Subclinical Hypothyroidism (SHypo), a condition that characteristically presents with normal Thyroid Hormone (TH) levels coexisting with elevated Thyroid-Stimulating Hormone (TSH) levels, has been associated with cognitive impairment. Nonetheless, its neurobiological effects remain somewhat unclear, forming the basis of this study. Herein, using a multimodal neuroimaging approach, we explored cortical thinning and disrupted Functional Connectivity (FC) in SHypo patients—particularly focusing on their relationship with cognitive deficits. Brain areas such as the Prefrontal Cortex (PFC) and Cingulate Gyrus (CG) exhibited substantial cortical thinning. Additionally, a marked decrease in FC was observed between the CG and regions associated with visuospatial processing. Furthermore, serum-free thyroxine (FT4) levels correlated negatively with Cortex Thickness (CT) of the right cuneus. Notably, FC also correlated positively with neuropsychological tests. Besides highlighting the potential for early neural alterations in SHypo, these findings also underscore the significance of early detection and intervention to mitigate cognitive decline.

Objective Quetiapine is an atypical antipsychotic with a broad spectrum of use including anti-anxiety and mood stabilizing properties and has proved effective in mood disorders, such as major depressive disorder and bipolar depression. An integration of cognitive behavioral therapy (CBT) with pharmacological treatment has shown to outperform drugs alone in reducing suicide risk for patients with mood disorders. In this study, we investigated the effect of adding cognitive behavioral therapy (CBT) to quetiapine on suicide risk, depressive symptoms, and coping style in adult patients with mood disorders. Methods One hundred and thirty-seven patients were randomized to QUE group (n = 70) and QUE + CBT group (n = 67). The primary outcome was suicide risk assessed by the Nurses’ Global Assessment of Suicide Risk (NGASR) scale. The secondary outcomes were depressive symptoms assessed by the 24-item Hamilton Depression Rating Scale (HDRS-24) and coping style assessed by the Simplified Coping Style Questionnaire (SCSQ). Results The QUE + CBT group showed a significantly lower percentage with high suicide risk in the modified intention-to-treat population than the QUE group after 12-week intervention (χ2 = 5.50; p = 0.02). The analysis of covariance (ANCOVA) controlling for baseline scores indicated a significantly main effect of treatment in scores of NGASR [F(1, 135) = 25.30, p < 0.01, partial η2 = 0.16], HDRS-24 [F(1, 135) = 27.00, p < 0.01, partial η2 = 0.17], positive coping [F(1, 135) = 10.00, p < 0.01, partial η2 = 0.07] and negative coping of SCSQ [F(1, 135) = 26.70, p < 0.01, partial η2 = 0.17], suggesting that lower scores of NGASR and HDRS-24, a higher positive coping score, and a lower negative coping score in the QUE + CBT group than in the QUE group after 12-week intervention. Conclusion These results suggest that adding CBT to quetiapine could decrease suicide risk, improve depressive symptoms, and enhance coping style for adult patients with mood disorders.

The characteristics of non-suicidal self-injury (NSSI) remain largely unknown during depressive episodes, particularly in early adulthood. This study aimed to explore the risk factors of non-suicidal self-injury (NSSI) among young adult inpatients with depressive episodes. A total of 771 inpatients with depression were recruited from Nanjing Brain Hospital. The patients were divided into NSSI group (n = 91) and non-NSSI group (n = 680). Univariate and multivariate logistic regression were used to analyze the risk factors for NSSI in depressive patients. A nomogram prediction model was constructed. The detection rate of NSSI behavior among these inpatients with depressive episodes was 10.5

Major depressive disorder (MDD) in youth is associated with higher suicide risk. Although white matter and functional connectivity abnormalities have been reported in MDD patients with suicidal ideation (SI), how brain structure and function interact abnormally remains unclear. We conducted a cross-sectional study of participants aged 15–30, including 97 drug-naive MDD patients with SI, 44 without SI (nSI), and healthy controls (HC). We analyzed global and local structural-functional connectivity (SC-FC) coupling across groups and assessed its correlation with clinical features. The study revealed significant differences in SC-FC coupling among the three groups (SI, nSI, and HC). At the local level, differences were identified in the left superior temporal gyrus (STG.L) and left Heschl’s gyrus (HES.L). Specifically, the SI group exhibited the weakest negative SC-FC coupling in the HES.L compared to both the nSI group and HC group (PFDR < 0.001). Additionally, a decrease in negative SC-FC coupling in the STG.L was observed in the SI group when compared to the HC group (PFDR = 0.003). The HES.L SC-FC coupling alterations were negatively correlated with clinical symptoms of rumination and suicidal risk in the SI group. The findings suggest that MDD patients with SI exhibit disrupted SC-FC coupling, particularly in the HES.L and STG.L regions. These alterations were associated with higher levels of rumination and suicidal risk, underscoring the potential of SC-FC coupling as a candidate neurobiological correlate of suicidal ideation in MDD.

BACKGROUND:Major depressive disorder (MDD) is often accompanied by anxiety and may co-occur with Hashimoto's thyroiditis (HT), an autoimmune thyroid disease linked to mood disturbances. Patients with comorbid HT often present with more severe anxiety, yet the neurobiological mechanisms underlying this comorbidity remain unclear. METHODS:The study included 44 MDD patients without HT (MDDHT-), 45 MDD patients with comorbid HT (MDDHT+), 48 HT patients, and 80 healthy controls (HC). Participants completed self-report questionnaires, blood sampling, and MRI scans. MDD patients were additionally evaluated with the Hamilton Depression (HAMD-17) and Anxiety (HAMA) Rating Scales. Cortical morphology was analyzed with FreeSurfer. Generalized linear models were employed to examine the main and interactive effects of MDD and HT, controlling for age, sex, eTIV, education, and medication load index. Partial correlation analyses were conducted to explore associations between cortical alterations and clinical measures. RESULTS:Depression diagnosis was independently associated with reduced surface area in the left cuneus and pericalcarine gyrus, while HT was independently linked to reduced surface area in the left cuneus. Moreover, a significant interaction between depression and HT was observed in the surface area of the left middle temporal gyrus. In MDDHT+ patients, the left cuneus surface area was negatively correlated with anxiety/somatization factor and GAD-7 scores. Furthermore, Tg-Ab levels were positively correlated with anxiety/somatization factor and GAD-7 scores in the MDDHT+ group. CONCLUSION:MDD and HT exert distinct effects on cortical surface area. These alterations, together with Tg-Ab levels, may jointly contribute to anxiety symptoms in MDDHT+ patients.

Background Major depressive disorder (MDD) is clinically heterogeneous, posing a persistent challenge for personalized treatment. While neuroimaging offers a promising path, existing symptom-based stratification schemes have proven inadequate in predicting antidepressant response. Crucially, studies focusing on white matter (WM) heterogeneity — a potential source of neurobiological subtypes— have failed to address this critical gap. Here, we bridge this divide by investigating WM-based MDD subtypes and their predictive value for treatment outcomes. Methods We used non-negative matrix factorization biclustering of diffusion MRI data from 311 MDD patients (discovery: n=209; validation: n=102) to identified neuroanatomical subgroups with distinct WM microstructural signatures. Subgroups were characterized via neuroanatomical profiling, clinical phenotyping (symptom domains/treatment responses), and WM-symptom associations. Baseline WM features predicted 4-week treatment outcomes (overall/dimension-specific symptom reduction) across five antidepressant therapies using support vector regression. Results Three robust MDD subgroups emerged: (1) frontoparietal-corticospinal alterations linked to anxiety/hopelessness; (2) cerebellar-visual circuit disruptions tied to cognitive-psychomotor deficits; (3) fornix-centered abnormalities associated with attenuated symptom severity. Subgroup-specific WM networks predicted treatment outcomes with high cross-cohort consistency (discovery: r =0.24–0.58; validation: r =0.27–0.67; all p <0.05), notably for cognitive symptoms (max r =0.59). Importantly, baseline WM patterns—converging on limbic/default mode networks—reflected neuroplasticity reserve, enabling generalizable prediction across mechanistically distinct therapies. Conclusions Our findings establish WM-derived biotypes as robust, pathophysiologically distinct subtypes of MDD and validate baseline WM topology as a biomarker capable of predicting antidepressant treatment response, potentially by reflecting and individual’s neuroplasticity reserve.

Major depressive disorder (MDD) is a severe mood disorder with genetic and environmental interactions. Subtypes with childhood trauma (CT) tend to have higher rates of suicide attempt (SA). The amygdala (AMY) and medial prefrontal cortex (mPFC) are integral to the neurocircuitry underlying emotional processing, with dysregulation of these regions being posited as a pathophysiological hallmark both in CT and SA. However, the specific neural mechanisms linking CT and SA are unclear. Here, we examined local neural oscillatory patterns and interregional connectivity within mPFC and AMY during sad emotion processing. 88 MDD patients (44 with CT, 44 without CT) and 44 healthy control (HC) participants underwent an emotion recognition task during magnetoencephalography (MEG) recording. Time-frequency analysis was used to examine inter-trial phase coherence (ITPC) and neural oscillatory power at bilateral mPFC and AMY. In addition, directed connectivity between mPFC and AMY was examined using Granger causality. MDD without CT demonstrated less ITPC at bilateral mPFC and bottom-up dysconnectivity from the AMY.R to the mPFC.R compared to HC. Theta power (bilateral mPFC and left AMY), ITPC (bilateral AMY and mPFC) and top-down functional connectivity from the mPFC.L to the AMY.L were reduced in MDD with CT relative to MDD without CT. Furthermore, the mPFC.L theta ITPC mediated the association between SA and CT. Overall, the results suggest that abnormal theta power modulation, phase coherence, and hypo-connectivity between the mPFC and AMY may underlie impaired sad emotion processing in MDD with CT, partially explaining the increased SA rate in this subgroup.

Youth major depressive disorder (MDD) is a debilitating condition associated with high rates of suicidal behavior. Although abnormal neuroimaging alterations have been reported in MDD patients with suicidal ideation (SI), little is known about the mechanisms of brain dynamics at high temporal resolution. This cross-sectional study included 177 participants aged 15–30 years: 95 with drug-naïve MDD (53 with SI, 42 without SI) and 82 healthy controls. All participants underwent a standardized 5-minute resting-state electroencephalography (EEG) acquisition. Comprehensive clinical assessments were administered, including the collection of psychosocial data and evaluation of suicide risk using the Beck Scale for Suicide Ideation (BSI-C). Group differences in microstate parameters were analyzed, and correlations between these parameters and clinical variables were examined. Resting-state EEG microstate analysis indicated that the SI group, relative to the NSI group, exhibited higher occurrence, coverage, and duration of microstate A, along with decreased indices for microstate B and reduced occurrence (but not coverage or duration) of microstate D. Alterations in transition probabilities were most prominent in microstates A and B, highlighting specific network-level differences associated with SI. In the SI group, BSI-C scores were positively correlated with the transition probability from C to B. Our findings suggest that young individuals with MDD and SI show specific changes in microstates, especially A and B. These findings reveal altered EEG microstate dynamics associated with SI in young MDD patients and may inform future research on neurophysiological correlates of suicidal ideation.

BACKGROUND:Individuals with major depressive disorder (MDD) exhibit a blunted neural response to happy (relative to neutral) facial feedback, indicated by attenuated feedback-related negativity (FRN). However, the relationship between FRN and suicide risk remains unclear. METHODS:The study included 110 MDD patients and 70 healthy controls (HCs) who completed an electroencephalogram social incentive delay task. According to the suicide risk module of the Mini International Neuropsychiatric Interview (MINI), patients were divided into low-suicide-risk (LSR, n = 34), moderate-suicide-risk (MSR, n = 36), and high-suicide-risk (HSR, n = 40) groups. FRN data were analyzed with repeated-measures analysis of variance across the groups. FRN source localization was conducted with standardized low-resolution brain electromagnetic tomography (sLORETA). RESULTS:A significant group × condition interaction was found (F3, 176 = 3.138, p = 0.028, η2p = 0.070). HCs showed significant mean amplitude differences between gain and neutral feedback (p = 0.028), but MDD groups did not (all ps > 0.05). Post-hoc analyses showed the HSR group had the lowest FRN amplitudes. Furthermore, FRN under the gain condition (FRN-gain) was correlated with clinical variables, including consummatory anhedonia and suicide risk (all ps < 0.05). FRN-gain source localization showed reduced orbitofrontal cortex, right fusiform gyrus, and insula activation, but increased left superior temporal gyrus activation in the HSR group. CONCLUSIONS:The findings indicate the possibility of blunted neurophysiological responses to happy (vs. neutral) facial feedback and abnormal brain activation in high-suicide-risk MDD patients, which may be associated with increased suicide risk. Nevertheless, because the task lacked loss and non-social control conditions, the specificity of these findings to reward or social processing remains to be determined.

The incidence and clinical manifestations of major depressive disorder (MDD) differ between sexes. This implies distinct neuropathological mechanisms. This study aimed to investigate sex-specific brain patterns in MDD by stratifying patients according to both sex and disease course. We recruited 1170 participants (811 MDD patients and 359 healthy controls) who underwent T1-weighted and resting-state functional magnetic resonance imaging. We explored duration-stage-related, sex-specific differences in gray matter (GM), amplitude of low-frequency fluctuation (ALFF), and structural-functional coupling. We also used the structural covariance network (SCN) to assess morphological connectivity reorganization. Finally, we explored the relationship between key brain measures derived from the preceding multimodal analyses and clinical features. GM abnormalities in both sexes were observed first appeared in areas supporting sensorimotor and interoceptive functions, and later extended to areas involved in cognitive and emotional processing. Critically, we found distinct sex-specific epicentres of pathology. In male patients, the right postcentral gyrus (PoCG) exhibited early GM atrophy and decreased betweenness centrality within the SCN. In female patients, the left inferior temporal gyrus (ITG) showed early GM atrophy, increased degree centrality within the SCN, reduced ALFF values, and a two-stage evolution of structural-functional coupling with a transition lasting 3 years. Clinically, GM volumes of the right PoCG in male patients were negatively associated with insomnia-early, genital symptoms, and weight loss, while in female patients, GM volumes of the left ITG were negatively associated with depressed mood, work and interest, and psychic anxiety. This study shows a sex-specific neuropathological origin in MDD, with the left ITG serving as the core pathological area in females and the right PoCG in males. These conclusions not only advance our insight into the sex-dependent mechanisms underlying MDD but also provide a stage-informed framework for individualized interventions, suggesting that the early years of the disease may be a critical period for structure-targeted therapies. Sex-specific hub pathological regions identified: left ITG in females, right PoCG in males. Atrophy begins in sensorimotor areas and later extends to cognitive regions, following sex-divergent trajectories. The female left ITG uniquely shows atrophy, increased centrality, reduced ALFF, and a pattern of structural-functional over-coupling. Male PoCG atrophy correlates with insomnia and somatic symptoms; female ITG atrophy correlates with mood, interest, and anxiety symptoms.

BACKGROUND:Early identification of bipolar disorder (BD) is challenging, particularly when the first episode presents as depression and is misdiagnosed as major depressive disorder (MDD). Misclassification delays appropriate treatment. While prior studies focused on static imaging features, emerging evidence suggests that transient, frequency-specific neural dynamics may offer more sensitive candidate indicators. METHODS:We included 87 patients with MDD and 55 with BD. During follow-up, 33 MDD patients converted to BD (tBD), and 54 remained unipolar (UD). Baseline resting-state MEG and MRI data were analyzed using the DyNeMo model to characterize millisecond-level oscillatory states. Group differences in dynamic metrics were assessed with permutation ANCOVA. RESULTS:Six dynamic brain states were identified. Significant group effects emerged for the switching rate (SR) of State 2 and for both fractional occupancy (FO) and SR of State 4. tBD and UD groups exhibited elevated SR in States 2 and 4 compared to the BD and HC groups, with tBD showing the highest SR in State 4. LIMITATIONS:The sample size of this study was limited, diagnostic transitions in UD could not be fully verified, and residual confounding from education level and medication use cannot be completely excluded. CONCLUSION:Heightened instability of the low-power background network characterizes tBD and may reflect disrupted baseline neural homeostasis. This dynamic feature may serve as a candidate neuroimaging indicator for identifying individuals at elevated risk of conversion from UD to BD.

Dysfunctions in brain network dynamics have been linked to emotional disorders. However, there is limited research exploring the connection between resting-state EEG brain networks and cognitive functions in individuals with Major Depressive Disorder (MDD). The objective of this study is to examine irregular brain network activity and its relationship with cognitive performance, utilizing EEG microstates, in order to shed light on the underlying neuropathological mechanisms of MDD. This study included 68 drug-naïve MDD individuals and 50 healthy control participants (HCs). Demographic data were collected, and cognitive function assessments were performed. Concurrently, resting-state brain activity was captured using a 64-channel EEG. Additionally, Pearson correlation analysis was used to explored the relationship between these factors in MDD patients. We identified four distinct EEG microstate topographic maps. In comparison with the healthy control group, the coverage, duration, and occurrence of microstates A and D were significantly diminished, whereas those of microstate B were markedly increased. The performance on various neurocognitive tests (Trail Making Test [TMT], Symbol Digit Modalities Test [SDMT], Stroop Color-Word Test [SCWT]) for the MDD group was consistently lower than that of the HCs. In the MDD patients, all parameters of microstate A exhibited a negative correlation with Stroop’s color-naming and word-color time, while the coverage and duration of microstate D correlated positively with scores on the SDMT. Our study indicated that individuals with MDD display aberrant microstate dynamics, and these results corroborate the link between alterations in microstate activity and cognitive function in MDD patients.

Major depressive disorder (MDD) is frequently accompanied by self-harm behaviors, including non-suicidal self-injury (NSSI) and suicide attempts (SA), which are important risk factors for suicide and poor clinical outcomes. Although neuroimaging studies have identified structural brain abnormalities related to suicidal behaviors in MDD, the neurobiological distinctions between NSSI and SA remain poorly understood. In particular, few studies have simultaneously compared MDD patients with NSSI, MDD patients with SA, and MDD patients without self-harm behaviors. Therefore, this study aimed to investigate gray matter volume (GMV) alterations and their associations with clinical symptoms in early adulthood (aged 18–30 years) MDD patients using voxel-based morphometry (VBM). A total of 54 MDD patients with NSSI (MDD/NSSI), 68 MDD patients without NSSI (sMDD), 50 MDD patients with SA (MDD/SA), and 66 healthy controls (HCs) were included. VBM was used to examine GMV differences using high-resolution T1-weighted MRI scans. Age, sex, education, and intracranial volume were included as covariates. One-way ANOVA with Gaussian random field (GRF) correction was performed, followed by post-hoc t-tests. Correlations between GMV and clinical measures of depression (HAMD), anxiety (HAMA), and suicide risk (NGASR) were assessed. Significant GMV differences were observed in the superior/middle frontal gyrus, superior frontal gyrus, bilateral caudate, superior/middle temporal gyrus, and middle cingulate gyrus (voxel-level p < 0.001, GRF corrected p < 0.05). Post-hoc analyses showed reduced GMV in the MDD/SA group compared with the MDD/NSSI group in several regions. However, supplementary GLM analyses indicated that NSSI-related characteristics showed more consistent independent associations with regional GMV, whereas SA history was not independently associated with GMV in any examined region. Correlations between GMV and clinical measures did not survive FDR correction. MDD patients with NSSI and SA may exhibit distinct patterns of gray matter alterations; however, these differences likely reflect clinical heterogeneity across self-harm subgroups rather than SA-specific structural abnormalities. Supplementary analyses further suggest that NSSI-related characteristics show stronger independent associations with GMV than SA history. These findings highlight the importance of distinguishing self-harm subtypes in the neurobiological characterization of MDD. All results should be interpreted cautiously given the cross-sectional design and the lack of robust associations after multiple-comparison correction. Not applicable.

BACKGROUND:Bipolar disorder (BD) is often misdiagnosed as major depressive disorder (MDD), especially in late adolescence and young adulthood, due to delayed emergence of distinguishing symptoms. This prospective nested case-control study aimed to identify neurobiological markers for early identification of BD from MDD in this age group. METHODS:The study comprised 139 patients with bipolar depressive disorder (BDD), 148 patients with unipolar depression (UD) and 128 healthy controls (HC). During follow-up, we additionally identified 62 patients who transitioned from MDD to BD (tBD). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) at baseline. Functional network analyses were performed based on large-scale brain networks, along with graph-theoretical analyses. RESULTS:Patients with depressive episodes showed reduced FC between the sensorimotor network (SMN) and visual network (VN) and within the subcortical network (SubN). Compared to HC, all patient groups showed reduced assortativity. Sigma was elevated in BDD and tBD, with reduced maximum sparsity in BDD and increased gamma in tBD. The UD showed reduced clustering coefficient and local efficiency. Compared to UD, BDD and tBD showed higher sigma and gamma, and tBD also showed higher local efficiency. In tBD, network metrics were associated with depressive severity, anxiety, suicide risk, and aggression. CONCLUSIONS:BDD and tBD showed highly modular organization in the SMN, VN and SubN, whereas UD was characterized by reduced local efficiency. These patterns may represent neural signatures with diagnostic potential for early identification of BD from depressive episodes in late adolescence and early adulthood.

OBJECTIVE:Suicide is a major cause of mortality in bipolar disorder (BD), yet its neural underpinnings remain insufficiently understood. Suicide risk is thought to involve impaired cognitive-emotional flexibility arising from fundamental disturbances in brain dynamics. This study aimed to test this hypothesis by characterizing the energetic and dynamical constraints underlying suicide vulnerability in BD. METHODS:We applied energy landscape modeling to resting-state fMRI data from 123 individuals with BD (61 suicide attempters, 62 non-attempters) and 68 healthy controls. Brain activity was modeled as transitions between functional states, enabling quantification of neural rigidity. Group-level comparisons and correlation analyses were conducted to identify attractor stability, transition patterns, and their associations with clinical and cognitive measures. RESULTS:Four dominant attractor basins were identified. Basins A and D showed progressively reduced appearance frequency and stability from healthy controls to non-attempters and suicide attempters. Increasing suicide risk was associated with greater neural rigidity, reflected in a more constrained transition architecture with shorter and more repetitive transition paths in suicide attempters. Lower stability of basin A was associated with higher suicide risk, with cognitive impairment statistically accounting for part of this association in mediation analyses. CONCLUSION:Suicide vulnerability in BD is associated with entrenched functional brain states, reduced transition diversity, and elevated energetic constraints that may limit adaptive brain-state reconfiguration. These findings provide a mechanistic account of neural rigidity and suggest that altered brain-state dynamics may serve as a potential biomarker of suicide risk in BD.

OBJECTIVE:The aim was to investigate the differences between major depressive disorder (MDD) patients with non-suicidal self-injury and suicide attempts in the resting state in terms of regional homogeneity and fractional amplitude of low-frequency fluctuations (fALFF). METHODS:54 MDD patients with NSSI (MDD/NSSI), 50 MDD patients with SA (MDD/SA), 68 MDD patients without NSSI (sMDD), and 66 matched healthy controls (HC) were recruited for the study. Each of the four groups underwent a 3.0 T resting-state functional magnetic resonance scan. Whole brain ReHo and fALFF values were calculated, and one-way ANOVA was performed on the ReHo and fALFF values of the four groups of subjects. Two-by-two comparisons were made on the basis of brain regions where differences were identified, and multiple comparisons were corrected using a Gaussian random field (GRF) to investigate the differences in functional brain imaging between MDD/NSSI and MDD/SA. RESULTS:A statistically significant difference in the fALFF values of the right ITG, left MTG, left SFG, left ITG, right INS, and right SFG was identified (p < 0.05). MDD/SA patients had increased ReHo values in the left STG and left SFG and decreased ones in the right MTG and right ITG, as well as increased fALFF values in the right SFG, compared to MDD/NSSI patients (p < 0.05). CONCLUSIONS:MDD/SA and MDD/NSSI patients have different brain imaging damage patterns, which may contribute to a more profound comprehension of the pathological mechanisms that differentiate these two groups.

Importance:Depression is a significant global public health issue, with somatic symptoms being a common and challenging aspect of its management. Objective:This study aimed to evaluate the efficacy and safety of toludesvenlafaxine hydrochloride sustained-release tablets (Roxylin®) for somatic symptoms of major depressive disorder (MDD). Design Setting and Participants:Prospective, single-arm, multicenter clinical study conducted between June 1, 2023 and May 1, 2024, enrolling patients diagnosed with MDD with somatic symptoms at four hospitals across China. Intervention:All participants received toludesvenlafaxine hydrochloride monotherapy for 8 weeks. Main Outcomes and Measures:The primary outcomes were improvements in somatic depression symptoms measured by PHQ-15 and SSS-CN at baseline and weeks 2, 4, and 8, while secondary outcomes included changes in depressive symptoms (HAMD-17), pain intensity (VAS), fatigue (MFI-20), and functional impairment (SDS), with adverse events monitored. Results:Out of 72 screened patients, 61 were enrolled. The mean age of the participants was 30.1 ± 9.0 years, ranging from 18 to 53 years, with 29.6% being male and 70.4% female. After 8 weeks of treatment, significant reductions were observed in PHQ-15 scores (-5.8 ± 4.4, P < 0.001) and SSS-CN scores (-12.8 ± 10.3, P < 0.001), indicating improvement in somatic symptoms. Secondary outcomes also showed significant improvements in depressive symptoms (HAMD-17: -15.3 ± 7.4, P < 0.001), pain intensity (VAS: -1.97 ± 2.44, P < 0.001), fatigue (MFI-20: -12.8 ± 14.1, P < 0.001), and functional disability (SDS: -8.3 ± 6.5, P < 0.001). The occurrence of adverse events was 52.5%, with no serious adverse events reported. Conclusion:Toludesvenlafaxine hydrochloride significantly improved somatic symptoms in patients with MDD and somatic symptoms, with a favorable safety profile, supporting its use as an effective treatment option. Clinicaltrialsgov Identifier:NCT05849272.