BACKGROUND: The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). METHODS: We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18 years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. RESULTS: The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80 mg/day and subsequently maintained the maximal dose up to 160 mg/day while the predictive curves of nefazodone were fairly flat in different dosages. CONCLUSIONS: Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit. REGISTRATION No. CRD42023427480; https://www.crd.york.ac.uk/prospero/display_record.php?
Humans ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Dose-Response Relationship, Drug ; Randomized Controlled Trials as Topic

Major depressive disorder (MDD) affects people all over the world, and yet, its etiology is complex and remains incompletely understood. In this review, we aim to assess recent advances in understanding depression and its regulation, as well as its interaction with circadian rhythms. Circadian rhythms are internalized representations of the periodic daily light and dark cycles. Accumulating evidence has shown that MDD and the related mental disorders are associated with disrupted circadian rhythms. In particular, depression has often been linked to abnormalities in circadian rhythms because dysregulation of the circadian system increases susceptibility to MDD. The fact that several rhythms are disrupted in depressed patients suggests that these disruptions are not restricted to any one rhythm but rather involve the molecular circadian clock core machinery. The sleep-wake cycle is one rhythm that is often disrupted in depression, which often leads to disturbances in other rhythms. The circadian disruptions manifested in depressed patients and the effectiveness and fast action of chronobiologically based treatments highlight the circadian system as a key therapeutic target in the treatment of depression. This review assesses the evidence on rising depression rates and examines their contributing factors, including circadian misalignment. We discuss key hypotheses underlying depression pathogenesis, potential etiology, and relevant animal models, and underscore potential mechanisms driving depression's growing burden and how understanding these factors is critical for improving prevention and treatment strategies.
Humans ; Circadian Rhythm/physiology* ; Depressive Disorder, Major/therapy* ; Animals ; Sleep/physiology* ; Depression/therapy*

BACKGROUND: Acupuncture therapy provides a complementary and alternative approach to treating major depressive disorder (MDD), but its efficacy and safety have still not been comprehensively assessed. Recently published systematic reviews remain confusing and inconclusive. OBJECTIVE: This systematic review evaluated the efficacy and safety of acupuncture therapy alone or combined with antidepressants for adult patients with mild and moderate MDD. SEARCH STRATEGY: Chinese Biomedical Literature Database, China National Knowledge Infrastructure Database, Wanfang Database, Chinese Science and Technology Journal Database, PubMed, Embase, and Cochrane Library were searched from their inceptions to March 2025. INCLUSION CRITERIA: Randomized controlled trials that compared acupuncture therapy with antidepressants, or acupuncture therapy plus antidepressants with acupuncture therapy or antidepressants for adult patients with mild and moderate MDD were included. DATA EXTRACTION AND ANALYSIS: Five reviewers independently extracted data from original literature using a standardized form, and the data were verified by two reviewers to ensure accuracy. Statistical meta-analyses, publication bias analyses, and subgroup analyses were performed by using Review Manager 5.3 software. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the certainty of the evidence. RESULTS: A total of 60 eligible studies including 4675 participants were included. Low-certainty evidence showed that compared with antidepressants, acupuncture therapy (standardized mean difference [SMD] = -0.57; 95% confidence interval [CI] = [-0.87, -0.27]; I² = 86%; P = 0.006) or acupuncture therapy plus antidepressants (SMD = -1.00; 95% CI = [-1.18, -0.81]; I² = 77%; P < 0.00001) may reduce the severity of depression at the end of treatment. Low-certainty evidence indicated that compared with acupuncture therapy alone, acupuncture therapy plus antidepressants slightly reduced the severity of depression at the end of treatment (SMD = -0.38; 95% CI = [-0.61, -0.14]; I² = 18%; P = 0.002). Similar results were also found for acupuncture's relief of insomnia. The reported adverse effects of acupuncture therapy were mild and transient. For most of the subgroup analyses, acupuncture type, scale type, and the course of treatment did not show a significant relative effect. CONCLUSION Acupuncture therapy may provide antidepressant effects and relieve insomnia with mild adverse effects for adult patients with mild and moderate MDD. But the certainty of evidence was very low. More high-quality, well designed, large-scale studies with long-term follow-up are needed in the future. Please cite this article as: Kuang HJ, Yang HS, Feng YX, Tang H, Fan Q, Xu YQ, Cui S, Musil R, Luxenburger H, Zhang YX, Zhao H, Zhang YQ. Efficacy and safety of acupuncture therapies for adult patients with mild and moderate major depressive disorder: A systematic review and meta-analysis. J Integr Med. 2025; 23(5):471-491.
Humans ; Acupuncture Therapy/methods* ; Depressive Disorder, Major/therapy* ; Adult ; Antidepressive Agents/therapeutic use* ; Treatment Outcome ; Randomized Controlled Trials as Topic

Depressive disorder is manifested as emotional and physical abnormality. Theoretically, the governor vessel is distributed along the spine, related to the brain and communicated with five zang and six fu organs. It is the key meridian for understanding the various symptoms of depressive disorder. Depressive disorder is caused by dysfunction, stagnation or emptiness of the governor vessel, resulting in malnutrition of the brain. In clinical diagnosis and treatment, based on the theory of the governor vessel, the etiology and pathogenesis are analyzed in the patients with depressive disorder. In order to achieve harmonizing mutually the mental and physical conditions, acupuncture is delivered to adjust the spirit and physical state, moving cupping is to regulate the governor vessel, tuina manipulation is to promote meridians and collaterals and physical exercise is to coordinate the body and the spirit.
Humans ; Acupuncture Therapy/methods* ; Meridians ; Acupuncture ; Brain ; Depressive Disorder ; Acupuncture Points

BACKGROUND: Patients with schizophrenia (SCZ) and major depressive disorder (MDD) share significant clinical overlap, although it remains unknown to what extent this overlap reflects shared neural profiles. To identify the shared and specific abnormalities in SCZ and MDD, we performed a whole-brain voxel-based meta-analysis using magnetization transfer imaging, a technique that characterizes the macromolecular structural integrity of brain tissue in terms of the magnetization transfer ratio (MTR). METHODS: A systematic search based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted in PubMed, EMBASE, International Scientific Index (ISI) Web of Science, and MEDLINE for relevant studies up to March 2022. Two researchers independently screened the articles. Rigorous scrutiny and data extraction were performed for the studies that met the inclusion criteria. Voxel-wise meta-analyses were conducted using anisotropic effect size-signed differential mapping with a unified template. Meta-regression was used to explore the potential effects of demographic and clinical characteristics. RESULTS: A total of 15 studies with 17 datasets describing 365 SCZ patients, 224 MDD patients, and 550 healthy controls (HCs) were identified. The conjunction analysis showed that both disorders shared higher MTR than HC in the left cerebellum ( P =0.0006) and left fusiform gyrus ( P =0.0004). Additionally, SCZ patients showed disorder-specific lower MTR in the anterior cingulate/paracingulate gyrus, right superior temporal gyrus, and right superior frontal gyrus, and higher MTR in the left thalamus, precuneus/cuneus, posterior cingulate gyrus, and paracentral lobule; and MDD patients showed higher MTR in the left middle occipital region. Meta-regression showed no statistical significance in either group. CONCLUSIONS The results revealed a structural neural basis shared between SCZ and MDD patients, emphasizing the importance of shared neural substrates across psychopathology. Meanwhile, distinct disease-specific characteristics could have implications for future differential diagnosis and targeted treatment.
Humans ; Depressive Disorder, Major/drug therapy* ; Schizophrenia/pathology* ; Brain/pathology* ; Prefrontal Cortex ; Frontal Lobe ; Magnetic Resonance Imaging/methods*

Humans ; Transcranial Magnetic Stimulation ; Pain Management ; Psychotic Disorders/therapy* ; Depressive Disorder, Major ; Treatment Outcome ; Transcranial Direct Current Stimulation

OBJECTIVE: To observe the impacts of acupuncture on depressive mood and sleep quality in patients with comorbid mild-to-moderate depressive disorder and insomnia, and explore its effect mechanism. METHODS: A total of 60 patients with comorbid mild-to-moderate depressive disorder and insomnia were randomly divided into an observation group (30 cases, 1 case dropped off) and a control group (30 cases, 2 cases dropped off). In the observation group, acupuncture and low frequency repeated transcranial magnetic stimulation (rTMS) were combined for the intervention. Acupuncture was applied to Baihui (GV 20), Yintang (GV 24⁺), Neiguan (PC 6) and Yanglingquan (GB 34), etc., the needles were retained for 30 min; and the intradermal needles were embedded at Xinshu (BL 15) and Danshu (BL 19) for 2 days. After acupuncture, the rTMS was delivered at the right dorsolateral prefrontal cortex (R-DLPFC), with 1 Hz and 80% of movement threshold, lasting 30 min in each treatment. In the control group, the sham-acupuncture was adopted, combined with low frequency rTMS. The acupoint selection and manipulation were the same as the observation group. In the two groups, acupuncture was given once every two days, 3 times weekly; while, rTMS was operated once daily, for consecutive 5 days a week. The duration of treatment consisted of 4 weeks. Hamilton depression scale-17 (HAMD-17) and Pittsburgh sleep quality index (PSQI) scores were observed before and after treatment, as well as 1 month after the treatment completion (follow-up period) separately. Besides, the levels of nerve growth factor (BDNF) and γ-aminobutyric acid (GABA) in the serum were detected before and after treatment in the two groups. RESULTS: After treatment and in follow-up, the HAMD-17 scores were lower than those before treatment in the two groups (P<0.05), and the scores in the observation group were lower than the control group (P<0.05). After treatment, the total scores and the scores of each factor of PSQI were reduced in the two groups in comparison with those before treatment except for the score of sleep efficiency in the control group (P<0.05); the total PSQI score and the scores for sleep quality, sleep latency, sleep efficiency and daytime dysfunction in the observation group were all lower than those in the control group (P<0.05). In the follow-up, except for the scores of sleep duration and sleep efficiency in the control group, the total PSQI score and the scores of all the other factors were reduced compared with those before treatment in the two groups (P<0.05); the total PSQI score and the scores of sleep quality, sleep latency, sleep duration, sleep efficiency and daytime dysfunction in the observation group were lower than the control group (P<0.05). After treatment, the levels of serum BDNF and GABA were increased in comparison with those before treatment in the observation group (P<0.05), and the level of serum BDNF was higher than that in the control group (P<0.05). CONCLUSION Acupuncture relieves depressive mood and improves sleep quality in patients with comorbid mild-to-moderate depressive disorder and insomnia. The effect mechanism may be related to the regulation of BDNF and GABA levels and the promotion of brain neurological function recovery.
Humans ; Sleep Initiation and Maintenance Disorders/therapy* ; Transcranial Magnetic Stimulation ; Brain-Derived Neurotrophic Factor ; Treatment Outcome ; Acupuncture Therapy ; Acupuncture Points ; gamma-Aminobutyric Acid ; Depressive Disorder

Professor HAN Wei 's clinical experience of acupuncture and moxibustion with Tongyang Xingshen (promoting yang and regaining consciousness) for adolescent depressive disorder is introduced. It is believed that the internal causes of adolescent depressive disorder are mostly emotional and physical factors, while the external causes are mainly social factors, and yang-qi stagnation and emotional disorder are the key pathogenesis. The key of acupuncture and moxibustion with Tongyang Xingshen is warming and regulating the governor vessel. The governor vessel acupoints at head, neck and back are selected. At head, Baihui (GV 20) and Yintang (GV 24⁺) are selected; at neck, Fengfu (GV 16) and Dazhui (GV 14) are selected; at back, Taodao (GV 13), Shenzhu (GV 12), Shendao (GV 11), Zhiyang (GV 9) and Jinsuo (GV 8) are selected. The combination of disease differentiation and syndrome differentiation should be highly valued, and the moxibustion with Tongyang and acupuncture with Xingshen should be used simultaneously, and the strong stimulation is suggested.
Adolescent ; Humans ; Moxibustion ; Acupuncture Therapy ; Acupuncture Points ; Physical Examination ; Depressive Disorder

Electroconvulsive therapy (ECT) is an interventional technique capable of highly effective neuromodulation in major depressive disorder (MDD), but its antidepressant mechanism remains unclear. By recording the resting-state electroencephalogram (RS-EEG) of 19 MDD patients before and after ECT, we analyzed the modulation effect of ECT on the resting-state brain functional network of MDD patients from multiple perspectives: estimating spontaneous EEG activity power spectral density (PSD) using Welch algorithm; constructing brain functional network based on imaginary part coherence (iCoh) and calculate functional connectivity; using minimum spanning tree theory to explore the topological characteristics of brain functional network. The results show that PSD, functional connectivity, and topology in multiple frequency bands were significantly changed after ECT in MDD patients. The results of this study reveal that ECT changes the brain activity of MDD patients, which provides an important reference in the clinical treatment and mechanism analysis of MDD.
Humans ; Depressive Disorder, Major/therapy* ; Electroconvulsive Therapy ; Brain ; Algorithms ; Electroencephalography

OBJECTIVES: Major depressive disorder (MDD) patients with anhedonia tend to have a poor prognosis. The underlying imaging basis for anhedonia in MDD remains largely unknown. The relationship between nodal properties and anhedonia in MDD patients need to be further investigated. Herein, this study aims to explore differences of cerebral functional node characteristics in MDD patients with severe anhedonia (MDD-SA) and MDD patients with mild anhedonia (MDD-MA) before and after the antidepressant treatment. METHODS: Ninety participants with current MDD were recruited in this study. 24-Item Hamilton Depression Scale (HAMD-24) and Snaith-Hamilton Pleasure Scale (SHAPS) were used to assess the severity of depression and anhedonia at baseline and the end of 6-months treatment. The MDD patients who scored above the 25th percentile on the SHAPS were assigned to an MDD-SA group (n=19), while those who scored below the 25th percentile were assigned to an MDD-MA group (n=18). All patients in the 2 groups received antidepressant treatment. Functional magnetic resonance imaging (fMRI) images of all the patients were collected at baseline and the end of 6-months treatment. Graph theory was applied to analyze the patients' cerebral functional nodal characteristics, which were measured by efficiency (e_i) and degree (k_i). RESULTS: Repeated measures 2-factor ANCOVA showed significant main effects on group on the e_i and k_i values of left superior frontal gyrus (LSFG) (P=0.003 and P=0.008, respectively), and on the e_i and k_i values of left medial orbital-frontal gyrus (LMOFG) (P=0.004 and P=0.008, respectively). Compared with the MDD-MA group, the significantly higher e_i and k_i values of the LSFG (P=0.015 and P=0.021, respectively), and the significantly higher e_i and k_i values of the LMOFG (P=0.015 and P=0.037, respectively) were observed in the MDD-SA group at baseline. Meanwhile, higher SHAPS scores could result in higher e_i and k_i values of LSFG (P=0.019 and P=0.026, respectively), and higher e_i value of LMOFG (P=0.040) at baseline; higher SHAPS scores could result in higher e_i values of LSFG (P=0.049) at the end of 6-months treatment. The multiple linear regression analysis revealed that sex were negatively correlated with the e_i and k_i values of LSFG (r= -0.014, P=0.004; r=-1.153, P=0.001, respectively). The onset age of MDD was negatively correlated with the k_i value of LSFG (r=-0.420, P=0.034) at the end of 6-months treatment. We also found that SHAPS scores at baseline were positively correlated with the HAMD-24 scores (r=0.387, P=0.022) at the end of 6-months treatment. CONCLUSIONS There are obvious differences in nodal properties between the MDD-SA and the MDD-MA patients, such as the high e_i of LSFG in the MDD-SA patients, which may be associated with the severity of anhedonia. These nodal properties could be potential biomarkers for the prognosis of MDD. The increased e_i and k_i values in the LSFG of MDD-SA patients may underlie a compensatory mechanism or protective mechanism. The mechanism may be an important component of the pathological mechanism of MDD-SA. The poor prognosis in the MDD-SA patients suggests that anhedonia may predict a worse prognosis in MDD patients. Sex and onset age of MDD may affect the nodal properties of LSFG at baseline and the end of 6-months treatment.
Anhedonia ; Antidepressive Agents/therapeutic use* ; Depressive Disorder, Major/drug therapy* ; Humans ; Infant ; Infant, Newborn ; Magnetic Resonance Imaging ; Prefrontal Cortex