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

對兩組患者在接受治療后的血糖水平控制情況及治療效果進行統計、對比。①血糖水平控制情況包括對患者治療前后的空腹及餐后2 h血糖水平進行檢測、統計，空腹及餐后2 h血糖水平應分別控制在7.0 mmol/L及10 mmol/L范圍以下；②療效判定指標：顯效：經治療后，患者血糖水平控制較好，每日血糖波動不明顯；有效：經治療后，患者血糖水平獲得一定改善，且盡在餐后出現明顯血糖波動；無效：經治療后，患者血糖水平無明顯改善或加劇，且血糖水平處于較高波動狀態。

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.

主治醫生告訴楊女士，腸道息肉雖然是一種常見的疾病，但不積極治療仍會給身體帶來嚴重后果。據了解，目前已明確有相當高比例的大腸癌是從腸息肉一步一步“演化”過來的。

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.

選定滾轉角wz的模糊論域WZ={-2,-1,0,1,2}；模糊集為{NB,NS,Z,PS,PB}，分別對應“負大”、“負小”、“零”、“正小”、“正大”；隸屬度函數種類選擇為“trimf”，隸屬度函數參數分別為：[-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.

醫生落實知情同意制度不到位， 自費項目無“知情同意”。有些醫生沒有按照醫保政策執行自費項目知情確認制度，全自費的藥品、醫療材料、檢查、治療項目，沒有跟患者或家屬溝通征得其同意并簽字，沒能確保患者“知情同意”。究其原因，醫生專注于疾病本身的診治，對醫保政策不重視，忽視了費用方面的“知情同意”及“自費告知”，或不了解自費項目內容而忽略。導致患者醫保結算時對費用不滿，是患者投訴的主要因素。

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).

民國 《潼關縣新志》。該志成書于民國二十年（1931），是趙鵬超于民國二十年回故鄉避暑時主持編寫的。是志記事始于上古，迄于民國十九年。全書分兩卷，正文分八門（《地理志》《建置志》《田賦志》《官師志》《人物志》《選舉志》《兵事志》 和 《藝文志》），約七萬字。據《凡例》記載：“篇內資料，多取舊志”[3]，但趙鵬超在采用舊志史料的同時簡要地補入了嘉慶二十二年（1817）至民國十九年間（1930）的人事史料。其體例無創新之處，內容太簡。如人物、官師等門，對舊志刪十之七、八，新增亦常以“無事可記”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).

國土資源所檔案管理存在的問題和對策（張穎萍） ......................................................................................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日中國尿素出口價格指數（CNEI）為1992.61點，環比下跌62.62點，跌幅為3.05%；比基期上漲133.61點，漲幅為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