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It has been revealed that abnormal voxel-mirrored homotopic connectivity (VMHC) is present in patients with schizophrenia, yet there are inconsistencies in the relevant findings. Moreover, little is known about their association with brain gene expression profiles. In this study, transcription-neuroimaging association analyses using gene expression data from Allen Human Brain Atlas and case-control VMHC differences from both the discovery (meta-analysis, including 9 studies with a total of 386 patients and 357 controls) and replication (separate group-level comparisons within two datasets, including a total of 258 patients and 287 controls) phases were performed to identify genes associated with VMHC alterations. Enrichment analyses were conducted to characterize the biological functions and specific expression of identified genes, and Neurosynth decoding analysis was performed to examine the correlation between cognitive-related processes and VMHC alterations in schizophrenia. In the discovery and replication phases, patients with schizophrenia exhibited consistent VMHC changes compared to controls, which were correlated with a series of cognitive-related processes; meta-regression analysis revealed that illness duration was negatively correlated with VMHC abnormalities in the cerebellum and postcentral/precentral gyrus. The abnormal VMHC patterns were stably correlated with 1287 genes enriched for fundamental biological processes like regulation of cell communication, nervous system development, and cell communication. In addition, these genes were overexpressed in astrocytes and immune cells, enriched in extensive cortical regions and wide developmental time windows. The present findings may contribute to a more comprehensive understanding of the molecular mechanisms underlying VMHC alterations in patients with schizophrenia.

Abstract This study was conducted to investigate the effects of long-term low-dose lithium adjunct to antipsychotic agent use on the cognitive performance, whole-brain gray-matter volume (GMV), and interleukin-6 (IL-6) level in drug-naive patients with first-episode schizophrenia, and to examine relationships among these factors. In this double-blind randomized controlled study, 50 drug-naive patients with first-episode schizophrenia each took low-dose (250 mg/day) lithium and placebo (of the same shape and taste) adjunct to antipsychotic agents (mean, 644.70 ± 105.58 and 677.00 ± 143.33 mg/day chlorpromazine equivalent, respectively) for 24 weeks. At baseline and after treatment completion, the MATRICS Consensus Cognitive Battery (MCCB) was used to assess cognitive performance, 3-T magnetic resonance imaging was performed to assess structural brain alterations, and serum IL-6 levels were quantified by immunoassay. Treatment effects were assessed within and between patient groups. Relationships among cognitive performance, whole-brain GMVs, and the IL-6 level were investigated by partial correlation analysis. Relative to baseline, patients in the lithium group showed improved working memory, verbal learning, processing speed, and reasoning/problem solving after 24 weeks of treatment; those in the placebo group showed only improved working memory and verbal learning. The composite MCCB score did not differ significantly between groups. The whole-brain GMV reduction was significantly lesser in the lithium group than in the placebo group (0.46% vs. 1.03%; P

Abstract Introduction The Davos Assessment of Cognitive Biases Scale (DACOBS) is widely used to assess cognitive biases in patients who have schizophrenia. However, the lack of a modified Chinese‐language version of the DACOBS (MCL‐DACOBS) precludes Chinese schizophrenic patients from treatment aimed at normalizing cognitive biases, impacting their prognosis. Here, we aimed to produce a DACOBS for China and test the validity and reliability of the resultant MCL‐DACOBS. Methods Eighteen researchers collaborated to develop the MCL‐DACOBS: A total of 15 researchers modified and translated the English version of the DACOBS, 1 native‐English‐speaking researcher back‐translated the scale, and 2 Chinese sinologists localized and optimized the language of the MCL‐DACOBS. Forty‐two volunteers checked the scale items’ comprehensibility, and the two sinologists performed further localization and optimization based on their feedback. The final version of the MCL‐DACOBS used in this study was thus derived from the harmonized English‐language version of the scale. Confirmatory factor analyses (CFAs) were used to examine the best latent structure of the MCL‐DACOBS. Cronbach's α and intraclass correlation coefficients (ICCs) were used to check the reliability. The discriminative ability of the MCL‐DACOBS was assessed according to the area under the receiver operating characteristic curve. Results The CFA showed that all items loaded onto factors with loadings >0.400. A two‐factor structure showed a good model fit (root mean square error of approximation = .018, Tucker–Lewis index = .978, comparative fit index = .984). Promax rotation demonstrated that each item had a high factor load (0.432–0.774). Cronbach's α coefficient and ICC for the MCL‐DOCABS were .965 and .957, respectively, indicating that the scale has ideal reliability. Conclusion The MCL‐DACOBS has good validity and good reliability, and its psychometric properties indicate that it is a valid tool for measuring cognitive biases in Chinese patients with schizophrenia.

Abstract Lithium (Li) is a well-established mood disorder treatment and may be neuroprotective. Bi-directional regulation (i.e. affecting manic symptoms and depressive symptoms) by Li has not been demonstrated. This study explored: (1) bidirectional regulation by Li in murine models of depression, mania, and bipolar disorder (BP); and (2) potential Li synergism with antidepressant/anti-mania agents. The chronic unpredictable mild stress (CUMS) and ketamine-induced mania (KM) models were used. These methods were used in series to produce a BP model. In vivo two-photon imaging was used to visualize Ca2+ activity in the dorsolateral prefrontal cortex. Depressiveness, mania, and cognitive function were assessed with the forced swim task (FST), open field activity (OFA) task, and novel object recognition task, respectively. In CUMS mice, Ca2+ activity was increased strongly by Li and weakly by lamotrigine (LTG) or valproate (VPA), and LTG co-administration reduced Li and VPA monotherapy effects; depressive immobility in the FST was attenuated by Li or LTG, and attenuated more strongly by LTG-VPA or LTG-Li; novel object exploration was increased strongly by Li and weakly by LTG-Li, and reduced by LTG, VPA, or LTG-VPA. In KM mice, Li or VPA attenuated OFA mania symptoms and normalized Ca2+ activity partially; Li improved cognitive function while VPA exacerbated the KM alteration. These patterns were replicated in the respective BP model phases. Lithium had bi-directional, albeit weak, mood regulation effects and a cognitive supporting effect. Li co-administration with antidepressant/-manic agents enhanced mood-regulatory efficacy while attenuating their cognitive-impairing effects.

BackgroundPatient-reported outcomes, or subjective evaluations directly reflecting the patient’s views, feelings, and judgments, are now being used to evaluate the outcomes of care and treatment of people with schizophrenia. In this study, we used an updated tool, the patient-reported impact of symptoms in schizophrenia scale (PRISS), translated into Chinese languages to assess the subjective experiences of schizophrenia patients.ObjectiveThis study aimed to test the psychometrics of the Chinese languages PRISS (CL-PRISS).MethodThis study used the Chinese version of PRISS (CL-PRISS), acquired from the harmonized English-language version. A total of 280 patients enrolled in this study were asked to complete the CL-PRISS, the positive and negative syndrome scale (PANSS), and the World Health Organization Disability Assessment Schedule (WHO-DAS). Construct and concurrent validity was tested using the confirmatory factor analysis (CFA) and Spearman correlation coefficient, respectively. The reliability of CL-PRISS was tested using Cronbach’s α coefficient and the internal correlation coefficient.ResultsConfirmatory factor analysis (CFA) analysis demonstrated three major factors in CL_PRISS: the first factor is productive experiences, the second factor is affective-negative, and the third factor experiences. The factor loadings between items and factors ranged from 0.436 to 0.899 (RMSEA = 0.029, TLI = 0.940, CFI = 0.921). The correlation coefficient between the CL_PRISS and PANSS was 0.845, and between the CL-PRISS and WHO-DAS was 0.886. The ICC of the total CL_PRISS was 0.913, and Cronbach’s α was 0.903.ConclusionThe Chinese version of the PRISS (CL_PRISS) can be effectively used for assessing the subjective experience of Chinese patients with schizophrenia.

BackgroundA Suicide Screening Questionnaire-Observer Rating (SSQ-OR) has been used to assess risk of suicide among individuals and to help clinicians identify and rescue individuals attempting suicide. To prevent the risk of suicide in China, a Chinese language SSQ-OR (CL-SSQ-OR) needs to be introduced.ObjectiveTo test the validity and reliability of a CL-SSQ-OR.MethodA total of 250 individuals were enrolled in this study. Each completed a CL-SSQ-OR assessment, Patient Health Questionnaire-9, and the Beck Scale for Suicide Ideation. Confirmatory factor analysis (CFA) was adopted to determine structural validity. Spearman correlation coefficients were adopted to determine criterion validity. An internal correlation coefficient (ICC) was used to test inter-consistency and Cronbach’s α coefficient was used to test split-half reliability.ResultsCFA was conducted with use of the maximum variance method to evaluate the item results. All of the items received scores >0.40. In addition, good model fit indices were observed for the two-factor structure RMSEA = 0.046, TLI = 0.965, CFI = 0.977. The items’ factor loading of the CL-SSQ-OR in the first factor ranged from 0.443 to 0.878. The items’ factor loading of the CL-SSQ-OR in the second factor ranged from 0.400 to 0.810. The ICC of the total CL-SSQ-OR was 0.855. Cronbach’s α was 0.873.ConclusionThe CL-SSQ-OR described here demonstrates ideal psychometric properties and is found to be a suitable tool for screening Chinese children/adolescents who are at risk of suicide.

BackgroundWork addiction (WA), which can impair personal relationships, engagement in recreational activities, and/or health, is a behavioral addiction. A tool for the early detection of WA in China is needed.ObjectiveThe aim of this study was to develop and determine the validity and reliability of a Chinese version of the Bergen Work Addiction Scale (C-BWAS).MethodsTwo hundred social workers who provided post-discharge services for adolescents with non-suicidal self-injury (NSSI) were enrolled in this study. The construct validity of the C-BWAS was assessed by confirmatory factor analysis (CFA). Criterion validity was assessed by conducting Pearson correlation analyses of C-CWAS scores with Hamilton Depression Scale (HAM-D) and Hamilton Anxiety Scale (HAM-A) scores. Cronbach’s α and the intra-class correlation coefficient (ICC) were used to evaluate the reliability of the C-BWAS.ResultsCFA confirmed a one-dimensional structure of the C-BWAS with good construct validity indices [comparative fit index (CFI) = 0.964, Tucker–Lewis index (TLI) = 0.951, root-mean-square error of approximation (RMSEA) = 0.079, and minimum discrepancy Ĉ/degrees of freedom (Cmin/DF) = 0.362]. The standardized regression weights ranged from 0.523 to 0.753. All C-BWAS items loaded on one major factor (loading weights, 0.646–0.943). Coefficients of correlation between C-BWAS scores and HAM-D and HAM-A scores were 0.889 and 0.933, respectively. The Cronbach’s α coefficient and ICC for the instrument was 0.837 and 0.905, respectively.ConclusionThe presently developed C-BWAS showed very good reliability and acceptably validity. It can be employed as a useful tool for assessing WA severity in social workers who provide post-discharge services for adolescents with NSSI.

Abstract The negative symptoms of schizophrenia can be present at any clinical stage, but evaluating the negative symptoms always remains challenging. To screen the negative symptoms effectively, self‐evaluation should be introduced. To date, professional psychiatrists used almost all of the scales available to screen the negative symptoms but could not obtain an accurate outcome. At the same time, an advanced self‐assessment scale is needed to accompany the patients’ self‐feeling‐based treatment strategies to understand their feelings about their symptoms. Hence, Chinese self‐evaluation of negative symptoms (SNS) should be introduced in China. This study aims to examine the validity and reliability of the Chinese version of SNS. Two hundred patients with schizophrenia were included in this study and were evaluated entirely with the self‐assessed negative symptoms by the Chinese version. The correlation analysis was performed between SNS and the Scale for Assessment of Negative Symptoms (SANS) to assess the criterion validity of SNS for screening negative symptoms. Exploratory factor analysis was used to determine the constructive validity of the SNS. Two senior professional psychiatrists were involved in this assessment based on their clinical experience and capability to define the severity of the negative symptoms. Receiver operating characteristic curve (ROC) analysis was performed to assess the cutoff point of SNS. Cronbach's alpha coefficient and intraclass correlation (ICC) coefficient were used to determine the reliability of SNS. We have the following findings: The Chinese version of SNS demonstrated a significant correlation with the SANS (r = .774, p

Abstract Schizophrenia is a severe mental illness, as the efficacies of current antipsychotic medications are far from satisfactory. An improved understanding of the signaling molecules involved in schizophrenia may provide novel therapeutic targets. Acid sphingomyelinase (ASM) catalyzes cellular membrane sphingomyelin into ceramide, which is further metabolized into sphingosine-1-phophate (S1P). ASM, ceramide, and S1P at the cell surface exert critical roles in the regulation of biophysical processes that include proliferation, apoptosis, and inflammation, and are thereby considered important signaling molecules. Although research on the ASM/ceramide system is still in its infancy, structural and metabolic abnormalities have been demonstrated in schizophrenia. ASM/ceramide system dysfunction is linked to the two important models of schizophrenia, the dopamine (DA) hypothesis through affecting presynaptic DA signaling, and the vulnerability-stress-inflammation model that includes the contribution of stress on the basis of genetic predisposition. In this review, we highlight the current knowledge of ASM/ceramide system dysfunction in schizophrenia gained from human and animal studies, and formulate future directions from the biological landscape for the development of new treatments. Collectively, these discoveries suggest that aberrations in the ASM/ceramide system, especially in ASM activity and levels of ceramide and S1P, may alter cerebral microdomain structure and neuronal metabolism, leading to neurotransmitter (e.g., DA) dysfunction and neuroinflammation. As such, the ASM/ceramide system may offer therapeutic targets for novel medical interventions. Normalization of the aberrant ASM/ceramide system or ceramide reduction by using approved functional inhibitors of ASM, such as fluvoxamine and rosuvastatin, may improve clinical outcomes of patients with schizophrenia. These transformative findings of the ASM/ceramide system in schizophrenia, although intriguing and exciting, may pose scientific questions and challenges that will require further studies for their resolution.

Abstract Background Schizophrenia is a complex and heterogeneous syndrome with high clinical and biological stratification. Identifying distinctive subtypes can improve diagnostic accuracy and help precise therapy. A key challenge for schizophrenia subtyping is understanding the subtype-specific biological underpinnings of clinical heterogeneity. This study aimed to investigate if the machine learning (ML)-based neuroanatomical and symptomatic subtypes of schizophrenia are associated. Methods A total of 314 schizophrenia patients and 257 healthy controls from four sites were recruited. Gray matter volume (GMV) and Positive and Negative Syndrome Scale (PANSS) scores were employed to recognize schizophrenia neuroanatomical and symptomatic subtypes using K-means and hierarchical methods, respectively. Results Patients with ML-based neuroanatomical subtype-1 had focally increased GMV, and subtype-2 had widespread reduced GMV than the healthy controls based on either K-means or Hierarchical methods. In contrast, patients with symptomatic subtype-1 had severe PANSS scores than subtype-2. No differences in PANSS scores were shown between the two neuroanatomical subtypes; similarly, no GMV differences were found between the two symptomatic subtypes. Cohen’s Kappa test further demonstrated an apparent dissociation between the ML-based neuroanatomical and symptomatic subtypes (P > 0.05). The dissociation patterns were validated in four independent sites with diverse disease progressions (chronic vs. first episodes) and ancestors (Chinese vs. Western). Conclusions These findings revealed a replicable dissociation between ML-based neuroanatomical and symptomatic subtypes of schizophrenia, which provides a new viewpoint toward understanding the heterogeneity of schizophrenia.

Abstract Antipsychotic pharmacotherapy has been widely recommended as the standard of care for the treatment of acute schizophrenia and psychotic symptoms of other psychiatric disorders. However, there are growing concerns regarding antipsychotic-induced side effects, including weight gain, metabolic syndrome (MetS), and extrapyramidal motor disorders, which not only decrease patient compliance, but also predispose to diabetes and cardiovascular diseases. To date, most studies and reviews on the mechanisms of antipsychotic-induced metabolic side effects have focused on central nervous system mediation of appetite and food intake. However, disturbance in glucose and lipid metabolism, and hepatic steatosis induced by antipsychotic drugs might precede weight gain and MetS. Recent studies have demonstrated that the mechanistic/mammalian target of rapamycin (mTOR) pathway plays a critical regulatory role in the pathophysiology of antipsychotic drug-induced disorders of hepatic glucose and lipid metabolism. Furthermore, antipsychotic drugs promote striatal mTOR pathway activation that contributes to extrapyramidal motor side effects. Although recent findings have advanced the understanding of the role of the mTOR pathway in antipsychotic-induced side effects, few reviews have been conducted on this emerging topic. In this review, we synthesize key findings by focusing on the roles of the hepatic and striatal mTOR pathways in the pathogenesis of metabolic and extrapyramidal side effects, respectively. We further discuss the potential therapeutic benefits of normalizing excessive mTOR pathway activation with mTOR specific inhibitors. A deeper understanding of pathogenesis may inform future intervention strategies using the pharmacological or genetic inhibitors of mTOR to prevent and manage antipsychotic-induced side effects.

Abstract Brain pathological features during manic/hypomanic and depressive episodes in the same patients with bipolar disorder (BPD) have not been described precisely. The study aimed to investigate depressive and manic-phase-specific brain neural activity patterns of BPD in the same murine model to provide information guiding investigation of the mechanism of phase switching and tailored prevention and treatment for patients with BPD. In vivo two-photon imaging was used to observe brain activity alterations in the depressive and manic phases in the same murine model of BPD. Two-photon imaging showed significantly reduced Ca2+ activity in temporal cortex pyramidal neurons in the depression phase in mice exposed to chronic unpredictable mild stress (CUMS), but not in the manic phase in mice exposed to CUMS and ketamine. Total integrated calcium values correlated significantly with immobility times. Brain Ca2+ hypoactivity was observed in the depression and manic phases in the same mice exposed to CUMS and ketamine relative to naïve controls. The novel object recognition preference ratio correlated negatively with the immobility time in the depression phase and the total distance traveled in the manic phase. With recognition of its limitations, this study revealed brain neural activity impairment indicating that intrinsic emotional network disturbance is a mechanism of BPD and that brain neural activity is associated with cognitive impairment in the depressive and manic phases of this disorder. These findings are consistent with those from macro-imaging studies of patients with BPD. The observed correlation of brain neural activity with the severity of depressive, but not manic, symptoms need to be investigated further.

BackgroundBorderline personality disorder (BPD) is characterized by behavioral patterns that promote suffering in many adolescents and their guardians. Currently, early diagnosis of BPD mainly depends on the effective assessment of pathological personality traits (i.e., borderline personality features) and using the indicated scales. The Borderline Personality Features Scale for Children-Short Form (BPFSC-SF) is widely used and the introduction of a Chinese version of the BPFSC-SF, can improve the diagnosis and prognosis of Chinese patients with BPD.ObjectiveThe aim of the present study was to assess the validity and reliability of the Chinese version of the BPFSC-SF.Method120 adolescents with BPD were enrolled in the present study and completed the BPFSC-SF and the Personality Belief Questionnaire-Short Form (PBQ-SF) assessments. Confirmatory factor analysis (CFA) was used to test assessment validity. Test-retest correlations and the Cronbach's α coefficients were used to determine reliability.ResultsCFA analysis identified primary factors of BPFSC, with each item ranging from 0.597~0.899. The Spearman rank correlation coefficient was 0.877 between CL-BFSFC-SF and the state vs. trait loneliness scale. The Cronbach's α of the scale was 0.854 in the clinical group. The test-retest reliability correlation coefficient (interclass correlation coefficients.ICC) was 0.937.ConclusionThe Chinese version of BPFSC-SF is a valid and reliable tool for adolescent Chinese patients with BPD.

Alterations in the global brain gray matter volume (gGMV) and global functional connectivity density (gFCD) play a pivotal role in the cognitive impairment and further deterioration in schizophrenia. This study aimed to assess the correlation between alterations in the gGMV and gFCD at baseline (ΔgGMV and ΔgFCD), and the subsequent alterations of cognitive function in schizophrenia patients after 2-year antipsychotic treatment. Global-brain magnetic resonance imaging scans were acquired from 877 drug-naïve, first-episode schizophrenia patients at baseline and after two years of antipsychotic treatment with adequate dosage and duration, and 200 healthy controls. According to ΔgGMV at baseline, schizophrenia patients were divided into mild, moderate, and severe alteration groups. The MATRICS consensus cognitive battery and Global Deficit Score (GDS) were used to assess cognitive impairment. We found that ΔgGMV and ΔgFCD at baseline were significantly correlated with the severity of the cognitive deterioration (ΔGDS). The correlation coefficient indicated a significant positive correlation between baseline ΔgFCD and subsequent cognitive deterioration, with a relatively stronger relation in the mild alteration group (r = 0.31). In addition, there was a significant positive correlation between baseline ΔgGMV and subsequent cognitive deterioration, with a stronger relation in the moderate and severe alteration groups (r = 0.303; r = 0.302, respectively). Our results showed that ΔgGMV and ΔgFCD are correlated with the severity of cognitive deterioration after completion of a 2-year antipsychotic treatment in schizophrenia patients. These findings suggest that baseline alterations in gGMV and gFCD hold potential for predicting subsequent cognitive decline in schizophrenia.

The occurrence of heavy menstrual bleeding (HMB) induced by pharmacological agents has been reported in young adult women. This study aimed to investigate a possible association between the occurrence rates of HMB and different treatment methods such as antidepressant agents alone and in combination with other pharmacological agents. The examined cohort included young women (age 18–35 years, n = 1,949) with bipolar disorder (BP) or major depressive disorder (MDD). Menstruation history for 24 months was recorded and evaluated according to pictorial blood loss assessment charts of HMB. Multivariate analyses were conducted to determine odds ratios (ORs) and 95% confidence intervals. The examined antidepressant agents had varying ORs for patients with BP vs. those with MDD. For example, the ORs of venlafaxine-induced HMB were 5.27 and 4.58 for patients with BP and MDD, respectively; duloxetine-induced HMB, 4.72 and 3.98; mirtazapine-induced HMB, 3.26 and 2.39; fluvoxamine-induced HMB, 3.11 and 2.08; fluoxetine-induced HMB, 2.45 and 1.13; citalopram-induced HMB, 2.03 and 1.25; escitalopram-induced HMB, 1.85 and 1.99; agomelatine-induced HMB, 1.45 and 2.97; paroxetine-induced HMB, 1.19 and 1.75; sertraline-induced HMB, 0.88 and 1.13; reboxetine-induced HMB, 0.45 and 0.45; and bupropion-induced HMB, 0.33 and 0.37, in each case. However, when antidepressant agents were combined with valproate, the OR of HMB greatly increased, with distinct profiles observed for patients with BP vs. those with MDD. For example, the ORs of HMB induced by venlafaxine combined with valproate were 8.48 and 6.70 for patients with BP and MDD, respectively; for duloxetine, 5.40 and 4.40; mirtazapine, 5.67 and 3.73; fluvoxamine, 5.27 and 3.37; fluoxetine, 3.69 and 4.30; citalopram, 5.88 and 3.46; escitalopram, 6.00 and 7.55; agomelatine, 4.26 and 5.65; paroxetine, 5.24 and 3.25; sertraline, 4.97 and 5.11; reboxetine, 3.54 and 2.19; and bupropion, 4.85 and 3.46, in each case. In conclusion, some antidepressant agents exhibited potential risks of inducing HMB. Therefore, a combined prescription of antidepressant agents and valproate should be carefully considered for young women with HMB.

Accurate assessment of anxiety disorders and their symptomatology in schizophrenic patients is important for prognosis and treatment. Measuring anxiety on the traditional anxiety assessment scales such as the Hamilton Anxiety Rating (HAMA) Scale or the self-rating depression scale (SAS) is challenging and often considered unsuitable for assessing anxiety symptoms in patients with schizophrenia. The Staden schizophrenia anxiety rating scale (S-SARS) has been shown to reliably measure specified and undifferentiated anxiety in schizophrenia. The present study aims to test the reliability and validity of the S-SARS version, thereby facilitating Chinese psychiatrists in assessing anxiety symptoms in schizophrenic patients. A total of 300 patients meeting ICD-10 diagnostic criteria of schizophrenia were recruited by convenience sampling. We used the exploratory factor analysis (EFA) to evaluate the structural validity of S-SARS and receiver operating characteristic (ROC) curves to acquire the cutoff point of S-SARS to define the severity of anxiety. Internal consistency was assessed using Cronbach's and Krippendorff's α scores. 1-week test-retest reliability was assessed using the intra-class correlation coefficient (ICC). Correlation analysis with HAMA was used to determine the Chinese version of S-SARS criterion validity. We have the following results: Our version of S-SARS showed Cronbach's α score as 0.899, Krippendorff's α as 0.874, and a correlation coefficient of 0.852 between S-SARS and HAMA. The EPA demonstrated that the contribution rate of major factors was 69.45%. All the items of S-SARS were located in one factor and showed a high factor load (0.415–0.837). The correlation coefficient of S-SARS and HAMA was 0.852. Our results indicated that Chinese version of S-SARS showed good constructive validity and reliability. It also showed better criterion validity compared to HAMA. The S-SARS and its Chinese version can thus serve as an effective tool for assessing anxiety symptoms in patients with schizophrenia.

BackgroundThere is no standard effective treatment for schizophrenia-associated cognitive impairment. Efforts to use non-invasive brain stimulation for this purpose have been focused mostly on the frontal cortex, with little attention being given to the occipital lobe.Materials and methodsWe compared the effects of nine intervention strategies on cognitive performance in psychometric measures and brain connectivity measured obtained from functional magnetic resonance imaging analyses. The strategies consisted of transcranial direct current stimulation (t-DCS) or repetitive transcranial magnetic stimulation (r-TMS) of the frontal lobe or of the occipital alone or with adjunct lithium, or lithium monotherapy. We measured global functional connectivity density (gFCD) voxel-wise.ResultsAlthough all nine patient groups showed significant improvements in global disability scores (GDSs) following the intervention period (vs. before), the greatest improvement in GDS was observed for the group that received occipital lobe-targeted t-DCS with adjunct lithium therapy. tDCS of the occipital lobe improved gFCD throughout the brain, including in the frontal lobes, whereas stimulation of the frontal lobes had less far-reaching benefits on gFCD in the brain. Adverse secondary effects (ASEs) such as heading, dizziness, and nausea, were commonly experienced by patients treated with t-DCS and r-TMS, with or without lithium, whereas ASEs were rare with lithium alone.ConclusionThe most effective treatment strategy for impacting cognitive impairment and brain communication was t-DCS stimulation of the occipital lobe with adjunct lithium therapy, though patients often experienced headache with dizziness and nausea after treatment sessions.

Bipolar disorder (BD) is associated with a high risk of suicide. We used proton magnetic resonance spectroscopy (1H-MRS) to detect biochemical metabolite ratios in the bilateral prefrontal white matter (PWM) and hippocampus in 32 BD patients with suicidal ideation (SI) and 18 BD patients without SI, identified potential brain biochemical differences and used abnormal metabolite ratios to predict the severity of suicide risk based on the support vector machine (SVM) algorithm. Furthermore, we analyzed the correlations between biochemical metabolites and clinical variables in BD patients with SI. There were three main findings: (1) the highest classification accuracy of 88% and an area under the curve of 0.9 were achieved in distinguishing BD patients with and without SI, with N-acetyl aspartate (NAA)/creatine (Cr), myo-inositol (mI)/Cr values in the bilateral PWM, NAA/Cr and choline (Cho)/Cr values in the left hippocampus, and Cho/Cr values in the right hippocampus being the features contributing the most; (2) the above seven features could be used to predict Self-rating Idea of Suicide Scale scores (r = 0.4261, p = 0.0302); and (3) the level of neuronal function in the left hippocampus may be related to the duration of illness, the level of membrane phospholipid catabolism in the left hippocampus may be related to the severity of depression, and the level of inositol metabolism in the left PWM may be related to the age of onset in BD patients with SI. Our results showed that the combination of multiple brain biochemical metabolites could better predict the risk and severity of suicide in patients with BD and that there was a significant correlation between biochemical metabolic values and clinical variables in BD patients with SI.

Lithium monotherapy has been proposed to have antidepressant and antimanic effects in patients with bipolar disorder (BP). However, so far, it is lack of evidence to support this proposition. The main aim of this study was to test the hypothesis that lithium bidirectionally regulates depression- and mania-related brain functional abnormalities in patients with BP. We also assessed the effects of lithium, alone and in combination with other pharmacological treatments, on patients' cognitive performance. We enrolled 149 drug-naïve patients with BP; 99 patients experiencing first depressive episodes were allocated randomly to four treatment groups [lithium (DP/Li), lithium with lamotrigine (LTG; DP/Li+LTG), LTG (DP/LTG), and valproate (VPA) with LTG (DP/VPA+LTG)], and 50 experiencing first hypo-manic episodes were allocated to two treatment groups (MA/Li and MA/VPA). For comparative analysis, 60 age-matched healthy individuals were also recruited. Whole-brain global and regional resting-state cerebral blood flow (rs-CBF) and cognitive alterations were examined before and after 12-week treatment. We have the following findings: DP/Li+LTG, and to a lesser extent DP/Li, alleviated the depression-related reduction in rs-CBF. MA/VPA and MA/Li reversed the mania-related elevation of rs-CBF completely and partially, respectively. Lithium alone improved cognitive performance during depressive and manic episodes; other tested treatments have no such effect or worsened cognitive ability. Our results showed that lithium bidirectionally regulates depression- and mania-associated brain functional abnormalities in patients with BP. Lithium monotherapy has a better antimanic effect than VPA, is superior to other tested treatments in improving cognition during the course of BP, and has satisfactory antidepressant effects in patients with BP.

Cognitive impairment is highly prevalent in patients with major psychiatric disorders (MPDs), including schizophrenia (SCZ), bipolar disorder, major depressive disorder, in whom it can be highly disruptive to community functioning and worsen prognosis. Previously, genetic factors and cognitive impairments in MPD patients have been examined mostly in isolated circuits rather than in the whole brain. In the present study, genetic, neuroimaging, and psychometric approaches were combined to investigate the relationship among genetic factors, alterations throughout the brain, and cognitive impairments in a large cohort of patients diagnosed with SCZ, with a reference healthy control (HC) group. Single nucleotide polymorphisms (SNPs) in SCZ-risk genes were found to be strongly related to cognitive impairments as well as to gray matter volume (GMV) and functional connectivity (FC) alterations in the SCZ group. Annotating 136 high-ranking SNPs revealed 65 affected genes (including PPP1R16B, GBBR2, PDE4B, CANCNA1C, SLC12AB, SATB2, MAG12, and SATB2). Only one, a PDE4B SNP (rs1006737), correlated with GMV (r = 0:19 p = 0.015) and FC (r = 0.21, p = 0.0074) in SCZ patients. GMV and FC alterations correlated with one another broadly across brain regions. Moreover, the present data demonstrate three-way SNP-FC-GMV associations in patients with SCZ, thus providing clues regarding potential genetic bases of cognition impairments in SCZ. SNP-FC-GMV relationships correlated with visual learning and reasoning dimensions of cognition. These data provide evidence that SCZ-related cognitive impairments may reflect genetically underlain whole-brain structural and functional alterations.

BackgroundCognitive performance improves clinical outcomes of patients with major psychiatric disorder (MPD), but is impaired by hyperglycemia. Psychotropic agents often induce metabolism syndrome (MetS). The identification of modifiable metabolic risk factors of cognitive impairment may enable targeted improvements of patient care.ObjectiveTo investigate the relationship between MetS and cognitive impairment in young women with MPD, and to explore risk factors.MethodsWe retrospectively studied women of 18–34 years of age receiving psychotropic medications for first-onset schizophrenia (SCH), bipolar disorder (BP), or major depressive disorder (MDD). Data were obtained at four time points: presentation but before psychotropic medication; 4–8 and 8–12 weeks of psychotropic therapy; and enrollment. MATRICS Consensus Cognitive Battery, (MCCB)—based Global Deficit Scores were used to assess cognitive impairment. Multiple logistic analysis was used to calculate risk factors. Multivariate models were used to investigate factors associated with cognitive impairment.ResultsWe evaluated 2,864 participants. Cognitive impairment was observed in 61.94% of study participants, and was most prevalent among patients with BP (69.38%). HbA1c within the 8–12 week-treatment interval was the most significant risk factor and highest in BP. Factors in SCH included pre-treatment waist circumference and elevated triglycerides during the 8–12 weeks treatment interval. Cumulative dosages of antipsychotics, antidepressants, and valproate were associated with cognitive impairment in all MPD subgroups, although lithium demonstrated a protect effect (all P < 0.001).ConclusionsCognitive impairment was associated with elevated HbA1c and cumulative medication dosages. Pre-treatment waist circumference and triglyceride level at 8–12 weeks were risk factors in SCH. Monitoring these indices may inform treatment revisions to improve clinical outcomes.

There has been limited studies examining treatment-induced heavy menstrual bleeding (HMB) in women with severe mental illnesses. The aim of this study was to examine HMB prevalence and HMB-associated factors in young women (18–34 years old) diagnosed with bipolar disorder (BP), major depressive disorder (MDD), or schizophrenia (SCZ) who have full insight and normal intelligence. Eighteen-month menstruation histories were recorded with pictorial blood loss assessment chart assessments of HMB. Multivariate analyses were conducted to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Drug effects on cognition were assessed with the MATRICS Consensus Cognitive Battery (MCCB). HMB prevalence were: BP, 25.85%; MDD, 18.78%; and SCH, 13.7%. High glycosylated hemoglobin (HbA1c) level was a strong risk factor for HMB [BP OR, 19.39 (16.60–23.01); MDD OR, 2.69 (4.59–13.78); and SCZ OR, 9.59 (6.14–12.43)]. Additional risk factors included fasting blood sugar, 2-h postprandial blood glucose, and use of the medication valproate [BP: OR, 16.00 (95%CI 12.74–20.22); MDD: OR, 13.88 (95%CI 11.24–17.03); and SCZ OR, 11.35 (95%CI 8.84–19.20)]. Antipsychotic, antidepressant, and electroconvulsive therapy use were minor risk factors. Pharmacotherapy-induced visual learning impairment was associated with HMB [BP: OR, 9.01 (95%CI 3.15–13.44); MDD: OR, 5.99 (95%CI 3.11–9.00); and SCZ: OR, 7.09 (95%CI 2.99–9.20)]. Lithium emerged as a protective factor against HMB [BP: OR, 0.22 (95%CI 0.14–0.40); MDD: OR, 0.30 (95%CI 0.20–0.62); and SCZ: OR, 0.65 (95%CI 0.33–0.90)]. In SCZ patients, hyperlipidemia and high total cholesterol were HMB-associated factors (ORs, 1.87–2.22). Psychiatrist awareness of HMB risk is concerningly low (12/257, 2.28%). In conclusion, prescription of VPA should be cautioned for women with mental illness, especially BP, and lithium may be protective against HMB.

Depressive disorders are a severe psychiatric and social problem that affect more than 4% of the global population. Depressive disorders have explicit hereditary characteristics; however, the precise driving genetic force behind these disorders has not yet been clearly illustrated. In the present study, we recruited a three-generation Chinese pedigree in which 5 of 17 members had long-term depression. We conducted whole-exome sequencing to identify the genetic mutation profiles of the family, and a list of susceptible genetic variations that were highly associated with depression onset was revealed via multiple omics analysis. In particular, a non-synonymous single nucleotide variation in the oxoglutarate dehydrogenase-like (OGDHL) gene, rs2293239 (p.Asn725Ser), was identified as one of the major driving genetic forces for depression onset in the family. This variant causes an important conformational change in the transketolase domain of OGDHL, thus reducing its binding affinity with the cofactor thiamine pyrophosphate and eventually resulting in the abnormal accumulation of glutamate in the brain. Brain imaging analysis further linked the rs2293239 variant with an enlarged amygdala and cerebellum in depressive family members. In summary, the present study enhances the current genetic understanding of depressive disorders. It also provides new options for prioritizing better clinical therapeutic regimens, as well as identifying a new protein target for the design of highly specific drugs to treat depressive disorders.

Background: In the treatment of patients with bipolar disorder (BP), antidepressant-induced mania is usually observed. The rate of phase switching (from depressive to manic) in these patients exceeds 22%. The exploration of brain activity patterns during an antidepressant-induced manic phase may aid the development of strategies to reduce the phase-switching rate. The use of a murine model to explore brain activity patterns in depressive and manic phases can help us to understandthe pathological features of BP. The novel object recognition preference ratio is used to assess cognitive ability in such models.Objective: To investigate brain Ca2+ activity and behavioral expression in the depressive and manic phases in the same murine model, to aid understanding of brain activity patterns in phase switching in BP.Methods: In vivo two-photon imaging was used to observe brain activity alterations in a murine model in which induce depressive-like and manic-like behaviors were induced sequentially. The immobility time was used to assess depressive-like symptoms and the total distance traveled was used to assess manic-like symptoms.Results: In vivo two-photon imaging revealed significantly reduced brain Ca2+ activity in temporal cortex pyramidal neurons in the depressive phase in mice exposed to chronic unpredictable mild stress compared with naïve controls. The brain Ca2+ activity correlated negatively with the novel object recognition preference ratio within the immobility time. Significantly increased brain Ca2+ activity was observed in the ketamine-induced manic phase. However, this activity did not correlate with the total distance traveled. The novel object recognition preference ratio correlated negatively with the total distance traveled in the manic phase.

ObjectiveAlzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive deterioration of memory and cognition. Mild cognitive impairment (MCI) has been implicated as a prodromal phase of AD. Although abnormal functional connectivity (FC) has been demonstrated in AD and MCI, the clinical differentiation of AD, MCI, and normal aging remains difficult, and the distinction between MCI and normal aging is especially problematic. We hypothesized that FC between the hippocampus and other brain structures is altered in AD and MCI, and that measurement of abnormal FC could have diagnostic utility for the classification of different AD stages.MethodsElderly adults aged 60–85 years were assigned to AD, MCI, or normal control (NC) groups based on clinical criteria. Functional magnetic resonance scanning was completed by 119 subjects. Five dimension reduction/classification methods were applied, using hippocampus-derived FC strengths as input features. Classification performance of the five dimensionality reduction methods was compared between AD, MCI, and NC groups.ResultsFCs between the hippocampus and left insula, left thalamus, cerebellum, right lingual gyrus, posterior cingulate cortex, and precuneus were significantly reduced in AD and MCI. Support vector machine learning coupled with sparse principal component analysis demonstrated the best discriminative performance, yielding classification accuracies of 82.02% (AD vs. NC), 81.33% (MCI vs. NC), and 81.08% (AD vs. MCI).ConclusionHippocampus-seed-based FCs were significantly different between AD, MCI, and NC groups. FC assessment combined with widely used machine learning methods can improve AD differential diagnosis, and may be especially useful to distinguish MCI from normal aging.

Abstract Introduction This study was aimed to determine how different patterns of alcohol consumption drive changes to brain structure and function and their correlation with cognitive impairments in young adult alcohol drinkers. Methods In this study, we enrolled five groups participants and defined as: long‐term abstinence from alcohol (LA), binge drinking (BD), long‐term low dosage alcohol consumption but exceeding the safety drinking dosage (LD), long‐term alcohol consumption of damaging dosage (LDD), and long‐term heavy drinking (HD). All participants underwent magnetic resonance imaging (MRI) and functional MRI (fMRI) to acquire data on brain structure and function, including gray matter volume (GMV), fractional amplitude of low‐frequency fluctuation (fALFF), regional homogeneity (ReHo), functional connectivity (FC), and brain network properties. The cognitive ability was evaluated with the California Verbal Learning Test (CVLT), intelligence quotient (IQ), and short delay free recall (SDFR). Results Compared to LA, GMV significantly decreased in the brain regions in VN, SMN, and VAN in the alcohol‐drinking groups (BD, LD, LDD, and HD). ReHo was significantly enhanced in the brain regions in VN, SMN, and VAN, while fALFF significantly increased in the brain regions in VN and SMN. The number of intra‐ and inter‐modular connections within networks (VN, SMN, sensory control network [SCN], and VAN) and their connections to other modules were abnormally changed. These changes adversely affected cognition (e.g., IQ, CVLT, SDFR). Conclusion Despite the small sample size, this study provides new evidence supporting the need for young people to abstain from alcohol to protect their brains. These findings present strong reasoning for updating anti‐alcohol slogans and guidelines for young people in the future.

This study investigated the role of ErbB4, the schizophrenia susceptibility gene, in synaptogenesis and synaptic transmission and its association with the pathogenesis of schizophrenia. We found that there was no significant difference in the size of inhibitory synapsin Gephyrin clusters in the dendrites of gamma-aminobutyric acid (GABA) neurons in the cultured cortex of ErbB4 knockout (ErbB4−/−) mice and ErbB4+/+ mice. The density and area of PSD-95 clusters in GABA-labelled neurons were not significantly different from those in the control group (p > 0.05). Specific pIkBα labelling of the pyramidal neurons and the axon initiation segments showed that the number of neuronal dendrites and the inhibitory postsynaptic proteins Gephyrin in the ErbB4 knockout group were significantly lower than those in the control group, whereas the size of the Gephyrin cluster remained unchanged. The number and area of the VGAT clusters on the somaclonal and axonal surfaces of the pyramidal neurons were also similar. ErbB4 knockout influenced excitatory synapses in intermediate neuronal cells and inhibitory synapses in pyramidal neurons, however, did not affect the inhibitory synapses in intermediate neuronal cells and excitatory synapses in pyramidal neurons. The number and area of PSD-95 clusters on the neuronal surface were significantly lower than those of the 1NMPP1 group, but the number and area of Gephyrin clusters on the neuronal surface were not changed (p > 0.05). These findings demonstrated that ErbB4 gene had no effect on the inhibitory synapses in interneurons and the excitatory synapses in pyramidal neurons.

Visual cortex functional deficits can be observed in schizophrenia patients and in individuals at high risk of schizophrenia. However, to date, few studies have investigated methods to improve these functional deficits. This study aimed to investigate the pathological change in the primary visual cortex of a prenatal MK-801-induced high-risk mouse model of schizophrenia (HRMMS) and to test the effect of paroxetine on visual cortex activity. Pregnant mice were given a systemic injection of MK-801, and male offspring that did not present schizophrenia-like behaviors in early adulthood were defined as HRMMS. Some of the HRMMS mice were treated with pharmacological agents beginning at 4 weeks of age. After 4 weeks of treatment with risperidone and/or paroxetine, two-photon calcium imaging was performed to analyze the primary visual cortex activity. The sucrose preference test and the prepulse inhibition (PPI) apparatus test were used to assess the cognitive and behavioral performance. HRMMS mice with or without risperidone treatment had impairments in the primary visual cortex as observed by reduced neuronal calcium activity. Risperidone plus paroxetine and paroxetine alone treatments increased the neuronal calcium activity in the primary visual cortex. Notably, the neuronal calcium activity was higher in mice treated with paroxetine alone. Treatment with paroxetine alone also improved the cognitive and behavioral performance better than treatment with risperidone plus paroxetine. Our pioneering animal model showed that treatment with paroxetine alone improves visual cortex impairments in HRMMS mice better than treatment with risperidone plus paroxetine, indicating that antipsychotics cannot normalize visual cortex impairments.

BACKGROUND: To investigate the effects of adjunct ketamine treatment on depressive symptoms and brain activity in chronic treatment-resistant schizophrenia (CTRS) patients with treatment-resistant depressive (TRD) symptoms. METHODS: Calgary Depression Scale for Schizophrenia (CDSS), positive and negative syndrome scale (PANSS), and regional homogeneity (ReHo) results were compared before versus after ketamine treatment in 12 CTRS patients with TRD symptoms. RESULTS: From 7 days to 14 days after the first ketamine administration, CDSS and PANSS total scores were reduced by 63.8% and 12.9%, respectively. By day 21, ReHo values had increased in the main components of the default mode network (DMN) and bilateral orbitofrontal cortex (OFC) after family-wise error correction. ReHo alterations did not correlate with TRD symptom changes. TRD symptoms relapsed by the 21-day time point, while increased ReHo was sustained. No adverse secondary effects (ASEs) necessitating medical intervention occurred. CONCLUSIONS: Adjunct ketamine alleviation of TRD symptoms lasted only a week, whereas increased ReHo in DMN regions and the OFC in CTRS patients was maintained beyond 2 weeks, indicating that adjunct ketamine is not well-suited for CTRS patients with TRD symptoms and that effects on functional activity dissociate from effects on TRD symptoms. This small-sample pilot study provides clues for further research into therapy for TRD symptoms in CTRS patients.

Background: The present study aimed to systematically evaluate three prolactin-sparing antipsychotics for treating schizophrenia. Methods: We performed a meta-analysis of three prolactin-sparing antipsychotics in patients with schizophrenia. Endpoints of interest were the Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions-Severity (CGI-S) and acceptability (all cause discontinuation). Results: A total of 12 trials (2,723 patients) and three drugs (aripiprazole, quetiapine, and ziprasidone) were included. On the PANSS scale, aripiprazole (mean difference [MD]: −6.98, 95% CrI: −12.35, −1.38) was statistically more effective than placebo. When assessed by BPRS, aripiprazole (MD: −9.01, 95% CrI: −15.81, −3.12), quetiapine (MD: −7.13, 95% CrI: −9.78, −4.29) and ziprasidone (MD: −4.97, 95% CrI: 9.96, −0.21) had greater efficacy, when compared to placebo. Regarding CGI-S, quetiapine (MD: −0.55, 95% CrI: −0.82, −0.25) was significantly superior to placebo. In terms of acceptability, aripiprazole (OR: 0.54, 95% CrI: 0.41, 0.73), quetiapine (OR: 0.49, 95% CrI: 0.36, 0.68) and ziprasidone (OR: 0.68, 95% CrI: 0.48, 0.96) were more acceptable than placebo. The benefit risk analysis revealed that quetiapine has the best efficacy and acceptability profile among the three prolactin-sparing antipsychotics. Conclusions: Quetiapine may offer an optimal benefit-risk balance when a prolactin-sparing antipsychotic is indicated.

Background: Cardio-renal profiles are available from cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs).Methods: A comprehensive systematic review of Embase, Medline, Web of Knowledge, and CENTRAL databases was conducted. Randomized controlled cardiovascular outcome trials of type 2 diabetes mellitus (T2DM) patients administered GLP-1 RAs were included. The following primary outcomes were examined: cardiovascular death, major adverse cardiovascular events (MACE), myocardial infarction, stroke, mortality, heart failure, hypoglycemia, pancreatitis, and thyroid carcinoma. Secondary outcomes included: composite kidney outcome, worsening kidney function, macroalbuminuria, and retinopathy.Results: Seven trials involving 56,004 patients and eight interventions were identified. Albiglutide was associated with fewer MACE and myocardial infarction events compared with lixisenatide. Lixisenatide was related to a greater number of stroke events and cardiovascular deaths compared to once-weekly semaglutide and oral semaglutide, respectively. Improved mortality was associated with oral semaglutide compared with once-weekly semaglutide, albiglutide, dulaglutide, exenatide, or lixisenatide. Risks of heart failure, thyroid carcinoma, and pancreatitis were similar among all the treatments. Weighting of the nine primary outcomes identified oral semaglutide as first among the eight treatments examined. Among three of the secondary outcomes, once-weekly semaglutide ranked first. Better composite kidney outcome was observed with once-weekly semaglutide than with dulaglutide or exenatide; once-weekly semaglutide improved macroalbuminuria compared with exenatide or lixisenatide; and albiglutide, exenatide, and placebo was associated with fewer cases of retinopathy compared with once-weekly semaglutide. Meanwhile, kidney function was less likely to worsen with dulaglutide than with lixisenatide or placebo.Conclusion: Semaglutide should be considered when GLP-1 RAs are indicated for T2DM patients.

This study aimed to investigate the safety and efficacy of high-dose vitamin B6 (vB6) as an adjunct treatment for antipsychotic-induced hyperprolactinemia (AIHP) in male patients with treatment-resistant schizophrenia (TRS). In this randomized double-blinded controlled study, patients were randomized (1:1) into a control group given aripiprazole (ARI; 10 mg/day; n = 100) or an intervention group given vB6 (300 mg/12 h for 16 weeks; n = 100). Prolactin levels, psychotic symptoms [Positive and Negative Syndrome Scale (PANSS)], cognitive function [MATRICS Consensus Cognitive Battery (MCCB)], liver function, kidney function, growth hormone level, micronutrient levels, blood lipids, and adverse secondary effects (ASEs)[Treatment Emergent Symptom Scale (TESS) and Barnes-Akathisia scale] were monitored. After a 16-week treatment period, the vB6 group showed a 68.1% reduction in serum prolactin levels (from 95.52 ± 6.30 μg/L to 30.43 ± 18.65 μg/L) while the ARI group showed only a 37.4% reduction (from 89.07 ± 3.59 μg/L to 55.78 ± 7.39 μg/L). During weeks 1–4, both treatments reduced prolactin similarly. Subsequently, the ARI effect plateaued, while the vB6 effect remained robust. The vB6 group showed better alleviation of psychotic symptoms and cognitive impairment. No serious ASEs were observed; ASEs were more frequent in the ARI group. AIHP reduction efficacy of vB6 was associated with baseline prolactin and triglyceride levels, total vB6 dosage, and education level. In conclusion, compared with the ARI group, TRS patients given vB6 showed better attenuation of AIHP, lower ASE scores, and greater improvements in clinical symptoms and cognitive impairments. These results support further consideration of vB6 as a putative treatment for AIHP.Trial Registration: ChiCTR1800014755

Abstract Introduction Patients with schizophrenia frequently present with visual disturbances including hallucination, and this symptom is particularly prevalent in individuals with comorbid depressive disorders. Currently, little is known about the neurobiological mechanisms of such psychiatric symptoms, and few explanations for the co‐occurrence of schizophrenia, depression, and visual disturbances are available. Methods In this study, we generated a mouse schizophrenia model in which depressive symptoms were also induced. We adopted in vivo two‐photon calcium imaging and ex vivo electrophysiological recording of the primary visual cortex to reveal the synaptic transmission and neural activity in the mouse schizophrenia model. Results In vivo two‐photon calcium imaging and ex vivo electrophysiological recording of the primary visual cortex revealed impaired synaptic transmission and abnormal neural activity in the schizophrenia model, but not in the depression model. These functional deficits were most prominent in the combined schizophrenia and depression model. Conclusion Overall, our data support a mechanism by which the visual cortex plays a role in visual disturbances in schizophrenia.

Background: Bipolar disorder is a serious mental disease marked by episodes of depression, mania, hypomania, or mixed states. Patients with bipolar disorder may present with different symptoms at first onset. The aim of this study is to compare demographic and clinical variables based on a patient's first episode of bipolar disorder, including risk of recurrence over a 2-year period.Methods: A large cohort (N = 742) of patients with bipolar disorder in China was analyzed. Patients were divided into two groups according to their first episode of bipolar disorder, either depression or mania. Patients in mixed state first episode were classified based on predominant symptoms. Three hundred eighteen patients of the cohort had a first episode of mania and 424 patients had initial symptoms of depression. Demographic and clinical data were collected. All patients were followed up for 24 months. Data on compliance with follow-up appointments and recurrence of symptoms after 6, 12, 18, and 24 months were collected. Clinical characteristics (course of disease, age of onset, psychiatric family history, etc.) were compared between the mania group and depression groups.Results: More patients with bipolar disorder had a first episode of depression than mania (57.14 vs. 42.86%). Compared with the depression group, the mania group had later age of diagnosis of bipolar disorder [(38.64 ± 13.50) vs. (36.34 ± 14.94), P = 0.028], lower education level [(9.37 ± 4.34) vs. (10.17 ± 4.81), P = 0.017] and longer latency between an initial episode of psychiatric symptoms and formal bipolar diagnosis [(10.80 ± 10.76) vs. (8.85 ± 9.90), P = 0.012]. More patients in the mania group were male and without psychotic symptoms (all P < 0.05). In comparison with the mania group, more patients in the depression group were female, with higher frequency of a reported precipitating event before first mood episode (all P < 0.05). Compared with the depression group, the mania group had more recurrences of illness at the end of 12 months (Z =-2.156, P = 0.031), 18 months (Z =-2.192, P = 0.028), and 24 months (Z = −2.364, P = 0.018).Conclusions: In our study, there are a number of differences in demographic and clinical characteristics of patients with different onset syndromes of bipolar disorder. These differences include gender, education level, diagnosis age, the rate of recurrences, and others. These data of a cohort of Chinese patients add to the growing international literature on the relationship between index episode of bipolar disorder and clinical variables and outcomes. These results and further study may allow clinicians to offer patients and families more reliable prognostic information at the onset of disease.

Abstract Background Data on differences in brain features between monozygotic (MZ) twins with and without schizophrenia are scarce. Methods We compared brain features of female MZ twins with and without first‐episode schizophrenia and healthy controls (n = 20 each). Voxel‐based morphometry and tract‐based spatial statistics were used to analyze differences in brain structure. Whole‐brain effective connectivity (EC) and functional connectivity (FC) networks were constructed using resting‐state functional magnetic resonance imaging (rs‐fMRI) data. Results Female twins with schizophrenia exhibited abnormal gray matter volume (GMV) in the basal ganglia and prefrontal and parietal cortices, impairments in the arcuate fasciculus, and significant disruptions (primarily decreases) in nine EC networks. They exhibited rs‐EC alterations involving the limbic areas and subcortex. Combined rs‐EC and rs‐FC data distinguished twins with first‐episode schizophrenia with high accuracy. Combined consideration of structural and functional features enabled the distinction of female MZ twins with schizophrenia from those without schizophrenia and healthy controls with 100% accuracy. Conclusions Female MZ twins with schizophrenia exhibited increased GMV, white matter impairment, and disruptions in EC and FC networks. The combination of rs‐EC + rs‐FC data could distinguish female twins with schizophrenia from twins without schizophrenia and healthy controls with 97.4% accuracy, and the addition of structural brain features yielded a 100% accuracy rate. These findings may provide pivotal insight for further study of the mechanisms underlying schizophrenia.

Abstract Background Auditory verbal hallucinations (AVHs) and depressive symptoms are highly prevalent in schizophrenia, and recent progress has been made in understanding the reciprocal deterioration of both symptoms through structural and functional brain imaging studies. To date, there is limited literature on this topic. In this review, we synthesized the recent literature on the neuroimaging features of schizophrenia patients with concurrent AVHs and depressive symptoms. Methods A literature search was conducted with the major databases using the keywords, mainly including schizophrenia, AVHs, depression, neuropsychiatric disorders, brain imaging, and magnetic resonance imaging. Results The existing studies have shown that AVHs and depressive symptoms reciprocally deteriorate in patients with schizophrenia, which has challenged the conventional treatment of the disease. Interestingly, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) therapies have emerged as two efficacious brain stimulation treatments that can normalize the brain regions associated with the symptoms, as shown through functional and structural brain imaging studies. In light of these important findings, there is an urgent need to conduct in‐depth neuronal mechanistic studies to identify targets for stimulation therapy. Conclusions These new findings may elucidate the pathological mechanisms underlying schizophrenia with concurrent AVHs and depressive symptoms. Furthermore, this review has important clinical implications for developing novel therapeutic strategies to alleviate the reciprocal deterioration AVHs and depressive symptoms of schizophrenia patients.

Objective This study was performed to investigate the effects and associated global functional connectivity density (gFCD) alterations associated with the use of atypical antipsychotics in healthy individuals with auditory verbal hallucinations (Hi-AVHs) using gFCD mapping techniques. Methods A magnetic resonance imaging database of 38 Hi-AVHs with chronic or severe AVH symptoms was generated. The Hi-AVHs were administered an atypical antipsychotic (risperidone) for 24 weeks and monitored for a treatment response. All patients underwent functional magnetic resonance imaging pre- and post-treatment. Results gFCD alterations were found in the auditory-memory-language and visual circuit regions pre- and post-treatment. However, gFCD alterations differed between patients with strong and weak treatment responses. Conclusion This is the first report to show that atypical antipsychotics can improve the symptoms of AVHs and that the treatment effects are associated with gFCD alterations in the auditory-memory-language circuit. These findings provide a foundation for future exploration of new treatment strategies for Hi-AVHs.

Abstract Introduction While the psychiatric benefits of ketamine have been verified through clinical trials, there is limited information about ketamine augmentation in patients with treatment‐resistant bipolar depression (TRBPD). Hence, in the present study, we investigate the therapeutic efficacy and functional brain alterations associated with multi‐infusion ketamine augmentation in patients with TRBPD. Methods The present three‐week study included 38 patients with TRBPD, all of whom received a series of nine ketamine injections over the study period. The Hamilton Depression Rating Scale (HAMD) was used to assess the effects of multi‐infusion ketamine combined with mood stabilizers. Brain function was evaluated by global functional connectivity density (gFCD). Results Adjunctive treatment with multiple infusions of ketamine, when combined with a mood stabilizer, could effectively alleviate depressive symptoms for one week, yet the symptoms began to relapse during the second week. Functional brain alterations were detected via gFCD. Specifically, gFCD reductions were mainly found in the bilateral insula, right caudate nucleus, and bilateral inferior frontal gyrus, while increased gFCD was mainly located in the bilateral postcentral gyrus, subgenual anterior cingulate cortex, bilateral thalamus, and cerebellum. Although gFCD alterations were sustained for up to three weeks after the first ketamine infusion, the antidepressant effects of ketamine augmentation sharply declined from the end of the second week of treatment. Conclusions Multi‐infusion ketamine augmentation can rapidly alleviate depressive symptoms in patients with TRBPD. The clinical effects were primarily visible in the first week after treatment and partially sustained for two weeks; however, the therapeutic effects and related functional brain alterations sharply decreased from the end of the second week. Based on these findings, we demonstrated that the clinical efficacy and functional brain alterations induced by ketamine augmentation are transient.

Objective To explore concomitant neuroimaging and genetic alterations in patients with schizophrenia with or without auditory verbal hallucinations (AVHs), and to discuss the use of pattern recognition techniques in the development of an objective index that may improve diagnostic accuracy and treatment outcomes for schizophrenia. Methods The pilot study included patients with schizophrenia with AVHs (SCH-AVH group) and without AVHs (SCH-no AVH group). High throughput sequencing (HTS) was performed to explore RNA networks. Global functional connectivity density (gFCD) analysis was performed to assess functional connectivity (FC) alterations of the default mode network (DMN). Quantitative long noncoding (lnc) RNA and mRNA expression data were related to peak T values of gFCDs using Pearson’s correlation coefficient analysis. Results Compared with the SCH-no AVH group ( n = 5), patients in the SCH-AVH group ( n = 5) exhibited differences in RNA expression in RNA networks that were related to AVH severity, and displayed alterations in FC (reflected by gFCD differences) within the DMN (posterior cingulate and dorsal-medial prefrontal cortex), and in the right parietal lobe, left occipital lobe, and left temporal lobe. Peak lncRNA expression values were significantly related to peak gFCD T values within the DMN. Conclusion Among patients with schizophrenia, there are concomitant FC and genetic expression alterations associated with AVHs. Data from pattern recognition studies may inform the development of an objective index aimed at improving early diagnostic accuracy and treatment planning for patients with schizophrenia with and without AVHs.

Objectives Anxiety has been suggested to be associated with poor outcomes in patients with acute coronary syndrome (ACS). However, results of previous follow-up studies were inconsistent. The aim of this meta-analysis was to evaluate the association between anxiety and clinical outcomes in patients with ACS, and to investigate the potential role of depression underlying the above association.Design A meta-analysis of prospective follow-up studies.Setting Hospitals.Participants Patients with ACS.Interventions We included related prospective follow-up studies up through 20 July 2019 that were identified by searching PubMed and Embase databases. A random-effect model was used for the meta-analysis. Anxiety was evaluated by validated instruments at baseline.Primary and secondary outcome measures We determined the association between anxiety and risks of mortality and adverse cardiovascular events (MACEs) in patients with ACS.Results Our analysis included 17 studies involving 39 038 patients wqith ACS. Anxiety was independently associated with increased mortality risk (adjusted risk ratio (RR) 1.21, 95% CI 1.07 to 1.37, p=0.002) and MACEs (adjusted RR 1.47, 95% CI 1.24 to 1.74, p

Abstract Objectives To investigate the neuroimaging characteristics of auditory verbal hallucinations (AVHs) in patients with bipolar disorder (BP) experiencing depressive episodes with and without AVHs, and alterations in those characteristics after transcranial direct current stimulation (tDCS). Methods For a baseline pilot study, we recruited 80 patients with BP and depressive status (40 with and 40 without AVHs), and 40 healthy controls (HCs). Their global functional connectivity density (gFCD) was screened by functional magnetic resonance imaging (fMRI). Voxel‐wise one‐way analysis of covariance (ANCOVA) was conducted to detect intergroup differences in gFCD. In a follow‐up study, the effects of 5 weeks of tDCS augmentation treatment on clinical symptoms and gFCD were assessed in the 40 BP patients with AVHs. Results Compared to HCs, BP patients with and without AVHs exhibited increased gFCD in the central parietal lobe, insular lobe, and middle cingulate cortex, with decreased gFCD in the posterior parietal cortex, lateral prefrontal cortex, and occipital lobe (all bilateral). Only patients with AVHs showed increased gFCD in the Broca and Wernicke regions, and decreased gFCD in the hippocampus (all bilateral). After 5 weeks of tDCS, AVHs were slightly alleviated and gFCD abnormalities in the hippocampus were mildly attenuated. Conclusions Patients with BP and AVHs showed disturbances in the brain's communication capacity mainly in the left frontoparietal network, control network, and memory circuitry. Five weeks of tDCS alleviated AVHs slightly, without improving depressive symptoms, and attenuated hippocampal gFCD alterations in these patients.

Abstract Introduction Schizophrenia patients often experience auditory hallucinations (AHs) and visual hallucinations (VHs). However, the degree and type of brain and retinal alterations associated with combined AHs and VHs in schizophrenia patients remain unknown. There is an urgent need for a study that investigates the trajectory of brain and retinal alterations in patients with first‐episode untreated schizophrenia accompanied by combined AHs and VHs (FUSCHAV). Methods FUSCHAV patients (n = 120), divided into four groups according to AH and VH symptom severity (severe AHs combined with severe VHs [FUSCHSASV, 20 patients]; middle‐to‐moderate AHs combined with severe VHs [FUSCHMASV, 23 patients]; severe AHs combined with middle‐to‐moderate VHs [FUSCHSAMV, 28 patients]; and middle‐to‐moderate AHs combined with middle‐to‐moderate VHs [FUSCHMAMV, 26 patients]), were compared to healthy controls (n = 30). Gray matter volume (GMV) was adopted for brain structural alteration assessment. Total retinal thickness was adopted as a measure of retinal thickness impairment. Results In the pilot study, the rate of GMV reduction showed an inverted U‐shaped pattern across the different FUSCHAV patient groups according to AH and VH severity. The degree of retinal impairment remained stable across the groups. More notably, in the secondary follow‐up study, we observed that, after 6 months of treatment with antipsychotic agents, all the GMV reduction‐related differences across the different patient groups disappeared, and both GMV and retinal thickness demonstrated a tendency to deteriorate. Conclusions These findings indicate the need for heightened alertness on brain and retinal impairments in patients with FUSCHAV. Further deteriorations induced by antipsychotic agent treatment should be monitored in clinical practice.

Abstract Objective To explore shared brain structural alterations in patients diagnosed with mental disorders who experience own‐thought auditory verbal hallucinations (OTAVHs). Methods A cohort of 143 first‐diagnosis, nonmedicated patients with OTAVHs was enrolled: 25 with schizophrenia (FUSCH‐OTAVH), 20 with major depression disorder (FUMDD‐OTAVH), 28 with bipolar disorder (FUBD‐OTAVH), 22 patients with posttraumatic stress disorder (FUPTSD‐OTAVH), 21 with anxiety disorder (FUAD‐OTAVH), and 27 with borderline personality disorder (FUBPD‐OTAVH); 25 healthy controls (HCs) participated. The Auditory Hallucinations Rating Scale (AHRS), multiple psychometric scales, voxel‐based morphometry (VBM), tract‐based spatial statistics (TBSS), and multiple regression were used. Results Compared with HCs, patients had increased occipital cortex, dorsal prefrontal cortex (PFC), and striatum gray matter volumes (GMVs), a reduced insular cortex (IC) GMV, and an impaired frontooccipital fasciculus. The following differences were found versus HCs: FUSCH‐OTAVH, reduced PFC and occipital GMVs, increased striatum and thalamus GMVs, impaired arcuate fasciculus, u‐shaped bundle, optic tract, and upper longitudinal fasciculus (LF); FUMDD‐OTAVH, increased posterior frontotemporal junction and hippocampus GMVs; FUMN‐OTAVH, increased posterior frontotemporal junction and parietal cortex GMVs, reduced hippocampus GMV, impaired upper LF; FUPTSD‐OTAVH, increased temporal, hippocampus, and nucleus accumbens GMVs; FUBPD‐OTAVH, increased frontotemporal junction and hippocampus GMVs, impaired upper/lower LF; and FUAD‐OTAVH, increased frontal and temporal cortex, hippocampus GMVs. Conclusions The present findings provide evidence consistent with a bottom‐up and top‐down reciprocal action dysfunction hypothesis of AVHs and with the dopamine hypothesis of AVHs. We observed specific features related to OTAVHs in patients with different mental disorders. The findings, though complex, provide clues for further studies of specific mental disorders.

Comorbid depressive disorders confound the diagnosis and therapy of schizophrenia. Using a murine model incorporating both MK801 and chronic unpredictable mild stress exposures, we successfully replicated both psychosis and depression. Ex vivo patch clamp recordings and in vivo calcium imaging demonstrated impaired neural activity in the prefrontal cortex (PFC). We then administered triple-drug combinations consisting of two antidepressants (mirtazapine and venlafaxine) plus an antipsychotic (either clozapine or olanzapine), and found improved PFC neuronal activity and performance in behavioral assays. Moreover, the addition of metformin to both psychotropic drug combinations brought further improvements in depressive and schizophrenic-like behaviors and physiological parameters. In summary, our data modeled the neuropathophysiology of schizophrenia with comorbid depression, and may inform drug intervention strategies.

Abstract Objective To investigate the effects of adjunct ketamine treatment on chronic treatment‐resistant schizophrenia patients with treatment‐resistant depressive symptoms (CTRS‐TRD patients), including alterations in brain function. Methods Intravenous ketamine (0.5 mg/kg body weight) was administered to CTRS‐TRD patients over a 1‐hr period on days 1, 4, 7, 10, 13, 16, 19, 22, and 25 of our initial pilot study. This treatment method was subsequently repeated 58 days after the start of the pilot study for a secondary follow‐up study. Calgary Depression Scale for Schizophrenia (CDSS), Positive and Negative Syndrome Scale (PANSS), and regional homogeneity (ReHo) results were used to assess treatment effects and alterations in brain function throughout the entire duration of our studies. Results Between day 7 and day 14 of the first treatment, CDSS scores were reduced by 63.8% and PANSS scores were reduced by 30.04%. In addition, ReHo values increased in the frontal, temporal, and parietal lobes. However, by day 21, depressive symptoms relapsed. During the second treatment period, CDSS and PANSS scores exhibited no significant differences compared to baseline between day 58 and day 86. On day 65, ReHo values were higher in the temporal, frontal, and parietal lobes. However, on day 79, the increase in ReHo values completely disappeared. Conclusions Depressive symptoms in CTRS‐TRD patients were alleviated with adjunct ketamine treatment for only 1 week during the first treatment period. Moreover, after 1 month, the antidepressant effects of ketamine on CTRS‐TRD patients completely disappeared. Correspondingly, ReHo alterations induced by ketamine in the CTRS‐TRD patients were not maintained for more than 3 weeks. These pilot findings indicate that adjunct ketamine treatment is not satisfactory for CTRS‐TRD patients.