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Peripheral cytokines were found to be involved in the pathophysiology of neurocognition in individuals with major depressive disorder (MDD). However, whether there are sex differences in this association between cytokines and cognition in MDD remains unknown. Our aim is to examine sex differences in the relationship between plasma cytokines and cognition in MDD.One hundred and twenty-seven first episode drug naïve patients with MDD and sixty healthy controls (HCs) were recruited for present study. The MATRICS Consensus Cognitive Battery was administered to measure the cognition. Plasma concentrations of nineteen cytokines were measured using high sensitivity multiplex bead-based assays.Both female and male patients with MDD had significant cognitive impairment in verbal learning and visual learning and had higher levels of a range of cytokines than HCs (all p 0.05). Female patients performed worse in trail making (F = 4.442, p = 0.018) and had higher concentration of interleukin (IL)-4 (F = 7.775, p = 0.006) than males. In female MDD, a significant positive association between category frequency and level of IL-4 was observed (B = 8.040, p = 0.031). However, this association was not present in male MDD or HCs (p 0.05).Present study used a cross-sectional design.Female MDD patients had worse trail making performance and higher level of IL-4 than males. The elevated IL-4 in female MDD was positively associated with category fluency, suggesting that IL-4 may be involved in the pathophysiology related to specific cognitive domain in female MDD patients.

The resting-state functional magnetic resonance imaging (rs-fMRI) have been used to explore functional abnormality of the brain in MDD patients with suicidal ideation (SI). However, few studies reported the variability and concordance of alterations of rs-fMRI indices in MDD with SI. In this study, we aimed to explore the variability and concordance of alterations of rs-fMRI indices in MDD with SI.A sliding window analysis was performed among 36 MDD patients with SI, 66 MDD patients without SI (NSI), and 50 healthy controls (HCs). Furthermore, the correlation between voxel-wise concordance and cognitive function was examined in the SI group.The SI group had a lower dynamics degree centrality (dDC) value than the NSI group in left inferior occipital gyrus, and a lower voxel mirrored homotopic connectivity (dVMHC) value than the NSI group in the right and left inferior occipital gyrus. The mean values of volume wise concordance of HCs group shown higher than SI group and NSI group. SI group revealed decreased voxel-wise concordance in right cerebellum, left fusiform gyrus, left lingual gyrus, right middle temporal gyrus, left postcentral gyrus, and right supplementary motor area compared to NSI group. Moreover, the voxel-wise concordance of left middle occipital gyrus was negatively correlated with verbal learning and memory and working memory in the SI group.This is a cross-sectional analysis, limiting causal inferences.The abnormal voxel-wise concordance of left middle occipital gyrus could be useful in understanding the pathophysiology of MDD patients with SI.

Cognitive dysfunction is a common and core feature of major depressive disorder (MDD). Evidences exerted a potentially harmful role of obesity and higher peripheral levels of inflammation in cognitive function, but few studies have explored whether markers of peripheral inflammation might mediate the association between overweight/obesity and deficits in cognitive function. Our study aimed to examine the cognitive function in MDD patients and clarify the effects of overweight/obesity and inflammatory cytokines on cognitive dysfunction in this population.We used a cross-sectional design in this study. A total of 265 patients with MDD were enrolled and divided into underweight, normal weight and overweight/obese groups. The MATRICS Consensus Cognitive Battery (MCCB) was administered to measure the cognition. Plasma levels of nineteen cytokines were measured using high sensitivity multiplex bead-based assays.We found overweight/obese MDD patients associated with higher plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-8, and macrophage inflammatory protein (MIP)-1β and worse performance in speed of processing and working memory. The mediation analysis found higher levels of IL-8 (direct: β = -0.591 (95 % Confidence Interval (CI): -1.0 to -0.2), P = 0.002; indirect: β = 0.060 (95 % CI.: 0.0-0.2), P = 0.032) and TNF-α (direct: β = -0.589 (95 % CI.: -1.0 to -0.2), P = 0.002; indirect: β = 0.059 (95 % CI.: 0.1-0.2), P = 0.037) were associated with more deficits in speed of processing, and partially mediated the relationship between body mass index and speed of processing.Our results suggest that elevated inflammation might be one biological mechanism underlying the link between higher body mass and deficits in processing speed in patients with MDD.

Ketamine was proven to have short-term antidepressant effects. There is a paucity of studies focused on the long-term outcomes of repeated infusions of ketamine. This study aimed to examine the long-term outcomes of repeated ketamine infusions in patients with unipolar and bipolar depression METHODS: One hundred and eight patients with unipolar and bipolar depression completed the repeated treatment phase (administered ketamine three times weekly over a 12-day) and entered a 9-month naturalistic follow-up phase. Assessments were obtained at week 2, month 6, and month 9 after the repeated treatment phase. The Patient Health Questionnaire-9 (PHQ-9) Scale and the Global Assessment of Functioning (GAF) Scale were used to assess depressive symptoms and global functional status, respectively.Seventy-one (65.7%) of patients completed the 9-month follow-up. On month 9, the response and remission rate were 80.3% and 78.9%, respectively. Among 56 patients who achieved response after the repeated treatment phase, 26 (46.4%) of patients sustained response during 9-month follow-up and their GAF score remained over 70. Sixteen patients relapsed during the 9-month follow-up and 14 (85.7%) of the relapse occurred during the first 2-week follow-up.The major limitation of this study is the open-label design.This small sample study suggested that patients with unipolar and bipolar depression who response to repeated treatment with continued oral antidepressant may be a viable treatment option, and their global functional status improved with a follow-up. Relapse of depression tended to occur during the 2 weeks follow-up.

Recently, an animal model for depression has shown that ketamine, an N-methyl- d-aspartate receptor (NMDAR) antagonist, elicits a rapid-acting antidepressant effect by blocking NMDAR-dependent bursting in the lateral habenula (Hb). However, evidence from human studies remains scarce.This study explored the changes of resting-state functional connectivity (FC) of the Hb in responders and nonresponders who was diagnosed with unipolar or bipolar depression before and after ketamine treatment. The response was defined as a ≥50% reduction in the total MADRS score at Day 13 (24 h following the sixth infusion) in comparison with the baseline score. Correlation analyses were performed to identify an association between symptom improvement and the signals of the significantly different brain regions detected in the above imaging analysis.In the post-hoc region-of-interest analysis, an enhanced baseline FC between Hb and several hubs of the default mode network (including angulate cortex, precuneus, medial prefrontal cortex, and middle temporal cortex) was observed in responders (≥50% decrease in the Montgomery-Asberg Scale at 2 weeks) compared with nonresponders.These pilot findings may suggest a potential neural mechanism by which ketamine exerts its robust antidepressant efficacy via downregulation of aberrant habenular FC with parts of the default mode network.

Background Ketamine has rapid and robust antidepressant effects in depression, while its effects on cognitive measures are less clearly understood. This aim of the study herein is to determine whether ketamine has direct pro-cognitive effects in real-world treatment depression and/or suicidality. Methods Subjects with unipolar (n = 84) and bipolar (n = 27) depression suffering treatment resistance or suicidality received six infusions of ketamine (0.5 mg/kg) during a 12-day period. Depression symptoms were assessed using the Montgomery–Asberg Depression Rating Scale at baseline, day 13 and day 26. Cognitive domains, including processing speed, working memory, visual learning and verbal learning were also measured using the MATRICS Consensus Cognitive Battery at the same time-points. Results Significant improvement was observed in processing speed at day 13 (effect size [ES] = 0.501) and day 26 (ES = 0.654), and verbal learning at day 13 (ES = 0.362). Path analysis showed significant direct (β = 2.444, P = 0.017) and indirect (β = 1.220, P = 0.048) effect of ketamine on processing speed, indicating its improvement was partly independent of improvement in depressive symptoms. The direct effect (β = −1.963, P = 0.052) of ketamine on verbal learning was not significant, whereas the indirect effect (β = 1.386, P = 0.024) was significant, indicating treatment with ketamine indirectly improved verbal learning performance, via changes in depressive symptom. Conclusion Six infusions of ketamine have a potential mood independent pro-cognitive effect on processing speed in adults with treatment depression and/or suicidality. The potential pro-cognitive effects of ketamine provide the basis for hypothesizing that other clinical outcomes (e.g., suicidality, functional impairment) reported with ketamine treatment may be in part mediated by improvement in cognition.

Reduced signal on fluorodeoxyglucose-positron emission tomography (FDG-PET) is a valid proxy for neurodegeneration in Alzheimer's disease (AD). Perivascular space (PVS) is believed to be associated with AD pathology and cognitive decline.This study aimed to investigate the associations of PVS with FDG-PET and cognitive performance based on the burden of amyloid pathology.We used magnetic resonance imaging (MRI) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). MRI-visible PVS in basal ganglia (BG) and centrum semi-oval (CSO) were visually classified as: none/mild, moderate or frequent/severe. The association of PVS with brain FDG-PET was explored based on the burden of amyloid pathology, where a cerebrospinal fluid (CSF) t-tau/Aβ42 with the ratio≥0.27 was defined as high amyloid pathology. Moreover, the relationships between PVS and cognitive performance variables (ADNI-MEM and ADNI-EF) were studied.For participants with higher tau/Aβ42 ratio, CSO-PVS severity was independently associated with lower FDG-PET. There were significant interaction effects between moderate or frequent/severe CSO-PVS and time on FDG decline in people with high amyloid pathology. The interaction between CSO-PVS and time (follow-up) was consistently associated with ADNI-MEM and ADNI-EF decline in individuals with high amyloid pathology.The study established the differential utility of PVS in BG and CSO for predicting brain metabolism. These findings suggest that CSO-PVS serves as a contributing factor to brain metabolism and cognitive decline associated with amyloid pathology.

Detection of transient changes in interaural correlation is based on the temporal precision of the central representations of acoustic signals. Whether schizophrenia impairs the temporal precision in the interaural correlation process is not clear. In both participants with schizophrenia and matched healthy-control participants, this study examined the detection of a break in interaural correlation (BIC, a change in interaural correlation from 1 to 0 and back to 1), including the longest interaural delay at which a BIC was just audible, representing the temporal extent of the primitive auditory memory (PAM). Moreover, BIC-induced electroencephalograms (EEGs) and the relationships between the early binaural psychoacoustic processing and higher cognitive functions, which were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), were examined. The results showed that compared to healthy controls, participants with schizophrenia exhibited poorer BIC detection, PAM and RBANS score. Both the BIC-detection accuracy and the PAM extent were correlated with the RBANS score. Moreover, participants with schizophrenia showed weaker BIC-induced N1-P2 amplitude which was correlated with both theta-band power and inter-trial phase coherence. These results suggested that schizophrenia impairs the temporal precision of the central representations of acoustic signals, affecting both interaural correlation processing and higher-order cognitions.

Background Major depressive disorder (MDD) is a high risk factor for suicide, with up to 20% of MDD patients attempting suicide during their lifetime. Current treatments for MDD are slow onset of action, low efficiency, and the inability to control suicidal behaviors quickly and effectively. Intravenous ketamine has been shown to have a rapid but transient antidepressant effect, but there is still lack evidence on the efficacy and safety of intravenous esketamine in reducing suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. We designed a study to investigate the effect of short-term repeated intravenous infusion of esketamine three times in MDD patients with suicidal ideation. Methods This study features a randomized, double-blind, placebo-controlled trial (RCT) comparing short-term repeated intravenous infusions of esketamine with placebo as a supplement to conventional antidepressants with an intervention period of 6 days and one infusion every other day, followed by 4 weeks of follow-up. These methods support the examination of the efficacy, safety, tolerability, and mechanism of action of short-term repeated intravenous infusions of esketamine in MDD patients with suicidal ideation. Discussion This is the first RCT to explore the efficacy and safety of short-term repeated infusion of esketamine on suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. If proven effective and tolerated, it will provide evidence for rapid and effective treatment of suicidal ideation and depressive symptoms in MDD individuals with suicidal ideation. Trial registration Chinese Clinical Trial Register, ChiCTR2000041232. Registered 22 December 2020.

Background Subjective cognitive decline (SCD) is a putative Alzheimer’s disease (AD) precursor without objective neuropsychological deficits. The hippocampus plays an important role in cognitive function and emotional responses and is generally aberrant in SCD. However, previous studies have mainly focused on static functional connectivity (sFC) by resting-state functional magnetic resonance imaging (fMRI) in SCD individuals, and it remains unclear whether hippocampal dynamic functional connectivity (dFC) changes exist in SCD and whether those changes are associated with subtle changes in cognitive function or affect. Methods Seventy SCD patients and 65 healthy controls were recruited. Demographic data, comprehensive neuropsychology assessments, and resting-state fMRI data were collected. The bilateral anterior and posterior hippocampi were selected as seeds to investigate the static and dynamic functional connectivity alterations in SCD. Results Compared to healthy controls, subjects with SCD exhibited: (1) decreased sFC between the left caudal hippocampus and left precuneus; (2) decreased dFC variability between the bilateral caudal hippocampus and precuneus; (3) increased dFC variability between the bilateral rostral hippocampus and caudate nucleus; and (4) increased dFC variability between the left rostral hippocampus and left olfactory cortex. Additionally, the attention scores were positively correlated with dFC variability between the left posterior hippocampus and left precuneus, and the dFC variability between the bilateral anterior hippocampus and caudate nucleus was positively correlated with depression scores and negatively correlated with global cognition scores. Conclusion SCD individuals exhibited abnormal sFC and dFC in the anterior-posterior hippocampus, and abnormal dFC was more widespread than abnormal sFC. A combination of sFC and dFC provides a new perspective for exploring the brain pathophysiological mechanisms in SCD and offers potential neuroimaging biomarkers for the early diagnosis and intervention of AD.

The antidepressant effects of ketamine in patients with anxious depression (AD) remain unclear. Functional connectivity (FC) differences in the amygdala have been linked to depression improvement after ketamine treatment in depressed patients, but their role in AD patients is uncertain. We investigated the correlation between depression improvement after ketamine treatment and amygdala FC in AD patients.Thirty-one AD patients and 18 non-anxious depression (NAD) patients received six intravenous ketamine infusions (0.5 mg/kg) over two weeks. AD patients were further divided into responders (defined as a ≥50% MADRS total score reduction on day 13) and non-responders. The FC of the amygdala subregions, including the laterobasal amygdala (LBA), centromedial amygdala (CMA), and superficial amygdala, were compared between the groups. Receiver operating characteristic curves were used to predict treatment response after ketamine infusions.The baseline FC difference in the left LBA and the left precuneus between responders and non-responders among AD patients was found to be associated with depression improvement and was a significant predictor of treatment response to ketamine. A marked reduction in baseline LBA-precuneus FC after ketamine infusion was observed in responders. Unlike in patients with NAD, a lower right CMA-right middle temporal gyrus FC was found in AD patients.The sample size is rather small.Our findings may suggest that amygdala FC is a significant predictor of treatment response to ketamine infusions in patients with AD. Further studies exploring the potential antidepressant mechanisms of ketamine may aid in the treatment of AD patients.

The present study aimed to compare temporal variability in the spontaneous fluctuations of activity and connectivity between amnestic MCI (aMCI) and nonamnestic MCI (naMCI), which enhances the understanding of their different pathophysiologies and provides targets for individualized intervention.Sixty-five naMCI and 48 aMCI subjects and 75 healthy controls were recruited. A sliding window analysis was used to evaluate the dynamic amplitude of low-frequency fluctuations (dALFF), dynamic regional homogeneity (dReHo), and dynamic functional connectivity (dFC). The caudal/rostral hippocampus was selected as the seeds for calculating dFC.Both aMCI and naMCI exhibited abnormal dALFF, dReHo, and hippocampal dFC compared with healthy controls. Compared with individuals with naMCI, those with aMCI exhibited (1) higher dALFF variability in the right putamen, left Rolandic operculum, and right middle cingulum, (2) lower dReHo variability in the right superior parietal lobule, and (3) lower dFC variability between the hippocampus and other regions (left superior occipital gyrus, middle frontal gyrus, inferior cerebellum, precuneus, and right superior frontal gyrus). Additionally, variability in dALFF, dReHo, and hippocampal dFC exhibited different associations with cognitive scores in aMCI and naMCI patients, respectively. Finally, dReHo variability in the right superior parietal lobule and dFC variability between the right caudal hippocampus and left inferior cerebellum exhibited partially mediated effects on the different memory scores between people with aMCI and naMCI.The aMCI and naMCI patients exhibited shared and specific patterns of dynamic brain activity and connectivity. The dReHo of the superior parietal lobule and dFC of the hippocampus-cerebellum contributed to the memory heterogeneity of MCI subtypes. Analyzing the temporal variability in the spontaneous fluctuations of brain activity and connectivity provided a new perspective for exploring the different pathophysiological mechanisms in MCI subtypes.

Aim The glycaemic control of diabetes with depression was inconsistent from randomized controlled studies. This meta-analysis aimed to explore the effectiveness of intervention methods in diabetes with depression. Methods This study systematically searched electronic databases (PubMed, EBSCO, Elsevier, Springer, Wiley, and Cochrane) for studies published up to August 17, 2020. Standardized mean difference (SMD) and 95%CI were used to evaluate the effectiveness of interventions on HbA1c. Heterogeneity was estimated using the I2 statistic. Begg’s test was used to assess the possible publication bias among studies. Results Twelve studies of 2444 cases were included in this study. The overall SMD is −0.22 and 95%CI −0.33 to −0.10 in 0–6 months of intervention group. The I2 and P were 18.4% and 0.26. There are no publication bias tested (z = 0.37, P = 0.72). Conclusion Cognitive behavioral therapy and mindful self-compassion might be effective method to improve glycaemic control of diabetes with depression in 0–6 months.

Schizophrenia (SZ) is characterized by a series of cognitive impairments, including automatic processing impairment of basic auditory information, indexed by mismatch negativity (MMN). Existing studies mainly focus on MMN induced by deviant of single acoustic features, and relatively few studies have focused on complex acoustic stimuli, especially speech-induced MMN. Many cognitive impairments in SZ are related to speech function. Thus, the present study aimed to examine the reduction of phonetic MMN in SZ as a potential biomarker and its relationship with illness course and functional outcomes. Electroencephalogram (EEG) signals were recorded from 32 SZ and 32 healthy controls (HC) in a double oddball paradigm, with /da/ as the standard stimulus and /ba/ and /du/ as the deviant stimuli. MMN was computed for vowel and consonant deviants separately. Clinical symptoms were assessed using the Positive and Negative Symptom Rating Scale (PANSS). Illness duration and illness relapse were acquired by combining clinical interviews and electronic medical records. Functional outcomes were assessed using the Global Assessment of Functioning scale (GAF). Compared with HC, SZ showed lower amplitudes of phonetic MMN, especially for vowel deviants. In addition, the MMN amplitude of the vowel deviant was significantly correlated with illness duration, illness relapse, and functional outcomes among patients with SZ. These findings indicate that the pre-attentive automatic phonetic processing of SZ was impaired for both consonants and vowels, while the vowel processing deficit may be the key speech processing deficit in SZ, which could depict the illness course and predict the functional outcomes.

Background: Odor identification dysfunction occurs early in Alzheimer’s disease (AD) and is considered a preclinical symptom along with subjective cognitive decline (SCD). Nevertheless, whether subjects with SCD are co-symptomatic with odor identification dysfunction remains unclear. Objective: To compare the degree of odor identification dysfunction and assess the relation between odor identification and cognitive performance in the AD spectrum (including SCD, mild cognitive impairment (MCI), and AD). Methods: Patients (84 SCD, 129 MCI, 52 AD) and 35 controls underwent the Sniffin’ Sticks Screen 16 test and comprehensive neuropsychological examination. Results: Odor identification scores were progressively lower moving from normal older adult to SCD, MCI, and AD. Additionally,the proportion of odor identification dysfunction were increasingly higher in the AD spectrum (p for trend

Recently, the effects of ketamine on the circadian rhythm have suggested that ketamine’s rapid antidepressant effects are associated with and without sleep disturbance improvement. Here, we evaluated the antidepressant efficacy of repeated ketamine infusions in patients with sleep disturbances. This study included 127 patients with major depressive disorder or bipolar disorder who received ketamine treatments during a 12-day period. Sleep quality was assessed by the 17-item Hamilton Depression Rating Scale sleep disturbance factor (SDF) (items 4, 5 and 6). Serum brain-derived neurotrophic factor (BDNF) was measured at baseline, day 13 and day 26. This study was a post-hoc analysis. Significant differences were found in the HAMD-17 score at 13 post-infusion time points compared to baseline, as well as the scores in SDF score at each of the 7 post-infusion (4 h after each infusion excluded) time points among all patients. Logistic regression and linear correlation analyses revealed that a greater reduction in the SDF after 24 h of the first ketamine infusion resulted in a better antidepressant effect in the last two follow-up visits. Moreover, BDNF levels were significantly higher in sleep responders than in non-responders. In the 127 patients, six ketamine infusions induced better therapeutic effects in sleep responders than in sleep non-responders and patients without sleep disturbances. The sleep response after repeated ketamine infusions was positively associated with high serum BDNF levels. Early sleep disturbance improvement (as early as 24 h after the first ketamine injection) may predict the antidepressant effect of repeated-dose ketamine.

Background The ongoing global COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus first discovered at the end of 2019. It has led to more than 50 million confirmed cases and more than 1 million deaths across 219 countries as of 11 November 2020, according to WHO statistics. SARS-CoV-2, SARS-CoV, and MERS-CoV are similar. They are highly pathogenic and threaten public health, impair the economy, and inflict long-term impacts on society. No drug or vaccine has been approved as a treatment for these viruses. Efforts to develop antiviral measures have been hampered by the insufficient understanding of how the human body responds to viral infections at the cellular and molecular levels. Results In this study, journal articles and transcriptomic and proteomic data surveying coronavirus infections were collected. Response genes and proteins were then identified by differential analyses comparing gene/protein levels between infected and control samples. Finally, the H2V database was created to contain the human genes and proteins that respond to SARS-CoV-2, SARS-CoV, and MERS-CoV infection. Conclusions H2V provides molecular information about the human response to infection. It can be a powerful tool to discover cellular pathways and processes relevant for viral pathogenesis to identify potential drug targets. It is expected to accelerate the process of antiviral agent development and to inform preparations for potential future coronavirus-related emergencies. The database is available at: http://www.zhounan.org/h2v.

Affective temperaments and childhood-trauma experiences are associated with major depressive disorder (MDD). So far, how the covariation between distinct affective temperaments and childhood-trauma insulted brain functional connectivities (FCs) contribute to MDD remains unclear. Here, we aimed to investigate whether certain brain FC patterns are related to certain affective temperaments and whether the FCs contribute to depressive symptom dimensions of MDD patients. Twenty-nine medication-free MDD patients and 58 healthy controls underwent magnetic resonance imaging scanning and completed the Hamilton Depression Rating Scale (HDRS), the Hamilton Anxiety Rating Scale (HARS), the Childhood Trauma Questionnaire-Short Form (CTQ-SF), and the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS). Two multivariate analyses of partial least squares (PLS) regression were used to explore the associations among childhood-trauma related resting-state FCs, affective temperaments and depressive symptom dimensions. In all participants, a linear combination of 81 FCs (involving parahippocampus, amygdala, cingulate cortex, insula, frontal-temporal-parietal-occipital cortex, pallidum, and cerebellum) were associated with a linear combination of increased depressive, irritable, anxious, and cyclothymic temperaments. Moreover, the covariation between the PLS FC profile and the PLS affective-temperament profile were enhanced in the MDD patients compared to healthy controls. In MDD participants alone, the affective-temperament modulated FC profile (mainly of the lingual and temporal cortex) was associated with the somatization symptom dimension when age, sex, ill-duration, age-of-onset, and HARS scores were adjusted. The findings imply possible neural correlates of affective temperaments and may find applications in intervention of the somatization-depression symptoms by stimulation of the related neural correlates.

Insomnia is one of the major symptom relevant factors in major depressive disorder (MDD), but the neurological mechanisms underlying the multiple effect between insomnia and depression have not been well interpreted. This study aimed at exploring the potential mechanisms between insomnia and depression based on amygdala-based resting-state functional connectivity (RSFC).In total 56 MDD patients with low insomnia (MDD-LI) patients, 46 MDD patients with high insomnia (MDD-HI) patients, and 57 healthy controls (HCs) were employed and underwent a resting-state functional magnetic resonance imaging (fMRI) scan. ANOVA test was performed on RSFC value for three groups. Correlation analysis was conducted to evaluate the relationship between abnormal RSFC values and clinical features.We found that MDD-HI mainly showed increased RSFC in (bilateral superior temporal gyrus (STG), and decreased RSFC in left supplementary motor area (SMA) and bilateral postcentral gyrus (PoCG) compared with MDD-LI. Correlation analysis indicated that RSFC of the bilateral amygdala with STG were positively associated with the sleep disturbance score and adjust HAMD score.Our findings suggest that RSFC in temporal lobe and other specifically activated regions may be associated with neural circuits involved with insomnia in MDD. These provide new evidence for understanding the potential mechanisms of major depression and insomnia from the perspective of functional connectivity.

Background Evidences suggest that inflammatory marker-mediated neuroplasticity contributes critically to brain changes following antidepressant treatment. To date, no study has examined the relationship between changes in hippocampal volume, depressive symptoms, and inflammatory markers following repeated ketamine treatment. Methods Forty-four patients with major depressive disorder received six intravenous ketamine (0.5 mg/kg) infusions over 12 days. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess depressive symptoms, and peripheral blood was collected to test multiple cytokines and tryptophan (TRP) metabolites at baseline, 24 h and 14 days after the sixth infusion (day 13 and day 26). Magnetic resonance imaging (MRI) scans were carried out at baseline and day13, and FreeSurfer software was used to process the T1 images and analyze hippocampal volume. Results Following ketamine, a significant improvement in depressive symptoms, a small increase in right hippocampal volume and alterations in inflammatory markers was found. No significant association was found between changes in inflammatory markers and changes in hippocampal volume from baseline to day 13 (P>0.05), while a weak association was found between TRP metabolite changes and other cytokine changes from baseline to day 26 (beta=-0.357, t=−2.600, P = 0.013). Limitations The patients continued receiving previous medications during ketamine treatment, which may have impacted hippocampal volume and inflammatory markers. Conclusions Hippocampal volume increase following ketamine was an independent neurobiological effect that was not associated with changes in peripheral inflammatory markers, suggesting a likely complex neurobiological mechanism of the antidepressant effect of ketamine.

Abnormal subcortical structures have been associated with major depressive disorder (MDD) and could be reversed by antidepressant treatment. To date no study has examined the relationship between subcortical volumes and repeated ketamine treatment. The current study investigated volume changes in specific subcortical structures and hippocampal subfields after six ketamine infusions. Forty-four patients with MDD received six subanesthetic dose infusions of ketamine. Depressive symptoms were assessed and magnetic resonance imaging scans were performed before and after six ketamine infusions. FreeSurfer software was used to process the T1 images and analyze the volumes of the subcortical regions and hippocampal subfields. After six ketamine infusions, increases were observed in the volumes of the left amygdala; the right hippocampus; the cornu ammonis 4 body, granule cell and molecular layer of the dentate gyrus body in the left hippocampus; and the cornu ammonis 4 head and molecular layer head in the right hippocampus. Positive correlations were found between symptom improvement and the pretreatment volumes of the right thalamus (r = 0.501; P = 0.001) and left subiculum head of the hippocampus (r = 0.471; P = 0.002), and changes in the volumes of the left amygdala (r = −0.452; P = 0.003) and the left cornu ammonis 4 body (r = −0.537; P

Background: Ketamine produces significant rapid-onset and robust antidepressant effects in patients with major depressive disorder. However, this drug also has transient cardiovascular stimulatory effects, and there are limited data about potential predictors of these cardiovascular effects. Methods: A total of 135 patients with unipolar and bipolar depression received a total of 741 ketamine infusions (0.5 mg/kg over 40 min). Blood pressure and pulse were monitored every 10 min during the infusions and 30 min after the infusions. Depressive, psychotomimetic and dissociative symptom severity was assessed at baseline and 4 hours after each infusion. Results: The maximum blood pressure and pulse values were observed at 30–40 min during infusions. The largest mean systolic/diastolic blood pressure increases were 7.4/6.0 mmHg, and the largest mean pulse increase was 1.9 beats per min. No significant change in blood pressure and pulse was found in the second to sixth infusions compared with the first infusion. Patients who were older (age⩾50 years), hypertensive and receiving infusions while exhibiting dissociative symptoms showed greater maximal changes in systolic and diastolic blood pressure than patients who were younger (ageConclusions: Blood pressure and pulse elevations following subanaesthetic ketamine infusions are transient and do not cause serious cardiovascular events. Older age, hypertension, large ketamine dosage and dissociative symptoms may predict increased ketamine-induced cardiovascular effects.

Diabetes is one of the most common comorbid diseases in patients with schizophrenia. The present study examined the prevalence of diabetes and its clinical correlates in a large sample of Chinese patients with schizophrenia, which has not been examined systemically. In this cross-sectional study, a total of 1189 patients (males/females = 938/251; average age: 48.51 ± 10.09 years) were recruited. Fasting blood samples were collected to diagnose diabetes. Psychiatric symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). The prevalence of diabetes was 12.53% with a significant gender difference (males: 10.87% versus females: 18.73%). Compared to patients without diabetes, those with diabetes were older, had a later age of onset, had a higher BMI, had higher positive symptom scores and had higher level of metabolic indices, including triglyceride, cholesterol and HDL cholesterol. After stepwise binary logistic regression analysis, age, BMI, and triglyceride level remained significantly associated with diabetes. This study suggests that diabetes occur with high prevalence in Chinese schizophrenia patients. In addition, age, BMI, and triglyceride level possibly are useful markers predicting an increased risk for diabetes.

Mounting evidence suggests that function and connectivity of the striatum is disrupted in schizophrenia1–5. We have developed a new hypothesis-driven neuroimaging biomarker for schizophrenia identification, prognosis and subtyping based on functional striatal abnormalities (FSA). FSA scores provide a personalized index of striatal dysfunction, ranging from normal to highly pathological. Using inter-site cross-validation on functional magnetic resonance images acquired from seven independent scanners (n = 1,100), FSA distinguished individuals with schizophrenia from healthy controls with an accuracy exceeding 80% (sensitivity, 79.3%; specificity, 81.5%). In two longitudinal cohorts, inter-individual variation in baseline FSA scores was significantly associated with antipsychotic treatment response. FSA revealed a spectrum of severity in striatal dysfunction across neuropsychiatric disorders, where dysfunction was most severe in schizophrenia, milder in bipolar disorder, and indistinguishable from healthy individuals in depression, obsessive-compulsive disorder and attention-deficit hyperactivity disorder. Loci of striatal hyperactivity recapitulated the spatial distribution of dopaminergic function and the expression profiles of polygenic risk for schizophrenia. In conclusion, we have developed a new biomarker to index striatal dysfunction and established its utility in predicting antipsychotic treatment response, clinical stratification and elucidating striatal dysfunction in neuropsychiatric disorders. A new cross-validated neuroimaging biomarker that reflects striatal dysfunctioning can be used to distinguish patients with schizophrenia from healthy controls, and is associated with treatment response to antipsychotics.

Aims Amisulpride, a first-line schizophrenia treatment, has shown large interindividual variability in plasma/serum levels, often outside the reference range (100-320 ng/mL). This study aims to clarify the impact of dose, sex, age and related factors for the interpatient variability in amisulpride plasma/serum concentration. Methods Both English and Chinese databases were searched from their inception to May 16, 2019, using the terms: amisulpride and (plasma OR serum OR blood OR "drug monitoring" OR concentration). Studies reporting concentrations and either a dose, associated factor, clinical outcome or side effect were included. Results Fourteen studies with 1628 participants were eventually included. Eligible articles yielded data on drug concentration and dose, averaging 333.9 (95% confidence interval [CI]: 294.5-373.3) ng/mL and 636.2 (95% CI: 549.7-722.6) mg/d, respectively. The calculated mean concentration-to-dose (C/D) ratio was 0.60 (95% CI: 0.52-0.67) (ng/mL)/mg. Subgroup analysis suggested that female patients on combined lithium-amisulpride have higher concentration levels and C/D ratios. Age was slight positive associated with C/D ratio while not for plasma level. Smoker patients have high concentration level than nonsmoking patients but not for C/D. Responsive and nonresponsive groups did not differ in concentration and C/D. Conclusion Pooled concentration levels of amisulpride were higher than recommended with wide individual variation, especially in older patients, female patients and patients taking amisulpride combined with lithium. The specific therapeutic reference range for amisulpride may require reconstruction, which should consider the influence of age, sex, kidney function, drug-drug interactions, different dose regimens and sampling times in future study.

The prevalence of smoking is significantly higher in persons with schizophrenia (SCZ) than in the general population. However, the biological mechanisms of the comorbidity of smoking and SCZ are largely unknown. This study aimed to reveal shared biological pathways for the two diseases by analyzing data from two genome-wide association studies with a total sample size of 153,898. With pathway-based analysis, we first discovered 18 significantly enriched pathways shared by SCZ and smoking, which were classified into five groups: postsynaptic density, cadherin binding, dendritic spine, long-term depression, and axon guidance. Then, by using an integrative analysis of genetic, epigenetic, and expression data, we found not only 34 critical genes (e.g., PRKCZ, ARHGEF3, and CDKN1A) but also various risk-associated SNPs in these genes, which convey susceptibility to the comorbidity of the two disorders. Finally, using both in vivo and in vitro data, we demonstrated that the expression profiles of the 34 genes were significantly altered by multiple psychotropic drugs. Together, this multi-omics study not only reveals target genes for new drugs to treat SCZ but also reveals new insights into the shared genetic vulnerabilities of SCZ and smoking behaviors.

This study examined the structural brain differences across individuals of different BD stages and the risks of developing bipolar disorder (BD) associated with these brain differences. A total of 221 participants who were recruited from the Guangzhou Brain Hospital and the community were categorized into four groups: NC (healthy control) (N = 77), high risk (HR) (N = 42), ultra-high risk (UHR) (N = 38), and bipolar disorder (BD) (N = 64) based on a list of criteria. Their demographics, clinical characteristics, and diffusion magnetic resonance imaging (dMRI) data were collected. ANCOVA results showed that the HR group had significantly reduced mean diffusivity (MD) (p = 0.043) and radial diffusivity (RD) (p = 0.039) of the left portico-ponto-cerebellar tracts when compared with the BD group. Moreover, logistic regression results showed that the specific diffusivity measures of cerebellar tracts (e.g., cortico-ponto-cerebellar tract), particularly the RD and MD revealed differences between groups at different BD stages after controlling for the covariates. The findings suggested that specific diffusivity (RD and MD) of cerebellar tracts (e.g., cortico-ponto-cerebellar tract) revealed differences between groups at different BD stages which is helpful in detecting the trajectory changes in BD syndromes in the early stages of BD, particularly when the BD syndromes start from HR stage.

Suicide is a common issue among major depressive disorder (MDD) patients and suicidal ideation (SI) is the first step toward it. There are no definitive objective biomarkers of SI relative to MDD. In this study, a seed-based correlation analysis was performed among 36 MDD patients with SI, 66 MDD patients without SI (NSI), and 57 healthy controls (HCs) using amygdala resting-state functional connectivity (RSFC). Furthermore, the correlation between amygdala RSFC and clinical features was examined in the SI group. When compared to the NSI group, SI group exhibited increased RSFC between the left amygdala seed and left medial superior frontal gyrus (SFGmed) as well as left middle frontal gyrus (MFG). In turn, a decreased RSFC was observed between the left amygdala seed and the following brain regions including the left inferior parietal lobule (IPL), right precentral gyrus (PrCG), and left superior parietal lobule (SPL) in SI group compared to NSI group. Moreover, the SI group exhibited increased RSFC of the right amygdala with left middle temporal gyrus (MTG); In addition, the RSFC of the left amygdala with left MFG was negatively associated with learning and memory (VSM), speed of processing (SOP). The RSFC of the amygdala is distinct between MDD patients with SI and without SI. Our findings reveal the neurobiological characteristics of MDD with respect to SI and provide new clues regarding vulnerability to mental illness. It is necessary to carry out repeated and more longitudinal researches using multimodal approaches on SI in the future.

BackgroundPrevious analyses of grey and white matter volumes have reported that schizophrenia is associated with structural changes. Deep learning is a data-driven approach that can capture highly compact hierarchical non-linear relationships among high-dimensional features, and therefore can facilitate the development of clinical tools for making a more accurate and earlier diagnosis of schizophrenia.AimsTo identify consistent grey matter abnormalities in patients with schizophrenia, 662 people with schizophrenia and 613 healthy controls were recruited from eight centres across China, and the data from these independent sites were used to validate deep-learning classifiers.MethodWe used a prospective image-based meta-analysis of whole-brain voxel-based morphometry. We also automatically differentiated patients with schizophrenia from healthy controls using combined grey matter, white matter and cerebrospinal fluid volumetric features, incorporated a deep neural network approach on an individual basis, and tested the generalisability of the classification models using independent validation sites.ResultsWe found that statistically reliable schizophrenia-related grey matter abnormalities primarily occurred in regions that included the superior temporal gyrus extending to the temporal pole, insular cortex, orbital and middle frontal cortices, middle cingulum and thalamus. Evaluated using leave-one-site-out cross-validation, the performance of the classification of schizophrenia achieved by our findings from eight independent research sites were: accuracy, 77.19–85.74%; sensitivity, 75.31–89.29% and area under the receiver operating characteristic curve, 0.797–0.909.ConclusionsThese results suggest that, by using deep-learning techniques, multidimensional neuroanatomical changes in schizophrenia are capable of robustly discriminating patients with schizophrenia from healthy controls, findings which could facilitate clinical diagnosis and treatment in schizophrenia.

Kynurenic acid (KYNA) is a metabolite of tryptophan (TRP). KYNA levels have been reported with controversial findings in patients with schizophrenia.This study aimed to investigate the probable effects of medication and illness chronicity on peripheral KYNA levels in schizophrenia.We assessed peripheral (plasma) TRP metabolite levels in 38 drug-free patients with first-episode schizophrenia (FES), 65 patients with chronic schizophrenia (CHS), and 70 healthy controls by using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The symptom severity of patients was evaluated by using the Positive and Negative Syndrome Scale (PANSS). Finally, we analyzed the association of TRP metabolites with symptom severity.We found significantly higher KYNA levels in FES patients than in both healthy controls (In conclusion, elevated plasma KYNA levels may be a promising biomarker in FES patients. Medication and illness chronicity may affect peripheral KYNA levels with a currently unknown mechanism.

Odor identification (OI) impairment increases the risk of Alzheimer's disease and brain abnormalities in patients with late-life depression (LLD). However, it remains unclear whether abnormal functional connectivity (FC) of olfactory regions is involved in the relationship between OI impairment and dementia risk in LLD patients. The current study aims to explore the olfactory FC patterns of LLD patients and how olfactory FCs mediate the relationship between OI and cognition.A total of 150 participants underwent resting-state functional magnetic resonance imaging and psychometric and olfactory assessments. The primary and secondary olfactory regions were selected as regions of interest to investigate olfactory FC patterns and their association with OI and cognitive performance in LLD patients.Compared with LLD patients without OI impairment and normal controls, LLD patients with OI impairment exhibited increased FC between the left orbital frontal cortex (OFC) and left calcarine gyrus, between the left OFC and right lingual gyrus, between the right OFC and right rectus gyrus, and decreased FC between the right piriform cortex and right superior parietal lobule. Additionally, these abnormal FCs were associated with scores of OI, global cognition and language function. Finally, the FC between the right piriform cortex and right superior parietal lobule exhibited a partially mediated effect on the relationship between OI and MMSE scores.The present study did not exclude the possible effect of drugs.LLD patients with OI impairment exhibited more disrupted olfactory FC (a decrease in the primary olfactory cortex and an increase in the secondary olfactory cortex) than LLD patients with intact OI, and these abnormal FCs may serve as potential targets for neuromodulation in LLD patients to prevent them from developing dementia.

Background Treatment-resistant depression (TRD) and pain frequently coexist clinically. Ketamine has analgesic and antidepressant effects, but few studies have evaluated individual differences in antidepressant outcomes to repeated ketamine in TRD patients with comorbid pain. Our aims were to determine the difference in ketamine’s antidepressant effects in TRD patients with or without pain and then to examine whether inflammatory cytokines might contribute to ketamine’s effect. Methods Sixty-six patients with TRD received six infusions of ketamine. Plasma levels of 19 inflammatory cytokines were assessed at baseline and post-infusion (day 13 and day 26) using the Luminex assay. Plasma inflammatory cytokines of sixty healthy controls (HCs) were also examined. Results TRD patients with pain had a higher antidepressant response rate (χ2 = 4.062, P = 0.044) and remission rate (χ2 = 4.062, P = 0.044) than patients without pain. Before ketamine treatment, GM-CSF and IL-6 levels were higher in the pain group than in the non-pain and HC groups. In the pain group, levels of TNF-α and IL-6 at day 13 and GM-CSF, fractalkine, IFN-γ, IL-10, MIP-3α, IL-12P70, IL-17α, IL-1β, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, MIP-1β, and TNF-α at day 26 were lower than those at baseline; in the non-pain group, TNF-α levels at day 13 and day 26 were lower than those at baseline. In the pain group, the changes of IL-6 were associated with improvement in pain intensity (β = 0.333, P = 0.001) and depressive symptoms (β = 0.478, P = 0.005) at day 13. Path analysis showed the direct (β = 2.995, P = 0.028) and indirect (β = 0.867, P = 0.042) effects of changes of IL-6 on improvement in depressive symptoms both were statistically significant. Conclusion This study suggested that an elevated inflammatory response plays a critical role in individual differences in TRD patients with or without pain. Ketamine showed great antidepressant and analgesic effects in TRD patients with pain, which may be related to its effects on modulating inflammation. Trial registration ChiCTR, ChiCTR-OOC-17012239. Registered on 26 May 2017

The clinical manifestations of late-life depression (LLD) are highly heterogeneous. Currently, abnormal characteristics of resting-state electroencephalography (EEG) power and functional connectivity are considered trait markers of depressive symptoms in major depression. However, the relationship between EEG spectral features and functional connectivity in LLD remains unknown.Forty-one patients with LLD and 44 participants without depression underwent an eyes-closed resting-state EEG. EEG power spectra, alpha asymmetry, and functional connectivity were calculated and analyzed.Although alpha frontal asymmetry and cortical functional connectivity between the two groups showed no significant differences, the LLD group exhibited abnormal neural oscillation patterns of higher beta frequency activity in the parietal, central, and occipital lobes while alpha activity was increased in the parietal central electrodes.The number of EEG electrodes used in this study was low, and the sample size was limited.Increased alpha and beta frequency band powers were observed in patients with LLD. These abnormal patterns may be associated with a disturbed balance of cortical excitation, inhibition, and hyperactivity. In the future, a neurofeedback protocol based on the findings of neural oscillation patterns in certain types of LLD should be explored.

Ketamine has rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD), while its effects on functional outcomes have not been sufficiently evaluated. The aim was to evaluate the efficacy of ketamine treatment on both subjective and objective functioning, and to explore whether improvements in depressive symptom and cognition mediated changes in functioning.Adults (n=111) with TRD and/or suicidality received six infusions of ketamine (0.5mg/kg, thrice-weekly). Depression symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline, day 13 and day 26. Cognitive domains, including processing speed, working memory, visual learning and verbal learning were measured with the MATRICS Consensus Cognitive Battery, and subjective and objective functioning were measured with the Sheehan Disability Scale (SDS) and the Global Assessment of Functioning (GAF) at the same time-points.Significant improvement was observed in SDS total score (effect size [ES]=-1.563) and GAF score (ES=1.700) during the 26-day observation. Results from path analysis indicated that reductions of the total MADRS score and improvements in processing speed aggregately significantly mediated the reductions of SDS total score (total indirect effect coef=-3.993, 95%CI [-4.9, -3.2], direct effect coef=-1.374, 95%CI [-2.4, -0.4]) as well as the increases of GAF score (total indirect effect coef=6.022, 95%CI [4.5, 7.8], direct effect coef=3.987, 95%CI [2.1, 5.8]).Six infusions of ketamine was associated with improvements in functional outcomes in adults with TRD and/or suicidality. Depressive symptoms severity and processing speed performance were significant partial mediators of objective and subjective functioning improvements.

Objectives Evidence of the relationship between neurometabolic changes in the cortico-striato-cerebellar (CSC) circuit and bipolar disorder (BD) is still limited. To elucidate the pathogenesis of BD, we investigated the underlying neurometabolic changes and their effect on CSC lateralization circuits in unmedicated patients with bipolar II depression. Methods Forty unmedicated participants with bipolar II depression and forty healthy controls underwent proton magnetic resonance spectroscopy (1H-MRS). We obtained bilateral metabolic ratios of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr in the prefrontal white matter (PWM), anterior cingulate cortex (ACC), basal ganglia (BG) and the cerebellum. Metabolic ratios were characterized using a laterality index (LI) for left-right asymmetry. Results Overall, aberrant lateralization in the CSC circuit was characteristic in patients with bipolar II depression. Patients with bipolar II depression showed significantly lower NAA/Cr ratios in the left PWM, right ACC, left BG and left cerebellum when compared with the healthy controls. For bipolar II depression, we found lower NAA/Cr LI in the PWM, BG, and cerebellum, higher NAA/Cr LI in the ACC, and higher Cho/Cr LI in the BG and cerebellum when compared to the standard value (1.0). For healthy controls, we found lower NAA/Cr LI only in the BG and higher Cho/Cr LI in the cerebellum when compared to 1.0. Limitations As a cross-sectional study with a small sample size, progressive changes and complex metabolic interactions with treatment were not observed. Conclusions Our findings suggest that abnormal biochemical metabolism with aberrant lateralization in the CSC circuit may be an underlying pathophysiology of bipolar II depression.

Thyroid dysfunction was reported to be associated with depression; however, its role in suicide risk in patients with major depressive disorder (MDD) remains unclear. The objective of this study was to compare thyroid function between suicide attempters and non-suicide attempters in a large sample of first episode drug naïve (FEDN) MDD patients, which received little systemic investigation.A total of 1718 outpatients with diagnosis of MDD at their first episode were recruited. Their socio-demographic, clinical data and thyroid function parameters were collected. The positive subscale of the Positive and Negative Syndrome Scale (PANSS), Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD) were measured for psychotic, anxiety and depressive symptoms, respectively.Our results showed that compared with non-suicide attempters, suicide attempters had greater scores on HAMD, HAMA and PANSS psychotic symptoms and higher serum levels in thyroid stimulating hormone (TSH), anti-thyroglobulin (TgAb) and thyroid peroxidases antibody (TPOAb) (all p 0.001). Further logistic regression analysis indicated that suicide attempts were associated with severe anxiety with an adjusted odds ratio (OR) of 2.704 and TPOAb with an adjusted OR of 2.188.No causal relationship could be drawn due to the cross-sectional design.Our results indicate TSH, TgAb and TPOAb may be promising biomarkers of suicide risk in MDD, suggesting the importance of regular assessment of thyroid function parameters for suicide prevention, and possible treatment for impaired thyroid function for intervention of suicide in MDD patients.

Objectives: To determine the prevalence and risk factors associated with depression of outpatients in three general hospitals in southern China.Methods: This hospital-based, cross-sectional descrip...

BackgroundCompulsive behaviors in obsessive-compulsive disorder (OCD) have been related to impairment within the associative cortical-striatal system connecting the caudate and prefrontal cortex that underlies consciously-controlled goal-directed learning and behavior. However, little is known whether this impairment may serve as a biomarker for vulnerability to OCD.MethodsUsing resting-state functional magnetic resonance imaging (fMRI), we employed Granger causality analysis (GCA) to measure effective connectivity (EC) in previously validated striatal sub-regions, including the caudate, putamen, and the nucleus accumbens, in 35 OCD patients, 35 unaffected first-degree relatives and 35 matched healthy controls.ResultsBoth OCD patients and their first-degree relatives showed greater EC than controls between the left caudate and the orbital frontal cortex (OFC). Both OCD patients and their first-degree relatives showed lower EC than controls between the left caudate and lateral prefrontal cortex. These results are consistent with findings from task-related fMRI studies which found impairment in the goal-directed system in OCD patients.ConclusionsThe same changes in EC were present in both OCD patients and their unaffected first-degree relatives suggest that impairment in the goal-directed learning system may be a biomarker for OCD.

Burnout is a worked-related stress syndrome caused by long-term exposure to a stressful environment. Dysregulation of the hypothalamic- pituitary- adrenal (HPA) axis may be involved in both stress and burnout; an evaluation of genetic polymorphisms which alter activity in the HPA may be predictive of how likely an environment is to produce burnout.Using a cross-sectional design, this study examined whether corticotrophin-releasing hormone receptor 1 (CRHR1) gene polymorphism rs110402 is a risk factor for burnout; further, it explores whether the interaction of stress × CRHR1 gene predicts burnout in the healthcare workers in a Chinese Han population. House and Rizzo's work stress scale, Sources of Pressure Scale and Maslach Burnout Inventory-General Survey were administered to 712 participants from a large general hospital in Beijing. The CRHR1 rs110402 polymorphism was genotyped in 376 participants.Our results showed significant positive inter-correlations between stressor, work stress and depressive scores (all p 0.001) with only one exception. Males, younger age and higher educational level were associated with burnout (all p 0.05). The presence of the CRHR1 rs110402 genotype was not correlated with the presence of job stress or burnout. However, we found statistically significant interaction between CRHR1 rs110402 and job stress on burnout (p 0.05). Individuals homozygous for the A allele reported significantly higher emotional exhaustion than G allele carriers in the high stress group.The sample was only chosen from the medical professions, and the sample size was relatively small. Only one polymorphism in CRHR1 gene was analyzed, while only about half of the total individuals were genotyped.Our results suggest a close relationship between work-related stress and burnout and that the A allele of the CRHR1 rs110402 polymorphism may enhance feelings of emotional exhaustion when experiencing work-related stress.

Little is known about the association between sleep duration and health status in Chinese university students. This study examined the association between sleep duration and self-rated health in university students in China.Altogether, 2312 subjects (928 in Macao, 446 in Hong Kong, and 938 in mainland China) were recruited. Standardized measures of sleep and self-reported health were administered. Sleep duration was categorized in the following way: 6 h/day, 6 to 7 h/day, 7-9 h/day, and 9 h/day.Overall, 71% of university students reported poor health, 53% slept 7-9 h/day, 14% slept less than 6 h/day, 32% slept 6 to 7 h/day, and 1% slept 9 h/day. Univariate analysis revealed that compared to students with medium sleep duration (7-9 h/day), those with short sleep duration ( 6 h/day and 6 to 7 h/day) were more likely to report poor health. Multivariate logistic regression analysis found that after controlling for age, gender, body mass index, university location, being a single child, religious beliefs, interest in academic major, academic pressure, nursing major, pessimism about the future, and depression, sleep duration of less than 6 h/day (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.34-2.92, p 0.01) was independently and significantly associated with poor self-reported health.Poor health status is common in Chinese university students, which appears to be closely associated with short sleep duration. Further longitudinal studies are warranted to gain a better understanding of the interaction between sleep patterns and health status in university students.

Objective Cognitive impairment is common among patients with major depressive disorder (MDD), but its pathological mechanism is complex and not fully understood. Evidence suggests that the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression, but few studies have explored the association between the KYN pathway and cognitive impairment in MDD. Our aim was to examine the relationship between cognitive impairment and KYN pathway metabolites in patients with MDD. Methods A total of 146 patients with MDD according to DSM-V and 72 healthy controls (HCs) were enrolled, and the severity of depressive symptoms using the 17-item Hamilton Depression Rating Scale (HAMD-17) and cognitive performance including speed of processing, working memory, visual learning and verbal learning were assessed. Blood samples were collected, and serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by liquid chromatography-tandem mass spectrometry. Results In females with MDD, there was a significant negative association between the KYN level and verbal learning (B=-0.039, adjusted p = 0.018), and the KYN/TRP ratio was negatively correlated with speed of processing (B=-470.086, adjusted p = 0.029), verbal learning (B=-544.251, adjusted p = 0.002) and visual learning (B=-513.777, adjusted p = 0.004). Those associations were not present in male individuals with MDD or in HCs, except for a significant negative correlation between the KYNA/KYN ratio and category fluency (B=−0.373, adjusted p = 0.039) in female HCs. Conclusion Our results suggest that learning function and speed of processing in female MDD were associated with KYN serum level and the KYN/TRP ratio, potentially implicating the KYN pathway in the pathological mechanism of cognitive function in female MDD.

Objectives:Cognitive impairment in late-life depression is common and associated with a higher risk of all-cause dementia. Late-life depression patients with comorbid cardiovascular diseases (CVDs) or related risk factors may experience higher risks of cognitive deterioration in the short term. We aim to investigate the effect of CVDs and their related risk factors on the cognitive function of patients with late-life depression.Methods:A total of 148 participants were recruited (67 individuals with late-life depression and 81 normal controls). The presence of hypertension, coronary heart disease, diabetes mellitus, or hyperlipidemia was defined as the presence of comorbid CVDs or related risk factors. Global cognitive functions were assessed at baseline and after a one-year follow-up by the Mini-Mental State Examination (MMSE). Global cognitive deterioration was defined by the reliable change index (RCI) of the MMSE.Results:Late-life depression patients with CVDs or related risk factors were associated with 6.8 times higher risk of global cognitive deterioration than those without any of these comorbidities at a one-year follow-up. This result remained robust after adjusting for age, gender, and changes in the Hamilton Depression Rating Scale (HAMD) scores.Conclusions:This study suggests that late-life depression patients with comorbid CVDs or their related risk factors showed a higher risk of cognitive deterioration in the short-term (one-year follow up). Given that CVDs and their related risk factors are currently modifiable, active treatment of these comorbidities may delay rapid cognitive deterioration in patients with late-life depression.

Pretreatment characteristics of patients, symptom and function could be associated with antidepressant treatment outcome, but its predictive ability is not adequate. Our study aimed to identify predictors of acute antidepressant efficacy in patients with first-episode Major Depressive Disorder (MDD).187 patients with first-episode MDD were included and assessed clinical symptoms, cognitive function and global functioning using the 17-item Hamilton Depression Inventory (HAMD-17), MATRICS Consensus Cognitive Battery (MCCB) and Global Assessment of Functioning (GAF). Participants received treatment with a SSRI (escitalopram or venlafaxine) for 4 weeks. Logistic regression was used to analyze the association between patients' characteristics, symptom profiles, cognitive performance, and global functioning and the antidepressant outcome at the end of 4 weeks, and ROC curve analysis was performed for predictive accuracy with area under the receiver operating curve (AUC).Antidepressant improvement, response and remission rate at week 4 was 87.7%, 64.7% and 42.8%, respectively. The combination of pretreatment clinical profiles, speed of processing and global functioning showed moderate discrimination of acute improvement, response and remission with AUCs of 0.863, 0.812 and 0.734, respectively.The major limitation of the present study is the study did not combine pharmacogenomics from the perspective of antidepressant drug metabolism.Aside from the baseline clinical symptoms, cognitive function and global functioning could be predictors of acute treatment outcome in first episode MDD using escitalopram or venlafaxine. This relatively simple application based on clinical symptoms and function seems to be cost-effective method to identify individuals who are more likely to respond to antidepressant treatment.

The effect of the gut microbiome on the central nervous system and its possible role in mental disorders have received increasing attention. However, knowledge about the relationship between the gut microbiome and brain structure and function is still very limited. Here, we used 16S rRNA sequencing with structural magnetic resonance imaging (sMRI) and resting-state functional (rs-fMRI) to investigate differences in fecal microbiota between 38 patients with schizophrenia (SZ) and 38 demographically matched normal controls (NCs) and explored whether such differences were associated with brain structure and function. At the genus level, we found that the relative abundance of Ruminococcus and Roseburia was significantly lower, whereas the abundance of Veillonella was significantly higher in SZ patients than in NCs. Additionally, the analysis of MRI data revealed that several brain regions showed significantly lower gray matter volume (GMV) and regional homogeneity (ReHo) but significantly higher amplitude of low-frequency fluctuation in SZ patients than in NCs. Moreover, the alpha diversity of the gut microbiota showed a strong linear relationship with the values of both GMV and ReHo. In SZ patients, the ReHo indexes in the right STC (r = − 0.35, p = 0.031, FDR corrected p = 0.039), the left cuneus (r = − 0.33, p = 0.044, FDR corrected p = 0.053) and the right MTC (r = − 0.34, p = 0.03, FDR corrected p = 0.052) were negatively correlated with the abundance of the genus Roseburia. Our results suggest that the potential role of the gut microbiome in SZ is related to alterations in brain structure and function. This study provides insights into the underlying neuropathology of SZ.

Major depressive disorder (MDD) is one of the most common psychiatric disorders. Various clinical studies have shown that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid, robust, and sustained antidepressant effects. However, given the concerns about the adverse effects of ketamine on patients, it would be important to identify a set of biomarkers that could be used to predict clinical outcomes for its treatment. A total of 83 MDD patients received treatment with six ketamine infusions for up to 2 weeks and were classified into "responders" or "non-responders" based on an average change in the HAMD score >50% from baseline. A nested cross-validation approach was applied to prevent information leakage and overestimation of model performance. The initial dataset was divided randomly into training and test sets in a nested six-fold cross-validation. We first performed genome-wide logistic regression to find potentially significant variants related to treatment response and then selected the top SNPs based on the genetic association results using the random forests algorithm. Subsequently, six machine learning models were employed to construct prediction models by using ten-fold cross-validation. A series of model comparisons showed that the best performing fold was characterized by accuracy of 0.85, precision of 0.75, and a sensitivity of 1.00 with the support vector machine algorithm. Together, these findings demonstrated that the machine learning approach can predict the treatment outcomes of multiple ketamine infusions on the basis of the genotyping information of each participant.

Cytokines are involved in the pathophysiology of major depressive disorder (MDD) and treatment response. Efforts have been made to identify inflammatory markers but results are often contradictory. The present study explored the plasma levels of multiple cytokines in first-episode MDD using a longitudinal design, with the aim to determine the involvement of cytokines in depression and identify the inflammatory markers.Fifty-four first-episode drug naïve MDD patients and 60 healthy controls (HCs) were enrolled in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered and blood samples were collected at baseline and four-week posttreatment in MDD group, while blood samples were only collected once in HC group. Plasma levels of nineteen cytokines were examined by a multiplexed flow cytometric assay.Sixteen out of 19 cytokines levels in MDD group were significantly higher than those in HC group (all P0.05). After 4-week of antidepressant treatment, levels of the 14 cytokines elevated at baseline decreased to normal levels (all P0.05). Partial correlation showed that baseline level of interferon-inducible T cell alpha chemoattractant (ITAC) was negatively correlated with reduction in HAMD-17 score (r=-0.319, p=0.020), and multiple regression showed lower baseline ITAC level was associated with better treatment response (p = 0.020).The sample size was relatively small.A range of cytokines were abnormal in patients with first-episode drug naïve MDD and most of the cytokines could be normalized after antidepressant treatment. Furthermore, baseline ITAC level could be a predictive factor of antidepressant response.

Highlights • Schizophrenia classification was studied using a large sample data from eight sites. • Both brain images and genetic factors were used as features for classification. • Machine learning methods and leave-one-site-out cross-validation were performed., Previous brain structural magnetic resonance imaging studies reported that patients with schizophrenia have brain structural abnormalities, which have been used to discriminate schizophrenia patients from normal controls. However, most existing studies identified schizophrenia patients at a single site, and the genetic features closely associated with highly heritable schizophrenia were not considered. In this study, we performed standardized feature extraction on brain structural magnetic resonance images and on genetic data to separate schizophrenia patients from normal controls. A total of 1010 participants, 508 schizophrenia patients and 502 normal controls, were recruited from 8 independent sites across China. Classification experiments were carried out using different machine learning methods and input features. We tested a support vector machine, logistic regression, and an ensemble learning strategy using 3 feature sets of interest: (1) imaging features: gray matter volume, (2) genetic features: polygenic risk scores, and (3) a fusion of imaging features and genetic features. The performance was assessed by leave-one-site-out cross-validation. Finally, some important brain and genetic features were identified. We found that the models with both imaging and genetic features as input performed better than models with either alone. The average accuracy of the classification models with the best performance in the cross-validation was 71.6%. The genetic feature that measured the cumulative risk of the genetic variants most associated with schizophrenia contributed the most to the classification. Our work took the first step toward considering both structural brain alterations and genome-wide genetic factors in a large-scale multisite schizophrenia classification. Our findings may provide insight into the underlying pathophysiology and risk mechanisms of schizophrenia.

Mitochondria as a highly dynamic organelle continuously changes morphology and position during its life cycle. Mitochondrial dynamics including fission and fusion play a critical role in maintaining functional mitochondria for ATP production, which is directly linked to host defense against Mtb infection. However, how macrophages regulate mitochondrial dynamics during Mycobacterium tuberculosis (Mtb) infection remains elusive. In this study, we found that Mtb infection induced mitochondrial fusion through enhancing the expression of mitofusin 1 (MFN1), which resulted in increased ATP production. Silencing MFN1 inhibited mitochondrial fusion and subsequently reduced ATP production, which, in turn, severely impaired macrophage mycobactericidal activity by inhibiting autophagy. Impairment of mycobactericidal activity and autophagy was replicated using oligomycin, an inhibitor of ATP synthase. In summary, our study revealed MFN1-mediated mitochondrial fusion is essential for macrophage mycobactericidal activity through the regulation of ATP dependent autophagy. MFN1-mediated metabolism pathway might be targets for development of host direct therapy (HDT) strategy against TB.ImportanceHow mitochondrial dynamic is regulated in attempt to fight against Mtb remains elusive. Our study revealed that the fission/fusion dynamics of mitochondria during Mtb infection is regulated by MFN1, through which mitochondrial respiration and autophagy activity are affected. Our findings suggested that intervention of energy metabolism by targeting MFN1 might be a strategy against Mtb infection.

Early detection of patients with late-life depression (LLD) with a high risk of developing dementia contributes to early intervention. Odor identification (OI) dysfunction serves as a marker for predicting dementia, but whether OI dysfunction increases the risk of dementia in LLD patients remains unclear. The present study aimed to explore the interactive effect of LLD and OI dysfunction on the risk of dementia and its underlying neuroimaging changes. One hundred and fifty-seven LLD patients and 101 normal controls were recruited, and data on their OI, cognition, activity of daily living (ADL), and resting-state functional magnetic resonance imaging were collected. Two × two factorial analyses were used to analyze the interactive effects of LLD and OI dysfunction on neuropsychological and neuroimaging abnormalities. Mediation analyses were used to explore whether abnormalities detected by neuroimaging mediated the the associations between OI and cognition/ADL. The results suggested that LLD and OI dysfunction exhibited additive effects on reduced ADL, global cognition and memory scores, as well as neuroimaging variables including (i) increased fractional amplitude of low-frequency fluctuation (fALFF) in the right orbitofrontal cortex and right precentral cortex, and (ii) increased regional homogeneity (ReHo) in the left hippocampus/fusiform gyrus, etc. In addition, these increased fALFF and ReHo values were associated with reduced neuropsychological scores (ADL, global cognition, memory, and language). Moreover, ReHo of the left hippocampus/fusiform gyrus completely mediated the relationship between OI and ADL, and partially mediated the relationship between OI and global cognition. Overall, mediated by the hypersynchronization of the left hippocampus/fusiform gyrus, OI dysfunction may increase the risk of dementia in LLD patients.