Efficacy of acupuncture at ghost points combined with fluoxetine in treating depression: A randomized study

INTRODUCTION

Depression affects approximately 4.4% of the global population and is characterized by persistent mood depression, physical symptoms, intellectual disability, cognitive impairment, and decreased activity. It not only has adverse effects on physical and mental health, but also increases social and economic burden[1]. While selective serotonin reuptake inhibitors, tricyclic antidepressants, and other Western medicine treatments have satisfactory clinical effectiveness, they also have significant side effects, such as dependency and withdrawal reactions[2].

Previous studies have reported significantly lower TCM syndrome scores in an acupuncture group compared to a fluoxetine group after 8 wk of treatment; a greater clinical efficacy was achieved with acupuncture treatment[19,20]. In addition, the incidence of adverse reactions in the acupuncture group (5.71%) was significantly lower than that in the fluoxetine group (25.71%). This suggested that acupuncture at ghost points combined with fluoxetine had a greater clinical efficacy than fluoxetine alone in patients with mild to moderate depression. The results of the present study provide additional evidence for the efficacy of acupuncture in the treatment of depression. Acupuncture exerts its effectsmultiple targets and mechanisms; these comprise the regulation of neurotransmitters and receptors, nerve plasticity, the neuroendocrine-immune network, and the brain-gut axis. This study demonstrated that the combined use of acupuncture and pharmacotherapy may provide synergistic benefits in patients with mild to moderate depression. Additional studies are warranted to further investigate the efficacy of different acupuncture and drug combinations.

MATERIALS AND METHODS

Patient recruitment and inclusion criteria

A total of 160 patients diagnosed with mild to moderate depression between January 2019 and December 2021 were recruited. Patients were included if they (1) met the diagnostic criteria for depression, according to the fifth edition of the American Handbook on Diagnosis and Statistics of Mental Disorders[4,5]; (2) had a score between 17 and 24 points on the 17-item Hamilton depression rating scale (HAMD);and (3) were between 19 and 75 years of age. The exclusion criteria were as follows:history of brain tumor or cerebrovascular disease; cardiac or pulmonary dysfunction;infectious diseases; dementia or Alzheimer’s disease; other mental disorders; history of craniocerebral trauma or surgery; and other serious diseases. The study protocol was approved by the appropriate medical ethics committee, and all patients provided written informed consent prior to examination and treatment.

Wade：You have a birth mark. So what? Why would that scare me?

Treatment methods

对两组患者在接受治疗后的血糖水平控制情况及治疗效果进行统计、对比。①血糖水平控制情况包括对患者治疗前后的空腹及餐后2 h血糖水平进行检测、统计，空腹及餐后2 h血糖水平应分别控制在7.0 mmol/L及10 mmol/L范围以下；②疗效判定指标：显效：经治疗后，患者血糖水平控制较好，每日血糖波动不明显；有效：经治疗后，患者血糖水平获得一定改善，且尽在餐后出现明显血糖波动；无效：经治疗后，患者血糖水平无明显改善或加剧，且血糖水平处于较高波动状态。

The Dazhui acupoint (GV14) is located in the spinal region (in the subspinous depression of the seventh cervical spine and on the posterior median line). The Jizhong(GV6) acupoint is located in the subspinal depression of the 11th thoracic spine and is on the posterior median line. The Mingmen (GV4) acupoint is located in the subspinous depression of the second lumbar spine and on the posterior midline. The Shaoshang (LU11) acupoint is located approximately 2.5 mm above the metacarpophalangeal joint of the finger, the radial side of the distal segment of the thumb and the medial side of the nail root. The Yinbai (SP1) acupoint is 2.5 mm posterior to the distal segment of the most medial toe, at the toenail corner.

The assessment of the neurophysiology and neuroanatomy of affective disorders with fMRI can be used to facilitate the diagnosis of depression. Some studies have suggested that fALFF and regional homogeneity values can be used as indicators forthe early diagnosis and monitoring of depression[13]. After 8 wk of treatment in the present study, the fALFF values of the left posterior cingulate gyrus, left precuneus,left middle occipital gyrus, and left inferior occipital gyrus were significantly lower in the acupuncture group than in the control group. In contrast, the fALFF values of the right inferior frontal gyrus, right insula, and right hippocampus in the acupuncture group were higher than those in the control group[14,15]. These results suggest that the combined use of acupuncture at ghost points and fluoxetine has a greater effect on the regulation of neurological function compared to fluoxetine alone when used in patients with mild to moderate depression[16]. Acupuncture combined with fluoxetine may play an antidepressant role by reducing the fALFF values of patients in the frontal lobe, middle frontal gyrus, parietal lobe, anterior central gyrus, precuneus, and parietal lobule, which are higher than those of healthy people. The combined use of acupuncture and fluoxetine affects a wider range of brain regions than fluoxetine alone, thus indicating that each treatment may regulate brain functiondifferent mechanisms. Acupuncture may have a more significant regulatory role in a greater number of brain regions compared to pharmacotherapy[17,18].

Each patient assumed a sitting position and routine local skin disinfection was performed. A 40-mm disposable stainless-steel needle with a diameter of 0.25 mm(Huatuo brand) was first applied at the Du meridian pointsthe flat needling method. Patients then assumed a supine position and direct needling (with the retaining needle applied for 30 min) was performed at ghost acupointsthe Shangxingping acupuncture method. All acupuncture operators previously underwent uniform training and all operative procedures were standardized. Needles were retained in place for 30 min, 5 times a week (10 times as an observation course); a total of three treatment cycles were administered.

主治医生告诉杨女士，肠道息肉虽然是一种常见的疾病，但不积极治疗仍会给身体带来严重后果。据了解，目前已明确有相当高比例的大肠癌是从肠息肉一步一步“演化”过来的。

Fluoxetine capsules (20 mg/d for adult and elderly patients) were administered orally in accordance with the psychiatrist’s instructions. If necessary, the dose was reevaluated and adjusted within the first 3–4 wk of treatment as higher doses increase the risk of adverse reactions. Some patients did not experience any obvious effects with a standard 20 mg dose; in such cases, doses were gradually increased to a maximum of 60 mg.

Resting-state fMRI scans were performed after routine scans to confirm the absence of organic brain lesions. A conventional structural image scan was performed using the T1 weighted image merge sequence. The scanning parameters were as follows:repetition time = 2300 ms; echo time = 2.2 ms; field-of-view = 256 mm × 256 mm; voxel= 1 mm × 1 mm × 1 mm; matrix = 256 × 256; number of layers = 192; number of excitations = 1; and a scanning time of approximately 5 min. The scanning parametersfor functional imaging using the echo planner imaging sequence were as follows:repetition time = 2000 ms; echo time = 30 ms; field-of-view = 220 mm; slice thickness =3.5 mm; layer spacing = 0.6 mm; voxel = 3.44 mm × 3.44 mm × 3.44 mm; fractional anisotropy = 90; matrix = 64 × 64; number of layers = 33 (using layer-by-layer scanning); number of excitations = 1; time points = 240; and a scanning time of approximately 8 min. Pre- and post-treatment evaluations of fMRI parameters were performed and comparisons were made between the groups.

选定滚转角wz的模糊论域WZ={-2,-1,0,1,2}；模糊集为{NB,NS,Z,PS,PB}，分别对应“负大”、“负小”、“零”、“正小”、“正大”；隶属度函数种类选择为“trimf”，隶属度函数参数分别为：[-3, -2, -1] ，[-2, -1, 0] ，[-1, 0 ,1] ，[0, 1, 2] ，[1, 2, 3] 。

Clinical parameters and detection methods

Clinical parameters comprised the HAMD, self-rating depression scale (SDS), and traditional Chinese medicine (TCM) syndrome score. The HAMD consists of 17 test items[6]. Higher scores reflect more severe depression. The absence of depression is indicated by a score < 7. A total score in the range of 7–17 suggests that a patient may have depression, while a score between 17 and 24 confirms the diagnosis of depression. A total score > 24 indicates severe depression.

医生落实知情同意制度不到位， 自费项目无“知情同意”。有些医生没有按照医保政策执行自费项目知情确认制度，全自费的药品、医疗材料、检查、治疗项目，没有跟患者或家属沟通征得其同意并签字，没能确保患者“知情同意”。究其原因，医生专注于疾病本身的诊治，对医保政策不重视，忽视了费用方面的“知情同意”及“自费告知”，或不了解自费项目内容而忽略。导致患者医保结算时对费用不满，是患者投诉的主要因素。

The SDS contains 20 items[7]. Norm data from the Chinese population defines mild,moderate, and severe depression by scores of 53, 53–62, and 63–72 points, respectively.The TCM syndrome score is based on the “Criteria for Diagnosis and Efficacy of TCM Symptoms”[8], which includes the three main syndromes of impatience and irritability, chest tightness, and rib distension. The secondary syndromes comprise headache, red eyes, bitter mouth, noise, constipation, and short yellow urine. Scores reflecting the severity of the main syndromes range from 0–6, while those for the secondary syndromes range from 0–3. Higher scores reflect greater syndrome severity.

The HAMD reduction rate ([before treatment - after treatment]/before treatment ×100%) was used to evaluate the treatment efficacy[9]. Reduction rates of ≥ 90,70%–89%, and ≤ 69% indicated that the treatments were markedly effective, effective,and ineffective, respectively.

Statistical analysis

The combined use of acupuncture at ghost points and fluoxetine may be more effective than fluoxetine alone for the treatment of patients with mild to moderate depression.At the same time, it has a better effect on improving the TCM syndrome of patients and regulating the neurological function of brain functional areas.

RESULTS

There were no significant differences in HAMD or SDS scores between the acupuncture and control groups, before or after 4 wk of treatment. After 8 wk of treatment, the acupuncture group exhibited significantly lower HAMD and SDS scores than the control group (< 0.05). Within-group comparisons showed that HAMD and SDS scores in both groups were significantly lower after 4 and 8 wk compared to those recorded before treatment (< 0.05) (Table 2).

民国 《潼关县新志》。该志成书于民国二十年（1931），是赵鹏超于民国二十年回故乡避暑时主持编写的。是志记事始于上古，迄于民国十九年。全书分两卷，正文分八门（《地理志》《建置志》《田赋志》《官师志》《人物志》《选举志》《兵事志》 和 《艺文志》），约七万字。据《凡例》记载：“篇内资料，多取旧志”[3]，但赵鹏超在采用旧志史料的同时简要地补入了嘉庆二十二年（1817）至民国十九年间（1930）的人事史料。其体例无创新之处，内容太简。如人物、官师等门，对旧志删十之七、八，新增亦常以“无事可记”省略。

Comparisons between the groups before and after 4 wk of treatment did not yield significant differences in fractional amplitude of low frequency fluctuations (fALFF)values of the left posterior cingulate gyrus, left posterior cingulate gyrus, left anterior wedge leaf, left middle occipital gyrus, left inferior occipital gyrus, right inferior frontal gyrus, right cerebral island, or right hippocampus. After 8 wk of treatment, the fALFF values of the left posterior cingulate gyrus, left anterior wedge leaf, left middle occipital gyrus, and left inferior occipital gyrus were significantly lower in the acupuncture group than in the control group (< 0.05). The fALFF values of the right inferior frontal gyrus, right insula, and right hippocampus in the acupuncture group were significantly higher than those in the control group (< 0.05) (Table 3). TCM syndrome scores before treatment were not significantly different between the groups(Table 4). Plasma adrenocorticotropic hormone (ACTH), cortisol, and corticotropinreleasing hormone levels were not significantly different between the acupuncture and control groups. After 8 wk of treatment, the plasma ACTH and cortisol levels in the acupuncture group were significantly lower than those in the control group (< 0.05)(Table 5). Within-group comparisons showed that the plasma ACTH, cortisol, and corticotropin-releasing hormone levels in the two groups were lower than those before treatment (< 0.05). After 8 wk of treatment, 51.25% of the acupuncture group showed improvement, the effective rate was 41.25%, and the ineffective rate was 7.50%. The effective rate of the control group was 36.25%, the effective rate was 50.00%, and the ineffective rate was 13.75% (Table 6). The clinical effectiveness of the acupuncture group was significantly higher than that of the control group (< 0.05) (Table 7).

国土资源所档案管理存在的问题和对策（张颖萍） ......................................................................................12-49

DISCUSSION

The pathophysiology of depression is currently unclear, despite prior investigations of the intestinal flora hypothesis and the role of neurotransmitters, neurotrophic factors,and neuroendocrine-immune interactions[10]. Pharmacotherapy is the primary treatment modality for depression. Selective serotonin reuptake inhibitors and tricyclic antidepressants act on neurotransmitters, cytokines, and their receptors, thereby modifying complex inflammatory pathways. Although such drugs are highly effective in reducing symptoms, they are also associated with adverse reactions and relapse after drug withdrawal[11].

TCM theory postulates that the underlying basis of depression is a poor mood due to Qi stagnation, which leads to dysfunction of the viscera. Thus, acupuncture treatment for patients with depression often uses acupoints associated with soothing of the liver and depression relief, as well as tranquilization of the heart and mind.These acupoints include Baihui, Yintang, and other governor vessels. The selection of acupoints in patients with mild to moderate depression in the present study was based on the unique theory of Shen’s acupuncture treatment for depression syndrome, whichinvolves “regulating yang and eliminating pathogenic factors”[12]. After 4 and 8 wk of treatment, the HAMD and SDS scores in both the acupuncture and control groups were significantly lower than those before treatment.

11月5日中国尿素出口价格指数（CNEI）为1992.61点，环比下跌62.62点，跌幅为3.05%；比基期上涨133.61点，涨幅为7.19%。

Patients in the acupuncture group had significantly lower HAMD and SDS scores than patients in the control group. This suggests that the long-term clinical effect of acupuncture at ghost points combined with fluoxetine is better than fluoxetine alone for the treatment of mild to moderate depression. The decrease in scores between weeks 4 and 8 was not as notable as that observed from baseline to week 4. This could be attributed to the fact that the scores for each scale have a lower limit; indeed, both HAMD and SDS scores had entered a relatively stable range after 8 wk of treatment,even approaching values observed in patients without depression.

The Laogong (PC8) acupoint is in the metacarpal region. It is oriented horizontally to the proximal third of the metacarpophalangeal joint, while the second and third metacarpal bones are inclined towards the third metacarpal bone. The Shenmai (BL62)acupoint is in the ankle region, below the tip of the lateral malleolus and in the depression between the lower edge of the lateral malleolus and the calcaneus.

Patients were randomly allocated to receive either (1) acupuncture at ghost points combined with fluoxetine (acupuncture group,= 80); or (2) fluoxetine alone (control group,= 80). The following acupoints were selected: governor vessel, Dazhui, spine,and Mingmen, combined with 13 ghost points on the star (flat thorn), people, less business, Yinbai, Laogong, and Shenmai (Table 1). Procedures were conducted in accordance with the national acupoint positioning standard for the selection of acupoints, acupoint positioning, and acupuncture depth, the “acupoint name and positioning” standard (GB/T12346-2006).

Acupuncture is an effective auxiliary method for the treatment of clinical depression. It mainly stimulates the nerve-related signaling pathway by adjusting neurotransmitter redistribution via the integration of the central nervous system, thus facilitating brain function through self-regulation of the human body. Nevertheless, its effect on prognosis remains to be further analyzed. While the results of a previous study have suggested that acupuncture can promote the onset of selective 5-hydroxytryptamine reuptake inhibitors and reduce adverse reactions[3], the related mechanistic interactions are currently unclear. Therefore, this study explored the effect of acupuncture at ghost points combined with fluoxetine on clinical indicators of depression and resting-state functional magnetic resonance imaging (fMRI)parameters in patients with mild to moderate depression.

CONCLUSION

The distributions of the HAMD scores, SDS scores, and fMRI parameters were tested for normality. Following confirmation of approximate normal distributions (expressed as “mean ± SD”), the-test was used for comparisons between the two groups.Enumeration data were expressed as(%). Thetest was used to compare nominal variables such as sex, combined diseases, and the presence of adverse reactions. The groups were compared in terms of ordinal variables using the Mann–Whitneytest to evaluate differences in clinical efficacy. The Statistical Package for Social Science version 21.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. The level of statistical significance was set at α = 0.05.

Grade D (Fair): 0