Purpose:This study evaluated outcomes of venlafaxine treatment in Japanese patients with major depressive disorder (MDD) in routine clinical practice. Since anxiety is a common and clinically relevant feature of MDD, descriptive analyses were conducted based on the presence or absence of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) anxious distress. Patients and Methods:This 12-week, multicenter, single-arm, observational study consecutively enrolled adult patients with MDD initiating venlafaxine in Japan. DSM-5 anxious distress was assessed at baseline. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 12 or discontinuation. Secondary endpoints included MADRS response and remission rates, patient-reported outcomes, and safety. Analyses were descriptive and conducted by anxious distress status. Results:Among enrolled patients, 407 received venlafaxine and comprised the safety analysis set; 198 (48.6%) had anxious distress. MADRS total score decreased from baseline to week 12 or discontinuation in the overall population and in patients with and without anxious distress. Patients with anxious distress had higher baseline symptom severity but showed improvement over time. Similar improvements were seen across secondary patient-reported outcomes in both subgroups. Drug-related adverse events and discontinuations due to adverse events were numerically more frequent in patients with anxious distress. The safety profile was in line with established findings. Conclusion:Venlafaxine treatment in clinical practice improved depressive symptoms, anxiety, functioning, quality of life, and cognitive complaints in patients with MDD. Improvements were seen in patients with and without anxious distress. These results provide descriptive real-world evidence on treatment outcomes; however, they should be interpreted with caution given the non-comparative study design and other limitations. The findings may inform clinical decision-making in patients with heterogeneous presentations encountered in routine psychiatric practice.
Major depressive disorder (MDD) is increasingly recognized as a systemic disorder involving dysregulation of the heart-brain axis (HBA). Mounting evidence links impaired HBA signaling to the pathogenesis of major depressive disorder. Emerging data indicate that neuromodulation-mediated autonomic alterations correlate with depressive symptom remission. Although neuromodulatory therapies are widely deployed clinically, HBA-based biomarkers remain experimental, and no consistent physiological predictors of treatment response have been established to date. This review summarizes HBA dysfunction in depression across neural, biochemical, and mechanical pathways, integrating evidence from preclinical and clinical studies. We critically evaluate recent advances in leveraging these pathways to optimize neuromodulation strategies. Emerging evidence suggests that certain neuromodulation approaches-including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), and deep brain stimulation (DBS)-may modulate heart-brain axis function. It has been hypothesized that such modulation could represent a physiological pathway contributing to mood improvement, providing a rationale for a heart-oriented framework in neuromodulation research. However, the clinical utility of this framework and its underlying biomarkers remain to be established through rigorous long-term investigations. By bridging the conventional conceptual divide between psychiatric and cardiovascular diseases, this review offers a systems-level perspective on neuromodulation efficacy and highlights the potential of HBA-related biomarkers for assessing pathological states and guiding treatment strategies in depression and other psychosomatic conditions.
Purpose:Generalized anxiety disorder (GAD) impairs quality of life (QoL) and daily function; however, it remains under-recognized in Japan due to symptom overlap and a lack of approved treatments. This study estimated GAD prevalence among psychiatric outpatients using the Structured Clinical Interview for DSM (SCID), examined associated demographic and clinical factors, assessed health status and QoL, and evaluated the diagnostic validity of the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Kessler 6-item Psychological Distress scale (K6) versus SCID. Methods:This multicenter, cross-sectional study analyzed 407 patients across 22 sites. Prevalence was determined through SCID-based structured interviews. Demographics were obtained from paper questionnaires and clinical characteristics from medical records. Patient-reported outcomes quantified burden and screening accuracy. Results:Eighty-three of 407 patients (20.4%) met DSM-5 criteria for GAD using SCID. Prevalence was higher in females versus males (68.7% vs 31.3%) and more common among younger individuals. Comorbid depressive disorders were frequent (63.4%), with major depressive disorder being the most prevalent. Patients with GAD were more likely to have lower income, be students, and exhibit higher symptom severity on both the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) and the GAD-7. Patients with GAD (n=83) had higher QIDS-SR, GAD-7, and K6 scores than non-GAD patients, indicating greater depressive symptoms, anxiety, and psychological distress. Health-related QoL and functional impairment measured through EuroQol 5 Dimensions 5 Levels and the Sheehan Disability Scale indicated worse outcomes in GAD. GAD-7 and K6 demonstrated moderate diagnostic performance versus SCID. Conclusion:GAD was prevalent among Japanese psychiatric outpatients (20.4%), suggesting the potential under-recognition in clinical practice, with some patients receiving alternative diagnoses. The lack of approved treatments and recognized diagnostic procedures may exacerbate the patient's burden. Developing GAD-specific therapies and improving diagnostic awareness are critical to addressing this unmet need.
Background:Insomnia is closely associated with neuroinflammation, yet the therapeutic mechanism of electroacupuncture (EA) remains unclear. This animal study investigated whether EA attenuates hypothalamic neuroinflammation in para-chlorophenylalanine (PCPA)-induced insomnia rats by suppressing the TLR4/MyD88/NF-κB p65 pathway and M1 microglial activation, using TAK-242 (HY-11109), a selective TLR4 inhibitor, as a positive control. Methods:Forty Sprague-Dawley rats (20 male, 20 female, sex-balanced across groups) were randomly allocated to Control, Model, EA, and TAK-242 groups (n=10 per group). Insomnia was induced in the model, EA, and TAK-242 groups by intraperitoneal injection of PCPA (500mg/kg) for 2 consecutive days. The TAK-242 group received daily intraperitoneal injection of TAK-242 (3 mg/kg). The EA group received acupuncture at Baihui (GV20), bilateral Benshen (GB13), Shenmen (HT7) and Sanyinjiao (SP6), with ipsilateral Shenmen (HT7) and Sanyinjiao (SP6) connected to an electroacupuncture device using a 2 Hz continuous wavefor 20 minutes daily over 7 days. Sleep latency and total sleep duration were recorded via the pentobarbital sodium righting reflex test. Serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were assessed via the enzyme-linked immunosorbent assay (ELISA); Hypothalamic microglial M1 polarization was assessed by Iba-1/CD86 immunofluorescence co-localization. Protein and mRNA levels of TLR4, MyD88, NF-κB p65, TNF-α, and IL-6 were quantified by Western blot and RT-qPCR, respectively. All outcome assessments were performed by investigators blinded to group allocation. Results:Compared with the model group, both electroacupuncture and TAK-242 significantly shortened sleep latency and prolonged total sleep time (P < 0.01), and reduced serum levels of TNF-α and IL-6 (P < 0.01). Both interventions also attenuated CD86 fluorescence intensity (P < 0.01) and Iba-1/CD86 co-expression (P < 0.05), and down-regulated the protein and mRNA expression of TNF-α, IL-6, TLR4, MyD88, and NF-κB p65 in the hypothalamus (P < 0.01). The effects of electroacupuncture and TAK-242 on sleep parameters, CD86 fluorescence intensity, and Iba-1/CD86 co-expression were comparable, whereas TAK-242 exerted a more pronounced inhibitory effect than electroacupuncture on the expression of inflammatory cytokines and pathway-related proteins in the serum and hypothalamus (P < 0.05, P < 0.01). Conclusion:Electroacupuncture effectively improved sleep disturbances in PCPA-induced insomnia rats. The underlying mechanism may be associated with inhibition of the TLR4/MyD88/NF-κB p65 signaling pathway, suppression of M1 microglial activation, and downregulation of pro-inflammatory cytokines, thereby partly alleviating hypothalamic neuroinflammation.
Jingwen Zhang,1 Linjing Wang,1,2 Shuai Shi,1,3 Zhihong Liu,1 Jiajie Niu,1 Jingwen Zhao,1 Chunying Wang1,21The Second Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150040, People’s Republic of China; 2Department of Acupuncture, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150001, People’s Republic of China; 3Department of Geriatrics, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, 150001, People’s Republic of ChinaCorrespondence: Chunying Wang, Email wangchunying1208@126.comAbstract: Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition. Its pathophysiology extends beyond monoamine deficiency to encompass systemic dysregulation of the gut-brain axis—a bidirectional network integrating neural, immune, endocrine, and microbial signals. Accumulating evidence indicates that MDD patients frequently exhibit gut microbiota dysbiosis, impaired intestinal mucosal barrier integrity, and systemic low-grade inflammation. These gut-derived pathological alterations may collectively contribute to the onset and progression of depression through complex interactions involving microbial metabolites, immune signaling, and neuroendocrine pathways. Although several recent reviews have addressed gut-brain axis dysfunction in depression or the therapeutic effects of acupuncture individually, a systematic synthesis integrating neuroimmune, neuroendocrine, and microbiome mechanisms within a unified framework remains lacking. This review integrates three key regulatory dimensions—neuroimmune regulation, hypothalamic-pituitary-adrenal (HPA) axis homeostasis, and gut microbiota remodeling—through which acupuncture is proposed to modulate the gut-brain axis in MDD. Acupuncture, a core modality of Traditional Chinese Medicine (TCM), offers unique advantages in intervening in this complex system due to its multi-target regulatory properties. Modern studies have linked classical TCM principles to the vagus-adrenal axis, the endocannabinoid system, the HPA axis, and the TLR4/NF-κB pathways. Specifically, preclinical evidence suggests that acupuncture may induce systemic anti-inflammatory responses, suppress NLRP3 inflammasome activation, restore HPA axis negative feedback, and repair the intestinal barrier, while also reshaping gut microbiota composition, promoting short-chain fatty acid synthesis, and regulating tryptophan metabolism. These coordinated actions may generate synergistic multi-system antidepressant effects. Clinical evidence further suggests that acupuncture combined with pharmacotherapy may outperform medication alone, although high-quality clinical trials remain limited. This review critically appraises current evidence and methodological limitations, and proposes future directions including rigorous randomized controlled trials, multi-omics integrative approaches, and microbiome-guided precision acupuncture strategies, aiming to advance individualized acupuncture treatment for MDD.Keywords: acupuncture, gut-brain axis, major depressive disorder, neuroinflammation, gut microbiota
Alexander Balbir,1 Kayleigh Prowse,2 Julie Kim21eTMS Florida, Miami, FL, USA; 2Brain Treatment Center of San Diego, San Diego, CA, USACorrespondence: Alexander Balbir, eTMS Florida, 4651 Sailsbury Road, Suite 400, Jacksonville, FL, 32256, USA, Tel +1-410-428-3931, Email Alexander.Balbir@gmail.comIntroduction: Military members, particularly those who have been exposed to combat, face heightened risks of post-traumatic stress disorder (PTSD), which can significantly impair their overall quality of life. Current treatments are suboptimal, and despite published evidence, they do not provide therapy personalized to individual brain network activity.Materials and Methods: This is an uncontrolled open-label retrospective chart review of 94 active duty and retired servicemembers who self-reported symptoms related to PTSD. As part of the Operation Synchrony Program, participants received individually guided neuromodulation (α-rTMS) treatment, which was derived using a decision tree algorithm based on each participant’s multivariate endogenous rhythms. The full treatment comprised α-rTMS sessions delivered 5 days a week, 30 minutes each, for a total of four weeks. Side effects and clinical assessments were collected including the PTSD Checklist for DSM-5 (PCL-5), Patient Health Questionnaire (PHQ-9), Rivermead Post-Concussion Symptoms Questionnaire (RPQ-16), and Brief Resilience Scale (BRS), administered at baseline, week-2, and week-4. This chart review protocol was approved under an exemption by WCG (Western IRB and Copernicus Group) IRB Study #1-1763934-1.Results: α-rTMS treatment was well-tolerated by participants, with no serious adverse events recorded. Average PCL-5 scores decreased significantly by a total of 48% from baseline (M=35.9) to week-4 (M=18.8) with 31% of the decrease occurring by week-2 (M=24.7). A similar trend was observed for the other scales such that the average scores significantly decreased from baseline to week-4 by 46% for RPQ-16, 52% for PHQ-9, and 13% for BRS.Conclusion: Significant improvements in clinical symptoms were observed in this study. These results underscore the potential for α-rTMS treatment to address the gap in current treatment options by providing effective, safe, non-pharmacological treatment to reduce PTSD symptoms in military and civilian populations.Keywords: PTSD, α-rTMS, transcranial magnetic stimulation, military, neuromodulation, EEG-guided therapy
Yian Ling,1– 4,* Jing Li,5– 7,* Wanbin Liu,5– 7 Yejun Gao,1– 4 Lijuan Nie,1– 4 Cuizhen Zhu,1– 4 Qingrong Xia5– 71Affiliated Psychological Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui,People’s Republic of China; 2Brain Neurobiomedical Research Center, Hefei Fourth People’s Hospital, Hefei, Anhui, People’s Republic of China; 3Psychopharmacology Research Laboratory, Hefei Fourth People’s Hospital, Hefei, Anhui, People’s Republic of China; 4Anhui Clinical Research Center for Mental Disorders, Hefei Fourth People’s Hospital, Hefei, Anhui, People’s Republic of China; 5School of Pharmacy, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 6Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, Anhui, People’s Republic of China; 7The Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Medical University, Hefei, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingrong Xia, School of Pharmacy, Anhui Medical University, 81 Mei-Shan Road, Hefei, Anhui, 230032, People’s Republic of China, Fax +86 551 65161115, Email ahmcxqr@163.comIntroduction: Chronic stress is associated with depressive-like behaviors, dysregulation of the hypothalamic-pituitary-adrenal axis, and changes in inflammatory signaling. Celecoxib is a selective cyclooxygenase-2 inhibitor that has been investigated as a potential adjunctive treatment for depression; however, its effects in a chronic restraint stress model require further characterization.Methods: Male Sprague-Dawley rats were randomly assigned to a control group, chronic restraint stress (CRS) model group, CRS plus celecoxib group, or CRS plus fluoxetine group. The CRS procedure was conducted for 6 weeks, with restraint applied for 4 h per day. Celecoxib was administered by oral gavage at a dose of 20 mg/kg/day, and fluoxetine was administered at 10 mg/kg/day for 2 weeks throughout the CRS procedure. Depression-like and related behavioral changes were evaluated using the open field test, forced swimming test, Y-maze test, and sucrose preference test. Cytokine and corticosterone concentrations were measured in hippocampal homogenates. Hippocampal IBA-1 immunoreactivity and histological changes were evaluated using immunofluorescence, H&E staining, Nissl staining, and transmission electron microscopy.Results: Compared with control rats, CRS-exposed rats showed changes in open-field activity, forced-swimming behavior, Y-maze performance, and sucrose preference. Celecoxib treatment was associated with improved behavioral parameters compared with the CRS model group. Celecoxib was also associated with lower concentrations of IL-1β, IL-6, TNF-α, and corticosterone, reduced hippocampal IBA-1 immunoreactivity, and less pronounced histological and ultrastructural alterations.Discussion: These findings indicate that celecoxib was associated with improved behavioral outcomes and reduced inflammatory, endocrine, histological, and ultrastructural alterations in CRS-exposed rats.Keywords: celecoxib, chronic restraint stress, major depressive disorder, neuroinflammation
Keisuke Nomoto,1 Tempei Otsubo,2 Shingo Higa,1 Satoshi Matsuyama,1 Takeshi Inoue3,41Medical Affairs, Viatris Pharmaceuticals Japan G.K, Tokyo, Japan; 2Department of Psychosomatic and Psychiatric Medicine, Tokyo Women’s Medical University Adachi Medical Center, Tokyo, Japan; 3Department of Psychiatry, Sapporo Hanazono Hospital, Hokkaido, Japan; 4Department of Psychiatry, Tokyo Medical University, Tokyo, JapanCorrespondence: Keisuke Nomoto, Medical Affairs, Viatris Pharmaceuticals Japan G.K, 1-3-1 Azabudai, Minato-ku, Tokyo, 106-0041, Japan, Email keisuke.nomoto@viatris.comPurpose: Generalized anxiety disorder (GAD) impairs quality of life (QoL) and daily function; however, it remains under-recognized in Japan due to symptom overlap and a lack of approved treatments. This study estimated GAD prevalence among psychiatric outpatients using the Structured Clinical Interview for DSM (SCID), examined associated demographic and clinical factors, assessed health status and QoL, and evaluated the diagnostic validity of the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Kessler 6-item Psychological Distress scale (K6) versus SCID.Methods: This multicenter, cross-sectional study analyzed 407 patients across 22 sites. Prevalence was determined through SCID-based structured interviews. Demographics were obtained from paper questionnaires and clinical characteristics from medical records. Patient-reported outcomes quantified burden and screening accuracy.Results: Eighty-three of 407 patients (20.4%) met DSM-5 criteria for GAD using SCID. Prevalence was higher in females versus males (68.7% vs 31.3%) and more common among younger individuals. Comorbid depressive disorders were frequent (63.4%), with major depressive disorder being the most prevalent. Patients with GAD were more likely to have lower income, be students, and exhibit higher symptom severity on both the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) and the GAD-7. Patients with GAD (n=83) had higher QIDS-SR, GAD-7, and K6 scores than non-GAD patients, indicating greater depressive symptoms, anxiety, and psychological distress. Health-related QoL and functional impairment measured through EuroQol 5 Dimensions 5 Levels and the Sheehan Disability Scale indicated worse outcomes in GAD. GAD-7 and K6 demonstrated moderate diagnostic performance versus SCID.Conclusion: GAD was prevalent among Japanese psychiatric outpatients (20.4%), suggesting the potential under-recognition in clinical practice, with some patients receiving alternative diagnoses. The lack of approved treatments and recognized diagnostic procedures may exacerbate the patient’s burden. Developing GAD-specific therapies and improving diagnostic awareness are critical to addressing this unmet need.Keywords: generalized anxiety disorder, Japan, prevalence, DSM-5, structured interview, PRO
Yanyan Wang, Wenzhe Sun, Chensheng Pan, Zhou Zhu, Guo Li, Xin Zhao, Suiqiang ZhuDepartment of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Xin Zhao; Suiqiang Zhu, Email 2018tj5452@hust.edu.cn; zhusuiqiang@163.comBackground: Genetic polymorphisms in drug metabolism play an important role in the wide inter-individual variability in antidepressant efficacy. This study aimed to determine whether cytochrome P450 2C19 (CYP2C19) and cytochrome P450 2D6 (CYP2D6) genotypes predict treatment response to escitalopram (ESC) and venlafaxine (VEN), respectively, in patients with post-stroke depression (PSD).Methods: In this single-center prospective observational study, 313 acute stroke patients with PSD were consecutively enrolled and received ESC or VEN for 8 weeks. Efficacy was assessed using the 17-item Hamilton Depression Scale (HAMD-17). The primary outcome was the change in HAMD-17 score from baseline to week 8; secondary outcomes were response (≥ 50% reduction) and remission (score ≤ 7). Patients were stratified by CYP2C19 and CYP2D6 genotypes into fast- and slow-metabolizer subgroups. Subgroup comparisons utilized χ2-tests and Mann–Whitney U-tests.Results: At week 8, among 148 ESC-treated patients, CYP2C19 genotypes were distributed as poor/intermediate metabolizers (PM/IM) 82 (55.4%) and normal/rapid metabolizers (NM/RM) 64 (43.2%); among 113 VEN-treated patients, CYP2D6 genotypes showed marked imbalance (only 2 IM, 111 NM). No significant difference was found between ESC PM/IM and NM/RM subgroups in HAMD‑17 reduction (median: 10 vs 11, P=0.434), response (61.0% vs 69.7%, P=0.269), or remission (48.8% vs 51.5%, P=0.741). For patients treated with VEN, there was a significant imbalance in the distribution of CYP2D6 genotypes, which prevented us from further analyzing the association between CYP2D6 gene polymorphisms and the efficacy of VEN.Conclusion: No significant effect of CYP2C19 genetic polymorphism on ESC efficacy was observed in this study. These findings underscore the need for further exploration into the clinical utility of pharmacogenetics. Future antidepressant treatment should prioritize cost-effective, pragmatic approaches over costly genetic testing alone.Keywords: pharmacogenomics, cytochrome P450 enzymes, antidepressant, post-stroke depression
Yilin Xiong,1,* Ziyu Zhu,1,* Caijie Shen,2 Wei Deng,1,3 Yuqi Cheng11Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 3Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Deng, Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China, Email dengw@zju.edu.cn Yuqi Cheng, Affiliated Mental Health Center & Hangzhou Seventh People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China, Email yuqicheng@126.comAbstract: Major depressive disorder (MDD) is increasingly recognized as a systemic disorder involving dysregulation of the heart-brain axis (HBA). Mounting evidence links impaired HBA signaling to the pathogenesis of major depressive disorder. Emerging data indicate that neuromodulation-mediated autonomic alterations correlate with depressive symptom remission. Although neuromodulatory therapies are widely deployed clinically, HBA-based biomarkers remain experimental, and no consistent physiological predictors of treatment response have been established to date. This review summarizes HBA dysfunction in depression across neural, biochemical, and mechanical pathways, integrating evidence from preclinical and clinical studies. We critically evaluate recent advances in leveraging these pathways to optimize neuromodulation strategies. Emerging evidence suggests that certain neuromodulation approaches—including transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), vagus nerve stimulation (VNS), electroconvulsive therapy (ECT), and deep brain stimulation (DBS)—may modulate heart-brain axis function. It has been hypothesized that such modulation could represent a physiological pathway contributing to mood improvement, providing a rationale for a heart-oriented framework in neuromodulation research. However, the clinical utility of this framework and its underlying biomarkers remain to be established through rigorous long-term investigations. By bridging the conventional conceptual divide between psychiatric and cardiovascular diseases, this review offers a systems-level perspective on neuromodulation efficacy and highlights the potential of HBA-related biomarkers for assessing pathological states and guiding treatment strategies in depression and other psychosomatic conditions.Keywords: depression, neuromodulation, heart-brain axis, autonomic nervous system, heart rate variability, heart-brain coupling
Hitoshi Sakurai,1 Keisuke Nomoto,2 Tomoki Ito,2 Yasuyuki Matsumoto,1 Shingo Higa21Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan; 2Medical Affairs, Viatris Pharmaceuticals Japan G.K., Tokyo, JapanCorrespondence: Keisuke Nomoto, Medical Affairs, Viatris Pharmaceuticals Japan G.K., Azabudai Hills Mori JP Tower, 1-3-1 Azabudai, Minato-ku, Tokyo, 106-0041, Japan, Tel +81 3 5656 0400, Email keisuke.nomoto@viatris.comPurpose: This study evaluated outcomes of venlafaxine treatment in Japanese patients with major depressive disorder (MDD) in routine clinical practice. Since anxiety is a common and clinically relevant feature of MDD, descriptive analyses were conducted based on the presence or absence of Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) anxious distress.Patients and Methods: This 12-week, multicenter, single-arm, observational study consecutively enrolled adult patients with MDD initiating venlafaxine in Japan. DSM-5 anxious distress was assessed at baseline. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 12 or discontinuation. Secondary endpoints included MADRS response and remission rates, patient-reported outcomes, and safety. Analyses were descriptive and conducted by anxious distress status.Results: Among enrolled patients, 407 received venlafaxine and comprised the safety analysis set; 198 (48.6%) had anxious distress. MADRS total score decreased from baseline to week 12 or discontinuation in the overall population and in patients with and without anxious distress. Patients with anxious distress had higher baseline symptom severity but showed improvement over time. Similar improvements were seen across secondary patient-reported outcomes in both subgroups. Drug-related adverse events and discontinuations due to adverse events were numerically more frequent in patients with anxious distress. The safety profile was in line with established findings.Conclusion: Venlafaxine treatment in clinical practice improved depressive symptoms, anxiety, functioning, quality of life, and cognitive complaints in patients with MDD. Improvements were seen in patients with and without anxious distress. These results provide descriptive real-world evidence on treatment outcomes; however, they should be interpreted with caution given the non-comparative study design and other limitations. The findings may inform clinical decision-making in patients with heterogeneous presentations encountered in routine psychiatric practice.Keywords: mood disorder, cognitive symptoms, pharmacotherapy, quality of life, real-world practice, serotonin-norepinephrine reuptake inhibitor
Anxiety and depression Disorders play a crucial role in the global disease burden and impose significant effects. Depression markedly impacts psychosocial functioning and quality of life. Nevertheless, the effectiveness of mental health interventions is generally assessed through symptom reduction, the use of QoL as a patient-centered outcome is still not standardized. This systematic review aims to identify QoL instruments used in anxiety and depression interventions and analyze variations in their application in various global contexts. A systematic literature review was conducted in accordance with PRISMA 2020 guidelines and prospectively registered in PROSPERO (CRD420251109799). Literature searches were performed in PubMed, Embase.com, Scopus, and APA PsycInfo. Following screening and eligibility assessment, 17 studies were included in the final review. Interventions included psychotherapy, mindfulness, and body-based therapy, digital interventions, pharmacotherapy, and combined approaches. The most frequently used QoL instruments were SF-36/SF-12, EQ-5D, and WHOQOL-BREF. In general, interventions showed that physical activity has a positive impact on QoL, particularly in the psychological and social domains. However, instrument heterogeneity, the dominance of self-reports, and cultural context limitations were major challenges. Standardization of culturally sensitive QoL measurements is needed to improve the validity and comparability of global findings.
Meng Zhang,1,* Lian Liu,1,* Tian Tan,1 Lijuan He,1 Bingqing Hu,1 Sixian Li,2 Mengya Jiang,3 Peng Deng,2 Qingjia Ren21Acupuncture, Tuina, and Rehabilitation Center, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, People’s Republic of China; 2College of Acupuncture, Tuina, and Rehabilitation, Hunan University of Traditional Chinese Medicine, Changsha, People’s Republic of China; 3School of Medicine, Hunan University of Traditional Chinese Medicine, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lian Liu, Acupuncture, Tuina, and Rehabilitation Center, The Second Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, People’s Republic of China, Email 455546557@qq.comBackground: Insomnia is closely associated with neuroinflammation, yet the therapeutic mechanism of electroacupuncture (EA) remains unclear. This animal study investigated whether EA attenuates hypothalamic neuroinflammation in para-chlorophenylalanine (PCPA)-induced insomnia rats by suppressing the TLR4/MyD88/NF-κB p65 pathway and M1 microglial activation, using TAK-242 (HY-11109), a selective TLR4 inhibitor, as a positive control.Methods: Forty Sprague-Dawley rats (20 male, 20 female, sex-balanced across groups) were randomly allocated to Control, Model, EA, and TAK-242 groups (n=10 per group). Insomnia was induced in the model, EA, and TAK-242 groups by intraperitoneal injection of PCPA (500mg/kg) for 2 consecutive days. The TAK-242 group received daily intraperitoneal injection of TAK-242 (3 mg/kg). The EA group received acupuncture at Baihui (GV20), bilateral Benshen (GB13), Shenmen (HT7) and Sanyinjiao (SP6), with ipsilateral Shenmen (HT7) and Sanyinjiao (SP6) connected to an electroacupuncture device using a 2 Hz continuous wavefor 20 minutes daily over 7 days. Sleep latency and total sleep duration were recorded via the pentobarbital sodium righting reflex test. Serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were assessed via the enzyme-linked immunosorbent assay (ELISA); Hypothalamic microglial M1 polarization was assessed by Iba-1/CD86 immunofluorescence co-localization. Protein and mRNA levels of TLR4, MyD88, NF-κB p65, TNF-α, and IL-6 were quantified by Western blot and RT-qPCR, respectively. All outcome assessments were performed by investigators blinded to group allocation.Results: Compared with the model group, both electroacupuncture and TAK-242 significantly shortened sleep latency and prolonged total sleep time (P < 0.01), and reduced serum levels of TNF-α and IL-6 (P < 0.01). Both interventions also attenuated CD86 fluorescence intensity (P < 0.01) and Iba-1/CD86 co-expression (P < 0.05), and down-regulated the protein and mRNA expression of TNF-α, IL-6, TLR4, MyD88, and NF-κB p65 in the hypothalamus (P < 0.01). The effects of electroacupuncture and TAK-242 on sleep parameters, CD86 fluorescence intensity, and Iba-1/CD86 co-expression were comparable, whereas TAK-242 exerted a more pronounced inhibitory effect than electroacupuncture on the expression of inflammatory cytokines and pathway-related proteins in the serum and hypothalamus (P < 0.05, P < 0.01).Conclusion: Electroacupuncture effectively improved sleep disturbances in PCPA-induced insomnia rats. The underlying mechanism may be associated with inhibition of the TLR4/MyD88/NF-κB p65 signaling pathway, suppression of M1 microglial activation, and downregulation of pro-inflammatory cytokines, thereby partly alleviating hypothalamic neuroinflammation.Keywords: electroacupuncture, insomnia, microglia, inflammation
Purpose:To characterize serum lithium monitoring, clinician-recorded short-term outcomes, and treatment barriers in a clinically selected outpatient cohort of patients with bipolar disorder that was enriched for suicide risk. Patients and Methods:We retrospectively reviewed consecutive routine-care records from a specialist mood-disorders clinic between January 2024 and March 2025. The monitoring dataset comprised 188 patients and 562 valid serum lithium measurements. The outcome dataset comprised 124 patient-level records from initial or follow-up encounters, and a separate implementation dataset contained 13 patients with documented discontinuation or non-initiation. The serum lithium value closest to the clinical outcome assessment was used in exploratory analyses. Results:Among monitored patients, 124/188 (66.0%) had at least two measurements. Median serum lithium concentration was 0.62 mmol/L (interquartile range 0.50-0.84), and 18/562 measurements (3.2%) were >1.2 mmol/L. Clinician-recorded remission was documented in 72/124 outcome records (58.1%) and any improvement in 114/124 (91.9%). Any improvement was 90.0%, 96.1%, and 81.5% in the <0.4, 0.4-<0.8, and ≥0.8 mmol/L groups, respectively (exploratory unadjusted P=0.053). Remission did not differ across groups (P=0.952), and the continuous serum lithium value was not associated with remission (odds ratio per 0.1 mmol/L, 1.01; 95% confidence interval 0.86-1.18). Documented barriers included adverse effects, testing or logistical burden, toxicity concerns, and poor palatability. Conclusion:A single routine-care serum lithium concentration recorded near a clinical assessment was not associated with clinician-recorded remission. The analysis did not evaluate longitudinal exposure or confirmed steady-state trough concentrations, and improvement during comprehensive care cannot be attributed to lithium alone. These findings support an integrated lithium-care pathway that combines interpretable monitoring, accessible testing, early management of adverse effects, clear toxicity education, and suicide-specific safety planning.
Antipsychotic medications remain the conventional treatment for treatment-resistant schizophrenia (TRS), yet some patients exhibit poor responses. Due to the limitations of pharmacological interventions, physical therapies are increasingly recognized as essential supplements in managing TRS. This article systematically examines the current clinical applications and research advances of physical therapeutic techniques for TRS. Existing evidence suggests that electroconvulsive therapy (ECT), particularly when administered as an adjunct to antipsychotic medication, may improve positive symptoms and overall clinical outcomes in a subset of patients with TRS. However, its potential cognitive adverse effects and related ethical considerations warrant careful evaluation. As a non-invasive neuromodulatory technique, transcranial magnetic stimulation (TMS) may exert therapeutic effects by modulating frontotemporal cortical excitability and activity within associated neural circuits, thereby contributing to improvements in auditory hallucinations, negative symptoms, and cognitive function. Transcranial electrical stimulation (tES), including transcranial direct current stimulation (tDCS), is characterized by procedural simplicity, favorable safety, and good tolerability. Its clinical effects may be mediated through modulation of cortical excitability, synaptic plasticity, and functional connectivity. However, current studies remain highly heterogeneous with respect to sample size, stimulation parameters, treatment duration, outcome measures, and follow-up periods. Moreover, no physical therapy has yet been approved by the US. Food and Drug Administration (FDA) for the treatment of TRS. This article aims to synthesize the therapeutic efficacy of various physical interventions for TRS and summarize the current clinical evidence, thereby broadening the range of potential treatment options for patients with TRS and promoting a more comprehensive clinical understanding and management of this condition.
Objective:To investigate alterations in resting-state electroencephalography (rsEEG) functional connectivity (FC) in patients with atrial fibrillation (AF) and cognitive impairment, examine its independent association with cognitive dysfunction, and evaluate the potential neurophysiological biomarker value of rsEEG FC in AF-related cognitive impairment. Methods:A total of 141 participants were divided into three groups: controls without AF or cognitive impairment (HC, n = 41), patients with AF without cognitive impairment (PT-WoCI, n = 37), and patients with AF and cognitive impairment (PT-CI, n = 63). All participants underwent rsEEG and cognitive assessment using the Montreal Cognitive Assessment. EEG metrics, including power spectral density (PSD), FC, phase-amplitude coupling (PAC), and sample entropy (EnSA), were derived from rsEEG data. Candidate EEG features were further screened using LASSO regression. Multivariable logistic regression models were constructed to assess independent associations between rsEEG metrics and cognitive impairment. Receiver operating characteristic (ROC) curves were used to evaluate model discriminatory performance. Results:Compared with HC and PT-WoCI groups, the PT-CI group showed significantly reduced alpha-band FC. In multivariable logistic regression analysis, alpha-band wPLI remained independently associated with cognitive impairment in patients with AF (OR = 0.44, 95% CI: 0.24-0.72, P = 0.002). The model incorporating clinical variables and alpha-band wPLI showed good discriminatory ability (area under the ROC curve: 0.814 [95% CI: 0.729-0.900]). Conclusion:Impaired alpha-band FC is associated with cognitive impairment in patients with AF. Alpha-band wPLI showed an independent association with cognitive status, supporting the potential clinical utility of rsEEG FC as an objective marker of AF-related cognitive impairment.
Background:Acupuncture is used for depressive disorders, but the extent to which its effects are mediated by the microbiota-gut-brain axis (MGBA) remains uncertain. Objective:To determine whether current preclinical and clinical evidence supports gut microbiota as a mediator, amplifier, or biomarker of acupuncture-related antidepressant effects. Methods:Eight databases were searched from inception to 6 July 2026 for peer-reviewed studies of acupuncture in depressive disorders or validated depressive-like phenotypes that reported gut microbiota or microbiota-derived metabolite outcomes. Results:Twenty-six independent studies were included: 22 preclinical and 4 clinical studies. Animal experiments consistently showed acupuncture-induced behavioral improvements accompanied by shifts in gut microbial composition, with several studies also documenting changes in intestinal barrier function, inflammatory signaling, microbial metabolites, neuroendocrine indicators, and synaptic plasticity. However, reported alterations at the phylum and taxon levels were inconsistent, and most work merely identified parallel changes instead of establishing microbiota mediation. One electroacupuncture donor fecal microbiota transplantation study offered the strongest evidence that acupuncture-remodeled microbiota can transfer behavioral benefits, while a second bidirectional transplantation confirmed microbiota participation in the disease model but could not establish acupuncture-specific microbiota mediation. Clinical evidence was limited to postpartum and post-stroke depression and was constrained by nonrandomized allocation, add-on designs, incomplete longitudinal microbiota sampling, and confounding. Conclusion:Current evidence supports a host-mediated ecological framework whereby acupuncture remodels the intestinal niche and modulates MGBA signaling. Nonetheless, microbiota-mediated effects have not been verified across most preclinical models and remain unconfirmed in clinical settings.
Purpose:Premenstrual dysphoric disorder (PMDD) induces disabling anxiety and depression, impairing mental health and academic performance in Chinese female undergraduates with high prevalence. Auricular acupressure (AA), a non-invasive Traditional Chinese Medicine modality, has potential in emotional regulation but lacks robust evidence for PMDD. This pilot study seeks to evaluate the feasibility, adherence, preliminary safety and efficacy of AA for PMDD-related emotional symptoms, as well as its potential neurophysiological mechanisms, so as to inform the design of subsequent large-scale RCTs. Patients and Methods:Sixty-six eligible participants with PMDD will be randomly allocated in a 1:1 ratio to either the active AA group or the sham AA group. The intervention will be administered once weekly for 3 consecutive menstrual cycles, totaling 12 sessions; participants will perform self-acupressure three times daily for 10 minutes per session, with auricular plasters retained for at least 2 days per application to ensure compliance. Primary outcomes (severity of depressive and anxiety symptoms) will be assessed using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) at baseline and post each cycle's final intervention. Secondary outcomes include emotional state (measured by the Positive and Negative Affect Schedule-20 [PANAS-20]) and health-related quality of life (HRQoL). Additionally, brain activity will be quantified via electroencephalography. Adverse events will be closely monitored throughout the trial. Trial Registration Number:ITMCTR2025002451 (International Traditional Medicine Clinical Trial Registry). Expected Results and Conclusion:This study is designed to collect feasibility data and preliminary evidence on the safety and efficacy of AA, alongside initial insights into its underlying mechanisms. Findings will optimize protocols and sample size for future RCTs, facilitating AA's clinical translation for PMDD.
Objective:This study aimed to examine drawing characteristics in the Synthetic House-Tree-Person (S-HTP) drawing test among children with attention-deficit/hyperactivity disorder (ADHD) and to explore their associations with ADHD symptom severity. Methods:A total of 60 children aged 7-11 years (30 with clinically diagnosed ADHD and 30 healthy controls) completed the S-HTP drawing test and the SNAP-IV scale. Drawing characteristics were independently coded by two trained raters using predefined criteria. Group differences were analyzed using chi-square and rank-sum tests. Logistic regression analyses were performed to evaluate associations with ADHD status, and ROC analyses were used to assess discrimination. FDR correction and bootstrap internal validation were additionally applied. Results:Six drawing characteristics differed significantly between groups in the initial analyses, of which five remained significant after FDR correction. Seven drawing characteristics showed exploratory associations with SNAP-IV scores. After adjustment for age, gender, family structure, and Raven's Standard Progressive Matrices scores, three drawing characteristics remained associated with ADHD status: A3 (tracing in shaky lines; OR = 4.31, 95% CI: 1.10-16.94), A4 (lines jagged and not joined; OR = 5.45, 95% CI: 1.45-20.49), and A8 (more than seven different colors; OR = 0.20, 95% CI: 0.05-0.72). Exploratory ROC analyses indicated that combining these characteristics improved discriminatory performance. The combined model achieved an AUC of 0.835. Bootstrap internal validation yielded an optimism-corrected AUC of 0.812, indicating reasonable model stability within the present sample. Conclusion:Certain S-HTP drawing characteristics were associated with ADHD status and symptom severity in this sample. In particular, A3, A4, and A8 were identified as drawing characteristics of potential interest for future research. However, given the exploratory design, relatively small sample size, and lack of external validation, further studies are required before the clinical utility of these findings can be established.
Min-Qiang Bao,1,* Dan Xiao,2,* Xiang-Shun She,1 An-Feng Yin,1 Xiao-Ning Sheng,1 Shuang-Shuang Chen,1 Dandan Chu,1 Guo-Liang Gao,3 Yi-Nong Chen,1 Yu Wang21Department of Neurology, The Affiliated Xuancheng Hospital of Wannan Medical University, Xuancheng, Anhui, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China; 3Department of Electrocardiography, The Affiliated Xuancheng Hospital of Wannan Medical University, Xuancheng, Anhui, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yu Wang, Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China, Email yfy126330@fy.ahmu.edu.cn Yi-Nong Chen, Department of Neurology, The Affiliated Xuancheng Hospital of Wannan Medical University, Xuancheng, Anhui, People’s Republic of China, Email 2chenyinon@163.comObjective: To investigate alterations in resting-state electroencephalography (rsEEG) functional connectivity (FC) in patients with atrial fibrillation (AF) and cognitive impairment, examine its independent association with cognitive dysfunction, and evaluate the potential neurophysiological biomarker value of rsEEG FC in AF-related cognitive impairment.Methods: A total of 141 participants were divided into three groups: controls without AF or cognitive impairment (HC, n = 41), patients with AF without cognitive impairment (PT-WoCI, n = 37), and patients with AF and cognitive impairment (PT-CI, n = 63). All participants underwent rsEEG and cognitive assessment using the Montreal Cognitive Assessment. EEG metrics, including power spectral density (PSD), FC, phase–amplitude coupling (PAC), and sample entropy (EnSA), were derived from rsEEG data. Candidate EEG features were further screened using LASSO regression. Multivariable logistic regression models were constructed to assess independent associations between rsEEG metrics and cognitive impairment. Receiver operating characteristic (ROC) curves were used to evaluate model discriminatory performance.Results: Compared with HC and PT-WoCI groups, the PT-CI group showed significantly reduced alpha-band FC. In multivariable logistic regression analysis, alpha-band wPLI remained independently associated with cognitive impairment in patients with AF (OR = 0.44, 95% CI: 0.24– 0.72, P = 0.002). The model incorporating clinical variables and alpha-band wPLI showed good discriminatory ability (area under the ROC curve: 0.814 [95% CI: 0.729– 0.900]).Conclusion: Impaired alpha-band FC is associated with cognitive impairment in patients with AF. Alpha-band wPLI showed an independent association with cognitive status, supporting the potential clinical utility of rsEEG FC as an objective marker of AF-related cognitive impairment.Keywords: atrial fibrillation, resting-state electroencephalography, functional connectivity, alpha band, cognitive impairment
