Online Submissions: http://www.journaltcm.com J Tradit Chin Med 2015 October 15; 35(5): 507-513 info@journaltcm.com ISSN 0255-2922 2015 JTCM. All rights reserved. CLINICAL STUDY TOPIC Effect of soothing-liver and nourishing-heart acupuncture on early selective serotonin reuptake inhibitor treatment onset for depressive disorder and related indicators of neuroimmunology: a randomized controlled clinical trial Liu Yi, Feng Hui, Mo Yali, Gao Jingfang, Mao Hongjing, Song Mingfen, Wang Shengdong, Yin Yan, Liu Wenjuan aa Liu Yi, Mo Yali, Mao Hongjing, Song Mingfen, Wang Shengdong, Yin Yan, Liu Wenjuan, Department of Psychiatry, Seventh People's Hospital of Hangzhou, Hangzhou 310013, China Feng Hui, Department of Gastroenterology, Hangzhou Red Cross Hospital, Hangzhou 310000, China Gao Jingfang, Department of Mental Health, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou 310000, China Supported by 2013 Traditional Chinese Medicine Scientific Research Fund of Zhejiang Province (Study on Enhancing Clinical Effect and Neuroimmunology Mechanism with Acupuncture Combined with SSRIs Treating Depressive Disorder, No. 2013ZB107); 2014 Traditional Chinese Medicine Scientific Research Fund of Zhejiang Province (the Effect of Acupuncture of Soothing-Liver and Nourishing-Heart Method on Early Onset of SSRIs Treating Depressive Disorder and Blood Monoamine Neurotransmitters Related, No. 2014ZB090) Correspondence to: Prof. Gao Jingfang, Department of Mental Health, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou 310000, China. gaojingfang2013@sina.com; Dr. Mao Hongjing, Department of Psychiatry, Seventh People's Hospital of Hangzhou, Hangzhou 310013, China. 13777861972@163.com Telephone: +86-15868486627 Accepted: January 19, 2015 Abstract OBJECTIVE: To observe the effect of soothing-liver and nourishing-heart acupuncture on selective serotonin reuptake inhibitor (SSRIs) treatment effect onset in patients with depressive disorder and related indicators of neuroimmunology. METHODS: Overall, 126 patients with depressive disorder were randomly divided into a medicine and acupuncture-medicine group using a random number table. Patients were treated for 6 consecutive weeks. The two groups were evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS) and Side Effects Rating Scale (SERS) to assess the effect of the soothing-liver and nourishing-heart acupuncture method on early onset of SSRI treatment effect. Changes in serum 5-hydroxytryptamine (5-HT) and inflammatory cytokines before and after treatment were recorded and compared between the medicine group and the acupuncture-medicine group. RESULTS: The acupuncture-medicine group had significantly lower MADRS scores at weeks 1, 2, 4, and 6 after treatment compared with the medicine group (P < 0.01). The acupuncture group had significantly lower SERS scores at weeks 1, 2, 4, and 6 after treatment compared with the medicine group (P < 0.01). At 6 weeks after treatment, serum 5-HT in the acupuncture-medicine group was significantly higher compared with the medicine group (P < 0.01). Interleukin-6 (IL-6) in the acupuncture-medicine group was significantly lower than that in the medicine group (P < 0.01), whereas there was no significant difference in IL-1β between the groups (P > 0.05). Anti-inflammatory cytokines IL-4 and IL-10 were significantly higher in the acupuncture-medicine group compared with the medicine group (P < 0.01, P < 0.05, respectively). CONCLUSION: The soothing-liver and nourish- JTCM www. journaltcm. com 507
ing-heart acupuncture method can effectively accelerate the onset of SSRI effects when treating depressive disorder and can significantly reduce the adverse reactions of SSRIs. Moreover, acupuncture can enhance serum 5-HT and regulate the balance of pro-inflammatory cytokines and anti-inflammatory cytokines. 2015 JTCM. All rights reserved. Key words: Acupuncture; Soothing-liver and nourishing-heart method; Early onset; Serotonin uptake inhibitors; Depressive disorder; Serotonin; Inflammatory cytokines; Randomized controlled trial INTRODUCTION Depressive disorders are a class of mental disease that have a high prevalence and recurrence rate. According to epidemiologic data, the prevalence of depressive disorder is 10%-20%, and the morbidity ratio of males to females is 1 2. 1,2 The recurrence rate of depressive disorder is 21% in 1 year, and 75% in 10 years. 3 Depressive disorder has a high morbidity and relapse rate and severely affects mentality, social life, work, and study. 4 Although there are nonpharmacologic treatments for depressive disorder, such as psychotherapy and electroconvulsive therapy, medicine therapy is most commonly used and is convenient in the three phases of the disease: the acute phase, the consolidation period, and the maintenance period. 5 Selective serotonin re-uptake inhibitors (SSRIs) are the most widely used fist-line treatments for depressive disorder, and more than 50% of worldwide antidepressant prescriptions are SSRIs. 6,7 However, SSRIs require 4-6 weeks or even more before treatment effects are obvious. 8 This period can lead to many disadvantages during the treatment course depression, such as symptoms remitting slowly, reduction in treatment compliance, and increased suicide risk. 9 Therefore, accelerating the onset of SSRI effect is very important for depression treatment. 10 We aimed to perform a randomized clinical trial to study the effect of the soothing-liver and nourishing-heart acupuncture method on the onset of SSRI treatment effect for depression and explore the related neuroimmunology mechanism. MATERIALS AND METHODS Study design The study was a randomized controlled clinical trial. Patients were randomized using a random number table. Patients were unaware of their group allocation. One hundred twenty-six outpatients were coded from number 1 to 126. Each coded patient number corresponded to a random number. Those patients with odd random numbers were allocated to the medicine group and those with even numbers were allocated to the acupuncture-medicine group. The study met the standards of medical ethics and was approved by the ethics committee of Seventh People's Hospital of Hangzhou. All patients signed an informed consent form. Standards of inclusion Patients were included if they: (a) met the diagnostic criteria for major depressive disorder or recurrent depressive disorder according to the International Statistical Classification of Diseases and Related Health Problem 10th Revision (ICD-10); (b) scored 12 points in the Montgomery-Asberg depression rating scale (MADRS); (c) were aged 18 to 60 years old; and (d) had not taken SSRIs within 4 weeks of study inclusion or stopped taking other antidepressants for more than 4 weeks. Standards of exclusion Patients were excluded if they: (a) had physical illnesses, organic brain diseases, or were dependent on medications or alcohol; (b) were pregnant or lactating; (c) had adverse or allergic reactions; or (d) had psychotic symptoms. Standards of suspension Patients were suspended from the study if they: (a) could not tolerate the acupuncture or SSRI treatment; (b) had serious adverse reactions during the study; (c) refused to be treated with acupuncture or SSRIs, or used other medicines or treatment during the study; (d) failed to visit; (e) willingly quit the study because of unexpected conditions; or (f) had poor obedience with incomplete data during the study. Grouping and treatment Overall, 126 patients with depressive disorder were randomly divided into the medicine group and the acupuncture-medicine group. Each group eventually had 60 patients, with 5 patients that dropped out of the study from the medicine group and 1 patient from the acupuncture-medicine group. Medicine group: patients with depressive disorder were randomly treated with fluoxetine (Lilly Pharmaceutical Limited Company, Suzhou, China), paroxetine (Glaxo- SmithKline Pharmaceutical Limited Company, Tianjin, China), citalopram (Lundbeck Pharmaceutical Limited Company, Xian, China), sertraline (Pfizer Pharmaceutical Limited Company, Dalian, China), or fluvoxamine (Abbott Pharmaceutical Limited Company, Chatillon Sur Chalaronne, France). The starting dose of fluoxetine, paroxetine, and citalopram was 20 mg/ d, and dose adjustment was 20-60 mg/d. The starting dose of sertraline was 50 mg/d, and dose adjustment was 50-200 mg/d. The starting dose of fluvoxamine was 50 mg/d, and dose adjustment was 50-300 mg/d. Medications were administered orally 1-2 times/d, and JTCM www. journaltcm. com 508
doses were adjusted based on clinical symptoms and medicine reactions. Treatments were maintained continuously for 6 weeks. Acupuncture-medicine group: The pharmaceutical treatment in the acupuncture-medicine group was identical to that of the medicine group. However, the soothing-liver and nourishing-heart acupuncture method was also performed on each patient. The following acupoints were selected: Taichong (LR 3), Ququan (LR 8), Qimen (LR 14), Danzhong (CV 17), Shuigou (GV 26), Neiguan (PC 6), Shenmen (HT 7), and Xinshu (BL 15). The selected points were aimed at dispersing stagnated liver Qi to relieve Qi stagnation and tranquilizing by nourishing the heart. The selected acupuncture points were operated by a dedicated doctor of traditional Chinese medicine. Disposable sterile acupuncture needles of Xinglin brand, 0.30 mm in diameter and 30 mm or 40 mm in length, were used for acupuncture (produced by Tianyuheng Technology Limited Company, Beijing, China). When needling, slow piercing, Taichong (LR 3), Ququan (LR 8), Qimen (LR 14), and Danzhong (CV 17) were operated by the neutral drainage method; and Shuigou (GV 26), Neiguan (PC 6), Shenmen (HT 7), and Xinshu (BL 15) were operated by the neutral supplementation method. Needles were retained for 30 min after De Qi. Patients received one acupuncture treatment every other day for 6 weeks. Assessment of clinical symptoms MADRS score: The MADRS score can precisely reflect changes in depressive symptoms, especially antidepressant effect. The scale includes 10 items, and each item has 7 levels (0-6 points). Ratings range from 0-60 points, with higher scores indicating more severe depression. The medicine group and the acupuncture-medicine group were assessed before treatment and at weeks 1, 2, 4, and 6 after treatment. Side Effects Rating Scale (SERS) score: SERS can clearly evaluate adverse effects of antidepressants. The scale includes 14 items, and each item has 4 levels (0-3 points). Ratings range from 0-42 points, with higher scores indicating more severe antidepressant adverse effects. The MADRS and SERS scores in each group were exclusively evaluated by an associate chief psychiatrist. Detection of biological indicators Serum 5-Hydroxytryptamine (5-HT) and inflammatory cytokines secreted by TH1/TH2: Both groups gave 6-ml fasting venous blood in 2% ethylene diamine tetra-acetic acid anticoagulant tube from 8:00-9:00 AM before treatment and at 6 weeks after treatment. After centrifuging at 3200 r/min for 5 min to remove the supernatant, serum was stored at -70 until use. Serum 5-HT, interleukin-1 beta (IL-1β), IL-6, IL-4, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA) at the Molecular Biology Laboratory of Seventh People's Hospital of Hangzhou after all the samples were collected. The 5-HT ELISA Kit was provided by US Biological Technology Limited Company (Swampscott, MA, USA). IL-1β, IL-6, IL-4, and IL-10 ELISA Kits were provided by MultiSciences Biotech Limited Company (Hangzhou, China). Statistical analysis SPSS 13.0 software (SPSS China Software Shanghai Limited Company, Shanghai, China) was used to process data in the study. Measurement data are expressed as mean ± standard deviation ( xˉ ± s). Independent samples t-test was used to compare measurement data. χ 2 test was used to compare enumeration data. P < 0.05 was regarded as a statistical difference. RESULTS Patients Overall, 126 outpatients with depressive disorder were divided into a medicine group and acupuncture-medicine group from January 2013 to October 2013 in Seventh People's Hospital of Hangzhou. There were 60 patients in the medicine group, 30 males and 30 females, aged (37 ± 10) years and depression duration (4 ± 4) months. There were 60 patients in the acupuncture-medicine group, 29 males and 31 females, aged (36 ± 10) years and depression duration (4 ± 3) months. There were no significant differences in sex, age, or depression duration between the two groups (P > 0.05) (Figure 1). MADRS score There was no significant difference in MADRS score before treatment between the medicine group and the acupuncture-medicine group (P > 0.05). Compared with MADRS scores before treatment, there was significant difference in MADRS score at 1, 2, 4, and 6 weeks after treatment in the medicine group (t week 1 = 4.14, P < 0.01; t week 2 = 6.03, P < 0.01; t week 4 = 10.13, P < 0.01; t week 6 = 14.00, P < 0.01), and there was a significant difference in MADRS score at weeks 1, 2, 4, and 6 after treatment in the acupuncture-medicine group (t week 1 = 6.99, P < 0.01; t week 2 = 14.60, P < 0.01; t week 4= 22.10, P < 0.01; t week 6 = 27.83, P < 0.01). There was a significant difference in MADRS score at 1, 2, 4, and 6 weeks after treatment between the two groups (P < 0.01) (Table 1). SERS score There was a significant difference in SERS scores at weeks 1, 2, 4, and 6 after treatment between two groups (P < 0.01) (Table 2). Serum 5-HT and inflammatory cytokines There were no significant differences in serum 5-HT between two groups before treatment (t = 0.14, P > 0.05). There was a significant difference in serum 5-HT between the medicine group and the acupuncture-med- JTCM www. journaltcm. com 509
Evaluated whether entry the study according to standard of inclusion and exclusion Randomization (n = 126) Medicine group (n = 65) Acupuncture-drug group (n = 61) Loss of follow up (n = 1) Dropout due to adverse reactions (n = 4) Loss of follow up (n = 1) Analyze inclusion (n = 60) Analyze the dropout reason Analyze inclusion (n = 60) Figure 1 Study flowchart Medicine group: treated with selective serotonin reuptake inhibitor (SSRIs) for 6 weeks, dose adjustment of fluoxetine, paroxetine, and citalopram 20-60 mg/d, sertraline 50-200 mg/d, fluvoxamine 50-300 mg/d. Acupuncture-medicine group: treated with SSRIs and the soothing-liver and nourishing-heart acupuncture method for 6 weeks. Table 1 Comparison of MADRS scores in patients with depressive disorder before treatment and after treatment between two groups ( xˉ ± s) Time point Before treatment 1 week 2 week 4 week 6 week Medicine (n = 60) 26±3 23±3 a 21±5 a 18±5 a 15±5 a icine 6 weeks after treatment (t = 3.78, P < 0.01). There was no significant difference in IL-1β between Acupuncture-medicine (n = 60) 25±3 22±3 bc 18±3 bc 14±3 bc 11±3 bc the two groups before treatment (t = 0.21, P > 0.05). There was no significant difference in IL-1β between JTCM www. journaltcm. com 510 t value 0.652 3.784 4.606 5.637 5.739 P value Notes: medicine group: treated with selective serotonin reuptake inhibitor (SSRIs) for 6 weeks, dose adjustment of fluoxetine, paroxetine, and citalopram 20-60 mg/d, sertraline 50-200 mg/d, fluvoxamine 50-300 mg/d. Acupuncture-medicine group: treated with SSRIs and the soothing-liver and nourishing-heart acupuncture method for 6 weeks. MADRS: montgomery-asberg depression rating scale. Compared with MADRS score before treatment, at 1, 2, 4, and 6 weeks after treatment, in the medicine groups, a P < 0.01, in the acupuncture-medicine group, b P < 0.01; compared with MADRS score at 1, 2, 4, and 6 weeks after treatment in the medicine group, at the corresponding time points in the acupuncture-medicine group, c P < 0.01. Table 2 Comparison of SERS scores in patients with depressive disorder after treatment between two groups ( xˉ ± s) Time point 1 week 2 week 4 week 6 week Medicine (n = 60) 9.8±2.6 8.9±2.6 7.9±2.6 7.0±2.6 Acupuncture-medicine (n = 60) 7.5±2.9 a 5.7±3.0 a 3.9±2.7 a 2.8±2.4 a t value 4.46 6.14 8.41 9.27 0.516 P value Notes: medicine group: treated with selective serotonin reuptake inhibitor (SSRIs) for 6 weeks, dose adjustment of fluoxetine, paroxetine, and citalopram 20-60 mg/d, sertraline 50-200 mg/d, fluvoxamine 50-300 mg/d. Acupuncture-medicine group: treated with SSRIs and the soothing-liver and nourishing-heart acupuncture method for 6 weeks. 1 week: assessed at 1 week after treatment by SERS score; 2 week: assessed at 2 weeks after treatment by SERS score; 4 weeks: assessed at 4 weeks after treatment by SERS score; 6 weeks: assessed at 6 weeks after treatment by SERS score. SERS: rating scale for side effects; SSRIs: selective serotonin reuptake inhibitors. Compared with SERS score of medicine group at 1, 2, 4, and 6 weeks after treatment, at the corresponding time points in the acupuncture-medicine group, a P < 0.01.
the two groups 6 weeks after treatment (t = 0.22, P > 0.05). There was no significant difference in IL-6 between the medicine group and the acupuncture medicine before treatment (t = 0.46, P > 0.05). There was a significant difference in IL-6 between the two groups 6 weeks after treatment (t = 10.12, P < 0.01). There was no significant difference in IL-4 between the medicine group and the acupuncture-medicine before treatment (t = 0.07, P > 0.05). There was a significant difference in IL-4 between the two groups 6 weeks after treatment (t = 12.79, P < 0.01). There was no significant difference in IL-10 between the medicine group and the acupuncture-medicine before treatment (t = 0.16, P > 0.05). There was a significant difference in IL-10 between the two groups 6 weeks after treatment (t = 2.30, P < 0.05) (Table 3). DISCUSSION Currently, the first-line treatments in Western Medicine for depressive disorder are atypical antidepressants. SSRIs, a class of atypical antidepressants, account for more than 50% of antidepressant prescriptions worldwide. 11 Psychopharmacologically, SSRIs selectively inhibit 5-HT reuptake in the presynaptic neurons, but do not affect norepinephrine or dopamine. SSRIs have some adverse reactions and have a slow onset of treatment effect, which can cause problems in clinical treatment. Patients may not have relief of depressive symptoms and must bear some adverse reactions, which delays the patients' physiological, psychological and social recovery time. These problems lead to prolonged treatment, decreased adherence, and an increased risk of suicidal behavior. 9,12 Given the disadvantage of onset delay and adverse reactions, Chinese medicine in the treatment of depressive disorder has been increasingly focused, researched, and applied. Specifically, acupuncture in the treatment of depressive disorder has shown some advantages. 13 Acupuncture can influence the endogenous synthesis and metabolism of neuro-endocrine-immune substances via its mechanical stimulation. This effect can stimulate the body's self-healing capabilities. 14 Clinical studies have shown that, apart from the core symptoms of depression, acupuncture can significantly improve its accompanying symptoms including anxiety, sleep disorders, appetite disorders, and cognitive impairment. Furthermore, acupuncture shows fewer adverse reactions, good tolerance, and high compliance. However, acupuncture alone cannot adequately improve the core symptoms of moderate to severe depressive disorder. 15,16 Nevertheless, acupuncture combined with antidepressant therapy could mutually enhance their advantages and complement their disadvantages. 17 Clinical studies have shown that acupuncture combined with antidepressant therapy is clinically effective and has fewer adverse reactions. However, most studies involve acupuncture combined with a certain antidepressant, and studies on acupuncture combined with a class of antidepressant like SSRIs are rarer. Furthermore, the effect of acupuncture on the early onset of SSRIs treatment has not been reported at present. 18 In this study, we combined the broad treatment characteristics of acupuncture with the single neurotransmitter target of SSRIs to treat depressive disorder. We found that acupuncture combined with SSRIs has certain clinical advantages. After 6 weeks of treatment, the MADRS score in the acupuncture-medicine group was lower than that of the medicine group, which indicated that the soothing-liver and nourishing-heart acupuncture method can effectively accelerate the treatment effects of SSRIs. After 6 weeks of treatment, the SERS score in the acupuncture-medicine group was lower than that of the medicine group, which indicated that the soothing-liver and nourishing-heart acupuncture method can significantly decrease the number of SSRI adverse reactions. Although the sample size was somewhat small, acupuncture could reduce the dropout rate because of SSRI adverse reactions. Therefore, for the shortcomings of SSRIs, such as early onset and adverse reactions, can be ameliorated with the soothing-liver Table 3 Comparison of serum 5-HT and inflammatory cytokines secreted by TH1/TH2 in patients with depressive disorder before treatment and 6 weeks after treatment ( xˉ ± s) Index 5-HT (mmol/l) IL-1β (pg/ml) IL-6 (pg/ml) IL-4 (pg/ml) IL-10 (pg/ml) Before treatment 17.1±5.7 5.2±0.8 6.9±0.8 2.8±0.6 98.9±17.0 Medicine (n = 60) At 6 weeks after treatment 21.0±5.5 4.2±0.8 4.8±0.8 5.8±0.6 111.6±19.9 Acupuncture-medicine (n = 60) Before treatment 16.9±5.6 a 5.2±0.9 a 6.8±0.8 a 2.8±0.6 a 99.3±16.6 a At 6 weeks after treatment 24.9±5.7 b 4.2±0.8 c 3.3±0.8 b 7.3±0.6 b 118.9±14.2 d Notes: medicine group: treated with selective serotonin reuptake inhibitor (SSRIs) for 6 weeks, dose adjustment of fluoxetine, paroxetine, and citalopram 20-60 mg/d, sertraline 50-200 mg/d, fluvoxamine 50-300 mg/d. Acupuncture-medicine group: treated with SSRIs and the soothing-liver and nourishing-heart acupuncture method for 6 weeks. 5-HT: 5-hydroxytryptamine; IL-1β: interleukin-1 beta; IL-6: interleukin-6; IL-4: interleukin-4; IL-10: interleukin-10; SSRIs: selective serotonin reuptake inhibitors. Compared with the medicine group before treatment, a P > 0.05; compared with the medicine group 6 weeks after treatment, b P < 0.01, c P > 0.05, and d P < 0.05. JTCM www. journaltcm. com 511
and nourishing-heart acupuncture method. Moreover, the soothing-liver and nourishing-heart acupuncture method combined with SSRIs can increase confidence and reduce the risk of early suicide in depression. Although studies have shown that acupuncture can improve many symptoms in depressive disorders, the pattern identification in depressive disorder and typing and selection of acupuncture points is not uniform. Many studies have not proposed treatment laws for depressive disorder according to the literature. 19 According to a clinical study on pattern identification and typing of depressive disorder, depressive disorder is mainly related to the heart and liver, disharmony of the hepatic Qi, restlessness of the cardiac Qi, flaming of the cardiac fire, phlegm confusing the mind, and disharmony of channels and their collateral channels. These patterns accounted for 67.7% of the total pattern identification and typing of depressive disorder. 20,21 Therefore, the soothing-liver and nourishing-heart method should be used to treat depressive disorder. Research has shown that the pathogenesis of depressive disorder is not because of single neurotransmitter conduction disorders, but neuro-endocrine-immune system disorders. 11,22 A number of studies have confirmed that depressive disorder includes neuroimmune dysfunction. In fact, the "inflammatory response system model of depression," hypothesizes that depression is related to the activation of the inflammatory response system, which is a neuroimmune disorder. The peripheral immune activation occurs via the release of various inflammatory cytokines associated with depression causing neuroendocrine and neurochemical changes and interactions. 23,24 Therefore, depressive disorder not only results in low serum 5-HT but also immune imbalances, which mainly results in pro-inflammatory and anti-inflammatory cytokine imbalances secreted by TH1/ TH2. 25,26 Studies have shown that the proinflammatory cytokines IL-1β and IL-6 are harmful to controlling depressive symptoms, 27 and the anti-inflammatory cytokines IL-4 and IL-10 are beneficial to alleviating depressive symptoms. 28 Therefore, depressive disorders can be caused by the balance of proinflammatory and anti-inflammatory cytokines. 29 Most studies have shown that acupuncture can improve depression from the perspective of clinical symptomatology, but fewer have explored the treatment mechanism of depressive disorder regarding the neuro-endocrine system in its acute phase. 18 We found that, compared with single SS- RI treatment, the soothing-liver and nourishing-heart acupuncture method combined with SSRIs can not only improve serum 5-HT faster, but also more effectively reduce pro-inflammatory cytokines secreted by TH1 and increase anti-inflammatory cytokines secreted by TH2. This effect could explain the acceleration of SS- RI treatment effect. In conclusion, this study made use of the broad characteristics of acupuncture from Traditional Chinese Medicine to regulate the neuroimmune system and the single neurotransmitter target SSRIs to treat depressive disorder. The results showed that the soothing-liver and nourishing-heart acupuncture method can effectively accelerate the onset of SSRI treatment effects on depressive disorder and significantly reduce the adverse reactions of SSRIs. Furthermore, the mechanism of inflammatory factors in acupuncture combined with SS- RIs on depressive disorder was discussed. However, there are still some points worth further study. First, this study detected samples of peripheral blood 5-HT, which may not be fully representative of synaptic gap 5-HT. Second, the effect of acupuncture combined with other antidepressants has not been studied. 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