptions of acupuncture consist of (i) eight methods of LingGui: bilateral SP4 (Gongsun), bilateral PC6 (Neiguan), bilateral LU7 (Lieque), bilateral KI6 (Zhaohai), bilateral GB41(Zulinqi), bilateral TE5 (Waiguan), bilateral BL62 (Shenmai), bilateral SI3 (Houxi), (ii) regulating the qi of the internal organs: bilateral BL15 (Xinshu), bilateral BL18 (Ganshu), bilateral BL23 (Shenshu); (iii) regulating Yuan qi: bilateral KI3 (Taixi), bilateral ST25 (Tianshu), CV4 (Guanyuan), CV6 (Qihai), CV12 (Zhongwan), bilateral ST36 (Zusanli); (iv) soothing liver and regulating the spirit: bilateral HT7 (Shenmen), GV20 (Baihui), bilateral LR3 (Taichong). The positioning of acupoints will be determined according to the standards issued by the World Health Organization in 2010 [22] . Locations of the acupoints are presented in Table 2 and Figure 2. The acupuncture procedure is as follows: after skin disinfection, needles (0.25mm diameter × 25mm; Hua Tuo, Suzhou, China) will be inserted vertically or horizontally into each acupoint. All acupoints are inserted quickly, without hand-manipulating of needles, and no special requirements for needle sensations such as soreness, numbness, swelling and heaviness. The patients will be asked to sit on the treatment bed, and the group of acupoints for regulating the qi of the internal organs will be needled first, both with the needle handle upwards and the needle tip downwards in a flat stab, holding the patient’s shoulder back with one hand and the waist with the other, so that the patient’s legs are stretched out and slowly lie flat; Then select the opening acupoints of the eight methods of LingGui according to the time of needling (the eight acupoints are divided into four groups of acupoints, one of which) (online supplementary file); Finally, the acupoints of regulating Yuanqi and soothing liver and regulating the spirit will be performed. If the LingGui opening point is met with the SI3 (Houxi), HT 7 (Shenmen) is performed using acupuncture upward and flat, then the patient’s palm is pressed downward against the needle and SI3 (Houxi) will then be needled. The thermal design power lamp will be used to irradiate around KI 3 (Taixi) and CV 4 (Guanyuan) respectively, and the needle will be retained for 40min. During this period, the patient will be instructed to relax, close the eyes and breathe calmly and no hand-manipulating of needles. Patients will receive 36 sessions of acupuncture, 3 times a week for 12 weeks. All acupuncture operations will be performed by two trained and licensed acupuncturists. Follow-up visits were conducted every 4 weeks for the duration of the study. Paroxetine C ontrol G roup Patients in this group will receive daily early morning oral doses of paroxetine 10 mg per day (week 1), 20 mg per day (week 2); and 30 mg per day (weeks 3-12) [23, 24] . Follow-up visits will be every 4 weeks for the first 8 weeks of treatment and every 2 weeks for the remainder of the study. Each follow-up assessment included measures of efficacy, safety and adherence [23, 24] . Healthy Control Group Healthy subjects will not receive any treatment during the trial. Brain imaging data will be acquired only once. Throughout the study period, patients in both groups can be given the same type of medication as paroxetine for emergency treatment on the advice of the psychiatrist if their symptoms worsen acutely and do not resolve on their own, and detailed records will be kept. Multimodal Data Acquisition Multimodal data will be acquired within 1 week prior to treatment and within 1 week after 12 weeks of treatment. Magnetic Resonance Scanner (GE Discovery 750; Milwaukee, WI, USA) with a 16-channel phased array head coil at the Department of Radiology, the First Affiliated Hospital of Kunming Medical. Participants will be asked to lie in a supine position on an examination bed in a supine position, awake, keeping their heads still. Their head will be held still and their eyes will be closed and their ears plugged during the scan. Participants in both the acupuncture and drug control groups will be scanned at baseline and within one week of treatment, and healthy controls will be scanned after recruitment. Considering the possibility of changes related to the menstrual cycle, female participants will be obtained before or outside of their menstrual period. Firstly, three-dimensional T1-weighted (3D-T1) imaging will be obtained for each participant with high-resolution structural images with a voxel size of 1 mm3 using Repetition Time [TR], 6.008 ms; echo Time [TE], 1.7 ms; field of View [FOV], 256 × 256 mm2; Data Matrix. 256 × 256) [25, 26] . Second, a T2∗weighted gradient echo (GE) blood oxygen level dependent (BOLD) sequence (TR/TE = 2,420/30 ms, slice thickness = 3.0 mm, slice number = 44, field of view = 192 × 192 mm, flip angle = 90◦, matrix size = 64 × 64) will be recorded to obtain functional magnetic resonance imaging (fMRI) data [26] . Third, to detect any white matter abnormalities, diffusion tensor imaging (DTI) will be used to detect white matter abnormalities. Tensor imaging will be performed with the following parameters: TR, 8500 ms; TE, 84 ms; data matrix, 128 × 128; FOV, 256 × 256 mm2; slice thickness, 2 mm; 78 consecutive axial slices without gaps. Two diffusion-weighted sequences will be obtained, using gradient values b = 0 s/mm2 and 1,000 s/mm2 with a diffusion-sensitizing gradient and 64 nonlinear orientations [25, 26] . If the subject complains of discomfort, the scan will be terminated. A specialist staff member will examine the images qualitatively to detect any brain lesions or structural abnormalities. Sample size There is no acknowledged standard for estimating the sample size of acupuncture modulation of the functional brain network. According to the requirements of the brain functional network analysis technique [27] , a recommended sample size of 30 cases per group could achieve a relatively stable reproducibility. We planned to include 30 cases, 35 cases per group based on a 16% loss rate, and no loss in the healthy subjects group, for a total of 70 DWSI patients and 30 healthy subjects. Outcome Clinical Outcomes Data acquisition will be performed by independent assessors who have received professional training before the start of the study. The primary efficacy outcomes are the mean change in the HAMD-24 scores and the Beck scale for suicide ideation-Chinese version (BSI-CV) from baseline to week 20. The secondary outcomes are the mean change as follows from week 0 to week 20: (1) Depression Self-Rating Scale (SDS); (2) Clinical Global Impressions (CGI) Scale; (3) Asberg Antidepressant side effect scale (ASES); (4) World Health Organization Quality-of-Life Scale-Short Form (WHOQOL-BREF). The HAMD-24 is a questionnaire used to provide an indication of depression in adults and to evaluate recovery and remission, which includes 7 factors: anxiety/somatization, weight, cognitive impairment, day-night variability, retardation, sleep disturbance, and feelings of hopelessness. The higher the total score, the more severe the depression [28] . The BSI-CV is a self-assessment scale that can be used to quantify and assess suicidal ideation in depression, both in the last 1 week and at its most severe. It consists of 19 items, the higher the score, the stronger the suicidal ideation and the higher the risk of suicide [29] . The SDS scale includes 20 entries divided into four grade ratings according to the frequency of depression status in the past 7 days. The higher the total score, the higher the recorded level of depression [30] . The CGI Scale is an overall scale for assessing clinical outcomes, primarily for determining overall severity of illness and its change [31] . The ASES will be applied to assess the adverse effects of paroxetine. The WHOQOL-BREF is an international scale developed by the World Health Organization to measure the health-related quality of life of individuals [32] . MRI data In this study, the original data was first converted to Nifit format by using the Dcm2nii software in the Micron software package. Then, the PANDA toolbox [33] (http://www.nitrc.org/projects/panda/), an integrated toolbox, is used to preprocess the DTI data and construct the brain structural networks. Besides, network properties analysis was performed using the GRETNA toolbox [34] (www.nitrc.org /projects/gretna) and visualised by using the BrainNet Viewer toolbox [35] (www.nitrc.org / projects/bnv). Structural Network construction For Network Construction, we used a MATLAB-based open-source software PANDA [33] . Nodes and edges are the two fundamental elements of a network. In this study, we constructed a structural network using the following procedures: (1) removing the basal ganglia regions of the automated anatomical labeling 116 templates [36] to make template A; (2) the atlasing of the basal ganglia [37, 38] , including striatum, external globus pallidus, globu pallidus internal, red nucleus, substantia nigra, and subthalamic nucleus were assembled, and the overlapped parts were removed to make template B; (3) adding template A and template B, numbering each brain region. Finally, we got a brain template containing 124 brain regions. Individual T1-weighted images were co-registered to b0 images in DTI native space using an affine transformation. The converted T1 images were normalised to a T1 template in MNI space through nonlinear transformation. The 124-region template was used to distort the MNI space into the DTI native space through inverse transformation. Then diffusion MRI tractography was performed, and all tracts in the DTI dataset were computed by seeding each voxel with fractional anisotropy (FA) > 0.2. The tractography was terminated if it turned an angle >45 degrees or reached a voxel with an FA < 0.2. As a result, all fiber pathways between the 124 ROIs in the brain were constructed using the deterministic tractography method. For each pair of ROIs i and j , we defined the number of connected fiber number (FN) with two endpoints located in these two regions as the weight of the edge between ROIs i and j . For each participant, edge volumes were calculated and normalised by whole-brain white matter volume. Therefore, for each participant, an FN-weighted 124×124 structural connectivity matrix was constructed. FA-weighted structural connectivity matrix was constructed in the same way. DTI data preprocessing Briefly, the preprocessing procedure included skull-stripping, eddy-current and head-motion correction, FA calculation and whole-brain deterministic DTI fiber tractography [39] . In this preprocess, FA was calculated. Besides, Whole-brain fiber tractography was reconstructed by seeding at every voxel in the brain and using fiber assignment by continuous tracking (FACT) algorithm [40] . This algorithm computes fiber trajectories starting from the deep (white matter) WM regions and terminating at a voxel with a turning angle greater than 45° or reaching a voxel with FA less than 0.15. Different analytical methods will be used in the trial, including axial diffusivity (AD), FA, mean diffusivity (MD), and radial diffusivity (RD). These indices could be used to assess the cerebral structure’s integrity and connection [41] . Graph theoretical analysis of structural brain networks In this study, we mainly calculate global network characteristics and local network characteristics to better characterize the brain structural network topology changes, by using graph theoretical analysis [42] . The global network characteristics include clustering coefficient (C p ), characteristic path length (L p ) and “small-world” network attributes( σ ), global efficiency (E glob ), and local efficiency (E loc ); and local network parameters mainly include node efficiency (E nodal ). Clinical data analysis Clinical outcomes will be analysed using SPSS 26.0 statistical software (SPSS Inc., Chicago, IL, USA). All statistical analyses will be based on intention-to-treat principles. The last observation carry-over will be used to fill in missing data for participants who drop out. Qualitative data will be described as percentages or proportions and will be compared using chi-square (χ 2 ) tests. Quantitative data will be expressed as mean ± standard deviation. Shapiro-Wilk tests will be conducted to assess the normality of the data. Chi-square and Fisher exact tests will be performed to compare dichotomous variables. For continuous variables that are normally or non-normally distributed, independent two-sample t-tests or Wilcoxon rank sum tests will be conducted [26] . All hypothesis tests will be two-tailed analyses with statistical significance defined as p -value <0.05. Neuroimaging data analysis The structural MRI data will be analysed using the voxel-based morphometry (VBM) toolbox within SPM12. The steps include interlaminar time difference correction, spatial difference correction, head motion correction, normalization and Gaussian smoothing [43] . During head motion correction, images of subjects with translations of less than 1 mm and rotational movements of less than 2° will be involved in the subsequent analysis. MRI data will be analysed using PANDA, GRETNA and BrainNet Viewer toolboxes and SurfStat. The steps include removing the high-frequency component by band-pass filters, removing the average signal from the whole brain as well as the signal from the ventricles and white matter, and then registering the data to the surface space of FreeSurfer [43] . Multiple comparison corrections will be used for each brain region measured. A t-test and repeated measures ANOVA will be performed to investigate differences between brain regions in each group. Pearson correlation analysis will be used to examine the correlation between fMRI data and clinical variables [43] . Paired t-tests will be used to compare each group. ANOVA and Wilcoxon rank sum (if normality is not satisfied) will be used for comparison between groups. Safety assessments Routine blood, urine and stool tests, as well as an electrocardiogram, will be performed on each participant prior to trial entry [25] . Adverse events (AEs) are unintentional injuries or complications following intervention. At each visit, participants will be asked to disclose any aberrant responses or uncomfortable feelings experienced to the researchers. AEs caused by acupuncture, such as bleeding, haematoma, pain and syncope, or drug-induced symptoms such as headache, nausea and vomiting, will be recorded in detail in the case report forms (CRFs) [44] . Serious adverse events, such as death, life-threatening disability or the need for hospitalization, will be reported to the project leader, the research institution and the hospital ethics committee within 24 hours and recorded in the CRFs. AEs will be tracked until they are properly resolved. The research ethics committee will decide whether the trial should be terminated. Data management and quality control Outcome assessors will complete the initial data in the CRFs and all data will be entered into the EpiData database. To reduce data entry errors, double data entry and validation will be performed by two researchers and the value pairs will be reviewed for discrepancies by referring to paper. Laboratory test results must be printed on the computer. To ensure the smooth running of the study, the study leader will provide uniform training to all study staff before the study starts and will provide detailed operational training on the project implementation protocol and observation indicators to familiarise them with the study process and specific implementation details to ensure the reliability of the study results. Strict diagnostic, inclusion, and exclusion criteria will be applied to screen participants. Patients with DWSI and healthy subjects will be matched in terms of age and educational level. During the recruitment process, treatment will be selected according to the patient’s wishes to ensure compliance. The patient’s family will accompany the patient throughout the acupuncture treatment and provide timely feedback on the patient’s condition to ensure patient safety. MRI data collection will be carried out according to operational procedures and experimental design. The project leader should supervise and check the entire research process to confirm that all research data recording and reporting and case report forms are true, accurate, complete and consistent with the original data. Essential documents will be kept for at least 5 years after the last publication. In addition, any deviation from the protocol will be reported to the Ethics Committee, which will ultimately decide whether we must change the protocol or terminate the trial. Dissemination plans Te results of this research study will be completely disclosed in international peer-reviewed journals, with both positive and negative results reported. Discussion The mechanism of action of DWSI is not yet fully defined, and neurobiological modulation is the main mechanism, which involves neuroimaging, neurobiochemical, neuroendocrine and molecular genetic factors [45, 46] . Among them, neuroimaging techniques have been widely used in the study of neuropsychological-related disease mechanisms in recent years for their non-invasive and non-invasive advantages, and the central pathological mechanisms of DWSI are gradually being clarified in terms of structure and function through neuroimaging studies. It has been shown that differences in ventral prefrontal cortex (PFC) gray matter (GM) volume and fronto-limbic (including uncinate fasciculus (UF)) WM FA between patients with and without suicide attempts in patients with MDD and bipolar disorder (BD) [47] . Comparing patients with and without suicide attempts in mood disorders presents lower baseline ventral and rostral prefrontal gray matter volume and dorsomedial frontal, anterior limb of the internal capsule, and dorsal cingulum fractional anisotropy, as well as greater decreases over time in ventral and dorsal frontal FA, so that abnormalities of GM and WM in frontal systems and differences in developmental changes of frontal white matter may increase risk of suicide-related behavior [48] . Other magnetoencephalography studies have shown that brain regions such as the hippocampus, temporal lobe and occipital lobe are associated with suicide risk in patients with depression [49] . The study in fractional amplitude of low frequency fluctuation (fALFF) showed that depression with suicide attempts had a higher fALFF in the right superior temporal gyrus, left middle temporal gyrus and left middle occipital gyrus. Abnormalities in bilateral middle occipital gyrus brain function are associated with suicidal ideation and suicide risk in depression [50] Alterations in functional connectivity of the left orbitofrontal lobe to the left parietal lobe and right anterior cingulate gyrus are associated with suicidal attempt behavior in depression, and abnormal functional connectivity of the frontal-parietal and frontal-limbic networks may act as predictors of the occurrence of suicide attempts in depression [51] . In addition, memory information processing for suicidal ideation has also been associated with enhanced hippocampal activity [52] . The central pathology-related network in DWSI was further confirmed in a functional brain network study. It was found that suicidal ideation in patients with refractory MDD was significantly associated with regional glucose metabolism levels in the submarginal cortex of the brain and that a reduction in suicidal ideation following ketamine infusion was also associated with a reduction in glucose metabolism in the submarginal cortex of the brain, and no correlation was found in other brain regions, so the submarginal cortex may be associated with suicidal ideation [53] . Another study demonstrated abnormal functional connectivity between the cortical areas of the left hippocampus and some frontal lobes as the neurophysiological mechanism underlying suicide attempts in depressed patients [54] . Abnormal functional connectivity in the right inferior frontal gyrus, frontoparietal lobe, and hippocampus can contribute to suicidal ideation in depressed individuals [55-57] . In brain area network studies, brain networks with core brain areas such as the parahippocampal gyrus, nucleus accumbens, precentral gyrus, and inferior frontal gyrus are gradually being recognised as important pathological centers for DWSI, which together participate in the formation of the concepts of attitudes, impulses, and modalities of suicidal ideation in depressed patients and can be considered as key core functional networks for DWSI [45, 57-59] , as well as important central entry points for studying the modulation of acupuncture interventions. The three most commonly used neuroimaging modalities in acupuncture research are fMRI, sMRI and DTI [60] . Of these, MRI, which uses atomic nuclei resonating in a magnetic field to produce image signals that can be processed to study central structural and functional changes, is a non-invasive, non-invasive detection technique that is mostly used to study central mechanisms in patients with DWSI. The central brain imaging mechanisms of acupuncture for DWSI are currently unclear, and it is clear from existing studies on the central mechanisms of acupuncture for depression that acupuncture does modulate the structure and function of depression-related pathological centers [18] . Studies have shown that acupuncture of LR8, LR15 and CV14 can cause signals in the parieto-temporal-limbic cortices in the default mode network tract in depressed patients [61] . Electro-acupuncture stimulation (EAS) at GV20 induced increased functional connectivity (FC) between the precuneus/posterior cingulate cortex (PC/PCC) and bilateral anterior cingulate cortex (ACC), and decreased FC between the PC/PCC and left middle prefrontal cortex, left angualr gyrus and bilateral hippocampus/parahippocampus (HIPP/paraHIPP) in patients with MDD [62] , and EAS for depression also induces changes in the hippocampal metabolites n-acetylaspartate/creatine and choline-containing compounds [63] . The central mechanisms of acupuncture in the treatment of depression have been further elucidated in comparative studies of acupuncture and medication. The results of a paroxetine combined with acupuncture for depression showed that after treatment patients had increased ALFF signals in bilateral orbitofrontal, bilateral anterior cingulate gyrus, left caudate nucleus, right hippocampus, and left parahippocampal gyrus brain regions; and decreased ALFF signals in left cuneus, left dorsolateral prefrontal cortex, right temporal pole, right insula, right middle temporal gyrus, and right cerebellar brain regions, which suggested that acupuncture could modulate depressed patients’ cortico-striato-thalamic neural network in the limbic system [64] . Another study of ventral acupuncture combined with fluoxetine in the treatment of major depression showed that ventral acupuncture increased resting state functional connectivity (rsFC) between the left amygdala and subgenual anterior cingulate cortex (sgACC)/preguenual anterior cingulate cortex (pgACC)x in MDD, as well as between the right amygdala and left parahippocampus (Para)/putamen (Pu) [65] . When studied with the striatum as the seed point, ventral acupuncture combined with fluoxetine significantly increased rsFC between inferior ventral striatum and medial prefrontal cortex, ventral rostral putamen and amygdala/parahippocampus, as well as dorsal caudate and middle temporal gyru; and decreased rsFC between right ventral rostral putamen and right dorsolateral prefrontal cortex, and right dorsal caudate and bilateral cerebellar tonsil, which indicated that acupuncture may achieve treatment effects by modulating the corticostriatal reward/motivation circuitry in patients of MDD [66] . However, there are no properly designed randomised, controlled trials to demonstrate the effectiveness of acupuncture in the treatment of DWSI and to explain the relevant central mechanisms. The intervention method of this study is based on our team’s previous research results and combined with the traditional Chinese medicine etiology and pathogenesis of DWSI. The method is a comprehensive acupuncture method, which includes the dorsal points of the heart, liver and kidney, the points around the navel where the vital energy enters and exits the abdomen, the original or combined points of the heart, liver, kidney and stomach on the limbs, and the eight points of the LingGui where the twelve meridians and the eight extra-meridians meet, which can regulate the qi and blood of the internal organs as a whole and regulate the spirit of the mind. Adjustments have been made in the operation of the acupuncture technique to accommodate factors such as the number of acupoints, long duration of treatment, selection of acupoints in anterior and posterior body positions, retention of needles and spiritual nourishment so as to ensure patient compliance. Subjects in this study will be predominantly middle-aged because, in addition to making the MRI data more homogeneous, based on Canadian guidelines for the treatment of mood and anxiety, most first-line antidepressants, including paroxetine, have been shown to increase the risk of suicide in adolescents and older adults, but to significantly reduce suicidal ideation in middle-aged adults [67] . Strengths and limitations First, this study is the first to explore the central mechanisms of acupuncture on DWSI, which will clarify the mechanism of brain network regulation of DWSI by acupuncture. Second, brain imaging models of DWSI patients can be created by comparing healthy people with DWSI patients. Third, a comparison of the efficacy of acupuncture and paroxetine allows for better clarification of the efficacy mechanism of acupuncture. The present study has several limitations. First, Firstly, the principle of random allocation was difficult to apply due to the specificity of the patients recruited for our study who had suicidal ideation. We select the interventions according to the individual patient’s wishes and the placebo effect could not be excluded. Second, this study only included a single center and the reproducibility of this study could not be confirmed and more centers would be needed to evaluate our results. Third, the number of acupoints prescribed in the acupuncture group in this study will make it somewhat difficult for the acupuncturist physician to perform the procedure. Four, we include patients who are older and do not represent the full range of patients with DWSI, and studies of adolescent DWSI will be considered in the future. In summary, our study aims to evaluate the efficacy of acupuncture versus paroxetine for patients with DWSI. Using multimodal MRI data of brain structure and function, we will investigate the brain network mechanism of DWSI interventions by acupuncture versus paroxetine and provide reliable evidence for the mechanism of DWSI treatment by acupuncture. Trial status Recruitment started on 13 May 2022, and the study is intended to be completed by December 2024. Abbreviations WHO: World Health Organization; MDD: Major Depressive Disorder; DWSI: depression with suicidal ideation; HAMD: Hamilton Depression Rating Scale; GE: Gradient Echo; BOLD: Blood Oxygen Level Dependent; fMRI: Functional Magnetic Resonance Imaging; DTI: Diffusion Tensor Imaging; BSI-CV: Beck Scale for Suicide Ideation-Chinese Version; SDS: Depression Self-Rating Scale; CDI: Clinical Global Impressions; ASES: Asberg Antidepressant Side Effect Scale; WHOQOL-BREF: World Health Organization Quality-of-Life Scale-Short Form; FA: Fractional Anisotropy; FACT: Fiber Assignment by Continuous Tracking; FN: Fiber Number; AD: Axial Diffusivity; MD: Mean Diffusivity; RD: Radial Diffusivity; VBM: Voxel-Based Morphometry; AEs: Adverse events; CRFs: Case Report Forms; PFC: Pprefrontal Cortex; GM: Gray Matter; UF: Uncinate Fasciculus; BD: Bipolar Disorder; fALFF: Fractional Amplitude of Low Frequency Fluctuation; PC: Precuneus; PCC: Posterior Cingulate Cortex; ACC: Anterior Cingulate Cortex. Declarations Acknowledgments All authors are grateful for the support of all participants or participants who will join the trial, as well as the support of other institutions. Author contributors TPG and FRL are responsible for this research. QFL, TPG and GYZH designed the trial protocol and wrote the manuscript ZWC, XHZ, YH, XXZ, SWZ, XT, XMP, and RRZ participated in patient recruitment, data collection and assessment. TPG and QFL are responsible for acupuncture operations. YL and BKZ are responsible for the final assessment of the patients and for guiding the patient in the administration of medication and treatment in the acute phase. JBS and YL are responsible for imaging data collection and data analysis. BKZ contributed to the ethical application and the implementation of the trial. All authors approved the publication of this final manuscript. Funding This study has been funded by the National Natural Science Foundation of China (82060900), Yunnan Provincial Science and Technology Department Academician Expert Workstation Project-Liang Fanrong Workstation (2018IC101) and Top-notch Young Talent Project of Yunnan Ten Thousand Talents (YNWR-QNBJ-2019-257). The funding agencies do not play any role in the design, collection, analysis, or writing of manuscripts of the study. Availability of data and materials The datasets generated and analysed in this study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The trial protocol follows the principles of the Declaration of Helsinki and was approved by the Research Ethics Committee of the Kunming Psychiatry Hospital (approval no. 2022LLSC01). This trial has been registered with the Chinese Clinical Trials Registry (ID: ChiCTR2200059267). All participants will sign an informed consent form to participate in the study. Study results will be published in a peer-reviewed academic journal and disseminated electronically through conference presentations. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author details 1 School of Second Clinical Medicine/The Second Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, China. 2 The Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China. 3 Engineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xian, China. 4 Yunnan University of Chinese Medicine Teaching Hospital/Kunming Psychiatry Hospital, Kunming, China. 5 College of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China. References World Health Organization. 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Tables Table 1 Study schedule for data measurements STUDY PERIOD Enrolment Allocation Treatment phase Follow up week TIMEPOINT -1 0 4 8 12 16 20 Eligibility screen × Informed consent × Physical examination × Randomization × INTERVENTIONS: Acupuncture group (n=35) × × × × Paroxetine control group (n=35) × × × × Healthy control group (n=30) × ASSESSMENTS: HAMD-24 × × × × × × × BSI-CV × × × × × × × SDS × × × × × × CGI × × × × × × ASES × × × × × × WHOQOL-BREF × × × × × × MRI parameters × × PARTICIPANTS SAFETY AE × × × × × Laboratory test × × Abbreviations: HAMD-24, hamilton depression rating scale-24; BSI-CV, beck scale for suicide ideation-Chinese version; SDS, depression self-rating scale; CGI, clinical global impressions; ASES, asberg antidepressant side effect scale; WHOQOL-BREF, world health organization quality of life questionaire abbreviated version; MRI, magnetic resonance imaging; AE, adverse events Table 2 The location of acupoints Acupoints Location (i) eight methods of LingGui SP4 (Gongsun) On the medial aspect of the foot, anteroinferior to the base of the First metatarsal bone, at the border between the red and white flesh. PC6 (Neiguan) On the anterior aspect of the forearm, between the tendons of the palmaris longus and the flesor carpi radialis, 2 B-cun proximal to the palmar wrist crease. LU7 (Lieque) On the radial aspect of the forearm, between the tendons of the abductor pollicis longus and the extensor pollicis brevis muscles,in the groove for the abductor pollicis longus tendon,1.5 B-cun superior to the palmar wrist crease. KI6 (Zhaohai) On the medial aspect of the foot, 1 B-cun inferior to the prominence of the medial malleolus, in the depression inferior to the medial malleolus. GB41 (Zulinqi) On the dorsum of the foot, distal to the junction of the bases of the fourth and fifth metatarsal bones, in the depression lateral to the fifth extensor digitorum longus tendon. TE5 (Waiguan) On the posterior aspect of the forearm,midpoint of the interosseous space between the radius and the ulna, 2 B-cun proximal to the dorsal wrist crease. BL62 (Shenmai) On the lateral aspect of the foot,directly inferior to the prominence of the lateral malleolus, in the depression between the inferior border of the lateral malleolus and the calcaneus. SI3 (Houxi) On the dorsum of the hand,in the depression proximal to the ulnar side of the fifth metacarpophalangeal joint,at the border between the red and white flesh. (ii) regulating the Qi of the internal organs BL 15 (Xinshu) In the upper back region, at the same level as the inferior border of the spinous process of the fifth thoracic vertebra(T5), 1.5 B-cun lateral to the posterior median line. BL 18 (Ganshu) In the upper back region, at the same level as the inferior border of the spinous process of the ninth thoracic vertebra(T9)1.5 B-cun lateral to the posterior median line. BL 23 (Shenshu) In the upper back region, at the same level as the inferior border of the spinous process of the second lumbar vertebra(L2)1.5 B-cun lateral to the posterior median line. (iii) regulating Yuan Qi KI 3 (Taixi) On the posteromedial aspect of the ankle, in the depression between the prominence of the medial malleolus and the calcaneal tendon. ST 25 (Tianshu) On the upper abdomen, 2 B-cun lateral to the centre of the umbilicus. CV 4 (Guanyuan) On the lower abdomen, 3 B-cun inferior to the centre of the umbilicus, on the anterior median line. CV 6 (Qihai) On the lower abdomen, 1.5 B-cun inferior to the centre of the umbilicus, on the anterior median line. CV 12 (Zhongwan) On the upper abdomen, 4 B-cun superior to the centre of the umbilicus, on the anterior median line. ST 36 (Zusanli) On the anterior aspect of the leg, on the line connecting ST35 with ST41, 3 B-cun inferior to ST35. (iv) soothing liver and regulating the spirit HT 7 (Shenmen) On the anteromedial aspect of the wrist, radial to the flexor carpi ulnaris tendon, on the palmar wrist crease. GV 20 (Baihui) On the head, 5 B-cun superior to the anterior hairline, on the anterior median line. LR 3 (Taichong) On the dorsum of the foot, between the first and second metatarsal bones, in the depression distal to the junction of the bases of the two bones, over the dorsalis pedis artery. Additional Declarations No competing interests reported. Supplementary Files SPIRITFillablechecklist15Aug2013.doc ThemethodoftakingacupointsbythetimeoftheeightmethodsofLingGui.pdf Supplementary Material The method of taking acupoints by time of the eight methods of LingGui Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Renrui","middleName":"","lastName":"Zhang","suffix":""},{"id":172080883,"identity":"92ec7206-1c76-483a-bdcf-6f83fb509ba7","order_by":14,"name":"Taipin Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYHACNhAhx8befIBoDWAtxnw8xxJI05I4TyJHgTgd8vG9xx4X1NSltzHkMDD8qNhGWIvhMb504xnHDue2MZw9wNhz5jYRWtp4zKR5Gw7ktjH2JTAzthGvpS6djZnHgDgt8mxgLcwJbGzEajFgy0uT5jl2GGgbW8JBovwi33z2mDRPTZ28/PzHBx/8qCDGlgM8CM4BwupBtjTwEFY0CkbBKBgFIxwAAFXFM+umLs0vAAAAAElFTkSuQmCC","orcid":"","institution":"Yunnan University of Chinese Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Taipin","middleName":"","lastName":"Guo","suffix":""},{"id":172080885,"identity":"86e0b32c-f7ef-4465-84e0-ea0e714f9db1","order_by":15,"name":"Fanrong Liang","email":"","orcid":"","institution":"Chengdu University of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fanrong","middleName":"","lastName":"Liang","suffix":""}],"badges":[],"createdAt":"2022-12-23 15:14:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2409325/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2409325/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":32390263,"identity":"08742775-ed2e-4d68-8022-26927596502f","added_by":"auto","created_at":"2023-02-02 16:14:15","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38101,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study design\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2409325/v1/3545586dcda0e36fd53e5660.png"},{"id":32389710,"identity":"d2914aeb-e416-4b8e-ae0b-acee2a4aef37","added_by":"auto","created_at":"2023-02-02 16:06:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":591057,"visible":true,"origin":"","legend":"\u003cp\u003eLocations of acupoints\u003c/p\u003e","description":"","filename":"Figure2Locationsofacupoints.png","url":"https://assets-eu.researchsquare.com/files/rs-2409325/v1/5481258e09dea7c1c52efa6a.png"},{"id":32603873,"identity":"b2a6da74-efff-491e-bca1-66a8bf1748cd","added_by":"auto","created_at":"2023-02-07 16:44:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":939006,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2409325/v1/17d8d6a6-e30a-4d8c-935c-f5d460ce5e89.pdf"},{"id":32389712,"identity":"0315da5e-6a9f-42fe-9e54-01b7588e1207","added_by":"auto","created_at":"2023-02-02 16:06:15","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":128198,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITFillablechecklist15Aug2013.doc","url":"https://assets-eu.researchsquare.com/files/rs-2409325/v1/64e0c380e2157c6b1db47968.doc"},{"id":32389713,"identity":"78aa6ae1-230d-4a63-991f-28c143e1dad1","added_by":"auto","created_at":"2023-02-02 16:06:15","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":115442,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe method of taking acupoints by time of the eight methods of LingGui\u003c/p\u003e","description":"","filename":"ThemethodoftakingacupointsbythetimeoftheeightmethodsofLingGui.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2409325/v1/81776c57ba177479414e4fe8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of effects and brain imaging mechanisms of acupuncture and paroxetine for depressive patients with suicidal ideation: study protocol of a 20-week clinical trial","fulltext":[{"header":"Background","content":"\u003cp\u003eSuicide is an action to end one\u0026rsquo;s own life by self-selection and occurs in all areas and throughout the life cycle. According to the World Health Organization (WHO), more than 800,000 people die by suicide each year worldwide, with one suicide occurring every 40 seconds and more than 20 attempted suicides for every death by suicide\u0026nbsp;\u003csup\u003e[1]\u003c/sup\u003e. There is no single explanation for why someone dies by suicide, which is a complex behavior caused by a combination of personal, social, psychological, cultural, biological and environmental factors, with devastating and profoundly damaging effects on families, friends and communities, and is a major medical and social problem worldwide\u0026nbsp;\u003csup\u003e[1]\u003c/sup\u003e. The Mental Health Action Plan (2013-2020), directed by WHO, recommends that countries should aim for a 10% reduction in suicide rates\u0026nbsp;\u003csup\u003e[2]\u003c/sup\u003e. The key to reducing suicide rates lies in effective interventions for patients with suicidal ideation. Depression, especially major depressive disorder (MDD), is the main psychological manifestation preceding suicidal behavior and is an important risk factor for suicide\u0026nbsp;\u003csup\u003e[3]\u003c/sup\u003e. Effectively treating patients with depression with suicidal ideation (DWSI) is an effective means of reducing the rate of suicide. According to the WHO.\u003csup\u003e[2]\u003c/sup\u003e Depression affects approximately 322 million people worldwide, with 4.4% of the world\u0026rsquo;s population suffering from depression in 2015. An European psychiatric study showed that 10.92% of people with psychiatric abnormalities had major depression and 60.39% of them were at risk of suicide\u0026nbsp;\u003csup\u003e[4]\u003c/sup\u003e. In China, patients with MDD also show a high incidence of suicidal ideation\u0026nbsp;\u003csup\u003e[5, 6]\u003c/sup\u003e. Effective treatment of patients with DWSI is an effective means of reducing suicide rates and has been a focus of current clinical research.\u003c/p\u003e\n\u003cp\u003eSuicidal ideation is associated with malfunctioning of emotional control due to negative depressive emotions, and the regulation of depressive and ideational emotions in patients with DWSI so that they can normalize their emotional control is the key to treatment\u0026nbsp;\u003csup\u003e[7, 8]\u003c/sup\u003e. Some studies have used repetitive transcranial magnetic stimulation to treat DWSI showing some efficacy, but no consensus has been reached\u0026nbsp;\u003csup\u003e[9, 10]\u003c/sup\u003e. There is no published guideline for the treatment of patients with DWSI specifically and the main focus is on the treatment of depression. The current treatment of depression is mainly based on medication and psychotherapy, however only 50%-70% of those who complete the full course of treatment achieve remission, and about 30%-40% of patients with major depression have poor outcomes, and considering side effects and other factors, more and more patients are turning to acupuncture for treatment\u0026nbsp;\u003csup\u003e[11-13]\u003c/sup\u003e. Studies have shown that acupuncture has better overall clinical efficacy in the treatment of depression, with mild and transient adverse effects, and can enhance emotional control and effectively prevent suicidal ideation\u0026nbsp;\u003csup\u003e[12, 14, 15]\u003c/sup\u003e. Our team\u0026rsquo;s previous study also showed that acupuncture significantly reduced the\u0026nbsp;Hamilton Depression Rating Scale\u0026nbsp;(HAMD) and Beck suicidal ideation scores in patients with DWSI\u0026nbsp;\u003csup\u003e[16]\u003c/sup\u003e. Despite the current lack of high-quality evidence, acupuncture is recommended by many national guidelines for the management and treatment of depression\u0026nbsp;\u003csup\u003e[11, 17]\u003c/sup\u003e. Because of the widespread use of acupuncture, an increasing number of scholars have begun to focus on the elaboration of its central mechanisms. Studies have shown that acupuncture can modulate the structure and function of depression-related pathological centers\u0026nbsp;\u003csup\u003e[18]\u003c/sup\u003e. However, the central mechanisms of acupuncture on DWSI are still in the exploration stage.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTherefore, this study aims to carry out a clinical trial using multimodal brain imaging techniques to (1) confirm the clinical efficacy of acupuncture versus paroxetine in the treatment of patients with DWSI; (2) reveal the changes in brain structure and function in patients with DWSI, and clarify the correlation between the clinical efficacy of acupuncture and paroxetine on DWSI and the structural and functional changes in brain function; (3) investigate the mechanism of brain network regulation of DWSI by acupuncture. Here, we describe the protocol for this study.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eThis trial will be reported in accordance with the Standard Protocol Items: Recommendations for Intervention Trials (SPIRIT) guidelines\u0026nbsp;\u003csup\u003e[19]\u003c/sup\u003e (Supplementary material) and will follow the Consolidated Standards of Reporting Trials (CONSORT)\u0026nbsp;\u003csup\u003e[20]\u003c/sup\u003e and the Standards for Reporting Interventions in Clinical Trials of Acupuncture principles (STRICTA)\u0026nbsp;\u003csup\u003e[21]\u003c/sup\u003e. The protocol was approved by the Ethics Committee of Kunming Psychiatry Hospital (approval no. 2022LLSC01) (Supplementary material) and is registered with the Chinese Clinical Trial Registry (registration no. ChiCTR2200059267).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design and setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTe research will be carried out in two Yunnan-area hospitals: the Second Affiliated Hospital of Yunnan University of Traditional Chinese Medicine and Kunming Psychiatry Hospital. This non-randomised clinical trial will enroll 72 patients with DWSI and 30 healthy subjects. The study will last 20 weeks. For patients with DWSI, this will be followed by a 12-week treatment period and an 8-week follow-up period. The enrollment schedules, interventions, and assessments are summarised in Table 1. Relevant assessment scales and multimodalMRI scans will be performed at baseline. Clinical outcomes will be evaluated after treatment and during the follow-up. A study flowchart is presented in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment\u003c/strong\u003e \u003cstrong\u003eand informed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients with DWSI and healthy subjects will be recruited from outpatient and inpatient psychiatric departments of the Affiliated Hospital of Yunnan University of Traditional Chinese Medicine and Kunming Psychiatry Hospital or the community. Qualified psychiatrists will strictly follow the inclusion and exclusion criteria to determine whether patients are eligible for this study. To promote the recruitment, recruitment advertisements will be designed to recruit patients online or offline (e.g. WeChat public account, website).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll participants will be explained the purpose and nature of this study protocol and will be fully informed about the study, including the study procedures, benefits and potential risks. They will voluntarily sign an informed consent form before enrolment. Patients with DWSI will need to be accompanied by their family members at all times during each visit. All participants will be able to withdraw from the study at any time without penalty or loss of benefit, and without giving a reason. The reason for withdrawal will be recorded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e70 patients with DWSI and 30 healthy subjects will be recruited for this study. Inclusion criteria for patients with DWSI are as follows:\u003c/p\u003e\n\u003cp\u003e(1) right handed, Han nationality, length of education ≥ 6 years;\u003c/p\u003e\n\u003cp\u003e(2) aged 35-55 years;\u003c/p\u003e\n\u003cp\u003e(3) meet the diagnostic criteria for DSM-V of depression;\u003c/p\u003e\n\u003cp\u003e(4) Hamilton Depression Scale -24 items(HAND-24)score≥20;\u003c/p\u003e\n\u003cp\u003e(5) Beck Suicidal Ideation Scale rated as positive;\u003c/p\u003e\n\u003cp\u003e(6) suicidal ideation only, no experience of self-injury or suicidal behavior;\u003c/p\u003e\n\u003cp\u003e(7) signed the informed consent form and accompanied by family members throughout the study period.\u003c/p\u003e\n\u003cp\u003eExclusion criteria were as follows:\u003c/p\u003e\n\u003cp\u003e(1) with bidirectional depression and other psychiatric disorders in the DSM-V diagnosis;\u003c/p\u003e\n\u003cp\u003e(2) a history of self-injurious or suicidal behaviour;\u003c/p\u003e\n\u003cp\u003e(3) severe depression with unstable emotion and abnormal behaviour with difficulty in cooperating with the assessment;\u003c/p\u003e\n\u003cp\u003e(4) serious primary diseases such as cardiovascular system, liver, kidney and hematopoietic system;\u003c/p\u003e\n\u003cp\u003e(5) chronic pain (such as migraine, women with dysmenorrhea);\u003c/p\u003e\n\u003cp\u003e(6) pregnancy, lactation, or plans to become pregnant within 1 year;\u003c/p\u003e\n\u003cp\u003e(7) brain with definite organic lesions or severe asymmetry between the right and left side of the cranial structure;\u003c/p\u003e\n\u003cp\u003e(8) nuclear magnetic contraindications (such as metal implant, vascular stents, cardiac pacemakers, false tooth, claustrophobia, etc.);\u003c/p\u003e\n\u003cp\u003e(9) has received acupuncture treatment within 6 months;\u003c/p\u003e\n\u003cp\u003e(10) has taken antidepressant or other psychotropic drugs within 6 months and with drug dependence;\u003c/p\u003e\n\u003cp\u003e(11) transsexual, homosexuality, abnormal sexual orientation, special fetishes, alcohol addict, etc;\u003c/p\u003e\n\u003cp\u003e(12) participation in a similar study in the last 3 months.\u003c/p\u003e\n\u003cp\u003eInclusion criteria for healthy subjects are as follows:\u003c/p\u003e\n\u003cp\u003e(1) right handed, Han nationality, length of education ≥ 6 years\u003c/p\u003e\n\u003cp\u003e(2) aged 35-55 years;\u003c/p\u003e\n\u003cp\u003e(3) no history of any neurological or psychiatric disorders and family history of genetic disorders, with a HAMD-17 score \u0026lt;7;\u003c/p\u003e\n\u003cp\u003e(4) no physical abnormalities during the trial period(e.g. flu, fever, etc.);\u003c/p\u003e\n\u003cp\u003e(5) no drugs or alcohol for at least 2 days before participation in the trial, and no stimulant drug use for at least 1 month;\u003c/p\u003e\n\u003cp\u003e(6) signed the informed consent form.\u003c/p\u003e\n\u003cp\u003eHealthy subjects will be excluded if they meet the following criteria:\u003c/p\u003e\n\u003cp\u003e(1) serious primary diseases such as cardiovascular system, brain, liver, kidney, hematopoietic system, mental disease and obvious cognitive dysfunction;\u003c/p\u003e\n\u003cp\u003e(2) chronic pain (such as migraine, women with dysmenorrhea);\u003c/p\u003e\n\u003cp\u003e(3) women during pregnancy and lactation;\u003c/p\u003e\n\u003cp\u003e(4) brain with definite organic lesions or severe asymmetry between the right and left side of the cranial structure;\u003c/p\u003e\n\u003cp\u003e(5) nuclear magnetic contraindications (such as metal implant, vascular stents, cardiac pacemakers, false tooth, claustrophobia, etc.);\u003c/p\u003e\n\u003cp\u003e(6) has received acupuncture treatment within 6 months;\u003c/p\u003e\n\u003cp\u003e(7) transsexual, homosexuality, abnormal sexual orientation, special fetishes, alcohol or drug abuse, etc.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlinding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe trial is not randomised and the intervention is chosen according to the patient’s wishes, so it cannot be blinded to the patients and operators. This trial follows the principle of separation of researchers, evaluators, and statistical analysts.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDescription of intervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcupuncture group\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients in this group will receive acupuncture treatment\u0026nbsp;\u003csup\u003e[16]\u003c/sup\u003e. The prescriptions of acupuncture consist of (i) eight methods of LingGui: bilateral SP4 (Gongsun), bilateral PC6 (Neiguan), bilateral LU7 (Lieque), bilateral KI6 (Zhaohai), bilateral GB41(Zulinqi), bilateral TE5 (Waiguan), bilateral BL62 (Shenmai), bilateral SI3 (Houxi), (ii) regulating the qi of the internal organs: bilateral BL15 (Xinshu), bilateral BL18 (Ganshu), bilateral BL23 (Shenshu); (iii) regulating Yuan qi: bilateral KI3 (Taixi), bilateral ST25 (Tianshu), CV4 (Guanyuan), CV6 (Qihai), CV12 (Zhongwan), bilateral ST36 (Zusanli); (iv) soothing liver and regulating the spirit: bilateral HT7 (Shenmen), GV20 (Baihui), bilateral LR3 (Taichong). The positioning of acupoints will be determined according to the standards issued by the World Health Organization in 2010\u0026nbsp;\u003csup\u003e[22]\u003c/sup\u003e.\u0026nbsp;Locations of the acupoints are presented in Table 2 and Figure 2.\u003c/p\u003e\n\u003cp\u003eThe acupuncture procedure is as follows: after skin disinfection, needles (0.25mm diameter × 25mm; Hua Tuo, Suzhou, China) will be inserted vertically or horizontally into each acupoint. All acupoints are inserted quickly, without hand-manipulating of needles, and no special requirements for needle sensations such as soreness, numbness, swelling and heaviness. The patients will be asked to sit on the treatment bed, and the group of acupoints for regulating the qi of the internal organs will be needled first, both with the needle handle upwards and the needle tip downwards in a flat stab, holding the patient’s shoulder back with one hand and the waist with the other, so that the patient’s legs are stretched out and slowly lie flat; Then select the opening acupoints of the eight methods of LingGui according to the time of needling (the eight acupoints are divided into four groups of acupoints, one of which) (online supplementary file); Finally, the acupoints of regulating Yuanqi and soothing liver and regulating the spirit will be performed. If the LingGui opening point is met with the\u0026nbsp;SI3 (Houxi),\u0026nbsp;HT 7 (Shenmen)\u0026nbsp;is performed using acupuncture upward and flat, then the patient’s palm is pressed downward against the needle and\u0026nbsp;SI3 (Houxi)\u0026nbsp;will then be needled. The thermal design power lamp will be used to irradiate around KI 3 (Taixi) and CV 4 (Guanyuan) respectively, and the needle will be retained for 40min. During this period, the patient will be instructed to relax, close the eyes and breathe calmly and no hand-manipulating of needles. Patients will receive 36 sessions of acupuncture, 3 times a week for 12 weeks. All acupuncture operations will be performed by two trained and licensed acupuncturists. Follow-up visits were conducted every 4 weeks for the duration of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParoxetine\u003c/strong\u003e \u003cstrong\u003eC\u003c/strong\u003e\u003cstrong\u003eontrol\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eG\u003c/strong\u003e\u003cstrong\u003eroup\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients in this group will receive daily early morning oral doses of paroxetine 10 mg per day (week 1), 20 mg per day (week 2); and 30 mg per day (weeks 3-12)\u0026nbsp;\u003csup\u003e[23, 24]\u003c/sup\u003e.\u0026nbsp;Follow-up visits will be every 4 weeks for the first 8 weeks of treatment and every 2 weeks for the remainder of the study. Each follow-up assessment included measures of efficacy, safety and adherence\u0026nbsp;\u003csup\u003e[23, 24]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHealthy Control Group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHealthy subjects will not receive any treatment during the trial. Brain imaging data will be acquired only once.\u003c/p\u003e\n\u003cp\u003eThroughout the study period, patients in both groups can be given the same type of medication as paroxetine for emergency treatment on the advice of the psychiatrist if their symptoms worsen acutely and do not resolve on their own, and detailed records will be kept.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMultimodal Data Acquisition\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultimodal data will be acquired within 1 week prior to treatment and within 1 week after 12 weeks of treatment. Magnetic Resonance Scanner (GE Discovery 750; Milwaukee, WI, USA) with a 16-channel phased array head coil at the Department of Radiology, the First Affiliated Hospital of Kunming Medical. Participants will be asked to lie in a supine position on an examination bed in a supine position, awake, keeping their heads still. Their head will be held still and their eyes will be closed and their ears plugged during the scan. Participants in both the acupuncture and drug control groups will be scanned at baseline and within one week of treatment, and healthy controls will be scanned after recruitment. Considering the possibility of changes related to the menstrual cycle, female participants will be obtained before or outside of their menstrual period. Firstly, three-dimensional T1-weighted (3D-T1) imaging will be obtained for each participant with high-resolution structural images with a voxel size of 1 mm3 using Repetition Time [TR], 6.008 ms; echo Time [TE], 1.7 ms; field of View [FOV], 256 × 256 mm2; Data Matrix. 256 × 256)\u0026nbsp;\u003csup\u003e[25, 26]\u003c/sup\u003e. Second, a T2∗weighted gradient echo (GE) blood oxygen level dependent (BOLD) sequence (TR/TE = 2,420/30 ms, slice thickness = 3.0 mm, slice number = 44, field of view = 192 × 192 mm, flip angle = 90◦, matrix size = 64 × 64) will be recorded to obtain functional magnetic resonance imaging (fMRI) data\u0026nbsp;\u003csup\u003e[26]\u003c/sup\u003e. Third, to detect any white matter abnormalities, diffusion tensor imaging (DTI) will be used to detect white matter abnormalities. Tensor imaging will be performed with the following parameters: TR, 8500 ms; TE, 84 ms; data matrix, 128 × 128; FOV, 256 × 256 mm2; slice thickness, 2 mm; 78 consecutive axial slices without gaps. Two diffusion-weighted sequences will be obtained, using gradient values b = 0 s/mm2 and 1,000 s/mm2 with a diffusion-sensitizing gradient and 64 nonlinear orientations\u0026nbsp;\u003csup\u003e[25, 26]\u003c/sup\u003e. If the subject complains of discomfort, the scan will be terminated. A specialist staff member will examine the images qualitatively to detect any brain lesions or structural abnormalities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no acknowledged standard for estimating the sample size of acupuncture modulation of the functional brain network. According to the requirements of the brain functional network analysis technique\u0026nbsp;\u003csup\u003e[27]\u003c/sup\u003e, a recommended sample size of 30 cases per group could achieve a relatively stable reproducibility. We planned to include 30 cases, 35 cases per group based on a 16% loss rate, and no loss in the healthy subjects group, for a total of 70 DWSI patients and 30 healthy subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Outcomes\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData acquisition will be performed by independent assessors who have received professional training before the start of the study. The primary efficacy outcomes are the mean change in the HAMD-24 scores and the\u0026nbsp;Beck scale for suicide ideation-Chinese version\u0026nbsp;(BSI-CV)\u0026nbsp;from baseline to week 20. The secondary outcomes are the mean change as follows from week 0 to week 20: (1) Depression Self-Rating Scale (SDS); (2) Clinical Global Impressions (CGI) Scale; (3) Asberg Antidepressant side effect scale (ASES); (4) World Health Organization Quality-of-Life Scale-Short Form (WHOQOL-BREF).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe HAMD-24 is a questionnaire used to provide an indication of depression in adults and to evaluate recovery and remission,\u0026nbsp;which includes 7 factors: anxiety/somatization, weight, cognitive impairment, day-night variability, retardation, sleep disturbance, and feelings of hopelessness. The higher the total score, the more severe the depression\u0026nbsp;\u003csup\u003e[28]\u003c/sup\u003e.\u0026nbsp;The BSI-CV is a self-assessment scale that can be used to quantify and assess suicidal ideation in depression, both in the last 1 week and at its most severe. It consists of 19 items, the higher the score, the stronger the suicidal ideation and the higher the risk of suicide\u0026nbsp;\u003csup\u003e[29]\u003c/sup\u003e.\u0026nbsp;The SDS scale includes 20 entries divided into four grade ratings according to the frequency of depression status in the past 7 days.\u0026nbsp;The higher the total score, the higher the recorded level of depression\u0026nbsp;\u003csup\u003e[30]\u003c/sup\u003e.\u0026nbsp;The CGI Scale\u0026nbsp;is an overall scale for assessing clinical outcomes, primarily for determining overall severity of illness and its change\u0026nbsp;\u003csup\u003e[31]\u003c/sup\u003e.\u0026nbsp;The\u0026nbsp;ASES\u0026nbsp;will be applied to\u0026nbsp;assess the adverse effects of\u0026nbsp;paroxetine.\u0026nbsp;The\u0026nbsp;WHOQOL-BREF\u0026nbsp;is an international scale developed by the World Health Organization to measure the health-related quality of life of individuals\u0026nbsp;\u003csup\u003e[32]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMRI data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, the original data was first converted to Nifit format by using the Dcm2nii software in the Micron software package. Then, the PANDA toolbox\u0026nbsp;\u003csup\u003e[33]\u003c/sup\u003e (http://www.nitrc.org/projects/panda/), an integrated toolbox, is used to preprocess the DTI data and construct the brain structural networks. Besides,\u0026nbsp;network properties analysis was performed using the GRETNA toolbox\u0026nbsp;\u003csup\u003e[34]\u003c/sup\u003e (www.nitrc.org /projects/gretna) and visualised by using the BrainNet Viewer toolbox\u0026nbsp;\u003csup\u003e[35]\u003c/sup\u003e (www.nitrc.org / projects/bnv).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStructural Network construction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor Network Construction, we used a MATLAB-based open-source software PANDA\u0026nbsp;\u003csup\u003e[33]\u003c/sup\u003e. Nodes and edges are the two fundamental elements of a network. In this study, we constructed a structural network using the following procedures: (1) removing the basal ganglia regions of the automated anatomical labeling 116 templates\u0026nbsp;\u003csup\u003e[36]\u003c/sup\u003e to make template A; (2) the atlasing of the basal ganglia\u0026nbsp;\u003csup\u003e[37, 38]\u003c/sup\u003e,\u0026nbsp;including striatum, external globus pallidus, globu pallidus internal, red nucleus, substantia nigra, and subthalamic nucleus were assembled, and the overlapped parts were removed to make template B; (3) adding template A and template B, numbering each brain region. Finally, we got a brain template containing 124 brain regions. Individual T1-weighted images were co-registered to b0 images in DTI native space using an affine transformation. The converted T1 images were normalised to a T1 template in MNI space through nonlinear transformation. The 124-region template was used to distort the MNI space into the DTI native space through inverse transformation. Then diffusion MRI tractography was performed, and all tracts in the DTI dataset were computed by seeding each voxel with\u0026nbsp;fractional anisotropy (FA)\u0026nbsp;\u0026gt; 0.2. The tractography was terminated if it turned an angle \u0026gt;45 degrees or reached a voxel with an FA \u0026lt; 0.2. As a result, all fiber pathways between the 124 ROIs in the brain were constructed using the deterministic tractography method. For each pair of ROIs \u003cem\u003ei\u003c/em\u003e and \u003cem\u003ej\u003c/em\u003e, we defined the number of connected fiber\u0026nbsp;number\u0026nbsp;(FN) with two endpoints located in these two regions as the weight of the edge between ROIs \u003cem\u003ei\u003c/em\u003e and \u003cem\u003ej\u003c/em\u003e. For each participant, edge volumes were calculated and normalised by whole-brain white matter volume.\u0026nbsp;Therefore, for each participant, an FN-weighted 124×124 structural connectivity matrix was constructed. FA-weighted structural connectivity matrix was constructed in the same way.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDTI data preprocessing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBriefly, the preprocessing procedure included skull-stripping, eddy-current and head-motion correction, FA calculation and whole-brain deterministic DTI fiber tractography\u0026nbsp;\u003csup\u003e[39]\u003c/sup\u003e. In this preprocess, FA was calculated. Besides, Whole-brain fiber tractography was reconstructed by seeding at every voxel in the brain and using fiber assignment by continuous tracking (FACT) algorithm\u0026nbsp;\u003csup\u003e[40]\u003c/sup\u003e. This algorithm computes fiber trajectories starting from the deep (white matter) WM regions and terminating at a voxel with a turning angle greater than 45° or reaching a voxel with FA less than 0.15. Different analytical methods will be used in the trial, including axial diffusivity (AD), FA, mean diffusivity (MD), and radial diffusivity (RD). These indices could be used to assess the cerebral structure’s integrity and connection\u0026nbsp;\u003csup\u003e[41]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGraph theoretical analysis of structural brain networks\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study,\u0026nbsp;we mainly calculate global network characteristics and local network characteristics\u0026nbsp;to better characterize the brain structural network topology changes,\u0026nbsp;by using\u0026nbsp;graph theoretical analysis\u0026nbsp;\u003csup\u003e[42]\u003c/sup\u003e. The global network characteristics include clustering coefficient (C\u003csub\u003ep\u003c/sub\u003e), characteristic path length (L\u003csub\u003ep\u003c/sub\u003e) and “small-world” network attributes(\u003cem\u003eσ\u003c/em\u003e), global efficiency (E\u003csub\u003eglob\u003c/sub\u003e), and local efficiency (E\u003csub\u003eloc\u003c/sub\u003e); and local network parameters mainly include node efficiency (E\u003csub\u003enodal\u003c/sub\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical data analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical outcomes will be analysed using SPSS 26.0 statistical software (SPSS Inc., Chicago, IL, USA). All statistical analyses will be based on intention-to-treat principles. The last observation carry-over will be used to fill in missing data for participants who drop out. Qualitative data will be described as percentages or proportions and will be compared using chi-square (χ\u003csup\u003e2\u003c/sup\u003e) tests. Quantitative data will be expressed as mean ± standard deviation. Shapiro-Wilk tests will be conducted to assess the normality of the data. Chi-square and Fisher exact tests will be performed to compare dichotomous variables. For continuous variables that are normally or non-normally distributed, independent two-sample t-tests or Wilcoxon rank sum tests will be conducted\u0026nbsp;\u003csup\u003e[26]\u003c/sup\u003e. All hypothesis tests will be two-tailed analyses with statistical significance defined as \u003cem\u003ep\u003c/em\u003e-value \u0026lt;0.05.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNeuroimaging data analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe structural MRI data will be analysed using the voxel-based morphometry (VBM) toolbox within SPM12. The steps include interlaminar time difference correction, spatial difference correction, head motion correction, normalization and Gaussian smoothing\u0026nbsp;\u003csup\u003e[43]\u003c/sup\u003e. During head motion correction, images of subjects with translations of less than 1 mm and rotational movements of less than 2° will be involved in the subsequent analysis. MRI data will be analysed using PANDA, GRETNA and BrainNet Viewer toolboxes and SurfStat. The steps include removing the high-frequency component by band-pass filters, removing the average signal from the whole brain as well as the signal from the ventricles and white matter, and then registering the data to the surface space of FreeSurfer\u0026nbsp;\u003csup\u003e[43]\u003c/sup\u003e.\u0026nbsp;Multiple comparison corrections will be used for each brain region measured.\u0026nbsp;A t-test and repeated measures ANOVA will be performed to investigate differences between brain regions in each group. Pearson correlation analysis will be used to examine the correlation between fMRI data and clinical variables\u0026nbsp;\u003csup\u003e[43]\u003c/sup\u003e. Paired t-tests will be used to compare each group. ANOVA and Wilcoxon rank sum (if normality is not satisfied) will be used for comparison between groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety assessments\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRoutine blood, urine and stool tests, as well as an electrocardiogram, will be performed on each participant prior to trial entry\u0026nbsp;\u003csup\u003e[25]\u003c/sup\u003e. Adverse events (AEs) are unintentional injuries or complications following intervention. At each visit, participants will be asked to disclose any aberrant responses or uncomfortable feelings experienced to the researchers. AEs caused by acupuncture, such as bleeding, haematoma, pain and syncope, or drug-induced symptoms such as headache, nausea and vomiting, will be recorded in detail in the case report forms (CRFs)\u0026nbsp;\u003csup\u003e[44]\u003c/sup\u003e. Serious adverse events, such as death, life-threatening disability or the need for hospitalization, will be reported to the project leader, the research institution and the hospital ethics committee within 24 hours and recorded in the CRFs. AEs will be tracked until they are properly resolved. The research ethics committee will decide whether the trial should be terminated.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management and quality control\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOutcome assessors will complete the initial data in the CRFs and all data will be entered into the EpiData database. To reduce data entry errors, double data entry and validation will be performed by two researchers and the value pairs will be reviewed for discrepancies by referring to paper. Laboratory test results must be printed on the computer. To ensure the smooth running of the study, the study leader will provide uniform training to all study staff before the study starts and will provide detailed operational training on the project implementation protocol and observation indicators to familiarise them with the study process and specific implementation details to ensure the reliability of the study results. Strict diagnostic, inclusion, and exclusion criteria will be applied to screen participants. Patients with DWSI and healthy subjects will be matched in terms of age and educational level. During the recruitment process, treatment will be selected according to the patient’s wishes to ensure compliance. The patient’s family will accompany the patient throughout the acupuncture treatment and provide timely feedback on the patient’s condition to ensure patient safety. MRI data collection will be carried out according to operational procedures and experimental design. The project leader should supervise and check the entire research process to confirm that all research data recording and reporting and case report forms are true, accurate, complete and consistent with the original data. Essential documents will be kept for at least 5 years after the last publication. In addition, any deviation from the protocol will be reported to the Ethics Committee, which will ultimately decide whether we must change the protocol or terminate the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTe results of this research study will be completely disclosed in international peer-reviewed journals, with both positive and negative results reported.\u003c/p\u003e\n"},{"header":"Discussion","content":"\u003cp\u003eThe mechanism of action of DWSI is not yet fully defined, and neurobiological modulation is the main mechanism, which involves neuroimaging, neurobiochemical, neuroendocrine and molecular genetic factors\u0026nbsp;\u003csup\u003e[45, 46]\u003c/sup\u003e. Among them, neuroimaging techniques have been widely used in the study of neuropsychological-related disease mechanisms in recent years for their non-invasive and non-invasive advantages, and the central pathological mechanisms of DWSI are gradually being clarified in terms of structure and function through neuroimaging studies.\u003c/p\u003e\n\u003cp\u003eIt has been shown that differences in ventral prefrontal cortex (PFC) gray matter (GM) volume and fronto-limbic (including uncinate fasciculus (UF)) WM FA between patients with and without suicide attempts in patients with MDD and bipolar disorder (BD)\u0026nbsp;\u003csup\u003e[47]\u003c/sup\u003e. Comparing patients with and without suicide attempts in mood disorders presents lower baseline ventral and rostral prefrontal gray matter volume and dorsomedial frontal, anterior limb of the internal capsule, and dorsal cingulum fractional anisotropy, as well as greater decreases over time in ventral and dorsal frontal FA, so that abnormalities of GM and WM in frontal systems and differences in developmental changes of frontal white matter may increase risk of suicide-related behavior\u0026nbsp;\u003csup\u003e[48]\u003c/sup\u003e. Other magnetoencephalography studies have shown that brain regions such as the hippocampus, temporal lobe and occipital lobe are associated with suicide risk in patients with depression\u0026nbsp;\u003csup\u003e[49]\u003c/sup\u003e. The study in fractional amplitude of low frequency fluctuation (fALFF) showed that depression with suicide attempts had a higher fALFF in the right superior temporal gyrus, left middle temporal gyrus and left middle occipital gyrus. Abnormalities in bilateral middle occipital gyrus brain function are associated with suicidal ideation and suicide risk in depression\u0026nbsp;\u003csup\u003e[50]\u003c/sup\u003e Alterations in functional connectivity of the left orbitofrontal lobe to the left parietal lobe and right anterior cingulate gyrus are associated with suicidal attempt behavior in depression, and abnormal functional connectivity of the frontal-parietal and frontal-limbic networks may act as predictors of the occurrence of suicide attempts in depression\u0026nbsp;\u003csup\u003e[51]\u003c/sup\u003e. In addition, memory information processing for suicidal ideation has also been associated with enhanced hippocampal activity\u0026nbsp;\u003csup\u003e[52]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe central pathology-related network in\u0026nbsp;DWSI\u0026nbsp;was further confirmed in a functional brain network study. It was found that suicidal ideation in patients with refractory MDD was significantly associated with regional glucose metabolism levels in the submarginal cortex of the brain and that a reduction in suicidal ideation following ketamine infusion was also associated with a reduction in glucose metabolism in the submarginal cortex of the brain, and no correlation was found in other brain regions, so the submarginal cortex may be associated with suicidal ideation\u0026nbsp;\u003csup\u003e[53]\u003c/sup\u003e. Another study demonstrated abnormal functional connectivity between the cortical areas of the left hippocampus and some frontal lobes as the neurophysiological mechanism underlying suicide attempts in depressed patients\u0026nbsp;\u003csup\u003e[54]\u003c/sup\u003e. Abnormal functional connectivity in the right inferior frontal gyrus, frontoparietal lobe, and hippocampus can contribute to suicidal ideation in depressed individuals\u0026nbsp;\u003csup\u003e[55-57]\u003c/sup\u003e. In brain area network studies, brain networks with core brain areas such as the parahippocampal gyrus, nucleus accumbens, precentral gyrus, and inferior frontal gyrus are gradually being recognised as important pathological centers for\u0026nbsp;DWSI, which together participate in the formation of the concepts of attitudes, impulses, and modalities of suicidal ideation in depressed patients and can be considered as key core functional networks for\u0026nbsp;DWSI\u0026nbsp;\u003csup\u003e[45, 57-59]\u003c/sup\u003e, as well as important central entry points for studying the modulation of acupuncture interventions.\u003c/p\u003e\n\u003cp\u003eThe three most commonly used neuroimaging modalities in acupuncture research are fMRI, sMRI and DTI\u0026nbsp;\u003csup\u003e[60]\u003c/sup\u003e. Of these, MRI, which uses atomic nuclei resonating in a magnetic field to produce image signals that can be processed to study central structural and functional changes, is a non-invasive, non-invasive detection technique that is mostly used to study central mechanisms in patients with DWSI.\u003c/p\u003e\n\u003cp\u003eThe central brain imaging mechanisms of acupuncture for DWSI are currently unclear, and it is clear from existing studies on the central mechanisms of acupuncture for depression that acupuncture does modulate the structure and function of depression-related pathological centers\u0026nbsp;\u003csup\u003e[18]\u003c/sup\u003e. Studies have shown that acupuncture of LR8, LR15 and CV14 can cause signals in the parieto-temporal-limbic cortices in the default mode network tract in depressed patients\u0026nbsp;\u003csup\u003e[61]\u003c/sup\u003e. Electro-acupuncture\u0026nbsp;stimulation\u0026nbsp;(EAS) at GV20 induced increased\u0026nbsp;functional connectivity (FC) between the\u0026nbsp;precuneus/posterior cingulate cortex (PC/PCC) and bilateral anterior cingulate cortex (ACC), and decreased FC between the PC/PCC and left middle prefrontal cortex, left angualr gyrus and bilateral hippocampus/parahippocampus (HIPP/paraHIPP) in patients with MDD\u0026nbsp;\u003csup\u003e[62]\u003c/sup\u003e, and EAS for depression also induces changes in the hippocampal metabolites n-acetylaspartate/creatine and choline-containing compounds\u0026nbsp;\u003csup\u003e[63]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe central mechanisms of acupuncture in the treatment of depression have been further elucidated in comparative studies of acupuncture and medication. The results of a paroxetine combined with acupuncture for depression showed that after treatment patients had increased ALFF signals in bilateral orbitofrontal, bilateral anterior cingulate gyrus, left caudate nucleus, right hippocampus, and left parahippocampal gyrus brain regions; and decreased ALFF signals in left cuneus, left dorsolateral prefrontal cortex, right temporal pole, right insula, right middle temporal gyrus, and right cerebellar brain regions, which suggested that acupuncture could modulate depressed patients\u0026rsquo; cortico-striato-thalamic neural network in the limbic system\u0026nbsp;\u003csup\u003e[64]\u003c/sup\u003e. Another study of ventral acupuncture combined with fluoxetine in the treatment of major depression showed that ventral acupuncture increased resting\u0026nbsp;state\u0026nbsp;functional\u0026nbsp;connectivity (rsFC) between the left amygdala and subgenual anterior cingulate cortex (sgACC)/preguenual anterior cingulate cortex (pgACC)x in MDD, as well as between the right amygdala and left parahippocampus (Para)/putamen (Pu)\u0026nbsp;\u003csup\u003e[65]\u003c/sup\u003e. When studied with the striatum as the seed point, ventral acupuncture combined with fluoxetine significantly increased rsFC between inferior ventral striatum and medial prefrontal cortex, ventral rostral putamen and amygdala/parahippocampus, as well as dorsal caudate and middle temporal gyru; and decreased rsFC between right ventral rostral putamen and right dorsolateral prefrontal cortex, and right dorsal caudate and bilateral cerebellar tonsil, which indicated that acupuncture may achieve treatment effects by modulating the corticostriatal reward/motivation circuitry in patients of MDD\u0026nbsp;\u003csup\u003e[66]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eHowever, there are no properly designed randomised, controlled trials to demonstrate the effectiveness of acupuncture in the treatment of DWSI and to explain the relevant central mechanisms. The intervention method of this study is based on our team\u0026rsquo;s previous research results and combined with the traditional Chinese medicine etiology and pathogenesis of DWSI. The method is a comprehensive acupuncture method, which includes the dorsal points of the heart, liver and kidney, the points around the navel where the vital energy enters and exits the abdomen, the original or combined points of the heart, liver, kidney and stomach on the limbs, and the eight points of the LingGui where the twelve meridians and the eight extra-meridians meet, which can regulate the qi and blood of the internal organs as a whole and regulate the spirit of the mind. Adjustments have been made in the operation of the acupuncture technique to accommodate factors such as the number of acupoints, long duration of treatment, selection of acupoints in anterior and posterior body positions, retention of needles and spiritual nourishment so as to ensure patient compliance. Subjects in this study will be predominantly middle-aged because, in addition to making the MRI data more homogeneous, based on Canadian guidelines for the treatment of mood and anxiety, most first-line antidepressants, including paroxetine, have been shown to increase the risk of suicide in adolescents and older adults, but to significantly reduce suicidal ideation in middle-aged adults\u0026nbsp;\u003csup\u003e[67]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst, this study is the first to explore the central mechanisms of acupuncture on\u0026nbsp;DWSI, which will\u0026nbsp;clarify the mechanism of brain network regulation of\u0026nbsp;DWSI\u0026nbsp;by acupuncture.\u0026nbsp;Second, brain imaging models of\u0026nbsp;DWSI\u0026nbsp;patients can be created by comparing healthy people with\u0026nbsp;DWSI\u0026nbsp;patients. Third, a comparison of the efficacy of acupuncture and paroxetine allows for better clarification of the efficacy mechanism of acupuncture. The present study has several limitations. First, Firstly, the principle of random allocation was difficult to apply due to the specificity of the patients recruited for our study who had suicidal ideation. We select the interventions according to the individual patient\u0026rsquo;s wishes and the placebo effect could not be excluded. Second, this study only included a single center and the reproducibility of this study could not be confirmed and more centers would be needed to evaluate our results. Third, the number of acupoints prescribed in the acupuncture group in this study will make it somewhat difficult for the acupuncturist physician to perform the procedure. Four, we include patients who are older and do not represent the full range of patients with\u0026nbsp;DWSI, and studies of adolescent\u0026nbsp;DWSI\u0026nbsp;will be considered in the future.\u003c/p\u003e\n\u003cp\u003eIn summary, our study aims to evaluate the efficacy of acupuncture versus paroxetine for patients with DWSI. Using multimodal MRI data of brain structure and function, we will investigate the brain network mechanism of DWSI interventions by acupuncture versus paroxetine and provide reliable evidence for the mechanism of DWSI treatment by acupuncture.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRecruitment started on 13 May 2022, and the study is intended to be completed by December 2024.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eWHO: World Health Organization; MDD: Major Depressive Disorder; DWSI: depression with suicidal ideation; HAMD: Hamilton Depression Rating Scale; GE: Gradient Echo; BOLD: Blood Oxygen Level Dependent; fMRI: Functional Magnetic Resonance Imaging; DTI: Diffusion Tensor Imaging; BSI-CV: Beck Scale for Suicide Ideation-Chinese Version; SDS: Depression Self-Rating Scale; CDI: Clinical Global Impressions; ASES: Asberg Antidepressant Side Effect Scale; WHOQOL-BREF: World Health Organization Quality-of-Life Scale-Short Form; FA: Fractional Anisotropy; FACT: Fiber Assignment by Continuous Tracking; FN: Fiber Number; AD: Axial Diffusivity; MD: Mean Diffusivity; RD: Radial Diffusivity; VBM: Voxel-Based Morphometry; AEs: Adverse events; CRFs: Case Report Forms; PFC: Pprefrontal Cortex; GM: Gray Matter; UF: Uncinate Fasciculus; BD: Bipolar Disorder; fALFF: Fractional Amplitude of Low Frequency Fluctuation; PC: Precuneus; PCC: Posterior Cingulate Cortex; ACC: Anterior Cingulate Cortex.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors are grateful for the support of all participants or participants who will join the trial, as well as the support of other institutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributors\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTPG and FRL are responsible for this research. QFL, TPG and GYZH designed the trial protocol and wrote the manuscript ZWC, XHZ, YH, XXZ, SWZ, XT, XMP, and RRZ participated in patient recruitment, data collection and assessment. TPG and QFL are responsible for acupuncture operations. YL and BKZ are responsible for the final assessment of the patients and for guiding the patient in the administration of medication and treatment in the acute phase. JBS and YL are responsible for imaging data collection and data analysis. BKZ contributed to the ethical application and the implementation of the trial. All authors approved the publication of this final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been funded by the National Natural Science Foundation of China (82060900), Yunnan Provincial Science and Technology Department Academician Expert Workstation Project-Liang Fanrong Workstation (2018IC101) and Top-notch Young Talent Project of Yunnan Ten Thousand Talents (YNWR-QNBJ-2019-257). The funding agencies do not play any role in the design, collection, analysis, or writing of manuscripts of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analysed in this study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial protocol follows the principles of the Declaration of Helsinki and was approved by the Research Ethics Committee of the Kunming Psychiatry Hospital (approval no. 2022LLSC01). This trial has been registered with the Chinese Clinical Trials Registry (ID: ChiCTR2200059267). All participants will sign an informed consent form to participate in the study. Study results will be published in a peer-reviewed academic journal and disseminated electronically through conference presentations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eSchool of Second Clinical Medicine/The Second Affiliated Hospital, Yunnan University of Chinese Medicine, Kunming, China. \u003csup\u003e2\u003c/sup\u003eThe Department of Medical Imaging, The First Affiliated Hospital of Kunming Medical University, Kunming, China. \u003csup\u003e3\u003c/sup\u003eEngineering Research Center of Molecular and Neuro Imaging of the Ministry of Education, School of Life Science and Technology, Xidian University, Xian, China. \u003csup\u003e4\u003c/sup\u003eYunnan University of Chinese Medicine Teaching Hospital/Kunming Psychiatry Hospital, Kunming, China. \u003csup\u003e5\u003c/sup\u003eCollege of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eWorld Health Organization. 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Neuroimage Clin. 2016;12:746\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWang Z, Wang X, Liu J, Chen J, Liu X, Nie G, et al. Acupuncture treatment modulates the corticostriatal reward circuitry in major depressive disorder. J Psychiatr Res. 2017;84:18\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKennedy SH, Lam RW, McIntyre RS, Tourjman SV, Bhat V, Blier P, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. Can J Psychiatry. 2016;61(9):540\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e Study schedule for data measurements\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"563\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"7\" width=\"63.0550621669627%\"\u003e\n \u003cp\u003eSTUDY PERIOD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.676731793960924%\"\u003e\n \u003cp\u003eEnrolment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.321492007104796%\"\u003e\n \u003cp\u003eAllocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" width=\"21.847246891651864%\"\u003e\n \u003cp\u003eTreatment phase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"14.209591474245116%\"\u003e\n \u003cp\u003eFollow up\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"7\" valign=\"top\" width=\"63.0550621669627%\"\u003e\n \u003cp\u003eweek\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.9449378330373%\"\u003e\n \u003cp\u003eTIMEPOINT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.676731793960924%\"\u003e\n \u003cp\u003e-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.321492007104796%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.9449378330373%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eEligibility screen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003ePhysical examination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eRandomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.9449378330373%\"\u003e\n \u003cp\u003e\u003cstrong\u003eINTERVENTIONS:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eAcupuncture\u0026nbsp;group (n=35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eParoxetine control group (n=35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eHealthy control group (n=30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.9449378330373%\"\u003e\n \u003cp\u003e\u003cstrong\u003eASSESSMENTS:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eHAMD-24\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eBSI-CV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eSDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eCGI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eASES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eWHOQOL-BREF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eMRI parameters\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.9449378330373%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePARTICIPANTS SAFETY\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"36.9449378330373%\"\u003e\n \u003cp\u003eLaboratory test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.676731793960924%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"13.321492007104796%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.63765541740675%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"6.927175843694494%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"7.282415630550622%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u0026nbsp;\u003c/strong\u003eHAMD-24, hamilton depression rating scale-24; BSI-CV, beck scale for suicide ideation-Chinese version; SDS, depression self-rating scale; CGI, clinical global impressions; ASES, asberg antidepressant side effect scale; WHOQOL-BREF, world health organization quality of life questionaire abbreviated version; MRI, magnetic resonance imaging; AE, adverse events\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e The location of acupoints\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" width=\"27.816901408450704%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcupoints\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"72.1830985915493%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLocation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"8\" width=\"12.147887323943662%\"\u003e\n \u003cp\u003e\u0026nbsp;(i) eight methods of LingGui\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.669014084507042%\"\u003e\n \u003cp\u003eSP4\u003c/p\u003e\n \u003cp\u003e(Gongsun)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"72.1830985915493%\"\u003e\n \u003cp\u003eOn the medial aspect of the foot, anteroinferior to the base of the\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFirst metatarsal bone, at the border between the red and white flesh.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003ePC6\u003c/p\u003e\n \u003cp\u003e(Neiguan)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the anterior aspect of the forearm, between the tendons of the palmaris longus and the flesor carpi radialis, 2 B-cun proximal to the palmar wrist crease.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eLU7\u003c/p\u003e\n \u003cp\u003e(Lieque)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the radial aspect of the forearm, between the tendons of the abductor pollicis longus and the extensor pollicis brevis muscles,in the groove for the abductor pollicis longus tendon,1.5 B-cun superior to the palmar wrist crease.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eKI6\u003c/p\u003e\n \u003cp\u003e(Zhaohai)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the medial aspect of the foot, 1 B-cun inferior to the prominence of the medial malleolus, in the depression inferior to the medial malleolus.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eGB41\u003c/p\u003e\n \u003cp\u003e(Zulinqi)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the dorsum of the foot, distal to the junction of the bases of the fourth and fifth metatarsal bones, in the depression lateral to the fifth extensor digitorum longus tendon.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eTE5\u003c/p\u003e\n \u003cp\u003e(Waiguan)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the posterior aspect of the forearm,midpoint of the interosseous space between the radius and the ulna, 2 B-cun proximal to the dorsal wrist crease.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eBL62\u003c/p\u003e\n \u003cp\u003e(Shenmai)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the lateral aspect of the foot,directly inferior to the prominence of the lateral malleolus, in the depression between the inferior border of the lateral malleolus and the calcaneus.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eSI3\u003c/p\u003e\n \u003cp\u003e(Houxi)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the dorsum of the hand,in the depression proximal to the ulnar side of the fifth metacarpophalangeal joint,at the border between the red and white flesh.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" width=\"12.147887323943662%\"\u003e\n \u003cp\u003e\u0026nbsp;(ii) regulating the Qi of the internal organs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.669014084507042%\"\u003e\n \u003cp\u003eBL 15\u0026nbsp;(Xinshu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"72.1830985915493%\"\u003e\n \u003cp\u003eIn the upper back region, at the same level as the inferior border of the spinous process of the fifth thoracic vertebra(T5), 1.5 B-cun lateral to the posterior median line.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eBL 18\u0026nbsp;(Ganshu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"82.16432865731463%\"\u003e\n \u003cp\u003eIn the upper back region, at the same level as the inferior border of the spinous process of the ninth thoracic vertebra(T9)1.5 B-cun lateral to the posterior median line.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eBL 23\u0026nbsp;(Shenshu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"82.16432865731463%\"\u003e\n \u003cp\u003eIn the upper back region, at the same level as the inferior border of the spinous process of the second lumbar vertebra(L2)1.5 B-cun lateral to the posterior median line.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" width=\"12.147887323943662%\"\u003e\n \u003cp\u003e(iii) regulating Yuan Qi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.669014084507042%\"\u003e\n \u003cp\u003eKI 3 (Taixi)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"72.1830985915493%\"\u003e\n \u003cp\u003eOn the posteromedial aspect of the ankle, in the depression between the prominence of the medial malleolus and the calcaneal tendon.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eST 25\u0026nbsp;(Tianshu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the upper abdomen, 2 B-cun lateral to the centre of the umbilicus.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eCV 4 (Guanyuan)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the lower abdomen, 3 B-cun inferior to the centre of the umbilicus, on the anterior median line.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eCV 6 (Qihai)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the lower abdomen, 1.5 B-cun inferior to the centre of the umbilicus, on the anterior median line.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eCV 12\u003c/p\u003e\n \u003cp\u003e(Zhongwan)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the upper abdomen, 4 B-cun superior to the centre of the umbilicus, on the anterior median line.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eST 36 (Zusanli)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the anterior aspect of the leg, on the line connecting ST35 with ST41, 3 B-cun inferior to ST35.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" width=\"12.147887323943662%\"\u003e\n \u003cp\u003e(iv) soothing liver and regulating the spirit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.669014084507042%\"\u003e\n \u003cp\u003eHT 7 (Shenmen)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"72.1830985915493%\"\u003e\n \u003cp\u003eOn the anteromedial aspect of the wrist, radial to the flexor carpi ulnaris tendon, on the palmar wrist crease.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eGV 20 (Baihui)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the head, 5 B-cun superior to the anterior hairline, on the anterior median line.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.83567134268537%\"\u003e\n \u003cp\u003eLR 3 (Taichong)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.16432865731463%\"\u003e\n \u003cp\u003eOn the dorsum of the foot, between the first and second metatarsal bones, in the depression distal to the junction of the bases of the two bones, over the dorsalis pedis artery.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"suicidal ideation depression, acupuncture, paroxetine, multimodal magnetic resonance imaging, central mechanism, study protocol","lastPublishedDoi":"10.21203/rs.3.rs-2409325/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2409325/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e Suicide is a devastating and major medical and social problem, and effective management of depression with suicidal ideation (DWSI) is of significant importance in reducing suicide rates. Acupuncture has been less studied in DWSI, and its central mechanisms have not been elucidated. This study aims to carry out a clinical trial using multimodal brain imaging techniques to investigate the mechanism of brain network regulation of DWSI by acupuncture.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e A total of 70 patients with DWSI and 30 healthy subjects will be recruited for this study. This trial will include a 1-week baseline phase, a 12-week treatment phase, and a 8-week follow-up phase. Patients in the acupuncture group will receive 36 sessions of acupuncture, 3 times a week for 12 weeks. Patientsin the paroxetine control group will receive paroxetine 10 mg per day (week 1), 20 mg per day (weeks 2); and 30 mg per day (weeks 3-12). The primary outcomes are the mean change in the Hamilton Depression Rating Scale-24 scores and the Beck scale for suicide ideation. The secondary outcomes include the Depression Self-Rating Scale, Clinical Global ImpressionsScale, Asberg Antidepressant side effect scale and World Health Organization Quality of Life Questionaire abbreviated version. Magnetic resonance imaging data will be collected from each participant at baseline and each patient at the end of treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eThis study hypothesised that acupuncture therapy could treat DWSI by restoring the pathological center of suicidal ideation in brain. This study will clarify the mechanism of brain network regulation of DWSI by acupuncture.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration number\u003c/strong\u003e ChiCTR2200059267, registered on April 7, 2022.\u003c/p\u003e","manuscriptTitle":"Comparison of effects and brain imaging mechanisms of acupuncture and paroxetine for depressive patients with suicidal ideation: study protocol of a 20-week clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-02-02 16:06:10","doi":"10.21203/rs.3.rs-2409325/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d61ddd43-d271-47b0-bf64-a56f590ecced","owner":[],"postedDate":"February 2nd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-03-08T08:59:30+00:00","versionOfRecord":[],"versionCreatedAt":"2023-02-02 16:06:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2409325","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2409325","identity":"rs-2409325","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}