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Gang Wang,1 Tian-Mei Si,2 Lingjiang Li3,4 Yiru Fang,5 Chun-Xue Wang,6 Li-Na Wang,7 Kristin Hui Xian Tan,8 Anders Ettrup,9 Hanne-Lise Falgreen Eriksen,9 Si Luo,10 Lan Ge101Beijing An Ding Hospital, Capital Medical University, China National Clinical Research Center for Mental Disorders, Beijing, People’s Republic of China; 2Peking University Sixth Hospital & Peking University Institute of Mental Health, Beijing, 100191, People’s Republic of China; 3Key Laboratory of Mental Health, Ministry of Health (Peking University) &National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, People’s Republic of China; 4The Second Xiangya Hospital of Central South University, Changsha, People’s Republic of China; 5Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 6Beijing Tian Tan Hospital, Department of Neuropsychiatry and Behavioral Neurology, Capital Medical University, National Clinical Research Center for Neurological Disease, Beijing, People’s Republic of China; 7Tianjin Anding Hospital, Tianjin, People’s Republic of China; 8Lundbeck Singapore Pte Ltd, Singapore; 9H. Lundbeck A/S, Valby, Denmark; 10Lundbeck China, Beijing, People’s Republic of ChinaObjective: Cognitive symptoms in major depressive disorder (MDD) are common and may negatively impact clinical and functional outcomes. The Prospective Research Observation to Assess Cognition in Treated patients with MDD (PROACT) study aimed to assess the prevalence and course of cognitive symptoms, and their associations with clinical and functional outcomes during 6 months of antidepressant treatment, in a real-world setting among Chinese patients with MDD.Patients and methods: Outpatients (n=598) aged 18–65 years with MDD and a total score ≥17 on the Hamilton Depression Rating Scale – 17 Items (HAM-D17) were observed over 6 months after initiating new antidepressant monotherapy, with follow-up visits at months 1, 2, and 6. Cognitive symptoms were assessed using the Perceived Deficits Questionnaire – Depression (PDQ-D) and cognitive performance using the Digit Symbol Substitution Test (DSST).Results: At baseline, 76.9% of patients had indications of cognitive symptoms (PDQ-D total score ≥21); at month 6, this was reduced, but still present in 32.4%. Across the 6-month study period, patients improved across cognitive, clinical and functional assessments. High levels of cognitive symptoms (PDQ-D) consistently predicted worse clinical outcomes, ie, lower odds for remission and increased odds for relapse, as well as worse patient-reported functional outcomes and lower quality of life. In contrast, cognitive performance (DSST) predicted performance-based functioning but only a few patient-reported functional outcomes (absenteeism and quality of life), and no clinical outcomes. PDQ-D and DSST scores were uncorrelated at baseline.Conclusion: The study highlights the importance of assessing and targeting cognitive symptoms for increasing patients’ chances of recovery and restoring functioning in the treatment of MDD. The results further highlight the relevance of complementary assessment methods to fully capture aspects of cognitive symptoms in patients with depression.Keywords: MDD, antidepressants, cognitive performance, real-world evidence, PDQ-D, DSST

Shi-Ze Lin,1,2 Yan-Kun Wu,2–4 Yun-Ai Su,2–4 Tian-Mei Si2–41Quanzhou Mental Health Center, The Third Hospital of Quanzhou, Quanzhou, Fujian Province, People’s Republic of China; 2Institute of Mental Health, Peking University Sixth Hospital, Beijing, People’s Republic of China; 3National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, People’s Republic of China; 4NHC Key Laboratory of Mental Health, Peking University, Beijing, People’s Republic of ChinaAbstract: Prospective memory (PM) could be impaired in the non-psychotic first-degree relatives of patients with schizophrenia. This meta-analysis systematically examined the PM of non-psychotic first-degree relatives of patients with schizophrenia. Both Chinese and English databases were systematically searched for articles from the inception of the databases through November 13, 2018. Case-control studies of PM in non-psychotic first-degree relatives of patients with schizophrenia were included in the analyses. Confidence intervals (CIs) and standardized mean differences (SMDs) were calculated utilizing the random effects model. Four studies (n=268) that compared PM performance between non-psychotic first-degree relatives of patients with schizophrenia (n=136) and healthy controls (n=132) were included. Three studies were rated as “high quality”, while the quality of evidence of the three outcomes included in this meta-analysis was moderate. Compared with the healthy controls, the non-psychotic first-degree relatives of patients with schizophrenia showed impairments in overall PM (two studies, n=127; SMD: −0.46; 95% CI=−0.82, −0.11, P=0.01; I=0%), event-based PM (EBPM) (four studies, n=268; SMD: −0.56; 95% CI=−0.80, −0.31, P

Nan Li,1 Yu Feng,2 Huafei Lu,3 Shang Li Cai,3 Jianmin Zhuo,4 Tianmei Si,5,6 Lili Zhang3 1Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, People’s Republic of China; 2Regional Medical Affairs, Janssen Pharmaceutical Companies of Johnson and Johnson, Singapore; 3Medical Affairs, Xian Janssen Pharmaceutical Ltd, Beijing, People’s Republic of China; 4Department of Statistics, Janssen China Research and Development, Shanghai, People’s Republic of China; 5National Clinical Research Center for Mental Disorders and The Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, People’s Republic of China; 6Peking University Institute of Mental Health (The Sixth Hospital), Beijing, People’s Republic of China Background: Paliperidone palmitate once-monthly (PP1M) demonstrated symptomatic and functional remission in patients with schizophrenia. This post hoc analysis aimed to identify factors associated with improved clinical outcomes in patients switching to PP1M (75–150 mg eq.).Methods: The improved patient outcomes were observed as Positive and Negative Symptom Scale (PANSS, symptoms) score 70:34.3% (199/581), and Involvement Evaluation Questionnaire (IEQ, caregiver burden) reduction ≥6:50.2% (270/538). Independent variables including demographics, disease duration, employment status, and clinical scores were screened individually using a univariate analysis and subsequently, variables (cutoff p

Tianmei Si,1 Kerang Zhang,2 Jisheng Tang,3 Maosheng Fang,4 Keqing Li,5 Jianmin Zhuo,6 Yu Feng6 1Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health, Beijing, People’s Republic of China; 2Shanxi Medical University First Hospital, Shanxi, People’s Republic of China; 3Mental Health Center of Shandong Province, Shandong, People’s Republic of China; 4Mental Health Center, Tongji Medical College, Huazhong University of Science and Technology, Hubei, People’s Republic of China; 5Mental Health Center of Hebei Province, Hebei, People’s Republic of China; 6Janssen Research and Development, Beijing, People’s Republic of China Abstract: This open-label, single-arm, multicenter, 13-week, prospective study explored the efficacy, safety, and tolerability of paliperidone palmitate (150 milligram equivalents [mg eq] [day 1], 100 mg eq [day 8], both deltoid injections; 75–150 mg eq, deltoid/gluteal injection) in Chinese patients with acute schizophrenia (Positive and Negative Syndrome Scale [PANSS] total score ≥70), who previously had unsatisfactory therapeutic effect following oral antipsychotic treatment (without washout period). Primary efficacy endpoint was percentage of patients with ≥30% improvement in the PANSS total score at the end of 13 weeks. Secondary efficacy endpoints included change from baseline to end of week 13 in PANSS total score, PANSS subscale scores, Marder factor scores, Clinical Global Impressions–Severity score, and Personal and Social Performance Scale scores. Overall, 477/610 enrolled patients (full analysis set, 78.2%) completed the study (men: 55.1%; women: 44.9%; mean age: 31.5 years). Total, 443/610 (72.6%, full analysis set) patients achieved primary endpoint (mean [standard deviation] change from baseline: –30.9 [19.51]). All secondary endpoints demonstrated significant improvement at the end of 13 weeks. One death occurred during this acute phase. The most common (>5%) treatment-emergent adverse events were extrapyramidal disorders (8.4%). The efficacy and safety data are consistent with other short-term, placebo-controlled studies of paliperidone palmitate conducted in similar populations. Keywords: antipsychotic, long-acting injectable, PANSS

TianMei Si,1 QingRong Tan,2 KeRang Zhang,3 Yang Wang,4 Qing Rui4 1Peking University Institute of Mental health, Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 2Fourth Military Medical University, First Hospital, Xi’an, 3Shanxi Medical University, First Hospital, Shanxi, 4Janssen Research and Development, Beijing, People’s Republic of China Background: Antipsychotic medications facilitate the improvement of psychotic symptoms in patients with first-episode psychosis. Paliperidone extended-release (pali-ER), an atypical anti­psychotic, was assessed for efficacy and safety in Chinese patients with first-episode psychosis. Methods: In this 8-week, open-label, single-arm, multicenter study, patients with first-episode psychosis (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) and a Positive and Negative Syndrome Scale (PANSS) total score ≥70 were treated with flexible-dose pali-ER tablets (3–12 mg/day). The primary efficacy endpoint was the percentage of patients with an increase of ≥8 points in Personal and Social Performance (PSP) score from baseline to day 56 (8 weeks). Secondary endpoints included reduction in PANSS total score, improvement in Clinical Global Impression-Severity score, PSP score, Subjective Well-being under Neuroleptics Scale score, and relationship between duration of untreated psychosis and PANSS or PSP. Incidences of treatment-emergent adverse events were used to evaluate safety.Results: Overall, 283 of 294 patients (96%) achieved a ≥8-point increase in PSP (primary endpoint, analysis set). For the secondary efficacy endpoints, 284/306 patients (93%) had a ≥30% reduction in PANSS total score; 266/306 patients (87%) achieved a ≤3 Clinical Global Impression-Severity scale score, and 218/294 patients (74%) had a PSP score ≥71. The Subjective Well-being under Neuroleptics Scale score was improved from a baseline mean of 72.7 to 94.7 at endpoint. There was a negative correlation between duration of untreated psychosis and posttreatment PSP score and a positive correlation with posttreatment PANSS total score. The most common treatment-emergent adverse events were extrapyramidal symptoms (12%), and agitation, somnolence, and xerostomia (4% each).Conclusion: An 8-week, flexible-dose (3–12 mg/day) treatment with pali-ER resulted in significant improvements in psychotic symptoms and social functioning in Chinese patients with first-episode psychosis and was generally tolerable. Keywords: paliperidone, first-episode psychosis, Personal and Social Performance score

Background: This study examined the use of low doses of antipsychotic medications (300 mg/day CPZeq or less) in older Asian patients with schizophrenia and its demographic and clinical correlates.Methods: Information on hospitalized patients with schizophrenia, aged 55 years or older, was extracted from the database of the Research on Asian Psychotropic Prescription Patterns (REAP) study (2001-2009). Data on 1,452 patients in eight Asian countries and territories including China, Hong Kong, Japan, Korea, Singapore, Taiwan, India, and Malaysia were analyzed. Sociodemographic and clinical characteristics and antipsychotic prescriptions were recorded using a standardized protocol and data collection procedure.Results: The prescription frequency for low doses of antipsychotic medications was 40.9% in the pooled sample. Multiple logistic regression analysis of the whole sample showed that patients on low doses of antipsychotic medications were more likely to be female, have an older age, a shorter length of illness, and less positive symptoms. Of patients in the six countries and territories that participated in all the surveys between 2001 and 2009, those in Japan were less likely to receive low doses of antipsychotics.Conclusion: Low doses of antipsychotic medications were only applied in less than half of older Asian patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Early-life stress (ES) leads to cognitive dysfunction in female adolescents, but the underlying neural mechanisms remain elusive. Recent evidence suggests that the cell adhesion molecules NECTIN1 and NECTIN3 play a role in cognition and ES-related cognitive deficits in male rodents. In this study, we aimed to investigate whether and how nectins contribute to ES-induced cognitive dysfunction in female adolescents. Applying the well-established limited bedding and nesting material paradigm, we found that ES impairs recognition memory, suppresses prefrontal NECTIN1 and hippocampal NECTIN3 expression, and upregulates corticotropin-releasing hormone (Crh) and its receptor 1 (Crhr1) mRNA levels in the hippocampus of adolescent female mice. Genetic experiments revealed that the reduction of dorsal CA1 (dCA1) NECTIN3 mediates ES-induced object recognition memory deficits, as knocking down dCA1 NECTIN3 impaired animals' performance in the novel object recognition task, while overexpression of dCA1 NECTIN3 successfully reversed the ES-induced deficits. Notably, prefrontal NECTIN1 knockdown did not result in significant cognitive impairments. Furthermore, acute systemic administration of antalarmin, a CRHR1 antagonist, upregulated hippocampal NECTIN3 levels and rescued object and spatial memory deficits in stressed mice. Our findings underscore the critical role of dCA1 NECTIN3 in mediating ES-induced object recognition memory deficits in adolescent female mice, highlighting it as a potential therapeutic target for stress-related psychiatric disorders in women., (© 2024. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Vortioxetine is a novel multimodal antidepressant, but its precise efficacy and dose-response relationship for treating different symptoms in major depressive disorder (MDD) is still unclear. This umbrella review aims to assess the effectiveness, tolerability, and dose-response relationship of vortioxetine across a comprehensive range of clinical features in adults with MDD, including cognition, depression, anxiety, quality of life, and side effects. We meticulously searched eight electronic databases and included systematic reviews (SRs) and meta-analyses (MAs) of vortioxetine. The methodological quality of each included SR was independently assessed using the AMSTAR2 tool. To evaluate the credibility of the evidence, we utilized the GRADE framework and the Ioannidis criteria. In total, 35 SRs with 278 MAs met the inclusion criteria and based on these studies we performed 56 MAs of interest. While vortioxetine has been consistently shown to have positive effects on various domains, the evidence regarding cognitive performance and depression symptoms is notably robust compared to placebo, despite of relatively overall low quality of evidence. Finally, a dose-response relationship was observed across all categories within the treatment range of 5-20 mg/d and a dosage of vortioxetine 20 mg/d is recommended for adult MDD patients to achieve full functional recovery., Competing Interests: Declaration of competing interest The authors report no conflict of interests., (Copyright © 2024. Published by Elsevier B.V.)

Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: Musical hallucinations (MH) involve the false perception of music in the absence of external stimuli which links with different etiologies. The pathomechanisms of MH encompass various conditions. The etiological classification of MH is of particular importance and offers valuable insights to understand MH, and further to develop the effective treatment of MH. Over the recent decades, more MH cases have been reported, revealing newly identified medical and psychiatric causes of MH. Functional imaging studies reveal that MH activates a wide array of brain regions. An up-to-date analysis on MH, especially on MH comorbid psychiatric conditions is warranted., Aim: To propose a new classification of MH; to study the age and gender differences of MH in mental disorders; and neuropathology of MH., Methods: Literatures searches were conducted using keywords such as "music hallucination," "music hallucination and mental illness," "music hallucination and gender difference," and "music hallucination and psychiatric disease" in the databases of PubMed, Google Scholar, and Web of Science. MH cases were collected and categorized based on their etiologies. The t -test and ANOVA were employed ( P < 0.05) to compare the age differences of MH different etiological groups. Function neuroimaging studies of neural networks regulating MH and their possible molecular mechanisms were discussed., Results: Among the 357 yielded publications, 294 MH cases were collected. The average age of MH cases was 67.9 years, with a predominance of females (66.8% females vs 33.2% males). MH was classified into eight groups based on their etiological mechanisms. Statistical analysis of MH cases indicates varying associations with psychiatric diagnoses., Conclusion: We carried out a more comprehensive review of MH studies. For the first time according to our knowledge, we demonstrated the psychiatric conditions linked and/or associated with MH from statistical, biological and molecular point of view., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD., (© 2024. The Author(s).)

Background: As a central hub in cognitive and emotional brain circuits, the striatum is considered likely to be integrally involved in the psychopathology of bipolar disorder (BD). However, it remains unclear how alterations in striatal function contribute to distinct symptomatology of BD during different mood states., Methods: Behavioral assessment (i.e., emotional symptoms and cognitive performance) and neuroimaging data were collected from 125 participants comprising 31 (hypo)manic, 31 depressive, and 31 euthymic patients with BD, and 32 healthy control participants. We compared the functional connectivity (FC) of striatal subregions across BD mood states with healthy control participants and then used a multivariate data-driven approach to explore dimensional associations between striatal connectivity and behavioral performance. Finally, we compared the FC and behavioral composite scores, which reflect the individual weighted representation of the associations, among different mood states., Results: Patients in all mood states exhibited increased FC between the bilateral ventral rostral putamen and ventrolateral thalamus. Bipolar (hypo)mania uniquely exhibited increased ventral rostral putamen connectivity and superior ventral striatum connectivity. One latent component was identified, whereby increased FCs of striatal subregions were associated with distinct psychopathological symptomatology (more manic symptoms, elevated positive mood, less depressive symptoms, and worse cognitive performance). Patients with bipolar (hypo)mania had the highest FC and behavioral composite scores while bipolar patients with depression had the lowest scores., Conclusions: Our data demonstrated both trait features of BD and state features specific to bipolar (hypo)mania. The findings underscored the fundamental role of the striatum in the pathophysiological processes underlying specific symptomatology across all mood states., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1 -/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD., Competing Interests: Declaration of competing interest The authors report no conflict of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women., Competing Interests: Declaration of competing interest The authors report no conflict of interests., (Copyright © 2024. Published by Elsevier Inc.)

Major depressive disorder (MDD) is associated with functional disturbances in subcortical regions. In this naturalistic prospective study (NCT03294525), we aimed to investigate relationships among subcortical functional connectivity (FC), mood symptom profiles and treatment outcome in MDD using multivariate methods. Medication-free participants with MDD (n = 135) underwent a functional magnetic resonance imaging scan at baseline and completed posttreatment clinical assessment after 8 weeks of antidepressant monotherapy. We used partial least squares (PLS) correlation analysis to explore the association between subcortical FC and mood symptom profiles. FC score, reflecting the weighted representation of each individual in this association, was computed. Replication analysis was undertaken in an independent sample (n = 74). We also investigated the relationship between FC score and treatment outcome in the main sample. A distinctive subcortical connectivity pattern was found to be associated with negative affect. In general, higher FC between the caudate, putamen and thalamus was associated with greater negative affect. This association was partly replicated in the independent sample (similarity between the two samples: r = 0.66 for subcortical connectivity, r = 0.75 for mood symptom profile). Lower FC score predicted both remission and response to treatment after 8 weeks of antidepressant monotherapy. The emphasis here on the role of dorsal striatum and thalamus consolidates prior work of subcortical connectivity in MDD. The findings provide insight into the pathogenesis of MDD, linking subcortical FC with negative affect. However, while the FC score significantly predicted treatment outcome, the low odds ratio suggests that finding predictive biomarkers for depression remains an aspiration., (© 2024. The Author(s).)

Background: Exploring the neural basis related to different mood states is a critical issue for understanding the pathophysiology underlying mood switching in bipolar disorder (BD), but research has been scarce and inconsistent., Methods: Resting-state functional magnetic resonance imaging data were acquired from 162 patients with BD: 33 (hypo)manic, 64 euthymic, and 65 depressive, and 80 healthy controls (HCs). The differences of large-scale brain network functional connectivity (FC) between the four groups were compared and correlated with clinical characteristics. To validate the generalizability of our findings, we recruited a small longitudinal independent sample of BD patients (n = 11). In addition, we examined topological nodal properties across four groups as exploratory analysis., Results: A specific strengthened pattern of network FC, predominantly involving the default mode network (DMN), was observed in (hypo)manic patients when compared with HCs and bipolar patients in other mood states. Longitudinal observation revealed an increase in several network FCs in patients during (hypo)manic episode. Both samples evidenced an increase in the FC between the DMN and ventral attention network, and between the DMN and limbic network (LN) related to (hypo)mania. The altered network connections were correlated with mania severity and positive affect. Bipolar depressive patients exhibited decreased FC within the LN compared with HCs. The exploratory analysis also revealed an increase in degree in (hypo)manic patients., Conclusions: Our findings identify a distributed pattern of large-scale network disturbances in the unique context of (hypo)mania and thus provide new evidence for our understanding of the neural mechanism of BD.

Trace amine-associated receptor 1 (TAAR1) is a classical type of G-protein-coupled receptor, which is widely distributed in the brain of mammals, especially in the limbic system and the region rich in monoaminergic neurons, and it is a highly conserved TAAR subtype in all species. TAAR1 can specifically respond to endogenous trace amines in the central nervous system and peripheral tissues, and plays an important role in the pathophysiological mechanisms involving the dysregulation of monoamine system and glutamate system leading to mental disorders. In addition, TAAR1 modulator can act on inwardly rectifying potassium channels and regulate synaptic transmission and neuronal activity. According to the latest research findings, TAAR1 exerts a series of functions by regulating signal pathways and substrate phosphorylation, which is related to emotion, cognition, fear and addiction. Therefore, we conducted a detailed review of relevant studies on the TAAR1 signaling pathways, aiming at revealing the great potential of TAAR1 as a new target for drug treatment of neuropsychiatric disorders.

Background: The neural correlate of cognitive deficits in bipolar disorder (BD) is an issue that warrants further investigation. However, relatively few studies have examined the intrinsic functional connectivity (FC) underlying cognitive deficits involving sustained attention and executive function at both the region and network levels, as well as the different relationships between connectivity patterns and cognitive performance, in BD patients and healthy controls (HCs)., Methods: Patients with BD (n = 59) and HCs (n = 52) underwent structural and resting-state functional magnetic resonance imaging and completed the Wisconsin Card Sorting Test (WCST), the continuous performance test and a clinical assessment. A seed-based approach was used to evaluate the intrinsic FC alterations in three core neurocognitive networks (the default mode network [DMN], the central executive network [CEN] and the salience network [SN]). Finally, we examined the relationship between FC and cognitive performance by using linear regression analyses., Results: Decreased FC was observed within the DMN, in the DMN-SN and DMN-CEN and increased FC was observed in the SN-CEN in BD. The alteration direction of regional FC was consistent with that of FC at the brain network level. Decreased FC between the left posterior cingulate cortex and right anterior cingulate cortex was associated with longer WCST completion time in BD patients (but not in HCs)., Conclusions: These findings emphasize the dominant role of the DMN in the psychopathology of BD and provide evidence that cognitive deficits in BD may be associated with aberrant FC between the anterior and posterior DMN., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Cognitive dysfunction is a significant, untreated clinical need in patients with psychiatric disorders, for which preclinical studies are needed to understand the underlying mechanisms and to identify potential therapeutic targets. Early-life stress (ELS) leads to long-lasting deficits of hippocampus-dependent learning and memory in adult mice, which may be associated with the hypofunction of the brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB). In this study, we carried out eight experiments using male mice to examine the causal involvement of the BDNF-TrkB pathway in dentate gyrus (DG) and the therapeutic effects of the TrkB agonist (7,8-DHF) in ELS-induced cognitive deficits. Adopting the limited nesting and bedding material paradigm, we first demonstrated that ELS impaired spatial memory, suppressed BDNF expression and neurogenesis in the DG in adult mice. Downregulating BDNF expression (conditional BDNF knockdown) or inhibition of the TrkB receptor (using its antagonist ANA-12) in the DG mimicked the cognitive deficits of ELS. Acute upregulation of BDNF (exogenous human recombinant BDNF microinjection) levels or activation of TrkB receptor (using its agonist, 7,8-DHF) in the DG restored ELS-induced spatial memory loss. Finally, acute and subchronic systemic administration of 7,8-DHF successfully restored spatial memory loss in stressed mice. Subchronic 7,8-DHF treatment also reversed ELS-induced neurogenesis reduction. Our findings highlight BDNF-TrkB system as the molecular target of ELS-induced spatial memory deficits and provide translational evidence for the intervention at this system in the treatment of cognitive deficits in stress-related psychiatric disorders, such as major depressive disorder., (© 2023. The Author(s).)

Background: A recent study revealed disrupted topological organization of whole-brain networks in patients with major depressive disorder (MDD); however, these results were mostly driven by recurrent MDD patients, rather than first-episode drug-naïve (FEDN) patients. Furthermore, few longitudinal studies have explored the effects of antidepressant therapy on the topological organization of whole-brain networks., Methods: We collected clinical and neuroimaging data from 159 FEDN MDD patients and 152 normal controls (NCs). A total of 115 MDD patients completed an eight-week antidepressant treatment procedure. Topological features of brain networks were calculated using graph theory-based methods and compared between FEDN MDD patients and NCs, as well as before and after treatment., Results: Decreased global efficiency, local efficiency, small-worldness, and modularity were found in pretreatment FEDN MDD patients compared with NCs. Nodal degrees, betweenness, and efficiency decreased in several networks compared with NCs. After antidepressant treatment, the global efficiency increased, while the local efficiency, the clustering coefficient of the network, the path length, and the normalized characteristic path length decreased. Moreover, the reduction rate of the normalized characteristic path length was positively correlated with the reduction rate of retardation factor scores., Limitations: The interaction effects of groups and time on the topological features were not explored because of absence of the eighth-week data of NC group., Conclusions: The topological architecture of functional brain networks is disrupted in FEDN MDD patients. After antidepressant therapy, the global efficiency shifted toward recovery, but the local efficiency deteriorated, suggesting a correlation between recovery of retardation symptoms and global efficiency., Competing Interests: Conflict of interest All the other authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Trace amines are endogenous molecules distributed in the central nervous system and peripheral tissues that resemble common biogenic amines in terms of subcellular localization, chemical structure, and metabolism. Trace amine-associated receptor (TAAR) is a kind of evolutionarily conserved G-protein-coupled receptors in vertebrates, in which TAAR1 is a functional regulator of monoamine transmitters such as dopamine and serotonin. TAAR1 is widely considered as a potential therapeutic target for schizophrenia, depression and drug addiction. Moreover, TAAR1 is also expressed in peripheral tissues. The homeostasis imbalance of trace aminergic system can induce over-activation of peripheral immune system and central immune inflammatory response. TAAR1 modulators are becoming potential emerging drugs for the treatment of immune-related illnesses, because they may play a major role in the activation or modulation of immune response.

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress., (© 2022. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Despite a growing neuroimaging literature on the pathophysiology of major depressive disorder (MDD), reproducible findings are lacking, probably reflecting mostly small sample sizes and heterogeneity in analytic approaches. To address these issues, the Depression Imaging REsearch ConsorTium (DIRECT) was launched. The REST-meta-MDD project, pooling 2428 functional brain images processed with a standardized pipeline across all participating sites, has been the first effort from DIRECT. In this review, we present an overview of the motivations, rationale, and principal findings of the studies so far from the REST-meta-MDD project. Findings from the first round of analyses of the pooled repository have included alterations in functional connectivity within the default mode network, in whole-brain topological properties, in dynamic features, and in functional lateralization. These well-powered exploratory observations have also provided the basis for future longitudinal hypothesis-driven research. Following these fruitful explorations, DIRECT has proceeded to its second stage of data sharing that seeks to examine ethnicity in brain alterations in MDD by extending the exclusive Chinese original sample to other ethnic groups through international collaborations. A state-of-the-art, surface-based preprocessing pipeline has also been introduced to improve sensitivity. Functional images from patients with bipolar disorder and schizophrenia will be included to identify shared and unique abnormalities across diagnosis boundaries. In addition, large-scale longitudinal studies targeting brain network alterations following antidepressant treatment, aggregation of diffusion tensor images, and the development of functional magnetic resonance imaging-guided neuromodulation approaches are underway. Through these endeavours, we hope to accelerate the translation of functional neuroimaging findings to clinical use, such as evaluating longitudinal effects of antidepressant medications and developing individualized neuromodulation targets, while building an open repository for the scientific community., Competing Interests: One of the authors, Dr Qi-Yong Gong, is also the editor-in-chief of Psychoradiology. He was blinded from reviewing or making decisions on the manuscript., (© The Author(s) 2022. Published by Oxford University Press on behalf of West China School of Medicine/West China Hospital (WCSM/WCH) of Sichuan University.)

The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls., (© 2022. The Author(s).)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the prevalence of psychotic depression and the differences in sociodemographic and clinical characteristics and prescription patterns of psychotropic medications between patients with psychotic depression (PD) and patients with nonpsychotic depression (NPD) in China., Methods: We conducted a cross-sectional study in 13 major psychiatric hospitals or the psychiatric units of general hospitals in China from September 1, 2010, to February 28, 2011. PD was defined according to the psychotic disorder section of the Mini International Neuropsychiatric Interview (MINI). The sociodemographic and clinical characteristics and the prescription patterns of psychotropic medications were compared between the PD and NPD groups. Multivariate logistic regression analysis was used to investigate factors associated with an increased likelihood of PD., Results: Among 1172 MDD patients, the prevalence of psychotic features was 9.2% in the present study. The logistic regression analysis indicated that unmarried (OR = 2.08, p < 0.001), frequent depressive episodes (OR = 2.10, p = 0.020), depressive episodes with suicidal ideation and attempts (OR = 1.91, p = 0.004), and patients who were prescribed any antipsychotics (OR = 2.94, p < 0.001) were associated with psychotic features in patients with MDD., Limitations: Cross-sectional design, retrospective recall of some data CONCLUSION: The prevalence of PD is high in China, and there were some differences in demographic and clinical characteristics between patients with PD and patients with NPD. Clinicians should regularly assess psychotic symptoms and consider intensive treatment and close monitoring when treating subjects with PD., (Copyright © 2022. Published by Elsevier B.V.)

Objective: 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., Method: 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., Results: 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., Conclusion: 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., (Copyright © 2021. Published by Elsevier Inc.)

Major depressive disorder (MDD) is highly prevalent and is a significant cause of mortality and morbidity worldwide. Currently, conventional pharmacological treatments for MDD produce temporary remission in < 50% of patients; therefore, there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms. Accumulated evidence has shown that immune inflammation, particularly inflammasome activity, plays an important role in the pathophysiology of MDD. In this review, we summarize the evidence on nuclear receptors (NRs), such as glucocorticoid receptor, mineralocorticoid receptor, estrogen receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor, in modulating the inflammasome activity and depression-associated behaviors. This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD, and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest for this manuscript., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

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., (© 2021. The Author(s).)

Objectives: Genome-wide analyses of antidepressant response have suggested that genes initially associated with risk for schizophrenia may also serve as promising candidates for selective serotonin reuptake inhibitor (SSRI) efficacy. Protein tyrosine phosphatase, receptor-type, zeta-1 (PTPRZ1) has previously been shown to be associated with schizophrenia, but it has not been investigated as a predictor of antidepressant efficacy. The main objective of the study was to assess whether SSRI-mediated depressive and anxiety symptom remission in Chinese patients with major depressive disorder (MDD) are associated with specific PTPRZ1 variants., Methods: Two independent cohorts were investigated, the first sample (N = 344) received an SSRI (i.e. fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, or paroxetine) for 8 weeks. The second sample (N = 160) only received escitalopram for 8 weeks. Hamilton Depression and Hamilton Anxiety Rating Scale scores at 8-weeks post-baseline in both cohorts were used to determine remission status. Five PTPRZ1 variants (rs12154537, rs6466810, rs6466808, rs6955395, and rs1918031) were genotyped in both cohorts., Results: Anxiety symptom remission was robustly associated with PTPRZ1 rs12154537 (P = 0.004) and the G-G-G-G haplotype (rs12154537-rs6466810-rs6466808-rs6955395; P = 0.005) in cohort 2 but not cohort 1 (mixed SSRI use). Associations with depressive symptom remission did not survive correction for multiple testing., Conclusions: These findings suggest that PTPRZ1 variants may serve as a marker of escitalopram-mediated anxiety symptom remission in MDD., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Previous neuroimaging studies have revealed abnormal functional connectivity of brain networks in patients with major depressive disorder (MDD), but findings have been inconsistent. A recent big-data study found abnormal intrinsic functional connectivity within the default mode network in patients with recurrent MDD but not in first-episode drug-naïve patients with MDD. This study also provided evidence for reduced default mode network functional connectivity in medicated MDD patients, raising the question of whether previously observed abnormalities may be attributable to antidepressant effects. The present study (ClinicalTrials.gov identifier: NCT03294525) aimed to disentangle the effects of antidepressant treatment from the pathophysiology of MDD and test the medication normalization hypothesis. Forty-one first-episode drug-naïve MDD patients were administrated antidepressant medication (escitalopram or duloxetine) for 8 weeks, with resting-state functional connectivity compared between posttreatment and baseline. To assess the replicability of the big-data finding, we also conducted a cross-sectional comparison of resting-state functional connectivity between the MDD patients and 92 matched healthy controls. Both Network-Based Statistic analyses and large-scale network analyses revealed intrinsic functional connectivity decreases in extensive brain networks after treatment, indicating considerable antidepressant effects. Neither Network-Based Statistic analyses nor large-scale network analyses detected significant functional connectivity differences between treatment-naïve patients and healthy controls. In short, antidepressant effects are widespread across most brain networks and need to be accounted for when considering functional connectivity abnormalities in MDD., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Emerging evidence supports an essential role of trace amine-associated receptor 1 (TAAR1) in neuropsychiatric disorders such as depression and schizophrenia. Stressful events are critical contributors to various neuropsychiatric disorders. This study examined the role of TAAR1 in mediating the negative outcomes of stressful events. In mice that experienced chronic social defeat stress but not acute stress, a significant reduction in the TAAR1 mRNA level was found in the medial prefrontal cortex (mPFC), a brain region that is known to be vulnerable to stress experience. Conditional TAAR1 knockout in the mPFC mimicked the cognitive deficits induced by chronic stress. In addition, chronic treatment with the selective TAAR1 partial agonist RO5263397 ameliorated chronic stress-induced changes in cognitive function, dendritic arborization, and the synapse number of pyramidal neurons in the mPFC but did not affect chronic stress-induced anxiety-like behaviors. Biochemically, chronic stress reduced the ratio of vesicular transporters of glutamate-1 (VGluT1) / vesicular GABA transporter (VGAT) in the mPFC，most prominently in the prelimbic cortex, and RO5263397 restored the excitatory-inhibitory (E/I) imbalance. Together, the results of this study reveal an essential role of TAAR1 in mediating chronic stress-induced cognitive impairments and suggest that TAAR1 agonists may be uniquely useful to treat MDD-related cognitive impairments., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Functional specialization is a feature of human brain for understanding the pathophysiology of major depressive disorder (MDD). The degree of human specialization refers to within and cross hemispheric interactions. However, most previous studies only focused on interhemispheric connectivity in MDD, and the results varied across studies. Hence, brain functional connectivity asymmetry in MDD should be further studied., Methods: Resting-state fMRI data of 753 patients with MDD and 451 healthy controls were provided by REST-meta-MDD Project. Twenty-five project contributors preprocessed their data locally with the Data Processing Assistant State fMRI software and shared final indices. The parameter of asymmetry (PAS), a novel voxel-based whole-brain quantitative measure that reflects inter- and intrahemispheric asymmetry, was reported. We also examined the effects of age, sex and clinical variables (including symptom severity, illness duration and three depressive phenotypes)., Results: Compared with healthy controls, patients with MDD showed increased PAS scores (decreased hemispheric specialization) in most of the areas of default mode network, control network, attention network and some regions in the cerebellum and visual cortex. Demographic characteristics and clinical variables have significant effects on these abnormalities., Limitations: Although a large sample size could improve statistical power, future independent efforts are needed to confirm our results., Conclusions: Our results highlight the idea that many brain networks contribute to broad clinical pathophysiology of MDD, and indicate that a lateralized, efficient and economical brain information processing system is disrupted in MDD. These findings may help comprehensively clarify the pathophysiology of MDD in a new hemispheric specialization perspective., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Bipolar disorder (BD) is a major and highly heritable mental illness with severe psychosocial impairment, but its etiology and pathogenesis remains unclear. This study aimed to identify the essential pathways and genes involved in BD using weighted gene coexpression network analysis (WGCNA), a bioinformatic method studying the relationships between genes and phenotypes. Using two available BD gene expression datasets (GSE5388, GSE5389), we constructed a gene coexpression network and identified modules related to BD. The analyses of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways were performed to explore functional enrichment of the candidate modules. A protein-protein interaction (PPI) network was further constructed to identify the potential hub genes. Ten coexpression modules were identified from the top 5,000 genes in 77 samples and three modules were significantly associated with BD, which were involved in several biological processes (e.g., the actin filament-based process) and pathways (e.g., MAPK signaling). Four genes ( NOTCH1, POMC, NGF , and DRD2 ) were identified as candidate hub genes by PPI analysis and CytoHubba. Finally, we carried out validation analyses in a separate dataset, GSE12649, and verified NOTCH1 as a hub gene and the involvement of several biological processes such as actin filament-based process and axon development. Taken together, our findings revealed several candidate pathways and genes ( NOTCH1 ) in the pathogenesis of BD and call for further investigation for their potential research values in BD diagnosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Wu, Chen, Zhang, Lin, Wu, Zhang, Su, Li and Si.)

Major depressive disorder is a major psychiatric disorder and a leading cause of disability around the world. Females have about twice as high an incidence of depression as males. However, preclinical animal models of depression have seldom investigated the molecular alterations associated with higher depression risk in females. In this study, adopting the early-life stress (ELS) paradigm of limited bedding and nesting material, we found that ELS induced depression-like behaviors only in adult female mice, as evaluated by sucrose preference and tail suspension tests. We then examined the ELS effects on monoamine neurotransmission (transporters for monoamine reuptake and release) in depression-related brain regions in female mice. We found that ELS resulted in widespread changes of the expression levels of these transporters in four brain regions. Moreover, systemic 21-day treatment with vortioxetine, a novel multimodal antidepressant, successfully reversed depression-like behaviors and normalized some molecular changes, including that of the norepinephrine transporter in the medial prefrontal cortex, vesicular monoamine transporter 2 in nucleus accumbens core, and serotonin transporter in amygdala. Collectively, these results provide evidence for the validity of using the limited bedding and nesting material paradigm to investigate sex differences in depression and demonstrate that the region-specific alterations of monoamine neurotransmission may be associated with depression-like behaviors in female mice. This article is part of the special issue on 'Stress, Addiction and Plasticity'., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) is not only attacking physical health, but it is also increasing psychological suffering. This study aimed to observe the impact of the COVID-19 pandemic on mental health outcomes among patients with mild to moderate illness in Fangcang shelter hospitals., Methods: We conducted an observational, cross-sectional study of 129 patients with mild to moderate illness from Jiangxia Fangcang shelter hospitals in Wuhan, China. The participants were assessed by quantifying their symptoms of depression, anxiety, insomnia, and stressful life events and analyzing potential risk factors associated with these symptoms. Using correlation analysis, we examined associations between exposure to COVID-19 and subsequent psychological distress in response to the outbreak., Results: In total, 49.6% of participants had depressive or anxiety symptoms. The depressive and anxiety symptoms were highly related to sleep disturbances and hypochondriasis (all r  > 0.50, P  < 0.01). The impact of the event was positively related to depressive symptoms, anxiety symptoms, sleep disturbances, hypochondriasis and life events (all r  > 0.35, P  < 0.01) but was negatively related to psychological resilience ( r  = -0.41, P  < 0.01). The presence of the COVID-19 infection in this setting was associated with increased anxiety, depression and stress levels, and decreased sleep quality, and seriously affected patients' quality of life as well as adversely affecting the course and prognosis of physical diseases., Conclusion: The sleep quality, anxiety, and depression of COVID-19 patients in Fangcang shelter hospitals were significantly related to the impact of the epidemic., Competing Interests: None., (© 2020 Chinese Medical Association. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.)

Background: As the fight against the COVID-19 epidemic continues, medical workers may have allostatic load., Objective: During the reopening of society, medical and nonmedical workers were compared in terms of allostatic load., Methods: An online study was performed; 3,590 Chinese subjects were analyzed. Socio-demographic variables, allostatic load, stress, abnormal illness behavior, global well-being, mental status, and social support were assessed., Results: There was no difference in allostatic load in medical workers compared to nonmedical workers (15.8 vs. 17.8%; p = 0.22). Multivariate conditional logistic regression revealed that anxiety (OR = 1.24; 95% CI 1.18-1.31; p < 0.01), depression (OR = 1.23; 95% CI 1.17-1.29; p < 0.01), somatization (OR = 1.20; 95% CI 1.14-1.25; p < 0.01), hostility (OR = 1.24; 95% CI 1.18-1.30; p < 0.01), and abnormal illness behavior (OR = 1.49; 95% CI 1.34-1.66; p < 0.01) were positively associated with allostatic load, while objective support (OR = 0.84; 95% CI 0.78-0.89; p < 0.01), subjective support (OR = 0.84; 95% CI 0.80-0.88; p < 0.01), utilization of support (OR = 0.80; 95% CI 0.72-0.88; p < 0.01), social support (OR = 0.90; 95% CI 0.87-0.93; p < 0.01), and global well-being (OR = 0.30; 95% CI 0.22-0.41; p < 0.01) were negatively associated., Conclusions: In the post-COVID-19 epidemic time, medical and nonmedical workers had similar allostatic load. Psychological distress and abnormal illness behavior were risk factors for it, while social support could relieve it., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Patterns of clinical use of long-acting injectable (LAI) antipsychotic drugs in many countries, especially in Asia, for treatment of patients diagnosed with chronic psychotic disorders including schizophrenia are not well established., Methods: Within an extensive research consortium, we evaluated prescription rates for first- (FGA) and second-generation antipsychotic (SGA) LAI drugs and their clinical correlates among 3557 subjects diagnosed with schizophrenia across 15 Asian countries and region., Results: Overall, an average of 17.9% (638/3557; range: 0.0%-44.9%) of treated subjects were prescribed LAI antipsychotics. Those given LAI vs orally administered agents were significantly older, had multiple hospitalizations, received multiple antipsychotics more often, at 32.4% higher doses, were more likely to manifest disorganized behavior or aggression, had somewhat superior psychosocial functioning and less negative symptoms, but were more likely to be hospitalized, with higher BMI, and more tremor. Being prescribed an FGA vs SGA LAI agent was associated with male sex, aggression, disorganization, hospitalization, multiple antipsychotics, higher doses, with similar risks of adverse neurological or metabolic effects. Rates of use of LAI antipsychotic drugs to treat patients diagnosed with schizophrenia varied by more than 40-fold among Asian countries and given to an average of 17.9% of treated schizophrenia patients. We identified the differences in the clinical profiles and treatment characteristics of patients who were receiving FGA-LAI and SGA-LAI medications., Discussion: These findings behoove clinicians to be mindful when evaluating patients' need to be on LAI antipsychotics amidst multifaceted considerations, especially downstream adverse events such as metabolic and extrapyramidal side effects., (© 2020 John Wiley & Sons Australia, Ltd.)

To investigate effects of agomelatine and mirtazapine on sleep disturbances in patients with major depressive disorder. A total of 30 depressed patients with sleep disturbances, 27 of which completed the study, took agomelatine or mirtazapine for 8 weeks. Subjective scales were administered, and polysomnography was performed at baseline and at the end of week 1 and 8. Functional magnetic resonance imaging was performed at baseline and at the end of week 8. Compared with baseline, scores on the Hamilton Depression Scale, Hamilton Anxiety Scale, Pittsburgh Sleep Quality Index, Sleep Dysfunction Rating Scale, and Insomnia Severity Index after 8 weeks of treatment significantly decreased in both groups, with no significant differences between groups, accompanied by significant increases in total sleep time, sleep efficiency, and rapid eye movement (REM) sleep and significant decrease in wake after sleep onset. Mirtazapine treatment increased N3 sleep at week 1 compared with agomelatine treatment, but this difference disappeared at week 8. The increases in the percentage and duration of N3 sleep were positively correlated with increases in connectivity between right dorsal lateral prefrontal cortex (dlPFC) and right precuneus and between left posterior cingulate cortex and right precuneus in both groups, respectively. Functional connectivity (FC) between right dlPFC and left precuneus in mirtazapine group was higher compared with agomelatine group after 8 weeks of treatment. These findings indicated that both agomelatine and mirtazapine improved sleep in depressed patients, and the effect of mirtazapine was greater than agomelatine with regard to rapidly increasing N3 sleep and gradually improving FC in the brain., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Objective: Studies examining coprescription and dosages of mood stabilizers (MSs) with antipsychotics for psychotic disorders are infrequent. Based on sparse extant data and clinical experience, we hypothesized that adjunctive MS use would be associated with certain demographic (e.g., younger age), clinical factors (e.g., longer illness duration), and characteristics of antipsychotic treatment (e.g., multiple or high antipsychotic doses)., Methods: Within an Asian research consortium focusing on pharmaco-epidemiological factors in schizophrenia, we evaluated rates of MS coprescription, including high doses (>1000 mg/day lithium-equivalents) and clinical correlates., Results: Among 3557 subjects diagnosed with schizophrenia in 14 Asian countries, MSs were coprescribed with antipsychotics in 13.6% (n = 485) of the sample, with 10.9% (n = 53) on a high dose. Adjunctive MS treatment was associated (all p < 0.005) with demographic (female sex and younger age), setting (country and hospitalization), illness (longer duration, more hospitalizations, non-remission of illness, behavioral disorganization, aggression, affective symptoms, and social-occupational dysfunction), and treatment-related factors (higher antipsychotic dose, multiple antipsychotics, higher body mass index, and greater sedation). Patients given high doses of MSs had a less favorable illness course, more behavioral disorganization, poorer functioning, and higher antipsychotic doses., Conclusions: Schizophrenia patients receiving adjunctive MS treatment in Asian psychiatric centers are more severely ill and less responsive to simpler treatment regimens., (© 2020 John Wiley & Sons Ltd.)

Background: Patients with major depressive disorder (MDD) are at high risk for suicide. As the worst outcome of MDD and common self-concealment in patients with suicide risk, studies of biomarkers may provide useful tools for suicide prevention and treatment., Methods: This study recruited 168 patients with MDD from the Objective Diagnostic Markers and Personalized Intervention in MDD patients (ODMPIM), including 50 patients with suicide risk. Based on previous evidence and hypothesis, 23 targeted serum biomarkers involving immune-inflammation, neurotrophins, hypothalamic-pituitary-adrenal (HPA) axis and metabolism, were measured. We used path analysis and principal components analysis (PCA) to clarify the associations among serum biomarkers, childhood adversities, adulthood life events, severity of depression and suicide risk., Results: We identified that patients with suicide risk had a higher level of inflammatory markers in serum than patients without suicide risk (P < 0.001), especially chemokine (C-X-C motif) ligand 1 (CXCL-1). After using the Bonferroni correction, there were no differences in biomarkers related to neurotrophins, HPA-axis and metabolism. In addition, a higher proportion of patients with suicide risk had adulthood adversity (assessed by Life Events Scale) (P = 0.003). Intriguingly, path analysis demonstrated that the association between adulthood adversity and suicide risk mainly depended on severity of depression and inflammatory index., Conclusion: This study highlights the possible role of inflammation involved in suicide risk of MDD patients. Inflammatory markers have the potential for early identification and then reducing suicidal behaviors or becoming novel treatment targets in suicide risk management., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Chronic stress may disrupt the normal neurodevelopmental trajectory of the adolescent brain (especially the prefrontal cortex) and contribute to the pathophysiology of stress-related mental illnesses, but the underlying molecular mechanisms remain unclear. Here, we investigated how synaptic cell adhesion molecules (e.g., nectin3) are involved in the effects of adolescent chronic stress on mouse medial prefrontal cortex (mPFC). Male C57BL/6N mice were subjected to chronic social instability stress from postnatal days 29 to 77. One week later, the mice exposed to chronic stress exhibited impaired social recognition and spatial working memory, simplified dendritic structure, and reduced spine density in the mPFC. Membrane localization of nectin3 was also altered, and was significantly correlated with behavioral performance. Furthermore, knocking down mPFC nectin3 expression by adeno-associated virus in adolescent mice reproduced the stress-induced changes in behavior and mPFC morphology. These results support the hypothesis that nectin3 is a potential mediator of the effects of adolescent chronic stress on prefrontal structural and functional abnormalities.

Background: Disturbed self-regulation, taste reward, as well as somatosensory and visuospatial processes were thought to drive binge eating and purging behaviors that characterize bulimia nervosa. Although studies have implicated a central role of the striatum in these dysfunctions, there have been no direct investigations on striatal functional connectivity in bulimia nervosa from a network perspective., Methods: We calculated the functional connectivity of striatal subregions based on the resting-state functional Magnetic Resonance Imaging data of 51 bulimia nervosa patients and 53 healthy women., Results: Compared with the healthy women, bulimia nervosa patients showed increased positive functional connectivity in bilateral striatal nuclei and thalamus for nearly all of the striatal subregions, and increased negative functional connectivity in bilateral primary sensorimotor cortex and occipital areas for both ventral striatum and putamen subregions. Only for the putamen subregions, we observed reduced negative functional connectivity in the prefrontal (bilateral superior and middle frontal gyri) and parietal (right inferior parietal lobe and precuneus) areas. Several striatal connectivities with occipital and primary sensorimotor cortex significantly correlated with the severity of bulimia., Conclusions: The findings indicate bulimia nervosa-related alterations in striatal functional connectivity with the dorsolateral prefrontal cortex supporting self-regulation, the subcortical striatum and thalamus involved in taste reward, as well as the visual occipital and sensorimotor regions mediating body image, which contribute to our understanding of neural circuitry of bulimia nervosa and encourage future therapeutic developments for bulimia nervosa by modulating striatal pathway., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Objective: Reward deficits and associated striatal circuitry have been implicated in the onset and progression of major depressive disorder (MDD). This work was conducted to clarify how the striatal circuitry is involved in the established risk, acute episodes, and remission of MDD., Methods: Striatal subregion resting-state functional connectivity (RSFC) was calculated for 29 currently depressed and 28 remitted patients diagnosed with MDD per the Structured Clinical Interview for DSM-IV, 19 first-degree relatives of these patients, and 57 healthy controls (HCs) based on resting-state fMRI data collected between May 2007 and September 2014., Results: Compared with HCs, the other 3 groups showed increased RSFC between left dorsal caudate (DC) and right insula but reduced RSFC between right putamen and left cerebellum. The currently depressed group showed increased FC between right DC and superior frontal gyrus but reduced RSFC between putamen and right anterior cingulate as well as other striatal nuclei compared with the other 3 groups. Although no results were found in ventral striatum (VS) seeds during analysis of covariance, the comparison between currently depressed and remitted patients showed increased RSFC between right superior VS and left inferior frontal gyrus in currently depressed patients at a more linear threshold. Also, both superior and inferior VS showed increased RSFC with superior and inferior frontal gyri but reduced RSFC with cerebellum in relatives compared with HCs. Higher DC-superior frontal gyrus RSFC (r = 0.438, P = .022) was correlated with more severe depression, but lower within-putamen FC was correlated with more severe depression (r = -0.446, P = .02) and retardation (r = -0.465, P = .011)., Conclusions: The findings suggest that reduced VS-frontal, within-putamen, and putamen-cingulate RSFC in currently depressed patients is dependent on current depressive episode and has implications for symptomatic monitoring, while increased caudate-insular and reduced VS-cerebellar RSFC in remitted patients and first-degree relatives might be related to the disease itself and have potential for predicting risk for and recurrence of MDD., (© Copyright 2020 Physicians Postgraduate Press, Inc.)