Biomarkers of bipolar disorder based on metabolomics: A systematic review.

Bipolar disorder (BD) is a severe affective disorder characterized by recurrent episodes of depression or mania/hypomania, which significantly impair cognitive function, life skills, and social abilities of patients. There is little understanding of the neurobiological mechanisms of BD. The diagnosis of BD is primarily based on clinical assessment and psychiatric examination, highlighting the urgent need for objective markers to facilitate the diagnosis of BD. Metabolomics can be used as a diagnostic tool for disease identification and evaluation. This study summarized the altered metabolites in BD and analyzed aberrant metabolic pathways, which might contribute to the diagnosis of BD. Search of PubMed and Web of science for human BD studies related to metabolism to identify articles published up to November 19, 2022 yielded 987 articles. After screening and applying the inclusion and exclusion criteria, 16 untargeted and 11 targeted metabolomics studies were included. Pathway analysis of the potential differential biometabolic markers was performed using the Kyoto encyclopedia of genes and genomes (KEGG). There were 72 upregulated and 134 downregulated biomarkers in the untargeted metabolomics studies using blood samples. Untargeted metabolomics studies utilizing urine specimens revealed the presence of 78 upregulated and 54 downregulated metabolites. The targeted metabolomics studies revealed abnormalities in the metabolism of glutamate and tryptophan. Enrichment analysis revealed that the differential metabolic pathways were mainly involved in the metabolism of glucose, amino acid and fatty acid. These findings suggested that certain metabolic biomarkers or metabolic biomarker panels might serve as a reference for the diagnosis of BD.

Empathy deficit in male patients with schizophrenia and its relationships with impulsivity and premeditated violence.

Objective: To explore the pattern of empathy characteristics in male patients with schizophrenia (SCH) and to examine whether empathy deficit is associated with impulsivity and premeditated violence. Methods: One hundred and fourteen male SCH patients were enrolled in this study. The demographic data of all patients were collected and the subjects were divided into two groups, namely, the violent group, including 60 cases, and the non-violent group, comprising 54 cases, according to the Modified Overt Aggression Scale (MOAS). The Chinese version of the Interpersonal Reactivity Index-C (IRI-C) was used to evaluate empathy and the Impulsive/Predicted Aggression Scales (IPAS) was employed to assess the characteristics of aggression. Results: Among the 60 patients in the violent group, 44 patients had impulsive aggression (IA) and 16 patients had premeditated aggression (PM) according to the IPAS scale. In the violent group, the scores of the four subfactors of the IRI-C, i.e., perspective taking (PT), fantasy (FS), personal distress (PD), and empathy concern (EC), were significantly lower than in the non-violent group. Stepwise logistic regression showed that PM was independent influencing factor for violent behaviors in SCH patients. Correlation analysis revealed that EC of affective empathy was positively correlated with PM but not with IA. Conclusion: SCH patients with violent behavior had more extensive empathy deficits compared with non-violent SCH patients. EC, IA and PM are independent risk factors of violence in SCH patients. Empathy concern is an important index to predict PM in male patients with SCH.

Serum Metabolic Profile in Schizophrenia Patients With Antipsychotic-Induced Constipation and Its relationship With Gut Microbiome.

BACKGROUND AND HYPOTHESIS: Antipsychotics (APs), the cornerstone of schizophrenia treatment, confer a relatively high risk of constipation. However, the mechanisms underpinning AP-induced constipation are poorly understood. Thus, we hypothesized that (1) schizophrenia patients with AP-induced constipation have distinct metabolic patterns; (2) there is more than one mechanism at play in producing this adverse drug effect; and (3) AP-associated changes in the gut microbiome are related to the altered metabolic profiles. STUDY DESIGN: Eighty-eight schizophrenia patients, including 44 with constipation (C) and 44 matched patients without constipation (NC), were enrolled in this study. Constipation was diagnosed by Rome IV criteria for constipation and colonic transit time using radiopaque markers (ROMs) while severity was evaluated with the Bristol Stool Form Scale (BSS) and Constipation Assessment Scale (CAS). Fasting blood samples were drawn from all participants and were subjected to non-targeted liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. STUDY RESULTS: Eleven metabolites were significantly altered in AP-induced constipation which primarily disturbed sphingolipid metabolism, choline metabolism, and sphingolipid signaling pathway (P value < .05, FDR < 0.05). In the C group, changes in the gut bacteria showed a certain degree of correlation with 2 of the significantly altered serum metabolites and were associated with alterations in choline metabolism. CONCLUSIONS: Our findings indicated that there were disturbances in distinct metabolic pathways that were associated with AP-induced constipation. In addition, this study presents evidence of a link between alterations in the gut microbiome and host metabolism which provides additional mechanistic insights on AP-induced constipation.

Exosomes in schizophrenia: Pathophysiological mechanisms, biomarkers, and therapeutic targets.

While schizophrenia (SCZ) is a devastating psychiatric disorder that detrimentally affects a significant portion of the worldwide population, its diagnosis is traditionally based on a relatively subjective assessment of current symptoms and medical history, devoid of an objective diagnostic modality. Antipsychotic medications are commonly used in the treatment of SCZ; however, some patients have low remission rates or forsake treatment due to the associated multiple side effects, resulting in recurrent episodes of the disease and poor prognosis. These situations imply that the diagnosis, treatment, and prognosis of SCZ need to be improved to increase the odds of a better outcome. Mounting studies have found that extracellular vesicles (EVs) play essential roles in the central nervous system. They are implicated in several mechanisms closely associated with SCZ such as cellular communication and synaptic plasticity. They can additionally exhibit neuroprotective and therapeutic effects. Since they possess distinct constituents, are readily available, easily detectable, and dependent on the internal environment, they can potentially serve as reliable biomarkers for disease diagnosis. Moreover, their biological configuration along with their ability to increase the bioavailability of their constituents and modulate intricate intracellular reactions in target cells, propel EVs as new targets for treatment. This review paper summarizes relevant research pertaining to the roles of EVs in SCZ, with the aim of improving insights into SCZ pathogenesis and evaluating EVs as potential biomarkers in the diagnosis and treatment of SCZ.

Suicidality in the geriatric population.

Suicide in older adults is a major global concern in both public and mental health. With an ageing population on the rise, a surge in suicidal deaths is predicted in the coming years. The objectives of this paper are to review the risk factors, protective factors, assessment rating scales and current prevention strategies in the geriatric population. The identification of modifiable risk factors and strengthening of protective factors as well as staging according to suicidal ideation, behaviors and/or attempt(s) are necessary to devise appropriate personalized interventions in vulnerable older adults. A history or current psychiatric illness particularly depression, physical illnesses, previous suicide attempt, substance abuse, loneliness, marital status, financial stress, a family history of psychiatric illnesses or suicide in 1st degree relatives and low social support most commonly increase suicidal susceptibility in older adults. Conversely, factors that increase resilience in older adults include a good physical health and cognitive function, religiousness, good quality of life and life satisfaction, ability to perform activities of daily living, marital status, having friends and social connectedness. While the risk factors associated with suicide in the geriatric population are complex and multidimensional in nature, the current preventive strategies have provided no substantial decline in suicidal risk. Therefore, a combination of strategies applied via a multilevel prevention program at a primary, mental healthcare, societal and community level could mitigate suicidal risk. Further research and better preventive measures are warranted to diminish suicidal risk in older adults.

Altered intrinsic default mode network functional connectivity in patients with remitted geriatric depression and amnestic mild cognitive impairment.

OBJECTIVES: Patients with geriatric depression exhibit a spectrum of symptoms ranging from mild to severe cognitive impairment which could potentially lead to the development of Alzheimer's disease (AD). The aim of the study is to assess the alterations of the default mode network (DMN) in remitted geriatric depression (RGD) patients and whether it could serve as an underlying neuropathological mechanism associated with the risk of progression of AD. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 154 participants, comprising 66 RGD subjects (which included 27 patients with comorbid amnestic mild cognitive impairment [aMCI] and 39 without aMCI [RGD]), 45 aMCI subjects without a history of depression (aMCI), and 43 matched healthy comparisons (HC), were recruited. MEASUREMENTS: All participants completed neuropsychological tests and underwent resting-state functional magnetic resonance imaging (fMRI). Posterior cingulate cortex (PCC)-seeded DMN functional connectivity (FC) along with cognitive function were compared among the four groups, and correlation analyses were conducted. RESULTS: In contrast to HC, RGD, aMCI, and RGD-aMCI subjects showed significant impairment across all domains of cognitive functions except for attention. Furthermore, compared with HC, there was a similar and significant decrease in PCC-seed FC in the bilateral medial superior frontal gyrus (M-SFG) in the RGD, aMCI, and RGD-aMCI groups. CONCLUSIONS: The aberrations in rsFC of the DMN were associated with cognitive deficits in RGD patients and might potentially reflect an underlying neuropathological mechanism for the increased risk of developing AD. Therefore, altered connectivity in the DMN could serve as a potential neural marker for the conversion of geriatric depression to AD.

Altered Functional Connectivity of the Nucleus Accumbens Network Between Deficit and Non-deficit Schizophrenia.

Deficit schizophrenia (DS), which is marked by stable negative symptoms, is regarded as a homogeneous subgroup of schizophrenia. While DS patients have structurally altered nucleus accumbens (NAcc) compared to non-deficit schizophrenia (NDS) patients and healthy individuals, the investigation of NAcc functional connectivity (FC) with negative symptoms and neurocognition could provide insights into the pathophysiology of schizophrenia. 58 DS, 93 NDS, and 113 healthy controls (HCs) underwent resting-state functional magnetic resonance (rsfMRI). The right and left NAcc were respectively used as seed points to construct the functional NAcc network in whole-brain FC analysis. ANCOVA compared the differences in NAcc network FC and partial correlation analysis explored the relationships between altered FC of NAcc, negative symptoms and neurocognition. Compared to HCs, both DS and NDS patients showed decreased FC between the left NAcc (LNAcc) and bilateral middle cingulate gyrus, and between the right NAcc (RNAcc) and right middle frontal gyrus (RMFG), as well as increased FC between bilateral NAcc and bilateral lingual gyrus. Moreover, the FC between the LNAcc and bilateral calcarine gyrus (CAL) was lower in the DS group compared to NDS patients. Correlation analysis indicated that FC value of LNAcc-CAL was negatively correlated to negative symptoms. Furthermore, aberrant FC values within the NAcc network were correlated with severity of clinical symptoms and neurocognitive impairments in DS and NDS patients. This study demonstrated abnormal patterns of FC in the NAcc network between DS and NDS. The presence of altered LNAcc-CAL FC might be involved in the pathogenesis of negative symptoms in schizophrenia.

Antipsychotic-Induced Constipation: A Review of the Pathogenesis, Clinical Diagnosis, and Treatment.

Antipsychotic-induced gastrointestinal hypomotility and, in particular, its manifestation of constipation are common adverse effects in patients with schizophrenia in clinical practice. Serious complications of antipsychotic-induced constipation include ileus, ischaemic bowel disease, colon perforation, aspiration pneumonia, and bacterial septicaemia, which can be life threatening if left untreated, especially in patients prescribed clozapine. The aim of this paper is to review the latest research on the epidemiology, clinical examination methods, pathophysiology, and treatment options and preventive measures for antipsychotic-induced constipation. While clinicians are normally aware of the overall side effects caused by antipsychotics, constipation is often an under-recognized condition despite its relatively high incidence and its impact on daily living. The incidence of constipation differs among individual antipsychotics, but more than 50% of patients prescribed antipsychotics suffer from constipation. Limited fluid intake, poor dietary habits, and a sedentary lifestyle can also worsen constipation. The mechanisms of antipsychotic-induced constipation may be antagonism of cholinergic, histaminergic, and serotonergic receptors, with both parent drug and metabolite(s) contributing to the effects on gastrointestinal motility. Numerous methods, mainly divided into scale evaluations and objective examinations, are applied to evaluate antipsychotic-induced constipation; however, objective examinations have a greater ability to identify cases of gastrointestinal hypomotility since there is often an under-reporting of symptoms in subjective reporting and scale evaluation due to a higher pain threshold, an inability to express pain sensations, and a lack of symptom awareness in these patients. Antipsychotic drug-induced constipation should be closely monitored in patients receiving these medications, with timely intervention to avoid serious gastrointestinal consequences. There is currently no consensus on the efficacy of laxatives in these patients. Further in-depth studies should explore the underlying mechanisms and devise optimal therapeutic approaches to minimize constipation during antipsychotic treatment.

Long-term exercise-secreted extracellular vesicles promote browning of white adipocytes by suppressing miR-191a-5p.

AIMS: The purpose of the study is to explore the mechanism of transdifferentiation from white adipose tissue (WAT) to Brown adipose tissue (BAT). MATERIALS AND METHOD: In this study, we established a model of mouse obesity induced by a high-fat diet (HFD) before 30 days of forced exercise or sedentary mice. Then, we isolated extracellular vesicles (EVs) from plasma and identified them by transmission electron microscope, dynamic light scattering and western blot analysis. Body temperature and body weight were utilized for assessment of thermogenesis in vivo. Oil red O staining was used to measure triglyceride in vitro. Luciferase reporter assay was applied for the relationship between miR-191a-5p and Prdm16. KEY FINDINGS: As a result, mice that exercised for a long period time exhibited higher caloric expenditure, better weight maintenance and more WAT browning, as well as better resistance to obesity associated with a high-fat diet, compared to mice that lacked exercise. MircoRNA-191-5p (miR-191-5p) was found to be lowly expressed in the EVs from mice with long-term exercise (Exe-EVs). Functional experiments revealed that Exe-EVs promoted WAT browning by the silencing of miR-191-5p. At the molecular level, siRNA-mediated PRDM16 partly inhibited uncoupling protein-1(UCP-1) expression by miR-191-5p inhibitor in white adipocytes. Here, we observed that the lowly expressed miR-191-5p in Exe-EVs promoted the browning of WAT by negatively targeting the PRDM16-3'-untranslated region (PRDM16-3'UTR), thereby enhancing heat production and reducing obesity. SIGNIFICANCE: MiR-191-5p may serve as a potential target for the identification and treatment of obesity.

Caudothalamic dysfunction in drug-free suicidally depressed patients: an MEG study.

Major depressive disorder (MDD), characterized by low mood or anhedonia, is commonly associated with a greater suicidal susceptibility. There are numerous suicide-related findings pertaining to the dorsolateral prefrontal cortex (DLPFC), caudate nucleus and thalamus, which form a cortico-striato-thalamo-cortical (CSTC) circuit responsible for executive function and working memory. An aberrant CSTC circuitry is hypothesized to be implicated in depressed patients with a high suicidal risk. 27 MDD patients were assessed with the Nurses Global Assessment of Suicide Risk (NGASR), following which 14 patients were classified into a high suicide risk group (NGASR ≥ 12) and 13 patients were assigned to a low suicide risk group (NGASR < 6). All 27 patients were enrolled with 25 healthy controls for resting-state magnetoencephalography (MEG). Cross-frequency coupling (CFC) measured the phase of alpha-band (8-13 Hz) as it modulated to cortical gamma-band (30-48 Hz). There was a significantly lower alpha-to-gamma phase-amplitude coupling (PAC) between the right caudate and left thalamus in high-risk suicide group compared to both the low-risk suicide group and healthy controls. The presence of a weaker coupling between the right caudate and left thalamus is indicative of a caudothalamic abnormality in suicidally depressed patients. This implies that a disruption of CSTC loop could result in executive dysfunction and working memory impairment, leading to an increased suicidal risk in MDD patients. In the future, this preliminary study has the possibility of being replicated on a larger scale, and hence validates caudothalamic dysfunction as a reliable neuroimaging biomarker for suicide in depression.

Age-associated changes of resting energy expenditure, body composition and fat distribution in Chinese Han males.

Age-related alterations in whole body composition, particularly, reduced fat free mass (FFM) and increased fat mass (FM), lead to a progressive decline in resting energy expenditure (REE). Similarly, regional body composition and fat distribution changes with age might also contribute to an overall lower REE. This study investigated the influence of age on REE, regional body composition and fat distribution, including subcutaneous fat (SF) and visceral fat (VF), in a Chinese Han population as well as their contributions to age-related changes in REE. One hundred and two males aged 31-83 years old underwent dual-energy X-ray absorptiometry (DXA) which measured whole body and regional FM and FFM. SF and VF were measured by magnetic resonance imaging (MRI) and REE by indirect calorimetry. Age was significantly negatively correlated with REE (r = -0.37), total FFM (r = -0.25), upper limbs FFM (r = -0.32), lower limbs FFM (r = -0.34) and showed positive association with trunk FFM (ß=0.926). FM, SF and VF decreased in older age groups after an initial rise up to 55-65 years. REE correlated positively to FM, FFM, SF, VF and showed significant association with age (ß = -0.254) independent of age-associated changes in body composition. The regional alterations in body composition with age were explained by changes in trunk FFM (ß = 0.926). Age-related decline in REE were not solely due to alterations in FM and FFM. Therefore, the changes in regional body composition, fat distribution and REE which occur during aging could be explained by disparities in race, ethnicity, diet, physical activity, and lower specific metabolic rates of FFM components.