B-GOS alleviates olanzapine-induced lipid disturbances in mice by enriching Akkermansia and upregulation of PGRMC1-Wnt signaling.

Although olanzapine (OLZ) remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability issues related to its metabolic profile such as weight gain and dyslipidemia. Our previous studies have demonstrated that progesterone receptor membrane component 1 (PGRMC1) plays a key role in antipsychotic-induced metabolic side effects. Prebiotics showed positive effects on lipid metabolism, however, limited studies focused on their therapeutic potential and mechanisms in treating antipsychotic-induced lipid metabolic disorders. Herein, our study aims to explore the effects of the prebiotic B-GOS on lipid disturbances induced by OLZ and elucidate its underlying mechanisms via PGRMC1 pathway. In an 8-week study, long-term intraperitoneal administration of OLZ at a dosage of 8 mg/kg/day in mice induced lipid disturbances as manifested by significantly increased lipid indexes in plasma and liver. B-GOS effectively alleviated the OLZ-induced abnormal lipid metabolism by enhancing the diversity of the gut microbiota, with a 100-fold increase in Akkermansia abundance and a 10-fold decrease in Faecalibaculum abundance. Followed by the B-GOS related changes of gut microbiota, OLZ-induced substantial hepatic inhibition of PGRMC1, and associated protein factors of Wnt signaling pathway (Wnt3a, ß-catenin, and PPAR-γ) were reversed without affecting plasma levels of short-chain fatty acids. Taken together, prebiotics like B-GOS enriching Akkermansia offer a promising novel approach to alleviate antipsychotic-induced lipid disturbances by modulating the PGRMC1-Wnt signaling pathway.

Long non-coding RNAs in schizophrenia: Genetic variations, treatment markers and potential targeted signaling pathways.

Schizophrenia (SZ), a complex and debilitating spectrum of psychiatric disorders, is now mainly attributed to multifactorial etiology that includes genetic and environmental factors. Long non-coding RNAs (lncRNAs) are gaining popularity as a way to better understand the comprehensive mechanisms beneath the clinical manifestation of SZ. Only in recent years has it been elucidated that mammalian genomes encode thousands of lncRNAs. Strikingly, roughly 30-40% of these lncRNAs are extensively expressed in different regions across the brain, which may be closely associated with SZ. The therapeutic and adverse effects of atypical antipsychotic drugs (AAPDs) are partially reflected by their role in the regulation of lncRNAs. This begs the question directly, do any lncRNAs exist as biomarkers for AAPDs treatment? Furthermore, we comprehend a range of mechanistic investigations that have revealed the regulatory roles for lncRNAs both involved in the brain and the periphery of SZ. More crucially, we also combine insights from a variety of signaling pathways to argue that lncRNAs probably play critical roles in SZ via their interactive downstream factors. This review provides a thorough understanding regarding dysregulation of lncRNAs, corresponding genetic alternations, as well as their potential regulatory roles in the pathology of SZ, which might help reveal useful therapeutic targets in SZ.

Diminished treatment response in relapsed versus first-episode schizophrenia as revealed by a panel of blood-based biomarkers: A combined cross-sectional and longitudinal study.

There is a paucity of biomarkers for the prediction of treatment response in schizophrenia. In this study, we aimed to investigate whether diminished antipsychotic treatment response in relapsed versus first-episode schizophrenia can be revealed and predicted by a panel of blood-based biomarkers. A cross-sectional cohort consisting of 655 schizophrenia patients at different episodes and 606 healthy controls, and a longitudinal cohort including 52 first-episode antipsychotic-naïve schizophrenia patients treated with the same antipsychotic drugs during the 5-year follow-up of their first three episodes were enrolled. Plasma biomarker changes and symptom improvement were compared between the drug-free phase of psychosis onset and after 4 weeks of atypical antipsychotic drug (AAPD) treatment. In response to treatment, the extent of changes in the biomarkers of bioenergetic, purinergic, phospholipid and neurosteroid metabolisms dwindled down as number of episode and illness duration increased in relapsed schizophrenia. The changes of creatine, inosine, progesterone, allopregnanolone, cortisol and PE(16:0/22:6) were significantly correlated with the improvement of symptomatology. Inosine and progesterone at baseline were shown to be strong predictive biomarkers of treatment response. The results suggest that AAPD treatment response is diminished in the context of relapse, and our findings open new avenues for understanding the pathophysiology of treatment-resistance schizophrenia.

Olanzapine-induced lipid disturbances: A potential mechanism through the gut microbiota-brain axis.

Objective: Long-term use of olanzapine can induce various side effects such as lipid metabolic disorders, but the mechanism remains to be elucidated. The gut microbiota-brain axis plays an important role in lipid metabolism, and may be related to the metabolic side effects of olanzapine. Therefore, we explored the mechanism by which olanzapine-induced lipid disturbances through the gut microbiota-brain axis. Methods: Sprague Dawley rats were randomly divided into two groups, which underwent subphrenic vagotomy and sham surgery. Then the two groups were further randomly divided into two subgroups, one was administered olanzapine (10 mg/kg/day) by intragastric administration, and the other was administered normal saline by intragastric administration (4 ml/kg/day) for 2 weeks. The final changes in lipid parameters, gut microbes and their metabolites, and orexin-related neuropeptides in the hypothalamus were investigated among the different groups. Results: Olanzapine induced lipid disturbances as indicated by increased weight gain, elevated ratio of white adipose tissue to brown adipose tissue, as well as increased triglyceride and total cholesterol. Olanzapine also increased the Firmicutes/Bacteroides (F/B) ratio in the gut, which was even aggravated by subphrenic vagotomy. In addition, olanzapine reduced the abundance of short-chain fatty acids (SCFAs) metabolism related microbiome and 5-hydroxytryptamine (5-HT) levels in the rat cecum, and increased the gene and protein expression of the appetite-related neuropeptide Y/agouti-related peptide (NPY/AgRP) in the hypothalamus. Conclusion: The abnormal lipid metabolism caused by olanzapine may be closely related to the vagus nerve-mediated gut microbiota-brain axis.

Effect of Probiotic Supplements on Oxidative Stress Biomarkers in First-Episode Bipolar Disorder Patients: A Randomized, Placebo-Controlled Trial.

Background: Currently no study has examined the effects of probiotic administration on the symptoms of anxiety, depression, and mania, as well as their correlations with the biomarkers of oxidative stress in patients with bipolar disorder (BPD). The aim of this study is to determine the effects of probiotic supplementation on plasma oxidative stress-related biomarkers and different domains of clinical symptom in patients suffering from BPD. Methods: Eighty first-episode drug-naive patients with BPD were recruited. The subjects were randomized to receive psychotropic drugs supplementing with either probiotic or placebo and scheduled to evaluate with follow-ups for clinical symptom improvements and changes in the oxidative stress biomarkers. The Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Young Mania Rating Scale were used to assess the clinical symptomatology. The panel of plasma oxidative stress biomarkers were determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) at baseline and for 3 months of follow-up, i.e., at post-treatment month 1, 2, and 3. Results: After 3 months of intervention, decreased levels of plasma lysophosphatidylcholines (LPCs) were found in both placebo and probiotic groups. However, six other oxidative stress biomarkers (i.e., creatine, inosine, hypoxanthine, choline, uric acid, allantoic acid) increased in BPD patients after the two types of therapies. In addition, a positive correlation between changes of LPC (18:0) and YMRS scale was found in BPD patients and this association only existed in the probiotic group. Additionally, the mania symptom greatly alleviated (pretreatment-posttreatment, odds ratio = 0.09, 95%CI = 0.01, 0.64, p= 0.016) in patients who received probiotic supplements as compared with the placebo group. Conclusion: The changes in plasma biomarkers of oxidative stress in patients with BPD have a potential to be trait-like markers, and serve as prognostic indexes for bipolar patients. Daily intakes of probiotics have advantageous effects on BPD patients with certain clinical symptoms, especially manic symptoms. The treatment may be a promising adjunctive therapeutic strategy for BPD patients in manic episode.

Disturbance of neurotransmitter metabolism in drug-naïve, first-episode major depressive disorder: a comparative study on adult and adolescent cohorts.

Neurotransmitter metabolism plays a critical role in the pathophysiology of major depressive disorder (MDD). However, whether the neurotransmitter metabolism in adolescent MDD is differentiated from adult MDD is still elusive. In the current study, plasma concentrations of monoamine and amino acid neurotransmitters as well as their metabolites, including tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), glutamine (GLN), glutamate (GLU) and gamma-aminobutyric acid (GABA), were measured and compared in two cohorts of subjects (adult cohort: 31 first-episode MDD vs. 35 healthy controls; adolescent cohort: 33 first-episode MDD vs. 30 healthy controls). To assess the effects of antidepressant treatment, we also analyzed the concentrations of these indexes pre- and post-treatment in adult and adolescent cohorts. At baseline, the deficits of neurotransmitter metabolism in adult MDD were manifested in all the neurotransmitter systems. In contrast, for adolescent MDD, the dysregulation of neurotransmission was mainly indicated in the catecholaminergic systems. After antidepressant treatment, adult MDD showed increased TRP, KYN, KYNA and GLU levels, together with decreased levels of 5-HIAA and DOPAC. Adolescent MDD illustrated an increased level of 5-HT and decreased levels of TRP and GABA. The improvements of Hamilton total scores correlated with the changes in plasma TRP and the turnover of KYN/TRP after treatment in all MDD patients. However, these correlations were only manifested in the adult MDD rather than in adolescent MDD patients. The findings highlight the shared and distinguished neurotransmitter pathways in MDD and emphasize the different antidepressant responses between adults and adolescents. Potentially, the neurotransmitters above could serve as diagnostic biomarkers and provide a novel pharmacological treatment strategy for MDD.

Reduced erythrocyte membrane polyunsaturated fatty acid levels indicate diminished treatment response in patients with multi- versus first-episode schizophrenia.

Antipsychotic effects seem to decrease in relapsed schizophrenia patients and the underlying mechanisms remain to be elucidated. Based on the essential role of polyunsaturated fatty acids in brain function and the treatment of schizophrenia, we hypothesize that disordered fatty acid metabolism may contribute to treatment resistance in multi-episode patients. We analyzed the erythrocyte membrane fatty acids in 327 schizophrenia patients under various episodes (numbers of patients: first-episode drug naïve 89; 2-3 episodes 110; 4-6 episodes 80; over 6 episodes 48) and 159 age- and gender-matched healthy controls. Membrane fatty acid levels and PANSS scales were assessed at baseline of antipsychotic-free period and one-month of follow-up after treatment. Totally, both saturated and unsaturated fatty acids were reduced at baseline when compared to healthy controls. Subgroup analyses among different episodes indicated that in response to atypical antipsychotic treatment, the membrane fatty acids were only increased in patients within 3 episodes, and this therapeutic effects on omega-3 index were merely present in the first episode. Results of fatty acid ratios suggested that dysregulations of enzymes such as D6 desaturase, D5 desaturase, and elongases for polyunsaturated fatty acids in patients with multi-episode schizophrenia could account for the differences. Additionally, certain fatty acid level/ratio changes were positively correlated with symptom improvement. The alterations of C22:5n3 and omega-3 index, gender, and the number of episodes were significant risk factors correlated with treatment responsiveness. Using targeted metabolomic approach, we revealed the potential mechanisms underlying abnormal fatty acid metabolism responsible for reduced treatment response in patients with multi-episode schizophrenia.

Clozapine Induced Disturbances in Hepatic Glucose Metabolism: The Potential Role of PGRMC1 Signaling.

Newly emerging evidence has implicated that progesterone receptor component 1 (PGRMC1) plays a novel role not only in the lipid disturbance induced by atypical antipsychotic drugs (AAPD) but also in the deterioration of glucose homoeostasis induced by clozapine (CLZ) treatment. The present study aimed to investigate the role of PGRMC1 signaling on hepatic gluconeogenesis and glycogenesis in male rats following CLZ treatment (20 mg/kg daily for 4 weeks). Recombinant adeno-associated viruses (AAV) were constructed for the knockdown or overexpression of hepatic PGRMC1. Meanwhile, AG205, the specific inhibitor of PGRMC1 was also used for functional validation of PGRMC1. Hepatic protein expressions were measured by western blotting. Meanwhile, plasma glucose, insulin and glucagon, HbA1c and hepatic glycogen were also determined by assay kits. Additionally, concentrations of progesterone (PROG) in plasma, liver and adrenal gland were measured by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Our study demonstrated that CLZ promoted the process of gluconeogenesis and repressed glycogenesis, respectively mediated by PI3K-Akt-FOXO1 and GSK3ß signaling via inhibition of PGRMC1-EGFR/GLP1R in rat liver, along with an increase in fasting blood glucose, HbA1c levels and a decrease in insulin and hepatic glycogen levels. Furthermore, through PGRMC1-EGFR/GLP1R-PI3K-Akt pathway, knockdown or inhibition (by AG205) of PGRMC1 mimics, whereas its overexpression moderately alleviates CLZ-induced glucose disturbances. Potentially, the PGRMC1 target may be regarded as a novel therapeutic strategy for AAPD-induced hepatic glucose metabolism disorder.

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders.

Cognitive impairment is a shared abnormality between type 2 diabetes mellitus (T2DM) and many neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease (AD) and schizophrenia. Emerging evidence suggests that brain insulin resistance plays a significant role in cognitive deficits, which provides the possibility of anti-diabetic agents repositioning to alleviate cognitive deficits. Both preclinical and clinical studies have evaluated the potential cognitive enhancement effects of anti-diabetic agents targeting the insulin pathway. Repurposing of anti-diabetic agents is considered to be promising for cognitive deficits prevention or control in these neurodegenerative and neuropsychiatric disorders. This article reviewed the possible relationship between brain insulin resistance and cognitive deficits. In addition, promising therapeutic interventions, especially current advances in anti-diabetic agents targeting the insulin pathway to alleviate cognitive impairment in AD and schizophrenia were also summarized.

A Potential Mechanism Underlying the Therapeutic Effects of Progesterone and Allopregnanolone on Ketamine-Induced Cognitive Deficits.

Ketamine exposure can model cognitive deficits associated with schizophrenia. Progesterone (PROG) and its active metabolite allopregnanolone (ALLO) have neuroprotective effects and the pathway involving progesterone receptor membrane component 1 (PGRMC1), epidermal growth factor receptor (EGFR), glucagon-like peptide-1 receptor (GLP-1R), phosphatidylinositol 3 kinase (PI3K), and protein kinase B (Akt) appears to play a key role in their neuroprotection. The present study aimed to investigate the effects of PROG (8,16 mg kg-1) and ALLO (8,16 mg kg-1) on the reversal of cognitive deficits induced by ketamine (30 mg kg-1) via the PGRMC1 pathway in rat brains, including hippocampus and prefrontal cortex (PFC). Cognitive performance was evaluated by Morris water maze (MWM) test. Western blot and real-time quantitative polymerase chain reaction were utilized to assess the expression changes of protein and mRNA. Additionally, concentrations of PROG and ALLO in plasma, hippocampus and PFC were measured by a liquid chromatography-tandem mass spectrometry method. We demonstrated that PROG or ALLO could reverse the impaired spatial learning and memory abilities induced by ketamine, accompanied with the upregulation of PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway. Additionally, the coadministration of AG205 abolished their neuroprotective effects and induced cognitive deficits similar with ketamine. More importantly, PROG concentrations were markedly elevated in PROG-treated groups in hippocampus, PFC and plasma, so as for ALLO concentrations in ALLO-treated groups. Interestingly, ALLO (16 mg kg-1) significantly increased the levels of PROG. These findings suggest that PROG can exert its neuroprotective effects via activating the PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway in the brain, whereas ALLO also restores cognitive deficits partially via increasing the level of PROG in the brain to activate the PGRMC1 pathway.

Prognostic value of liver and kidney function parameters and their correlation with the ratio of urine-to-plasma paraquat in patients with paraquat poisoning.

Acute paraquat poisoning resulting from multiple organ failure usually has a high mortality rate. Liver and kidney, as the key oranges of paraquat detoxification and elimination, their injuries may suppress toxin excretion and enhance the toxicity of paraquat in other organs and worsen the prognosis. Therefore, we intended to explore the prognostic value of liver and kidney function parameters, and further evaluate their correlation with a more stable index urine-to-plasma paraquat (urine paraquat concentrations/plasma paraquat concentrations) instead of considering paraquat concentrations in plasma or urine alone. The study included 33 patients with acute paraquat poisoning admitted to four centres in China from January 2018 to December 2019. Seventeen patients (10 male/7 female) survived, whereas 16 patients (7 male/9 female, 48.48%) died from paraquat poisoning. Alanine aminotransferase (ALT) and the blood urea nitrogen (BUN) represent liver and kidney function parameters, respectively. The ratio of urine-to-plasma paraquat is negatively correlated with ALT (r = -0.94, P = 0 .02) and BUN (r = -0.82, P = 0.03). For receiver operating characteristic curve (ROC) analysis, ALT, BUN and urine-to-plasma paraquat have an AUC over 0.80. The study shows that the functional indexes of liver and kidney, as well as the ratio of urine-to-plasma paraquat, could be considered for evaluating the extent of organ injury and excretion rate of paraquat.

Gut microbiota: An intermediary between metabolic syndrome and cognitive deficits in schizophrenia.

Gut microbiome interacts with the central nervous system tract through the gut-brain axis. Such communication involves neuronal, endocrine, and immunological mechanisms, which allows for the microbiota to affect and respond to various behaviors and psychiatric conditions. In addition, the use of atypical antipsychotic drugs (AAPDs) may interact with and even change the abundance of microbiome to potentially cause adverse effects or aggravate the disorders inherent in the disease. The regulate effects of gut microbiome has been described in several psychiatric disorders including anxiety and depression, but only a few reports have discussed the role of microbiota in AAPDs-induced Metabolic syndrome (MetS) and cognitive disorders. The following review systematically summarizes current knowledge about the gut microbiota in behavior and psychiatric illness, with the emphasis of an important role of the microbiome in the metabolism of schizophrenia and the potential for AAPDs to change the gut microbiota to promote adverse events. Prebiotics and probiotics are microbiota-management tools with documented efficacy for metabolic disturbances and cognitive deficits. Novel therapies for targeting microbiota for alleviating AAPDs-induced adverse effects are also under fast development.