Acupuncture on 5-hydroxytryptamine levels and clinical outcomes in depression: A systematic review and meta-analysis of randomized controlled trials

Abstract

BACKGROUND

Depression is a prevalent global mental health issue with substantial disease burden. Although pharmacotherapy remains the first-line treatment, its efficacy and tolerability are limited. Acupuncture, a core modality in traditional Chinese medicine, has shown promise in improving depressive symptoms via neurotransmitter modulation. However, prior meta-analyses often considered manual and electroacupuncture together, increasing heterogeneity. This review focuses solely on traditional acupuncture to clarify its therapeutic role and provide evidence for standardized clinical application.

AIM

To evaluate the efficacy of acupuncture in patients with depression and explore its feasibility as an adjunctive treatment.

METHODS

Twenty randomized controlled trials on traditional acupuncture for depression—whose quality was assessed using the Cochrane tool—were included in this meta-analysis. Primary outcomes were the Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory-II (BDI-II), Self-Rating Depression Scale (SDS), and Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes were the Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAMA), Self-Rating Scale for the Side Effects (SERS), and serum 5-hydroxytryptamine (5-HT) levels. RevMan 5.4 software was employed for the meta-analysis.

RESULTS

Results revealed that acupuncture significantly reduced HAM-D, SDS, and MADRS scores. Although BDI-II scores improved in some studies, its overall effect was not statistically significant. Acupuncture also significantly improved HAMA and PSQI scores and increased serum 5-HT levels. Notably, SERS analysis indicated that acupuncture can significantly alleviate adverse reactions associated with antidepressants. However, most pooled results revealed substantial heterogeneity.

CONCLUSION

The efficacy of traditional acupuncture improving symptoms, sleep, and anxiety and alleviating antidepressant side effects is highly encouraging. However, the low quality of the included studies warrants cautious interpretation.

Key Words: Acupuncture; Depression; Meta-analysis; 5-hydroxytryptamine; Sleep disturbance; Anxiety

Core Tip: This meta-analysis focused exclusively on traditional manual acupuncture, excluding electroacupuncture, to determine its independent therapeutic effect on depression. Twenty randomized controlled trials were included. The findings reveal that acupuncture significantly improves depressive symptoms, anxiety, sleep quality, and serum 5-hydroxytryptamine levels, while reducing antidepressant-related side effects. By eliminating heterogeneity caused by different acupuncture modalities, this study provides stronger evidence for the clinical application of acupuncture as an effective adjunctive therapy for depression.

INTRODUCTION

Globally, depression is recognized as a leading mental health issue significantly affecting patients’ emotional well-being, cognition, and social functioning. Its close association with cardiovascular diseases and suicide risk contributes substantially to the global burden of disease[1,2]. Nearly 3.8% of the world’s population is estimated to suffer from depression[3]. In China, the incidence of depressive disorders has been increasing in recent years, with a reported lifetime prevalence of 6.8% among adults[4]. However, because of the concealed nature of the condition and societal stigma, the actual diagnostic rate may be lower than its prevalence.

Currently, the primary treatment options for depression include pharmacotherapy, psychotherapy, and physical therapies. First-line pharmacological treatments typically consist of noradrenergic and specific serotonergic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors[5]. However, the therapeutic efficacy of these antidepressants varies considerably among individuals. A systematic review reported that up to 40% of patients with depression poorly respond to existing antidepressants or even develop treatment resistance[6]. Additionally, these drugs frequently cause side effects, such as nausea, fatigue, sexual dysfunction, and weight change, causing some patients to discontinue treatment because of poor tolerability[7]. These limitations have spurred the search for alternative treatments that are not only effective but also better tolerated.

Acupuncture—a core element in traditional Chinese medical systems—has been widely used as an adjunct therapy for various conditions. Earlier research has confirmed its therapeutic benefits in managing common psychiatric-related disorders such as insomnia, anxiety, and perimenopausal syndrome[8-10]. Over the past few years, a growing number of clinical and basic studies have suggested that acupuncture may have a beneficial effect on depressive symptoms. The underlying mechanisms may not only involve the modulation of neurotransmitters, such as 5-hydroxytryptamine (5-HT), norepinephrine, and dopamine, but also the enhancement of brain-derived neurotrophic factor expression[11]. Although several systematic reviews and meta-analyses have preliminarily confirmed the effectiveness of acupuncture in treating depression, most do not clearly distinguish between different acupuncture modalities, such as manual and electroacupuncture[12-14]. The latter combines traditional needling with electrical stimulation, differing from the former in terms of stimulation intensity and underlying mechanisms, potentially impacting both efficacy and comparability[15]. Therefore, combining different acupuncture techniques in pooled analyses may introduce heterogeneity and bias, affecting the credibility and applicability of the results.

Therefore, this research intends to comprehensively assess the therapeutic effectiveness and safety profile of acupuncture in managing depression. Trials involving only electroacupuncture were explicitly excluded during study selection to better capture the specific effects of traditional acupuncture. This review seeks to provide evidence-based support for the standardized application of acupuncture in clinical practice for depression.

MATERIALS AND METHODS

Data sources and eligibility criteria

To ensure comprehensive coverage, we searched multiple global databases—including EMBASE, PubMed, MEDLINE, Cochrane Library, and ClinicalTrials.gov—to identify studies that met our eligibility criteria. The inclusion criteria were: Randomized controlled trials (RCTs) involving patients with a confirmed diagnosis of any type of depression and studies in which the intervention group received acupuncture and the control group received a comparator, with both groups sharing the same basic treatment measures (e.g., sham acupuncture, Western medicine, physical therapy, psychological intervention, or no additional treatment). No restriction on publication language was imposed. The exclusion criteria were: Studies that were not RCTs, duplicate publications, studies in which sham acupuncture involved skin penetration, studies only using electroacupuncture, publications available only in abstract form, and studies that did not provide specific or accurate data. No review protocol was registered or published for this study.

Search strategy

The search was conducted in English only. The time frame was set from the inception of each database to June 2025, ensuring the inclusion of all potentially relevant studies. A combination of free-text keywords was used retrieve the maximum number of studies related to depression and acupuncture. Keywords included “major depressive disorder”, “depression”, “depressive disorder”, “depressive symptoms”, “depressive episode”, “acupuncture”, “manual acupuncture”, “needle acupuncture”, “serotonin”, “5-HT”, and “5-hydroxytryptamine”. Additional databases were searched to identify clinical trial data from unpublished or grey literature. Literature screening and data extraction were independently performed by two reviewers to minimize bias and enhance study quality. Conflicts in study selection were resolved by consulting with a third reviewer.

Data extraction and risk of bias assessment

Each included study was independently assessed by two reviewers to extract key data, including the first author’s name, year of publication, country or region, sample size, type of depressive disorder, intervention details for both groups, outcome data, and quality-related information. The risk of bias of all included studies was assessed using the Cochrane risk of bias tool[16], which revealed whether each study was classified as having a low, unclear, or high risk of bias. Risk of bias assessment was conducted separately by two reviewers. Any discrepancies were resolved through discussion with a third reviewer until a consensus was reached.

Outcome

Improvement in depressive symptoms was the primary outcome of this study. This was assessed using multiple validated scales: The Self-Rating Depression Scale (SDS), Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory-II (BDI-II), and Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included changes in anxiety symptoms and sleep quality, evaluated using the Pittsburgh Sleep Quality Index (PSQI) and the Hamilton Anxiety Rating Scale (HAMA). Safety outcomes were assessed using the Self-Rating Scale for the Side Effects (SERS). Additionally, some studies reported serum 5-HT levels as a biological marker to objectively reflect changes resulting from the intervention.

Statistical analysis

Data analysis was performed using RevMan 5.4. All included outcomes were continuous variables, analyzed using mean differences (MDs) with 95% confidence intervals. Heterogeneity was assessed using the I² statistic: I² ≤ 25% indicated low heterogeneity, and a fixed-effect model was applied; I² ≤ 50% indicated moderate heterogeneity, and either a fixed-effect or random-effects model was selected based on the specific context; I² > 50% indicated substantial heterogeneity, and a random-effects model was used[17]. A subgroup analysis was performed to compare the effects of acupuncture combined with antidepressants vs antidepressants alone. To assess potential publication bias of the primary outcomes, funnel plots were generated for outcomes with sufficient studies and Egger’s regression tests were performed using the metafor package in R 4.4.3.

RESULTS

Systematic review of included studies

A total of 20 studies, encompassing 1971 individuals, were incorporated into the meta-analysis, as presented in Figure 1 and Table 1[18-37]. The studies were published between 2011 and 2025. Among them, 18 were conducted in China[19-24,26-37], 1 in the United Kingdom[25], and 1 in the Netherlands[18]. Nine were published in English[18,23,25,26,28,29,34,36,37] and eleven in Chinese[19-22,24,27,30-33,35]. As depicted in Figure 2, the risk of bias for most studies was assessed to be low for random sequence generation. However, many studies[18-22,24,27,28,30] had unclear risk regarding allocation concealment. Notably, owing to the inherent difficulty of blinding in acupuncture interventions, all studies demonstrated an unavoidable risk of bias in blinding of participants and personnel. The majority of studies were assessed to have low or uncertain risk regarding incomplete outcome data and selective reporting.

Figure 1  Flow diagram of study selection process.

Figure 2  Risk of bias assessment for included randomized controlled trials.

Table 1 Characteristics of included randomized controlled trials.

Ref.	Country or region	Language	Diagnosis	Sample size (intervention/control)	Control	Intervention	Frequency and duration of intervention	Follow-up	Outcomes
Bosch et al[18], 2015	The Netherlands	English	Depression	25/25	Wait-list control	Acupuncture	Weekly, 12 consecutive treatments	-	BDI-II
Gao et al[19], 2023	China	Chinese	Depression	36/35	SSRIs	Acupuncture + HAMA	3 times a week, continuous treatment for 8 weeks	12 weeks	HAMA
Huang et al[20], 2013	China	Chinese	Depressive episode	30/30	SSRIs	Acupuncture + SSRIs	3 times a week, continuous treatment for 6 weeks	-	HAM-D-17, SDS, SERS
Liu et al[21], 2013	China	Chinese	Depressive episode	45/45	SSRIs	Acupuncture + SSRIs	Treatment once in 2 days, continuous treatment for 4 weeks	-	HAM-D-17, SERS
Liu et al[22], 2015	China	Chinese	Depression episode	45/45	SSRIs	Acupuncture + SSRIs	Treatment once in 2 days, continuous treatment for 4 weeks	-	HAM-D-17, 5-HT
Liu et al[23], 2015	China	English	Depressive disorder	60/60	SSRIs	Acupuncture + SSRIs	Treatment once in 2 days, continuous treatment for 6 weeks	-	MADRS, SERS, 5-HT
Liu et al[24], 2018	China	Chinese	Depression	21/21	Fluoxetine hydrochloride	Acupuncture + fluoxetine hydrochloride	Once a day for the first 3 days and once every 3 days thereafter for a total of 8 weeks	-	SDS, MADRS
MacPherson et al[25], 2013	United Kingdom	English	Depression	294/128	Usual care	Acupuncture + usual care	1 session per week, up to 12 weeks	12 months	BDI-II
Qu et al[26], 2013	China	English	Major depressive disorder	51/43	Paroxetine	Manual acupuncture + paroxetine	3 sessions per week over 6 consecutive weeks	4 weeks	HAM-D-17, SDS
Wang et al[27], 2019	China	Chinese	Depression	30/30	Venlafaxine	Acupuncture + venlafaxine	3 times a week for 12 weeks	-	HAM-D-17, SERS
Wong et al[28], 2021	HKSAR, China	English	Depression	40/20	Wait-list control	Acupuncture	Twice per week for 3 consecutive weeks	-	HAM-D-17
Wu et al[29], 2025	China	English	Major depressive disorder	36/36	SSRIs	Intradermal acupuncture + SSRIs	Treatment for 10 times within 6 weeks	10 weeks	HAM-D-17, SDS
Xu et al[30], 2011	China	Chinese	Depressive episode	25/30	SSRIs	Acupuncture + SSRIs	3 times a week for 6 weeks	-	HAM-D-17
Yan et al[31], 2023	China	Chinese	Depressive disorder	30/30	Sertraline	Acupuncture + sertraline	3 sessions per week over 8 consecutive weeks	-	SDS
Yan et al[32], 2023	China	Chinese	Depressive disorder	29/28	False acupuncture + low-frequency rTMS	Acupuncture + low-frequency rTMS	3 times a week for 4 weeks	-	HAM-D-17
Yin et al[33], 2022	China	Chinese	Post-stroke depression	30/29	Western medicine + rTMS	Acupuncture + Western medicine + rTMS	5 times a week for 4 weeks	-	HAM-D-17, PSQI
You et al[34], 2020	China	English	Post-stroke depression	34/33	Sham wrist-ankle acupuncture + Fluoxetine	Thin wrist-ankle acupuncture + fluoxetine	6 days a week, a total of 4 weeks	8 weeks	HAM-D-17, SDS
Zhang et al[35], 2018	China	Chinese	Depression	30/30	Five elements music	Acupuncture + five elements music	5 days a week for 8 weeks	-	HAM-D-17, HAMA
Zhao et al[36], 2019	China	English	Depressive disorder	157/155	SSRIs	Manual acupuncture + SSRIs	3 times a week for 6 weeks	10 weeks	HAM-D-17, SDS, SERS
Zhao et al[37], 2023	China	English	Depressive episode	35/35	Sham-acupuncture	Real-acupuncture	17 sessions for eight consecutive weeks	16 weeks	HAM-D-17, PSQI, HAMA

BDI-II: Beck Depression Inventory-II; HAMA: Hamilton Anxiety Rating Scale; HAM-D: Hamilton Depression Rating Scale; MADRS: Montgomery-Åsberg Depression Rating Scale; PSQI: Pittsburgh Sleep Quality Index; SERS: Self-Rating Scale for the Side Effects; SDS: Self-Rating Depression Scale; SSRI: Selective serotonin reuptake inhibitor; rTMS: Repetitive transcranial magnetic stimulation; 5-HT: 5-hydroxytryptamine.

Improvement in HAM-D scores

As depicted in Figure 3A, 12 studies[20-22,27,28,30,32-37] explicitly reported HAM-D outcomes. Owing to substantial heterogeneity (I² = 96%), a random-effects model was used for the pooled analysis. The findings revealed that participants in the acupuncture group demonstrated significantly greater improvement in HAM-D scores than did those in the control group (MD = -2.82, P < 0.0001). Additionally, as depicted in Figure 3B, two studies[26,29] that reported only the change in HAM-D scores also favored the acupuncture group (MD = -4.21, P < 0.0001), albeit with considerable heterogeneity (I² = 70%). To investigate potential sources of high heterogeneity in HAM-D scores, we conducted a leave-one-out sensitivity analysis. As shown in Figure 3C, after sequentially excluding individual studies, the direction and statistical significance of the pooled effect size remained essentially unchanged, indicating that the results of this meta-analysis are robust.

Figure 3 Meta-analysis of acupuncture for Hamilton Depression Rating Scale scores. A: Forest plot of studies reporting Hamilton Depression Rating Scale (HAM-D) scores; B: Forest plot of studies using HAM-D change scores; C: Leave-one-out sensitivity analysis forest plot of Figure 3A; D: Funnel plot for publication bias. 95%CI: 95% confidence interval.

Figure 4 Meta-analysis of Hamilton Depression Rating Scale and Self-Rating Scale for the Side Effects scores in acupuncture plus antidepressant treatment. A: Forest plot of studies comparing antidepressants alone vs acupuncture combined with antidepressants (Hamilton Depression Rating Scale scores); B: Forest plot of studies using Self-Rating Scale for the Side Effects scores; C: Leave-one-out sensitivity analysis forest plot of Figure 4A; D: Leave-one-out sensitivity analysis forest plot of Figure 4B. 95%CI: 95% confidence interval.

Figure 5 Meta-analysis of Self-Rating Depression Scale scores. A: Forest plot of studies reporting Self-Rating Depression Scale (SDS) total scores; B: Forest plot of studies reporting SDS change scores; C: Leave-one-out sensitivity analysis forest plot of Figure 5A. 95%CI: 95% confidence interval.

Figure 6 Meta-analysis of Montgomery-Åsberg Depression Rating Scale and Beck Depression Inventory-II scores. A: Forest plot of studies reporting Beck Depression Inventory-II scores; B: Forest plot of studies reporting Montgomery-Åsberg Depression Rating Scale scores. 95%CI: 95% confidence interval.

Figure 7 Meta-analysis of Hamilton Anxiety Rating Scale and Pittsburgh Sleep Quality Index scores. A: Forest plot of studies reporting Hamilton Anxiety Rating Scale scores; B: Forest plot of studies reporting Pittsburgh Sleep Quality Index scores; C: Leave-one-out sensitivity analysis forest plot of Figure 7A. 95%CI: 95% confidence interval.

Figure 8  Meta-analysis of serum 5-hydroxytryptamine.

Comparison between acupuncture combined with antidepressants and antidepressants alone

As depicted in Figure 4A, a subgroup analysis including eight studies was conducted to explore the difference between acupuncture combined with antidepressants and antidepressants alone in the treatment of depression[20-22,27,30,33,34,36]. The results revealed that the combination therapy was significantly more effective in improving HAM-D scores than was the medication alone (MD = -2.69, P < 0.0001), although heterogeneity remained high (I² = 88%). Additionally, Figure 4B depicts the results for SERS scores, which assess adverse effects. A pooled analysis of five studies[20,21,23,27,36] demonstrated that the total adverse reaction scores in the combination group were significantly lower than in the medication-only group (MD = -3.05, P = 0.001), suggesting the potential for acupuncture to alleviate antidepressant-related side effects, despite substantial heterogeneity (I² = 92%). To investigate the potential sources of high heterogeneity in the HAM-D subgroups and SERS, we conducted a sensitivity analysis. As shown in Figure 4C and D, the direction and statistical significance of the pooled effect size remained largely unchanged after sequentially excluding individual studies, indicating that the results of this meta-analysis are robust.

Improvement in SDS scores

As depicted in Figure 5A, five studies[20,24,31,34,36] were included in the analysis of SDS scores. The results revealed that the acupuncture group demonstrated a significantly greater reduction in SDS scores than did the control group (MD = -8.85, P = 0.001), suggesting a marked improvement in patients’ subjective depressive experience, although the heterogeneity was substantial (I² = 94%). Furthermore, as shown in Figure 5B, two studies[26,29] that reported SDS change scores were analyzed that also revealed a greater improvement in the acupuncture group (MD = -8.22, P = 0.04). Despite the small sample size, these findings provide additional support for the efficacy of acupuncture. To investigate the sources of high heterogeneity in SDS, we conducted a sensitivity analysis. As shown in Figure 5C, after sequentially excluding individual studies, the direction and statistical significance of the pooled effect size remained unchanged.

Improvement in BDI-II and MADRS scores

As depicted in Figure 6A, two studies[18,25] assessed depressive symptoms using the BDI-II scale. The pooled analysis revealed no statistically significant difference between the acupuncture and control groups (MD = -1.99, P = 0.36), with moderate heterogeneity (I² = 42%), suggesting inconsistent efficacy of acupuncture using this measure. In contrast, as depicted in Figure 6B, the pooled analysis of two studies[23,24] using the MADRS scale demonstrated that the acupuncture group showed significantly greater improvement than did the control group (MD = -6.34, P = 0.01), although heterogeneity was high (I² = 90%). These results indicate that acupuncture may have a beneficial effect on relieving depressive symptoms, which warrants further investigation.

Improvement in anxiety and sleep scores

Regarding anxiety symptoms, as depicted in Figure 7A, an analysis of three studies[19,35,37] revealed that acupuncture significantly reduced HAMA scores (MD = -2.76, P = 0.04), suggesting its potential regulatory effect on anxiety, although heterogeneity remained high (I² = 89%). As depicted in Figure 7B, two studies[33,37] evaluating sleep quality demonstrated a significant reduction in PSQI scores in the acupuncture group compared to the control group (MD = -1.94,P = 0.02), indicating that acupuncture may improve sleep and thereby, indirectly, contribute to relieving depressive symptoms; however, heterogeneity remained substantial (I² = 87%). To investigate the sources of high heterogeneity in HAMA scores, we conducted a sensitivity analysis. As shown in Figure 7C, the direction of the pooled effect size remained unchanged after sequentially excluding individual studies.

Improvement in serum 5-HT levels

As depicted in Figure 8, two studies[22,23] reporting changes in 5-HT levels following acupuncture intervention were included. A fixed-effect model was used for analysis, and the results revealed that acupuncture significantly increased peripheral blood 5-HT concentrations (MD = 3.90, P < 0.00001), with no heterogeneity detected (I² = 0%), suggesting high consistency between studies. These findings support the significant effect of acupuncture on the restoration of 5-HT levels.

Publication bias analysis

Publication bias was assessed for the outcomes using Egger's regression test. As depicted in Table 2, the Egger's test for the HAM-D revealed a statistically significant asymmetry (P = 0.0424), suggesting possible publication bias. This result is also supported by the funnel plot in Figure 3D, revealing a slight asymmetry in the study distribution. In contrast, the Egger's test results for the HAM-D subgroup (antidepressants vs acupuncture + antidepressants, P = 0.6546), SDS (P = 0.5065), and SERS (P = 0.8065) were not statistically significant, suggesting that no significant publication bias was observed for these outcomes.

Table 2 Egger’s test for publication bias.

Outcome	Egger’s test P value	Publication bias
HAM-D	0.0424	Possible
HAM-D (antidepressants vs acupuncture + antidepressants)	0.6546	No
SDS	0.5065	No
SERS	0.8065	No

HAM-D: Hamilton Depression Rating Scale; SERS: Self-Rating Scale for the Side Effects; SDS: Self-Rating Depression Scale.

DISCUSSION

Acupuncture is widely used as an adjunctive treatment for various psychiatric disorders such as depression, anxiety, and insomnia[8,37]. This systematic review and meta-analysis of 20 RCTs from multiple countries and regions evaluated the efficacy of acupuncture in treating depression, specifically excluding studies involving electroacupuncture. It comprehensively assessed the impact of acupuncture on primary and secondary outcome measures, including HAM-D, SDS, BDI-II, MADRS, HAMA, PSQI, SERS, and 5-HT, to examine its independent therapeutic value in managing depressive disorders. Compared with antidepressant monotherapy, the results demonstrated the statistically significant advantages of adjunctive acupuncture intervention across multiple outcomes, suggesting its potential efficacy in alleviating depressive symptoms, reducing anxiety, improving sleep quality, and modulating neurotransmitter levels. However, because the high heterogeneity observed in many of the included results may limit the strength of some findings, certain outcomes should be interpreted with caution.

HAM-D is one of the most commonly used instruments in clinical studies of depression, encompassing multiple domains such as mood, sleep, cognition, and somatic functioning[38]. Previous meta-analyses investigating the effects of acupuncture on depression have indicated that acupuncture combined with antidepressants is significantly more effective than antidepressant monotherapy[12,39]. However, these studies did not distinguish between different forms of acupuncture, often mixing electroacupuncture with manual acupuncture and thereby limiting their interpretability. This study excluded interventions involving electroacupuncture and other electrical stimulation methods, thus enhancing the specificity and explanatory power of our findings. Although the HAM-D scale includes a 17-item version and several modified variants, in this study, we primarily included the 17-item version. Our results are consistent with prior evidence, demonstrating that traditional manual acupuncture significantly reduces HAM-D scores, especially when used in combination with pharmacological treatment, the synergistic effect of which is further supported by the significant reduction in SERS scores observed in the acupuncture group[40]. Both the SDS and the BDI-II are widely used self-rated instruments for depressive symptoms, while the MADRS is originally a clinician-rated tool, although self-rated versions were used in some included studies[41-43]. These scales offer valuable insights into patients’ subjective experience of depression. In our meta-analysis, acupuncture was associated with significant reductions in SDS and MADRS scores. Although the pooled effect on BDI-II scores was not statistically significant, some studies reported improvement. Given that the BDI-II is particularly sensitive to mild-to-moderate depression, some studies also suggest a more pronounced response to acupuncture in this patient subgroup, potentially because of its effects on somatic symptoms and sleep quality[44]. 5-HT is considered a key biological marker in antidepressant mechanisms[45]. Our study, which examined serum 5-HT levels, found that acupuncture significantly increased peripheral 5-HT concentrations, suggesting that its therapeutic effect may involve modulation of central neurotransmitter metabolism and associated pathways, contributing to the amelioration or reversal of depressive pathophysiology.

Despite their effectiveness in alleviating depressive symptoms, antidepressants are frequently associated with adverse effects such as gastrointestinal discomfort, weight changes, sexual dysfunction, and sleep disturbances[7]. The SERS is commonly used in clinical practice to systematically assess drug-related side effects, and quantify adverse reactions, enabling a more comprehensive evaluation of both drug efficacy and tolerability. The pooled analysis of SERS scores in this study suggest that acupuncture may significantly reduce antidepressant-associated adverse effects. This effect may be attributed to its broad impact on relieving gastrointestinal symptoms, insomnia, and headaches, providing a valuable adjunctive treatment to pharmacotherapy[36]. These clinical improvements suggest that acupuncture may exert protective effects by balancing the function of the hypothalamic-pituitary-adrenal axis, regulating immunity, and reducing pro-inflammatory cytokine levels. Moreover, anxiety and sleep disorders frequently co-occur with depression, compounding the overall disease burden and potentially diminishing treatment response while increasing the risk of relapse[46,47]. This meta-analysis reveals that acupuncture significantly improves HAMA and PSQI scores in patients with depression, indicating its potential therapeutic benefit in alleviating anxiety and improving sleep quality. The underlying mechanisms may involve modulation of pathways such as the hypothalamic-pituitary-adrenal axis, which could help restore circadian rhythm, reduce anxiety levels, and enhance overall emotional stability[48].

Compared with previous meta-analyses, our study demonstrates several notable strengths. We explicitly excluded electroacupuncture interventions, thereby enhancing the consistency of the included studies. Additionally, our analysis incorporated serum 5-HT as a biological marker, which had not been included in earlier reviews, providing a more comprehensive assessment of treatment effects. Nonetheless, this study has certain limitations. First, although rigorous inclusion criteria were applied, the suboptimal methodological quality of some included trials, particularly with respect to blinding and allocation concealment, may have introduced bias, affecting the robustness of the conclusions. Second, because several outcome measures were reported by only a limited number of studies, and substantial heterogeneity was observed, the generalizability of the findings are restricted. Third, many studies lacked long-term follow-up data, making it difficult to assess the sustained efficacy of acupuncture. Fourth, despite conducting sensitivity analyses to examine potential sources of heterogeneity, further research is needed to determine whether differences exist among studies in terms of acupuncture protocols, practitioner expertise, or subject characteristics. Finally, given the heterogeneity among the included studies and their predominant origin in China, the reliability of extrapolating these findings to other healthcare settings is questionable; therefore, the findings warrant cautious interpretation. In summary, because the mechanisms of acupuncture remain incompletely understood and standardization is still lacking, further high-quality, well-designed, and adequately blinded large-scale RCTs with consistent treatment protocols should be conducted to confirm its efficacy and elucidate the underlying mechanisms.

CONCLUSION

This meta-analysis provides evidence supporting manual acupuncture as an effective adjunctive treatment for patients with depression. This approach may help alleviate depressive symptoms, anxiety, and sleep disturbances, while also reducing the burden of adverse effects associated with antidepressants. Future research should clarify the underlying mechanisms and promote the standardization of intervention protocols to facilitate broader, more regulated application of acupuncture in the treatment of depression. However, given the substantial heterogeneity observed in several outcomes, these conclusions should be interpreted cautiously.