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Recently, functional homotopy (FH) architecture, defined as robust functional connectivity (FC) between homotopic regions, has been frequently reported to be altered in MDD patients (MDDs) but with divergent locations.In this study, we obtained resting-state functional magnetic resonance imaging (R-fMRI) data from 1004 MDDs (mean age, 33.88 years; age range, 18-60 years) and 898 matched healthy controls (HCs) from an aggregated dataset from 20 centers in China. We focused on interhemispheric function integration in MDDs and its correlation with clinical characteristics using voxel-mirrored homotopic connectivity (VMHC) devised to inquire about FH patterns.As compared with HCs, MDDs showed decreased VMHC in visual, motor, somatosensory, limbic, angular gyrus, and cerebellum, particularly in posterior cingulate gyrus/precuneus (PCC/PCu) (false discovery rate [FDR] q 0.002, z = -7.07). Further analysis observed that the reduction in SMG and insula was more prominent with age, of which SMG reflected such age-related change in males instead of females. Besides, the reduction in MTG was found to be a male-special abnormal pattern in MDDs. VMHC alterations were markedly related to episode type and illness severity. The higher Hamilton Depression Rating Scale score, the more apparent VMHC reduction in the primary visual cortex. First-episode MDDs revealed stronger VMHC reduction in PCu relative to recurrent MDDs.We confirmed a significant VMHC reduction in MDDs in broad areas, especially in PCC/PCu. This reduction was affected by gender, age, episode type, and illness severity. These findings suggest that the depressive brain tends to disconnect information exchange across hemispheres.

Aberrant topological organization of whole-brain networks has been inconsistently reported in studies of patients with major depressive disorder (MDD), reflecting limited sample sizes. To address this issue, we utilized a big data sample of MDD patients from the REST-meta-MDD Project, including 821 MDD patients and 765 normal controls (NCs) from 16 sites. Using the Dosenbach 160 node atlas, we examined whole-brain functional networks and extracted topological features (e.g., global and local efficiency, nodal efficiency, and degree) using graph theory-based methods. Linear mixed-effect models were used for group comparisons to control for site variability; robustness of results was confirmed (e.g., multiple topological parameters, different node definitions, and several head motion control strategies were applied). We found decreased global and local efficiency in patients with MDD compared to NCs. At the nodal level, patients with MDD were characterized by decreased nodal degrees in the somatomotor network (SMN), dorsal attention network (DAN) and visual network (VN) and decreased nodal efficiency in the default mode network (DMN), SMN, DAN, and VN. These topological differences were mostly driven by recurrent MDD patients, rather than first-episode drug naive (FEDN) patients with MDD. In this highly powered multisite study, we observed disrupted topological architecture of functional brain networks in MDD, suggesting both locally and globally decreased efficiency in brain networks.

Effective and targeted interventions for improving quality of life (QOL) in addition to achieving 'clinical remission' are imperatives for patients with major depressive disorder (MDD). This study aimed to examine potential predictors and moderators of QOL in depression. Data were obtained from the Algorithm Guided Treatment Strategies for Major Depressive Disorder (AGTs-MDD) study, a multisite, randomized controlled trial composed of 980 depressed patients. Mixed Model Repeated Measures (MMRM) analyses were conducted to identify baseline characteristics associated with QOL overall (predictors) and their interaction effects (moderators). Severe core depressive, anxiety and pain symptoms were found to be independently associated with poor QOL over the 12-week acute phase treatment. Severe depression, severe anxiety or pain symptoms, or severe suicidal ideation predicted a larger improvement of QOL during acute phase treatment, whereas males showed less improvement. None of the putative moderators were identified except for the educational level. Patients with lower educational level showed a larger improvement of QOL in the AGT started with escitalopram (AGT-E) group and AGT started with mirtazapine (AGT-M) group compared to the treatment as usual (TAU) group. These findings may help to instruct informed decision-making for heterogeneous patients with MDD in the view of full recovery.

Little is known how often depressive episodes are accompanied by gastrointestinal symptoms in major depressive disorders (MDD). The authors sought to determine the frequency and clinical correlates of gastrointestinal symptoms during episodes of depressive disorder.3,256 MDD patients from the National Survey on Symptomatology of Depression (NSSD), which was designed to investigate the magnitude of symptoms of current major depressive episodes in China, were enrolled and assessed for gastrointestinal symptoms in this study. Illness characteristics were compared in patients with a different frequency of gastrointestinal symptoms. Pearson correlation analysis and multiple linear regression analysis were employed to investigate the associations between gastrointestinal symptoms and psychological characteristics in the patients.More than 70% of the subjects with depressive episodes had concomitant gastrointestinal symptoms. A higher frequency of gastrointestinal symptoms was associated with an increased risk of suicide ideation, suicide attempts, anxious mood, depressed mood, insomnia, feeling a failure, poor concentration, body pain, hopelessness, anger, and irritability. Pearson correlation analysis indicated moderate but significant associations between gastrointestinal symptoms and psychological characteristics (p0.001). Multiple linear regression analysis showed that suicide ideation (β=0.161, p0.001), anxiety mood (β=0.166, p = 0.006), insomnia (β =0.262, p0.001), anger (β=0.144, p0.001), feeling a failure (β =0.365, p0.001), and body pain (β=0.581 p0.001) were independently associated with gastrointestinal symptoms in MDD patients.Gastrointestinal symptoms were one of the most prevalent clinical presentations of MDD. The associations between gastrointestinal symptoms and psychological characteristics may prove useful in expanding our understanding of how gastrointestinal symptoms contributes to MDD.

Background The co-occurrence of insomnia and hypersomnia symptoms in patients with major depressive disorder (MDD) is associated with suicidal ideation and functional impairment. The relationship between sleep disturbances and clinical features and outcomes may not be adequately studied. In this study, we measured the functional impairments and clinical features of co-occurring insomnia and hypersomnia symptoms in Chinese patients with MDD. Methods A post-hoc analysis was performed on data from the National Survey on Symptomatology of Depression (NSSD), which assessed the MDD patients in 32 hospitals by a clinician-rating questionnaire. The clinical features and outcomes were compared among the following four groups: insomnia symptom only, hypersomnia symptom only, both insomnia and hypersomnia symptoms, no sleep disturbance, respectively. Results Totally, 234 (7.15%) of 3275 participants with MDD co-occurred insomnia and hypersomnia symptoms. They had more depressive symptoms (27.41 ± 9.123), higher rate of suicide ideation (39.7%), more severe impairment in physical (58.1%), economic (32.9%), work (55.1%), and relationship with families (29.5%). Patients with both sleep disturbances were more likely to excessive worry about sleep, have suicidal ideation, the distress of social disharmony, more somatic symptoms, lack of energy, hyperphagia, loss of mood reactivity, and diurnal change, whereas less likely to have anxious mood. Limitations Sleep disorders were not diagnosed by current standard diagnostic criteria. Conclusions Patients co-occurring with both sleep disturbances are associated with a higher rate of suicide risk and poorer social function. Our study could provide implications for suicidal risk evaluation and the development of therapeutic strategies for depression.

Background This study aims to explore the changes in functional neuroimaging in bipolar depression patients with anxiety symptoms (BDP-A). Methods Forty-five BDP-A patients, 22 bipolar depression patients without anxiety symptoms (BDP-NA), and 48 healthy controls (HC) were finally involved. The low-frequency oscillation characteristics, functional connectivity (FC), and network properties among the three groups of participants were analyzed. Results Compared with the BDP-NA group, BDP-A patients exhibited significantly decreased amplitude of low-frequency fluctuation (ALFF) in the left middle frontal gyrus (MFG), superior occipital gyrus, and inferior parietal, but supramarginal and angular gyri (IPL). Enhanced FC from left IPL to middle temporal gyrus, from left precentral gyrus (PreCG) to bilateral angular gyri, medial superior frontal gyrus, and left superior frontal gyrus (SFG)/MFG were also revealed. Compared with HC, the BDP-A group showed remarkably increased ALFF in the left MFG/PreCG, right superior parietal gyrus, while decreased ALFF in the left inferior frontal gyrus, opercular part, and SFG. In addition, higher regional homogeneity in the left MFG/PreCG was found. Limitations The limitations are as follows: (1) relatively small sample size; (2) not all the patients were drug-naive; (3) lack of pure anxiety disorder patients as a controlled group; (4) mental health conditions of HC were not systemic evaluated. Conclusions BDP-A patients showed significant differences in resting-state fMRI properties when compared with BDP-NA or HC group. These results may infer the dysfunction of the dorsal attention network, the default network, and the fronto-limbic system as well as disrupted brain network efficiency in BDP-A patients.

Background Since the novel coronavirus disease (COVID-19) outbreak in Wuhan, thousands of medical workers have been dispatched to support Wuhan against the virus. The purpose of this study was to identify the independent risk factors for psychological distress in order to develop a more effective strategy and precise evidence-based psychological intervention for medical workers. Methods This multisite cross-sectional survey recruited doctors and nurses from local and nonlocal medical teams working at 16 hospitals in Wuhan to complete this online survey from February to March, 2020. Psychological status was evaluated through Perceived Stress Scales (PSS), Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder Scale (GAD-7) and Acute Stress Disorder Scale (ASDS). Results Of 966 participants, the prevalence of stress (95.9%), depression (46.0%) and anxiety (39.3%) were high. Local medical workers exhibited even higher scores of PSS, PHQ-9, GAD-7 and ASDS than those from outside Hubei (P

Background: Most patients with the major depressive disorder (MDD) have varying degrees of impaired social functioning, and functional improvement often lags behind symptomatic improvement. However, it is still unclear if certain neurobiological factors underlie the deficits of social function in MDD. The aim of this study was to investigate the biomarkers of social function in MDD using structural magnetic resonance imaging (MRI). Methods: 3T anatomical MRI was obtained from 272 subjects including 46 high-functioning (high-SF, Sheehan Disability Scale (SDS) rating < 18) and 63 low-functioning (low-SF, SDS score ≥ 18) patients with MDD and 163 healthy controls (HC). Voxel-based morphometry (VBM) was employed to locate brain regions with grey matter (GM) volume differences in relation to social function in MDD. Regions showing GM differences in relation to social function at baseline were followed up longitudinally in a subset of 38 patients scanned after 12-week treatment. Results: Volume of right parahippocampal gyrus (rPHG) was significantly reduced in low-SF patients with MDD when compared to high-SF ones (FDR-corrected p < 0.05). Over 12 weeks of follow-up, though SF improved overall, the high and low-SF subgroups continued to differ in their SF, but had no progressive changes in PHG volume. Limitations: Limited functional assessment, high drop-out rate and median-based grouping method. Conclusions: Greater GM volume (GMV) of the rPHG may mark better social function in patients with MDD.

Background In spite of numerous options, the most efficacious treatment for major depressive disorder (MDD) remains elusive. Algorithm-guided treatments (AGTs) are proposed to address inadequate remission and optimize treatment delivery. This study aimed to evaluate the clinical benefit of AGTs for MDD, and to explore specific moderators of treatment outcomes for individual patients. Methods The study recruited 987 patients with MDD across eight hospitals who were randomly assigned to AGT with escitalopram (AGT-E), AGT with mirtazapine (AGT-M), or treatment-as-usual (TAU). The outcomes were symptom remission, response rate, early improvement rate, subsymptom clusters improvement over time, the mean time to first remission, relapse rate at 6-months posttreatment follow-up, quality of life (QOL), and adverse events. Resutls No significant differences were observed across groups in outcome, except that TAU showed significantly poorer QOL, higher relapse rates at 6-months posttreatment follow-up, and marginally significantly worse maximal burden of adverse events than the AGT groups. After 6 weeks of treatment initiation, remission rate did not significantly increase with extended treatment. AGT-M outperformed the TAU and AGT-E in treating sleep symptoms. AGT-E was less effective than AGT-M and TAU in patients with severe depression and somatic symptoms (DSSS). The superiority of TAU over AGTs was observed in recurrent MDD patients. Conclusion Although the superiority of AGTs over TAU was limited by failure of alternative subsequent treatment, AGTs outperformed in QOL and relapse rate. Types of disease episode and DSSS were regarded as specific moderators in treatment of depression. These findings might contribute to future research on targeted antidepressant treatment.

Yun Wang,1 Xiaohua Liu,2,3 Daihui Peng,2 Yan Wu,2 Yun’ai Su,4 Jia Xu,5 Xiancang Ma,6 Yi Li,7 Jianfei Shi,8 Xiaojing Cheng,9 Han Rong,10 Yiru Fang1,3,11 1Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Psychiatry, Peking University Sixth Hospital, Peking, People’s Republic of China; 5Department of Psychiatry, Harbin First Specific Hospital, Harbin, People’s Republic of China; 6Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, People’s Republic of China; 7Department of Psychiatry, Wuhan Mental Health Center, Wuhan, People’s Republic of China; 8Department of Psychiatry, Hangzhou Seventh People’s Hospital, Hangzhou, People’s Republic of China; 9Department of Psychiatry, Shandong Mental Health Center, Shandong, People’s Republic of China; 10Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen, People’s Republic of China; 11CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, People’s Republic of ChinaCorrespondence: Daihui Peng; Yiru Fang Email pdhsh@126.com; yirufang@aliyun.comBackground: Fluoxetine, bupropion, cognitive behavioral therapy (CBT), and physical therapies (modified electroconvulsive treatment or repetitive transcranial magnetic stimulation) can be used to manage melancholic depression.Objective: To compare the efficacy and safety of various treatments in patients with melancholic depression.Methods: This was a preliminary multicenter randomized controlled trial that included patients with depression in their first or recurrent acute episode between September 2016 and June 2019, and randomized to fluoxetine, fluoxetine+CBT, fluoxetine+bupropion, and fluoxetine+bupropion+brain stimulation. The primary endpoint was the decrease in the 17-item Hamilton Depression Rating Scale (17-HDRS). The secondary endpoint included the scores from the Quick Inventory of Depressive Symptomatology (QIDS-SR), QOL-6, and safety. Adverse events (AEs) were monitored. The follow-ups were performed at the end of the 0th, 2nd, 4th, 6th, 8th, and 12th weeks of treatment.Results: Finally, 113 patients were included in the analyses: fluoxetine (n=37), fluoxetine+CBT (n=27), fluoxetine+bupropion (n=34), and fluoxetine+bupropion+brain stimulation (n=15). The 17-HDRS and QIDS-SR scores decreased in all four groups (all P< 0.05). There were no differences in the 17-HDRS scores among the four groups at the end of treatment (P=0.779), except for fluoxetine alone showing a better response regarding self-consciousness than fluoxetine+bupropion. The QOL-6 scores increased in all four groups. The occurrence of AEs among the four groups showed no significant difference (P=0.053).Conclusion: This preliminary trial suggests that all four interventions (fluoxetine, fluoxetine+CBT, fluoxetine+bupropion, and fluoxetine+bupropion+brain stimulation) achieved similar response and remission rates in patients with melancholic depression, but that fluoxetine had a better effect on self-consciousness than fluoxetine+bupropion. The safety profile was manageable.Keywords: major depressive disorder, melancholic depression, fluoxetine, bupropion, cognitive behavioral therapy, brain stimulation

Biological rhythm plays an important role in major depressive disorder (MDD). The efficacy of antidepressant in biological rhythm remains unclear. This study is designed to explore the efficiency of escitalopram and mirtazapine in improving circadian rhythm, diurnal mood variation(DMV) and daily activity in MDD patients.Four-hundred and fifty participants diagnosed with MDD were randomized to receive treatment with escitalopram (TWE), treatment with mirtazapine (TWM) or treatment as usual (TAU). Biological rhythm symptoms were assessed by relevant biological subscale in the Hamilton depression scale (HAMD) and the quick inventory of depressive symptomatology self-report (QIDS). The participants were assessed by trained evaluators at baseline and week 2, 4, 6 and 8.The differences of HAMD score among TWE(58%, 69%, 72%), TWM(56%, 64%, 76%) and TAU(49%, 57%, 68%) were significant(P0.05). But the differences were significant only in patients without DMV; (2) Sleep rhythm items (difficulty falling asleep and early-wake) were significantly improved in TWM (P0 .05) for both HAMD and QIDS. Decreased appetite and weight were significantly improved in TWM (P0 .05) for both scales. (3) For daily activity-related items, feeling slowed down and concentration were significantly improved in TWE. And the retardation was significantly improved in TWE and in TWM.Both escitalopram and mirtazapine have superior anti-depressive effect, especially for MDD patients without DMV. Escitalopram was significantly more effective in daily activity, feeling slowed down and concentration difficulty, while mirtazapine was significantly more effective in improving sleep, appetite and weight of MDD.

Significance Functional connectivity within the default mode network in patients with major depressive disorder has been frequently reported to be abnormal but with contradicting directions in previous studies with small sample sizes. In creating the REST-meta-MDD consortium containing neuroimaging data of 1,300 depressed patients and 1,128 normal controls from 25 research groups in China, we found decreased default mode network functional connectivity in depressed patients, driven by patients with recurrent depression, and associated with current medication treatment but not with disease duration. These findings suggest that default mode network functional connectivity remains a prime target for understanding the pathophysiology of depression, with particular relevance to revealing mechanisms of effective treatments., Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.

Background This study aimed to explore subtypes of treatment-resistant depression (TRD). Methods Latent class analysis (LCA) was performed on clinical and demographic data collected from 375 patients with TRD. Clinical variables were compared across subtypes. Treatment outcomes across subtypes of TRD were compared separately for those within each subtype with anxiety (those with a HRSD-17 anxiety/somatization factor score ≥ 7) and those without anxiety. LCA subtypes were compared using Cochran's and Mantel–Haenszel χ2 test, respectively. Unordered multinomial logistic regression was used to assess clinical correlates of TRD subtypes. Results Three categories were detected: severe depression (66%), moderate depression with anxiety (9%) and mild depression with anxiety/somatization (25%). Gender, age, age at first onset, family monthly income, number of hospitalizations, HRSD-17 and clinical global impression-severity (CGI) scores were significantly different across the three groups. Remission rates were significantly different among anxious cases with severe (43.75%), moderate (22.73%) and mild (26.25%) depression subtypes. Compared to cases in the mild depression group, those in the severe depression group had a greater likelihood of being male, having a later age of first onset, higher numbers of hospitalization, higher HRSD-17 and CGI total scores, and lower family income. Those in the moderate depression group were more likely to be male and have lower family income than those in the mild depression group. Limitations Representative bias, relatively small sample size, unbalanced group size and incomplete indicator variables might have a negative effect on the validity and generalization of the findings. Conclusions Depression severity could be a basis for subtype classification of patients with TRD. The classification of latent class of TRD observed in our study was similar to the structure found in MDD. Longitudinal research into the stability of the latent structure of TRD across illness course is merited as is research into treatment outcomes for TRD subtypes.

Somatic symptoms are prevalent in patients with major depressive disorder (MDD) and often associated with a high risk of suicide. However, which somatic symptoms display as significant risk factors for suicidal ideation (SI) is still poorly understood in MDD.Two thousand and seventeen Chinese patients with first-episode MDD from the National Survey on Symptomatology of Depression were included in this study. A doctor-rating assessment questionnaire was constructed to evaluate depression related somatic symptoms, and stepwise logistic regression analysis was performed to explore the relationship between somatic symptoms and SI.Our results showed a high prevalence of current SI in first-episode MDD (50.87%), while no significant gender differences (53.32% vs. 49.26%, P = 0.076) were observed. In addition, patients who have more somatic symptoms would be at the higher risk to elicit SI, and stepwise logistic regression analysis indicated that age (β = -0.020, P 0.001), Pre-verbal physical complaints (β = 0.356, P = 0.001), Sensory system complaints (β = 0.707, P = 0.000), Other pain conditions (β = 0.434, P 0.001), Late insomnia (β = 0.267, P = 0.008), Hypersomnia (β = 0.936, P 0.001), Weight loss (β = 0.272, P = 0.006), Hyposexuality (β = 0.513, P = P 0.001) were strongly associated with current SI in first-episode Chinese major depression.Somatic symptoms are strongly associated with SI in first-episode MDD. It is suggestive for clinicians to show concerns for patients' somatic symptoms in practice.

Bipolar disorder (BD) and major depressive disorder (MDD) have both common and distinct clinical features, that pose both conceptual challenges in terms of their diagnostic boundaries and practical difficulties in optimizing treatment. Multivariate machine learning techniques offer new avenues for exploring these boundaries based on clinical neuroanatomical features. Brain structural data were obtained at 3 T from a sample of 90 patients with BD, 189 patients with MDD, and 162 healthy individuals. We applied sparse partial least squares discriminant analysis (s-PLS-DA) to identify clinical and brain structural features that may discriminate between the two clinical groups, and heterogeneity through discriminative analysis (HYDRA) to detect patient subgroups with reference to healthy individuals. Two clinical dimensions differentiated BD from MDD (area under the curve: 0.76, P

Highlights • Two subtypes with distinct default mode network profiles exist in major depression. • Subtypes of major depression are robust in validation datasets across brain atlases. • Hyper- & hypo-connectivity DMN subgroups have comparable clinical symptom variables. • Future studies should examine whether two subtypes have differing treatment response., Background Major depressive disorder (MDD) is heterogeneous disorder associated with aberrant functional connectivity within the default mode network (DMN). This study focused on data-driven identification and validation of potential DMN-pattern-based MDD subtypes to parse heterogeneity of the disorder. Methods The sample comprised 1397 participants including 690 patients with MDD and 707 healthy controls (HC) registered from multiple sites based on the REST-meta-MDD Project in China. Baseline resting-state functional magnetic resonance imaging (rs-fMRI) data was recorded for each participant. Discriminative features were selected from DMN between patients and HC. Patient subgroups were defined by K-means and principle component analysis in the multi-site datasets and validated in an independent single-site dataset. Statistical significance of resultant clustering were confirmed. Demographic and clinical variables were compared between identified patient subgroups. Results Two MDD subgroups with differing functional connectivity profiles of DMN were identified in the multi-site datasets, and relatively stable in different validation samples. The predominant dysfunctional connectivity profiles were detected among superior frontal cortex, ventral medial prefrontal cortex, posterior cingulate cortex and precuneus, whereas one subgroup exhibited increases of connectivity (hyperDMN MDD) and another subgroup showed decreases of connectivity (hypoDMN MDD). The hyperDMN subgroup in the discovery dataset had age-related severity of depressive symptoms. Patient subgroups had comparable demographic and clinical symptom variables. Conclusions Findings suggest the existence of two neural subtypes of MDD associated with different dysfunctional DMN connectivity patterns, which may provide useful evidence for parsing heterogeneity of depression and be valuable to inform the search for personalized treatment strategies.

Xiaohua Liu,1,2,* Yun Wang,3,* Daihui Peng,3 Huifeng Zhang,3,* Yanqun Zheng,1 Yan Wu,3 Yun-Ai Su,4 Ming Liu,5 Xiancang Ma,6 Yi Li,7 Jianfei Shi,8 Xiaojing Cheng,9 Han Rong,10 Yiru Fang2,3,11 1Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 4Department of Psychiatry, Peking University Sixth Hospital, Peking, People’s Republic of China; 5Department of Psychiatry, Harbin First Specific Hospital, Harbin, People’s Republic of China; 6Department of Psychiatry, The First Affiliated Hospital of Xi’an Jiao Tong University, Xi’an, People’s Republic of China; 7Department of Psychiatry, Wuhan Mental Health Center, Wuhan, People’s Republic of China; 8Department of Psychiatry, Hangzhou Seventh People’s Hospital, Hangzhou, People’s Republic of China; 9Department of Psychiatry, Shandong Mental Health Center, Shandong, People’s Republic of China; 10Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen, People’s Republic of China; 11CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiru Fang; Daihui PengShanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 South Wan Ping Road, Shanghai 200030, People’s Republic of ChinaEmail yirufang@aliyun.com pdhsh@126.comBackground: Major depressive disorder (MDD) is a heterogeneous mental disease that encompasses different subtypes and specifiers. Clinically targeted treatments have not been identified yet, although standardized strategies are recommended by several clinical guidelines. The main aim of this study is to respectively identify the precise treatment for three different subtypes of MDD (ie, melancholic, atypical, and anxious).Methods: An 8-to-12-week, multicenter randomized controlled trial (RCT) with a parallel group design will be conducted to determine the most effective and appropriate treatment. A total of 750 adults diagnosed with MDD will be recruited, categorized into melancholic, atypical or anxious type based on the assessment of the Inventory of Depressive Symptomatology (IDS30) and the Hamilton Anxiety Scale (HAMA), and 1:1 randomly assigned to different intervention groups. Blood draw, EEG test, and MRI scan will be performed at baseline and endpoint. Clinical symptom and side-effects will be evaluated at critical decision points (CDP) including weeks two, four, six, eight, and 12 after treatment. The primary outcome is total score and reduction rate of the 17-Hamilton Depression Rating Scale (17-HDRS). The secondary outcomes include the scores of the Quick Inventory of Depressive Symptomatology-self-report (QIDS-SR), IDS30, HAMA and the Treatment Emergent Symptom Scale (TESS). All the data will be analyzed by SAS software.Discussion: The study commenced recruitment in August 2017 and is currently ongoing.Trial Registration: ClinicalTrials.gov Identifier: NCT03219008 (July 17, 2017).Keywords: major depressive disorder, MDD, subtype, antidepressant, physical therapy, computerized cognitive behavioral treatment, cCBT, randomized controlled trial, RCT

Background Robust evidence has shown that abnormal function networks, particularly the salience network (SN), are observed in depressed patients. Although white matter structural connectivity may predict time-varying functional connectivity, including symptom phenotype, in psychiatric disorders, there is still a gap in elucidating the concurrent dynamic functional and structural connectivity profiles of the SN in depressed patients. Methods We measured static and dynamic functional connectivity (FC) of the SN using resting-state fMRI BOLD time series in 76 subjects (21 with major depressive disorder (MDD), 27 with bipolar depression (BD), and 28 healthy controls (HC)). Hamilton Depression Scale total score was used to measure depression severity. Furthermore, we investigated the concurrent structural connectivity using diffusion kurtosis imaging (DKI)-based tractography. Results Our findings suggested that in the presence of MDD, both structural and dynamic (but not static) FC were reduced in the SN, particularly affecting the left prefronto-insular pathways (L.aPFC-L.insula). MDD patients showed decreased connectivity variability within the SN compared with HC. The aberrant dynamic FC in the prefronto-insular pathways of the SN related to severity of depressive symptoms in MDD. Furthermore, compared with BD patients, those with MDD showed significantly decreased dynamic FC in the left prefronto-parietal system (L.aPFC-lateral parietal cortex). Limitations The generalizability of our findings is, to some extent, constrained by the small sample size. Conclusions The integrity of SN connectivity, particularly the prefronto-insular pathway, appears to be a crucial signature of MDD. The perturbed dynamic interaction of SN with prefrontal regions may underlie the clinical severity in depressed patients.

The insular cortex appears to have a crucial role in emotional processing and cognitive control in bipolar disorder (BD). However, most previous studies focused on the entire insular region of BD, neglecting the topological profile of its subregions. Our study aimed to investigate its subregion topological characteristics using the resting-state functional connectivity (rsFC) in patients with BD on depression episode. The magnetic resonance imaging (MRI) data of 28 depressed BD patients and 28 age- and gender-matched healthy controls (HCs) were acquired. We observed that compared to HCs, depressed patients with BD exhibited significantly decreased rsFC between the right ventral anterior insula (vAI) and the left middle temporal gyrus/the right angular, the right dorsal anterior insula (dAI) and the left precuneus, as well as the right posterior insula and the right lingual gyrus. Furthermore, hyperconnectivity was observed between the left dAI and the left medial frontal gyrus, as well as right dAI and left superior temporal gyrus in BD depression. However, no significant group effect was observed between aberrant FC patterns and clinical variables. These findings revealed the functional connectivity patterns of insular subregions for the depressed BD patients, suggesting the potential neural substrate of insular subregions involved in depressive episode of BD. Hence, these results may provide a neural substrate for the potential treatment target of BD on depression episode.

Background: Major depressive disorder (MDD) is known to be characterized by altered brain functional connectivity (FC) patterns. However, whether and how the features of dynamic FC would change in patients with MDD are unclear. In this study, we aimed to characterize dynamic FC in MDD using a large multi-site sample and a novel dynamic network-based approach. Methods: Resting-state functional magnetic resonance imaging (fMRI) data were acquired from a total of 460 MDD patients and 473 healthy controls, as a part of the REST-meta-MDD consortium. Resting-state dynamic functional brain networks were constructed for each subject by a sliding-window approach. Multiple spatio-temporal features of dynamic brain networks, including temporal variability, temporal clustering and temporal efficiency, were then compared between patients and healthy subjects at both global and local levels. Results: The group of MDD patients showed significantly higher temporal variability, lower temporal correlation coefficient (indicating decreased temporal clustering) and shorter characteristic temporal path length (indicating increased temporal efficiency) compared with healthy controls (corrected p < 3.14×10−3). Corresponding local changes in MDD were mainly found in the default-mode, sensorimotor and subcortical areas. Measures of temporal variability and characteristic temporal path length were significantly correlated with depression severity in patients (corrected p < 0.05). Moreover, the observed between-group differences were robustly present in both first-episode, drug-naïve (FEDN) and non-FEDN patients. Conclusions: Our findings suggest that excessive temporal variations of brain FC, reflecting abnormal communications between large-scale bran networks over time, may underlie the neuropathology of MDD.

Purpose: This study aimed to investigate the clinical characteristics of somatic symptoms of patients in China who suffer from major depressive disorder (MDD). Method: 3273 patients who met the diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) MDD were recruited from 16 general hospitals and 16 mental health centers in China. Physicians and patients completed complementary customized depression disorder symptomatology questionnaires assessing the clinical characteristics of patients with MDD. Result: 1. In this study we analyzed physician-recorded data. The major somatic symptoms in patients with MDD in China were insomnia (64.6%), pre-verbal physical complaints (46.9%), weight loss (38.5%), low appetite (37.6%), circulatory system complaints (31.3%), headache (31.3%), hyposexuality (31.0%), gastrointestinal symptom complaints (29.6%), and respiratory system complaints (29.6%). 2. Compared with MDD patients who sought medical help from mental health centers, MDD patients who sought medical help from general hospitals were more likely to suffer from urinary system complaints, headache, sensory system complaints, trunk pain, and nervous system complaints. A lower prevalence rate of insomnia and hyposexuality was also observed among MDD patients who visited general hospitals (p

This study explored the magnitude and clinical correlates of anxiety in three groups of patients with major depressive disorder (MDD): those with comorbid anxiety disorders (the COM group), those with subthreshold core anxiety disorder symptoms that are the screening items for anxiety disorders on the MINI (the SUB group), and those with neither anxiety disorders nor subthreshold core anxiety disorder symptoms (the NON group). Anxiety symptomatology of 1052 patients from 8 psychiatric settings in mainland China, who met DSM-IV TR criteria for MDD, was assessed using the MINI. The presence of core anxiety symptoms was determined by patient endorsement of any screening item of panic disorder, agoraphobia, social anxiety disorder, or generalized anxiety disorder. The prevalences of comorbid subthreshold core anxiety symptoms and anxiety disorders were 13% and 28.7%, respectively. The SUB and COM cases showed similar patterns of clinical presentation. Both were more likely than the NON cases to be characterized by younger age, concurrent dysthymia and OCD, suicidal ideation and attempted suicides. These findings highlight the importance of assessing both anxiety symptoms and anxiety disorders in the presence of MDD, and suggest the need for novel assessments capable of addressing different levels of anxiety in depressed patients.

Aims Nonadherence is one of the leading challenges to treatment of the major depressive disorder (MDD). Few studies have systematically analyzed the relationship between clinical characteristics, especially symptoms of depressive patients and their therapeutic nonadherence over a relatively large sample. This study aimed to investigate factors of nonadherence in a nationwide survey in China. Methods Participants with MDD who met the criteria of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) were recruited from 32 sites throughout China. Patients were all over 16 years old. A doctor-rating questionnaire with 64 symptoms based on DSM-IV was constructed to evaluate depression-related feeling and behavior. Single-factor logistic regression was utilized to screen variables, and multifactor logistic regressive analysis was used to identify which factors were risk or protective for nonadherence. We included 882 patients of poor adherence and 857 patients of good adherence. Results Recurrence, untreated first episode, tricyclic antidepressant (TCA)-treated first episode, antidepressant-only-treated current episode, decrease or loss of interest, more somatic symptoms, and "atypical" symptoms were risk factors for nonadherence, whereas selective noradrenaline reuptake inhibitor (SNRI)-treated first episode was a protecting factor. Conclusion Clinical characteristics may play an important role in predicting nonadherence. Doctors may have to pay much attention on patients with these factors and should keep on discussing them with patients.

While gastrointestinal (GI) symptoms are very common in patients with major depressive disorder (MDD), few studies have investigated the neural basis behind these symptoms. In this study, we sought to elucidate the neural basis of GI symptoms in MDD patients by analyzing the changes in regional gray matter volume (GMV) and gray matter density (GMD) in brain structure.Subjects were recruited from 13 clinical centers and categorized into three groups, each of which is based on the presence or absence of GI symptoms: the GI symptoms group (MDD patients with at least one GI symptom), the non-GI symptoms group (MDD patients without any GI symptoms), and the healthy control group (HCs). Structural magnetic resonance images (MRI) were collected of 335 patients in the GI symptoms group, 149 patients in the non-GI symptoms group, and 446 patients in the healthy control group. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered to all patients. Correlation analysis and logistic regression analysis were used to determine if there was a correlation between the altered brain regions and the clinical symptoms.There were significantly higher HAMD-17 scores in the GI symptoms group than that of the non-GI symptoms group (P 0.001). Both GMV and GMD were significant different among the three groups for the bilateral superior temporal gyrus, bilateral middle temporal gyrus, left lingual gyrus, bilateral caudate nucleus, right Fusiform gyrus and bilateral Thalamus (GRF correction, cluster-P 0.01, voxel-P 0.001). Compared to the HC group, the GI symptoms group demonstrated increased GMV and GMD in the bilateral superior temporal gyrus, and the non-GI symptoms group demonstrated an increased GMV and GMD in the right superior temporal gyrus, right fusiform gyrus and decreased GMV in the right Caudate nucleus (GRF correction, cluster-P 0.01, voxel-P 0.001). Compared to the non-GI symptoms group, the GI symptoms group demonstrated significantly increased GMV and GMD in the bilateral thalamus, as well as decreased GMV in the bilateral superior temporal gyrus and bilateral insula lobe (GRF correction, cluster-P 0.01, voxel-P 0.001). While these changed brain areas had significantly association with GI symptoms (P 0.001), they were not correlated with depressive symptoms (P 0.05). Risk factors for gastrointestinal symptoms in MDD patients (p 0.05) included age, increased GMD in the right thalamus, and decreased GMV in the bilateral superior temporal gyrus and left Insula lobe.MDD patients with GI symptoms have more severe depressive symptoms. MDD patients with GI symptoms exhibited larger GMV and GMD in the bilateral thalamus, and smaller GMV in the bilateral superior temporal gyrus and bilateral insula lobe that were correlated with GI symptoms, and some of them and age may contribute to the presence of GI symptoms in MDD patients.

Background Symptomatology differences of major depressive disorder (MDD) in psychiatric and general hospitals in China leads to possible misdiagnosis. Looking at the symptomatology of first-visit patients with MDD in different mental health services, and identifying predictors of health-seeking behavior using machine learning may help to improve diagnostic accuracy. Methods 1500 patients first diagnosed with MDD were recruited from 16 psychiatric hospitals and 16 general hospitals across China. Socio-demographic characteristics, causal attribution, symptoms of depression within and outside Diagnostic and Statistical Manual of Mental Disorders (DSM) framework were collected using a self-made questionnaire. A predictive model of 62 variables was established using Random forest, symptom frequencies of patients in general hospitals and psychiatric hospitals were compared. Results The machine learning approach revealed that symptoms were strong predictors of health-seeking behavior among patients with MDD. General hospitals patients had higher frequencies of suicidal ideation (χ2=15.230, p Limitations Stigma and preference bias were not measured. Severity of current depressive episodes was not assessed. Data of previous episode(s) was not presented. Conclusions Symptom evaluation targeting specific patient population in different hospitals is crucial for diagnostic accuracy. Suicide prevention reliant on collaboration between general hospitals and psychiatric hospitals is required in the future construction of Chinese mental health system.

Background Measurement-based care (MBC) is a popular strategy of clinical management for patients with major depressive disorder (MDD). The consistency of self-report and clinical measurements is of importance, but whether individual symptom severity is in agreement for both self-report and clinician rating in MDD has not been comprehensively tested. This study aimed to test whether individual symptom severity of MDD was in agreement between self-report and clinician rating, and to explore factors affecting the agreement. Methods In the National Survey on Symptomatology of Depression (NSSD) of China, 3275 patients with a major depressive episode were evaluated by both self-report and a clinician-rated version of 62 questions. Results On average, 59% of all patients reached absolute agreement with their research clinicians. Among all questions, 73% returned with moderate positive strength of correlation, followed by 27% with low positive correlation. In 77% of the total questions, there was a tendency to rate higher in the self-report version compared with the clinician-rated version. After classifying the symptoms by six major domains, it was found that patients and clinicians showed more consistent answers in history and somatic questions (81% and 65% reached agreement), and that there were more differences in mood, energy, and anxiety questions (up to 56% in full agreement). “Outpatient”, “high financial status”, “poor working condition”, and “high education level” were found to be significant positive predictors for patients rating higher than clinicians or patients and clinicians reaching agreement as opposed to clinicians rating higher than patients. Limitations The cross-sectional nature of our study undermines the interpretation of the results across the MDD treatment course. Conclusions It is sufficient to use the self-report version of a questionnaire to screen, monitor, and detect remission for MDD symptoms. Complete assessment of depression severity should take both clinician-rated scales and self-reported measures into consideration. Factors other than source of admission, financial status, working condition, and education level should be further investigated for the discrepancy between self-report and clinician rating.

Neuroimaging shed light on the understanding of psychopathological mechanisms underlying major depressive disorder, despite its inconsistent findings. Noninvasive neuroimaging studies have indicated that various behavioral deficits in major depressive disorder are implicated with structural and functional abnormalities in specific brain regions. Moreover, disrupted brain morphological and functional properties may map out the underlying pathways from genetic and environmental factors to the prognosis of depression. Molecular neuroimaging studies have also provided novel method to probe transmitters and metabolites in brain regions rather than simply measuring brain morphological changes. Recent advanced neuroimaging approaches (e.g., pattern recognition) provides great opportunity to probe neuroimaging biomarkers that may contributes to improving diagnostic accuracy and predicting treatment outcomes. In this chapter, we conclude neuroimaging studies in the research field of depression from psychopathological, molecular, genetic/environmental, diagnostic, and therapeutic perspectives.

Recently, increasing evidence has indicated that dysfunction of microRNA-124 (miR-124) might be involved in the pathophysiology and treatment of major depressive disorder (MDD) in some animal models of depression. However, the role of miR-124 in MDD patients remains unclear. The objective of this study was to investigate whether the miR-124 expression levels in peripheral blood mononuclear cells (PBMCs) were associated with MDD and to evaluate the effects of antidepressant treatment on miR-124 levels. Quantitative real-time PCR was applied to detect miR-124 expression in 32 pre- and post-treatment MDD patients and 30 healthy controls. Our results showed that expression levels of miR-124 from PBMCs in MDD patients were significantly higher than those in healthy controls (p

This research was designed to investigate patient-reported and doctor-reported reasons for the discontinuation of pharmacological treatment in Chinese patients with major depressive disorder (MDD), which was part of the National Survey on Symptomatology of Depression (NSSD) from 2014 to 2015.This cross-sectional study included 649 patients who had discontinued antidepressant medications and 711 patients who had remained on them, selected from a group of 3516 candidates who have had at least one depressive episode. Differences in the two groups' sociodemographic factors, clinical characteristics, medication use, and self-reported reasons for drug discontinuation were compared via Student's t-test or chi-square test. Logistic regression analysis was then used to determine the association of all non-subjective dichotomous and ordinal categorical variables, including the additional 63 items of our physician-evaluated symptomatic assessment, with drug compliance.Compared to the spontaneous drug discontinuation (SDD) group, the drug adherence (DA) group had significantly lower rates of the following: family history of mental disease (9.0% vs 13.6%), highest level of education achieved being post-graduate or above (1.6% vs 4.7%), smoking (5.8% vs 9.7%), and other health problems (33.9% vs 42.4%) (p's 0.05). On the other hand, first-episode depression (48.5% vs 21.9%) and taking of mood stabilizer(s) (8.3% vs 5.6%) were higher in the former group than in the latter (p's 0.05). Logistic Regression Analysis showed that five symptoms, such as depressed mood, were correlated positively with SDD, while another six symptoms, such as psychomotor retardation, were correlated negatively with it. The receiver operating characteristic (ROC) curve of this model yielded an area under the curve (AUC) of 0.701 (95% CI, 0.673-0.729). Notably, there were three main reasons given by patients in the DA group as to why they discontinued their medication(s): (1) concern about long-term side effects (36.1%), (2) no perceived need for taking said medication(s) long-term (34.2%), and (3) believing oneself to have been cured completely (30.0%).The aforementioned factors may affect patient compliance and elicit maladaptive thinking even from patients with good educational backgrounds, increasing the risk of drug discontinuation. Compliance of pharmacological treatment might be improved by increasing clarification and elucidation of different symptom clusters to the patient and combating the main reasons for drug discontinuation.

Single Nucleotide Polymorphic (SNP) variations of proinflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) have been reported to be closely associated with the major depressive disorder (MDD). However, it is unclear if proinflammatory genetic burden adversely affects the regional gray matter volume in patients with MDD. The aim of this study was to test whether rs1799724, an SNP of TNF-α, contributes to the neuroanatomical changes in MDD. In this cross-sectional study, a total of 144 MDD patients and 111 healthy controls (HC) well matched for age, sex and education were recruited from Shanghai Mental Health Center. Voxel-based morphometry (VBM) followed by graph theory based structural covariance analysis was applied to locate diagnosis x genotype interactions. Irrespective of diagnosis, individuals with the high-risk genotype (T-carriers) had reduced volume in left angular gyrus (main effect of genotype). Diagnosis x genotype interaction was exclusively localized to the visual cortex (right superior occipital gyrus). The same region also showed reduced volume in patients with MDD than HC (main effect of diagnosis), with this effect being most pronounced in patients carrying the high-risk genotype. However, neither global nor regional network of structural covariance was found to have group difference. In conclusion, a genetic variation which can increase TNF-α expression selectively affects the anatomy of the visual cortex among the depressed subjects, with no effect on the topographical organization of multiple cortical regions. This supports the notion that anatomical changes in depression are in part influenced by the genetic determinants of inflammatory activity.

Background: Metabolic factors in the kynurenine pathway (KP) have been widely accepted as being a major mechanism in Major Depressive Disorder (MDD). However, the effects of these metabolites on the degree and pattern of MDD are still poorly understood, partly due to the elusiveness of the level of metabolites when diagnosing depression. This study aimed to explore a novel diagnostic method analyzing peripheral blood with mass spectrometry to assess metabolites from KP in patients with MDD and Bipolar Depression (BD).Methods: Thirty-three patients with MDD, 20 patients with BD, and 23 healthy control participants were enrolled Metabolic factors of KP from plasma including tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) were analyzed by UPLC-3Q-MS, and levels compared across three groups. Correlation between HAMD scores and metabolite levels conducted. Receiver operating characteristic (ROC) curve was used to determine the diagnostic value of metabolic factors in MDD.Results: Levels of KYNA, QUIN, KYNA/QUIN, and KYNA/KYN were statistically different across the three groups (P < 0.05); HAMD scores and TRP, KYN, KYNA/QUIN levels were negatively correlated in the MDD group (r = −0.633, −0.477, −0.418, P < 0.05); Accuracy of KYNA diagnosing MDD was 82.5% with the optimal diagnostic value being 15.48 ng/ml. Diagnostic accuracy was increased to 83.6% when KYNA and QUIN levels were used in combination.Conclusion: This results indicate that metabolic factors of KP play a crucial role in the occurrence and development of MDD, supporting the metabolic imbalance hypothesis of MDD. Furthermore, our study also provides a new diagnostic method to study MDD based on plasma KYNA level, and suggests that KYNA would be a potential biomarker in diagnosing depression patients.

Reported structural abnormalities of patients with bipolar disorder (BD) are inconsistent and the use of psychotropic medication is one of the sources of heterogeneity. A fairly small number of morphometric studies have involved comparison of BD on different mood stabilizers. Here in this study, we aimed to investigate the cortical thickness and subcortical volumes in euthymic BD patients on lithium and valproate and healthy controls (HC), and to elucidate the relationship between the use of medication and brain structure variations. We acquired structural magnetic resonance imaging data from 35 BD patients (19/valproate;16/lithium) and 30 HC subjects. Cortical thickness was compared in multiple locations across the continuous cortical surface, and subcortical volumes were compared on a structure-by-structure basis. Group analyses revealed widespread thinning of the prefrontal cortex in BD. Compared with BD on valproate, BD on lithium showed significant increased cortical thickness of the left rostral middle frontal cortex and right superior frontal cortex, while cortical thickness was not significantly different between BD on lithium and HC in the bilateral rostral middle frontal cortex. Moreover, no significant difference was observed in subcortical volume. Limitations of this study comprise the possible effect of other psychotropic drugs, small sample size and the cross-sectional design. Therefore, the results suggest medication-related neurobiological difference between BD patients on different mood stabilizers, but no casual role can be proposed. Our findings provided new evidence about the effects of psychotropic medication upon neuroanatomy in BD, and could help to explain the inconsistency of existing studies as well as contribute to the extraction of reliable neuroimaging biomarkers in BD.

Weiping Xia,1,2 Rubai Zhou,1 Guoqing Zhao,1 Fan Wang,1 Ruizhi Mao,1 Daihui Peng,1 Tao Yang,1 Zuowei Wang,1,3 Jun Chen,1 Yiru Fang1,4,5 1Division of Mood Disorders, Shanghai Mental Health Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 2Department of Medical Psychology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 3Mood Disorder Department, Hongkou District Mental Health Center of Shanghai, Shanghai, People’s Republic of China; 4State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, CAS, Shanghai, People’s Republic of China; 5Shanghai Key Laboratory of Psychotic Disorders, Shanghai, People’s Republic of China Background: Almost half of patients with major depressive disorder (MDD) also have clinically meaningful levels of anxiety. Anxious depression is a distinct clinical subtype of MDD, which has poor response to pharmacotherapy; however, the neural mechanisms behind are largely unknown. In the present study, we explored the white matter (WM) integrity traits of anxious depression in first-episode and medication-free (medication-naïve and medication washout) Chinese young adult patients by detecting differences in diffusion tensor imaging (DTI) with the tract-based spatial statistics (TBSS) method.Subjects and methods: DTI was obtained from 39 first-episode, medication-free anxious depressive patients, 45 nonanxious depressive patients, and 50 demographically similar healthy controls. All subjects underwent clinical assessments. TBSS was carried out to investigate the difference in WM integrity among three groups within DTI parameter maps. WM integrity was measured using fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity (RD). The correlations between WM integrity and clinical features were also computed.Results: When compared with nonanxious patients, lower FA values in anxious depressive patients were found in multiple regions of the brain, mainly involving left uncinate fasciculus (UF), superior longitudinal fasciculus (SLF), and forceps major and minor. Higher RD in forceps major and minor and SLF were also detected. The decreased FA values and increased RD values correlated with both anxiety level and depression level in the pooled depressive group.Conclusion: The anxious depressive patients had more abnormalities in WM integrity at the early phase than the nonanxious group. Alternations in WM integrity in fiber pathways, including SLF, UF, and forceps major and minor, may play a critical role in the neuropathology of anxious depression and might help to identify anxious MDD from nonanxious MDD. Further study with larger sample size, larger age range, and longitudinal design is needed to confer a robust inference to better understand the dynamic neurological change and neuropathology of WM integrity in anxious MDD. Keywords: diffusion tensor imaging, anxious depression, tract-based spatial statistics, micro-structure of whiter matter

This study aims to explore the intrinsic patterns of spontaneous activity of bipolar depression (BD) patients by analyzing the fractional amplitude of low frequency fluctuation (fALFF) that help differentiate BD from unipolar depressive disorder(UD). Twenty eight patients with BD, 47 patients with UD and 29 healthy controls were enrolled to receive the resting-state functional magnetic resonance imaging (rs-fMRI) scans. The group differences of fALFF values were calculated among three groups. In addition, the correlations between the clinical variables and mfALFF values were estimated. The brain regions with activation discrepancies among three groups are located in precuneus, the left middle temporal gyrus (MTG) and left inferior parietal lobe (IPL) and lingual gyrus. Compared with HC group, BD group shows decreased fALFF in precuneus, the left IPL and increased fALFF in lingual gyrus remarkably; UD group shows significantly decreased fALFF in precuneus, the left MTG and the left IPL. On the contrast of patients with UD, patients with BD have significantly increased fALFF value in the left precuneus, the left MGT and lingual gyrus. Furthermore, a negative correlation is found between the mfALFF values in precuneus and the scores of cognitive impairment factor in the UD group. The similar pattern of intrinsic activity in PCC suggests depressive state-dependent change. The aberrant patterns of intrinsic activity in precuneus, the IPL and lingual gyrus might be provide quantitative nodes that help to conduct further study for better distinguishing between BD and UD.

Background Major depressive disorder (MDD) has been assumed to be associated with aberrant brain connectivity. However, research suggests that brain connectivity abnormalities should not be restricted to extrinsic white matter connectivity, but may also impact on intrinsic gray matter connectivity. Therefore, our study aimed to investigate the intrinsic gray-matter connectivity in MDD. Methods The participants were 16 first-episode, drug-naive patients with MDD and 16 healthy controls matched on age and gender. All participants were scanned by 3.0T structural magnetic resonance imaging. Global and local intrinsic gray-matter connectivity were measured based on surface-based geodesic distances, including mean coritical separation distances (MSDs), perimeter function, and radius function. Results MDD patients had significantly lower MSDs in the left postcentral gyrus and higher MSDs in the left superior parietal cortex. Marginally significant correlation was observed between MSDs in the left postcentral gyrus and symptoms of depression. Compared with healthy controls, depressed subjects had abnormal local intrinsic gray-matter connectivity in the left postcentral gyrus, the left transverse temporal gyrus, the right lingual gyrus, the right lateral occipital cortex, and the right superior frontal gyrus. Furthermore, local intrinsic gray matter connections of these brain areas were associated with some symptoms of depression. Limitations The small sample size limited the interpretability of our potential conclusions. Conclusion Aberrant intrinsic gray-matter connectivity was observed in depressed subjects, indicating abnormal intrinsic wiring cost of brain architecture. This might help explain the aberrant topological properties of brain functional connectivity and provide insights into the vulnerability of MDD.

Background Suicide risk is greatly increased in depression. Detection of those at risk is clinically important. Hence, this study aimed to evaluate the prevalence and identify independent risk factors associated with suicidal ideation (SI) in a widespread symptomatology within and outside DSM framework. Methods This study was part of the National Survey on Symptomatology of Depression (NSSD) which was designed to investigate the magnitude of symptoms of current major depressive episode in China. Stepwise multivariable logistic regression was performed to examine the independent risk factors for SI, including variables that are statistically significant in univariate analysis. Receiver operating characteristic (ROC) was used to evaluate the performance of the regression model. Results A total of 3275 patients (1293 males and 1982 females) were included in our analysis. Of these, 1750 patients (53.4%) had SI. Independent risk predictors included crying (P = 0.000; odds ratio = 1.827), helplessness (P = 0.000; odds ratio = 1.514), worthlessness (P = 0.001; odds ratio = 1.359), hopelessness (P = 0.000; odds ratio = 1.805), unusually restless (P = 0.005; odds ratio = 1.276), self-harm (P = 0.000; odds ratio = 3.385), mood-incongruent psychosis (P = 0.000; odds ratio = 2.782), feeling losing control of oneself (P = 0.009; odds ratio = 1.352), hypersomnia (P = 0.000; odds ratio = 1.805), sensory system complaints (P = 0.000; odds ratio = 1.546), derealization (P = 0.006; odds ratio = 1.580), guilt (P = 0.002; odds ratio = 1.332), suicidal attempts (P = 0.000; odds ratio = 2.841), male gender (P = 0.001; odds ratio = 0.756), the total course of depression (P = 0.010; odds ratio = 1.003) in the regression model. In addition, the areas under the curve of the ROC and the accuracy for the regression model were 0.80 and 0.76, respectively. Conclusions This study provided an effective risk model for SI in MDD and indicated that all these factors in our model allow better the employment of preventative measures.

Background Immune system dysregulation is critical in the physiopathology of major depressive disorder (MDD) and bipolar disorder (BD). However, it is unclear whether both diseases present the same inflammatory patterns during depressive episodes. We explored the differences in pro- and anti-inflammatory cytokines between unipolar and bipolar depression (BDD) and the trajectory of these cytokines after acute-phase treatment. Methods Sixty-four MDD patients, 61 BDD patients, and 62 healthy controls (HCs) were enrolled. We assessed the clinical features and cytokines plasma levels at baseline and week 12. The pro-inflammatory cytokines (IL-6, TNF-α) and anti-inflammatory cytokines (IL-4, IL-13) of all subjects were assessed by multiplexed sandwich ELISA-based quantitative arrays. Results Before acute-phase treatment, the initial levels of TNF-α and IL-13 were significantly lower in the BDD patients than in the MDD patients. The results demonstrated that there was no relationship between each cytokine level and clinical features of unipolar and bipolar depressions. After 12 weeks, TNF-α, IL-4, and IL-13 levels became lower in MDD patients than in the other two groups regardless of the patients’ response to treatment while the levels of TNF-α and IL-4 increased only in the BDD responders. Limitations The effects of different drugs on inflammatory cytokines in MDD or BDD could not be explored further due to the relatively small sample size. Conclusion Even within the same depressive states, MDD and BDD patients present different inflammatory features, particularly in regard to pro-inflammatory TNF-α and anti-inflammatory IL-13. In addition, the fluctuations of cytokines induced by medication may provide a hint regarding the prediction of treatment response.

BackgroundEvidence from clinical and preclinical studies has demonstrated that stress can cause depressive-like symptoms including anhedonia and psychomotor retardation, namely, the manifestation of motivational deficits in depression. The proximate mediator of linking social-environmental stress with internal motivational deficits remains elusive, although substantial studies proposed neural endocrine mechanisms. As an endogenous danger-associated molecule, high mobility group box-1 (HMGB1) is necessary and sufficient for stress-induced sensitization of innate immune cells and subsequent (neuro)inflammation.AimThis review aims to provide evidence to unveil the potential mechanism of the relationship between motivational deficits and stress in depression.MethodsWe reviewed original case-control studies investigating the association between HMGB1-mediated inflammation and stress-induced depression. The literature search of Pubmed and Web of Science electronic database from inception up to March 28th, 2019 were conducted by two independent authors. We performed a qualitative systematic review approach to explore the correlation between HMGB1-mediated inflammation and anhedonia/psychomotor retardation in depression.ResultsA total of 69 studies based on search strategy were retrieved and seven eligible studies met the inclusion criteria. Studies showed that HMGB1 was implicated with depressive-like behaviors, which are similar with motivational deficits. Furthermore, HMGB1-mediated inflammation in depressive-like behaviors may be involved in Nod-like receptor family pyrin domain containing three (NLRP3) inflammasome and proinflammatory cytokines, abnormal kynurenine pathway and imbalance between neuroprotective and neurotoxic factors.ConclusionsWe found that stress-induced inflammation mediated by HMGB1 may affect motivational deficits through regulating dopamine pathway in corticostriatal neurocircuitry. The systematic review may shed light on the novel neurobiological underpinning for treatment of motivation deficits in depression.

In clinical practice, ketamine, an antagonist of the N-methyl-D-aspartate receptor (NMDAR), is used to alleviate depressive symptoms in patients with major depressive disorder (MDD), especially in those with treatment-resistant depression (TRD). Accordingly, the human gene coding for the 2B subunit of the NMDAR (GRIN2B) is considered a promising candidate gene for MDD susceptibility.The primary aim of this study is to examine whether potentially functional polymorphisms of GRIN2B confer risk for MDD, and second to investigate whether GRIN2B acts as a genetic predictor for TRD in MDD patients.We enrolled 178 TRD and 612 non-TRD patients as well as 779 healthy controls.Four potentially functional polymorphisms (rs1805502, rs890, rs1806201, and rs7301328) within GRIN2B were genotyped in all participants. The haplotype analysis found significant differences in the distribution of the G-T haplotype between the TRD and control groups (corrected P = 0.007), and the frequency of the G-T haplotype in TRD group was significantly higher than that in the controls (TRD/control ratio 0.31:0.21). Statistically significant differences in allele and genotype frequencies were detected between TRD and non-TRD groups for the rs1805502 polymorphism within GRIN2B. There was a significant allelic association between rs1805502 and TRD with an excess of the G allele in the TRD group, compared to non-TRD group (OR = 1.55, 95 % CI = 1.18-2.05, corrected P = 0.008).These initial findings strengthen the hypothesis that GRIN2B not only confers susceptibility to TRD, but also plays a genetic predictor for TRD in MDD patients.

Major depressive disorder (MDD) is accompanied by atypical brain structure. This study first presents the alterations in the cortical surface of patients with MDD using multidimensional structural patterns that reflect different neurodevelopment. Sixteen first-episode, untreated patients with MDD and 16 matched healthy controls underwent a magnetic resonance imaging (MRI) scan. The cortical maps of thickness, surface area, and gyrification were examined using the surface-based morphometry (SBM) approach. Increase of cortical thickness was observed in the right posterior cingulate region and the parietal cortex involving the bilateral inferior, left superior parietal and right paracentral regions, while decreased thickness was noted in the parietal cortex including bilateral pars opercularis and left precentral region, as well as the left rostral-middle frontal regions in patients with MDD. Likewise, increased or decreased surface area was found in five sub-regions of the cingulate gyrus, parietal and frontal cortices (e.g., bilateral inferior parietal and superior frontal regions). In addition, MDD patients exhibited a significant hypergyrification in the right precentral and supramarginal region. This integrated structural assessment of cortical surface suggests that MDD patients have cortical alterations of the frontal, parietal and cingulate regions, indicating a vulnerability to MDD during earlier neurodevelopmental process.

With the recent attention to the importance of evidence-based medicine in psychiatry, a number of treatment guidelines have been published. This survey investigated prescribing pattern and predictors for guideline disconcordance in the acute treatment of bipolar depression across mainland China. Pharmacological treatments of 1078 patients with bipolar depression were examined. Guidelines disconcordance was determined by comparing the medication(s) patients were prescribed with the recommendation(s) in the guidelines of the Canadian Network for Mood and Anxiety Treatments. Predictors for guidelines discordance were analyzed with logistic regression. Of the 1078 patients, 50.2% patients were treated against treatment guidelines recommendations. The patients who were treated in general hospitals (OR = 1.53, 95% CI 1.18-1.97), with a depressive episode (OR = 1.67, 95% CI 1.27-2.19) and an older age at first onset (OR = 1.62, 95% CI 1.15-2.28) were more likely to receive guideline-disconcordant treatment than their counterparts. In contrast, the patients with current mental comorbidity, an older age at study entry, a longer duration of disease, and more frequent episodes in past year were less likely to receive guideline-disconcordant treatments than their counterparts with an OR of 0.43 (95% CI 0.24-0.77), 0.52 (95CI% 0.36-0.75), 0.48 (95% CI 0.36-0.65), and 0.50 (95% CI 0.38-0.64), respectively. Our finding suggested the disconcordance with treatment guidelines in patients with an acute bipolar depression is common under naturalistic conditions in mainland China, and the predicting factors correlated with guidelines disconcordance include both psychiatrist-specific (clinicians from general hospitals) and patient-specific features (a depressive episode at first onset, no current co-morbidity with mental disorders, a younger age at study entry, an older age at first onset, shorter duration of disease, and non-frequent episodes in past year).

Major depressive disorder (MDD) is accompanied by atypical brain structure. This study first presents the alterations in the cortical surface of patients with MDD using multidimensional structural patterns that reflect different neurodevelopment. Sixteen first-episode, untreated patients with MDD and 16 matched healthy controls underwent a magnetic resonance imaging (MRI) scan. The cortical maps of thickness, surface area, and gyrification were examined using the surface-based morphometry (SBM) approach. Increase of cortical thickness was observed in the right posterior cingulate region and the parietal cortex involving the bilateral inferior, left superior parietal and right paracentral regions, while decreased thickness was noted in the parietal cortex including bilateral pars opercularis and left precentral region, as well as the left rostral-middle frontal regions in patients with MDD. Likewise, increased or decreased surface area was found in five sub-regions of the cingulate gyrus, parietal and frontal cortices (e.g., bilateral inferior parietal and superior frontal regions). In addition, MDD patients exhibited a significant hypergyrification in the right precentral and supramarginal region. This integrated structural assessment of cortical surface suggests that MDD patients have cortical alterations of the frontal, parietal and cingulate regions, indicating a vulnerability to MDD during earlier neurodevelopmental process.

Xiaohua Liu,1,* Tianhong Zhang,1,* Shen He,1 Bo Hong,1 Daihui Peng,1 Hui Su,1 Fei Li,1 Yingying Tang,1 Zhiguang Lin,2 Yiru Fang,1 Kaida Jiang11Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 2Biochemistry laboratory, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workBackground: Nerve growth factor (NGF) has received much attention for its role in mood disorders. The primary objective of the present study was to examine serum NGF levels in Chinese inpatients with depressive or manic episodes in the acute phase and to explore the changes in NGF levels after effective clinical treatments.Methods: One hundred and seven consecutive inpatients and outpatients with mood disorders (30with unipolar depression,23with bipolar depression, and54with bipolar mania), and50healthy controls were recruited. The serum NGF levels were detected by enzyme-linked immunosorbent assay.Results: Patients with bipolar mania presented higher serum NGF levels compared to those of healthy controls. After8weeks of medical treatment, there were significant improvements in symptoms in patients, but no significant changes in NGF levels.Conclusion: The present findings may help to strengthen and expand the understanding of the role of NGF in the acute stages of mood disorders.Keywords: neurotrophins, depression, mania, bipolar disorder, acute phase, clinical sample

Introduction Bioinformatic investigations indicate that has-mir-206 (microRNA-206, miRNA-206) could regulate BDNF protein synthesis by interfering with BDNF mRNA translation, which is disrupted in bipolar disorder (BPD). Objectives This study is to investigate whether miRNA-206 gene variants were associated with BPD susceptibility in a Han Chinese population. Methods 342 patients who met DSM-IV criteria for bipolar disorder type I (BPD-I) or type II (BPD-II) and 386 matched health controls were enrolled into this study. The miRNA-206 gene and +/-500bp were selected for gene sequencing. For the case-control genetic comparisons, differences in the genotype and allele distributions between patients and controls were examined using Pearson's χ 2 test. Results Gene sequencing showed that there are two polymorphisms rs16882131(C/T) and rs62408583 (A/C) located at the upstream of miRNA-206 gene, which are complete linkage disequilibrium. The association analysis showed that there was no significant difference for genotype frequencies (χ 2 = 2.075, df = 2, P = 0.354) or for allele frequencies (χ 2 = 0.041, df = 1, P = 0.839) between BPD patients and controls. Similarly, no significant difference was found between BPD-I patients and controls (genotype χ 2 = 1.411, df = 2, P = 0.494; allele χ 2 = 0.380, df = 1, P = 0.538). However, there was significant difference between BPD-II patients and controls (genotype χ 2 = 7.933, df = 2, P = 0.019; allele χ 2 = 5.403, df = 1, P = 0.020). Conclusions Our findings do not support that BPD susceptibility was associated with miRNA-206 gene polymorphisms in the studied Han Chinese population. The association between miRNA-206 gene polymorphisms and bipolar disorder type II is needed to be carefully interpreted. Further studies are necessary to elucidate the involvement miRNA-206 in the pathophysiology of BPD.

Background With the recent attention to evidence-based medicine in psychiatry, a number of treatment guidelines for bipolar disorders have been published. This survey investigated prescribing patterns and predictors for guideline disconcordance in the acute treatment of a manic and mixed episode across mainland China. Methods The pharmacological treatments of 2828 patients with a recent hypomanic/manic episode or mixed state were examined. Guidelines disconcordance was determined by comparing the medication(s) patients were prescribed with the recommendation(s) in the guidelines of the Canadian Network for Mood and Anxiety Treatments. Results The most common pattern of pharmacological treatments for an acute manic or mixed episode was a mood stabilizer plus an atypical antipsychotic (n = 1345, 47.6%), and the rate of guideline-disconcordant treatments was 11.1%. The patients who were treated in general hospitals were more likely to receive guideline-disconcordant treatments than those who were treated in psychiatric hospitals, with an OR of 1.84 (95% CI 1.44-2.36). Similarly, the patients with a mixed episode at study entry were more likely to receive guideline-disconcordant treatments than those with a manic episode, with an OR of 1.69 (95% CI 1.22-2.35). In contrast, the patients with a longer duration of disease (>5 years) were less likely to receive guideline-disconcordant treatments than those with a short duration, with an OR of 0.47 (95% CI 0.36-0.60). Conclusions In mainland China, the disconcordance with treatment guidelines for a most recent acute manic or mixed episode was modest under naturalistic conditions. The higher risk for disconcordance in general hospitals than in psychiatric hospitals suggests that special education based on treatment guidelines to practitioners in general hospitals is necessary in order to reduce the risk for disconcordant treatments.