New role of platelets in schizophrenia: predicting drug response.

Background: Elevated platelet count (PLTc) is associated with first-episode schizophrenia and adverse outcomes in individuals with precursory psychosis. However, the impact of antipsychotic medications on PLTc and its association with symptom improvement remain unclear. Aims: We aimed to investigate changes in PLTc levels following antipsychotic treatment and assess whether PLTc can predict antipsychotic responses and metabolic changes after accounting for other related variables. Methods: A total of 2985 patients with schizophrenia were randomised into seven groups. Each group received one of seven antipsychotic treatments and was assessed at 2, 4 and 6 weeks. Clinical symptoms were evaluated using the positive and negative syndrome scale (PANSS). Additionally, we measured blood cell counts and metabolic parameters, such as blood lipids. Repeated measures analysis of variance was used to examine the effect of antipsychotics on PLTc changes, while structural equation modelling was used to assess the predictive value of PLTc on PANSS changes. Results: PLTc significantly increased in patients treated with aripiprazole (F=6.00, p=0.003), ziprasidone (F=7.10, p<0.001) and haloperidol (F=3.59, p=0.029). It exhibited a positive association with white blood cell count and metabolic indicators. Higher baseline PLTc was observed in non-responders, particularly in those defined by the PANSS-negative subscale. In the structural equation model, PLTc, white blood cell count and a latent metabolic variable predicted the rate of change in the PANSS-negative subscale scores. Moreover, higher baseline PLTc was observed in individuals with less metabolic change, although this association was no longer significant after accounting for baseline metabolic values. Conclusions: Platelet parameters, specifically PLTc, are influenced by antipsychotic treatment and could potentially elevate the risk of venous thromboembolism in patients with schizophrenia. Elevated PLTc levels and associated factors may impede symptom improvement by promoting inflammation. Given PLTc's easy measurement and clinical relevance, it warrants increased attention from psychiatrists. Trial registration number: ChiCTR-TRC-10000934.

Frontostriatal circuitry and the tryptophan kynurenine pathway in major psychiatric disorders.

RATIONALE: An imbalance of the tryptophan kynurenine pathway (KP) commonly occurs in psychiatric disorders, though the neurocognitive and network-level effects of this aberration are unclear. OBJECTIVES: In this study, we examined the connection between dysfunction in the frontostriatal brain circuits, imbalances in the tryptophan kynurenine pathway (KP), and neurocognition in major psychiatric disorders. METHODS: Forty first-episode medication-naive patients with schizophrenia (SCZ), fifty patients with bipolar disorder (BD), fifty patients with major depressive disorder (MDD), and forty-two healthy controls underwent resting-state functional magnetic resonance imaging. Plasma levels of KP metabolites were measured, and neurocognitive function was evaluated. Frontostriatal connectivity and KP metabolites were compared between groups while controlling for demographic and clinical characteristics. Canonical correlation analyses were conducted to explore multidimensional relationships between frontostriatal circuits-KP and KP-cognitive features. RESULTS: Patient groups shared hypoconnectivity between bilateral ventrolateral prefrontal cortex (vlPFC) and left insula, with disorder-specific dysconnectivity in SCZ related to PFC, left dorsal striatum hypoconnectivity. The BD group had higher anthranilic acid and lower xanthurenic acid levels than the other groups. KP metabolites and ratios related to disrupted frontostriatal dysconnectivity in a transdiagnostic manner. The SCZ group and MDD group separately had high-dimensional associations between KP metabolites and cognitive measures. CONCLUSIONS: The findings suggest that KP may influence cognitive performance across psychiatric conditions via frontostriatal dysfunction.

Association of elevated levels of peripheral complement components with cortical thinning and impaired logical memory in drug-naïve patients with first-episode schizophrenia.

Schizophrenia has been linked to polymorphism in genes encoding components of the complement system, and hyperactive complement activity has been linked to immune dysfunction in schizophrenia patients. Whether and how specific complement components influence brain structure and cognition in the disease is unclear. Here we compared 52 drug-naïve patients with first-episode schizophrenia and 52 healthy controls in terms of levels of peripheral complement factors, cortical thickness (CT), logical memory and psychotic symptoms. We also explored the relationship between complement factors with CT, cognition and psychotic symptoms. Patients showed significantly higher levels of C1q, C4, factor B, factor H, and properdin in plasma. Among patients, higher levels of C3 in plasma were associated with worse memory recall, while higher levels of C4, factor B and factor H were associated with thinner sensory cortex. These findings link dysregulation of specific complement components to abnormal brain structure and cognition in schizophrenia.

Generation of Homogeneous Populations of Cortical Interneurons from Human Pluripotent Stem Cells.

Cortical interneurons (cINs), especially those that are derived from the medial ganglionic eminence (MGE) during early development, are associated with various neuropsychiatric disorders. Human pluripotent stem cell (hPSC)-derived cINs can provide unlimited cell sources for studying disease mechanisms and developing novel therapeutics. Here, we describe an optimized method to generate homogeneous cIN populations based on three-dimensional (3D) cIN sphere generation. This optimized differentiation system could sustain generated cINs relatively long term without compromising their survival or phenotypes.

Decreased plasma neuropeptides in first-episode schizophrenia, bipolar disorder, major depressive disorder: associations with clinical symptoms and cognitive function.

Background: There is an urgent need to identify differentiating and disease-monitoring biomarkers of schizophrenia, bipolar disorders (BD), and major depressive disorders (MDD) to improve treatment and management. Methods: We recruited 54 first-episode schizophrenia (FES) patients, 52 BD patients, 35 MDD patients, and 54 healthy controls from inpatient and outpatient clinics. α-Melanocyte Stimulating Hormone (α-MSH), ß-endorphin, neurotensin, orexin-A, oxytocin, and substance P were investigated using quantitative multiplex assay method. Psychotic symptoms were measured using the Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale (PANSS), manic symptoms using the Young Mania Rating Scale (YMRS), and depressive symptoms using 17 item-Hamilton Depression Rating Scale (HAMD). We additionally measured cognitive function by using a battery of tests given to all participants. Results: α-MSH, neurotensin, orexin-A, oxytocin, and substance P were decreased in the three patient groups compared with controls. Neurotensin outperformed all biomarkers in differentiating patient groups from controls. There were no significant differences for 6 neuropeptides in their ability to differentiate between the three patient groups. Higher neurotensin was associated with better executive function across the entire sample. Lower oxytocin and higher substance p were associated with more psychotic symptoms in FES and BD groups. ß-endorphin was associated with early morning wakening symptom in all three patient groups. Conclusion: Our research shows decreased circulating neuropeptides have the potential to differentiate severe mental illnesses from controls. These neuropeptides are promising treatment targets for improving clinical symptoms and cognitive function in FES, BD, and MDD.

YBX1-Mediated DNA Methylation-Dependent SHANK3 Expression in PBMCs and Developing Cortical Interneurons in Schizophrenia.

Schizophrenia (SCZ) is a severe psychiatric and neurodevelopmental disorder. The pathological process of SCZ starts early during development, way before the first onset of psychotic symptoms. DNA methylation plays an important role in regulating gene expression and dysregulated DNA methylation is involved in the pathogenesis of various diseases. The methylated DNA immunoprecipitation-chip (MeDIP-chip) is performed to investigate genome-wide DNA methylation dysregulation in peripheral blood mononuclear cells (PBMCs) of patients with first-episode SCZ (FES). Results show that the SHANK3 promoter is hypermethylated, and this hypermethylation (HyperM) is negatively correlated with the cortical surface area in the left inferior temporal cortex and positively correlated with the negative symptom subscores in FES. The transcription factor YBX1 is further found to bind to the HyperM region of SHANK3 promoter in induced pluripotent stem cells (iPSCs)-derived cortical interneurons (cINs) but not glutamatergic neurons. Furthermore, a direct and positive regulatory effect of YBX1 on the expression of SHANK3 is confirmed in cINs using shRNAs. In summary, the dysregulated SHANK3 expression in cINs suggests the potential role of DNA methylation in the neuropathological mechanism underlying SCZ. The results also suggest that HyperM of SHANK3 in PBMCs can serve as a potential peripheral biomarker of SCZ.

3,4-Dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide analogs act as potential AMPA receptor potentiators with antidepressant activity.

Major depressive disorder is a common psychiatric disorder, with ∼30% of patients suffering from treatment-resistant depression. Based on preclinical studies on ketamine, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation may be a promising therapeutic approach. In this study, we synthesized a series of novel 3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide analogs and analyzed their potential as AMPAR potentiators. Compounds 5aa and 7k exhibited high potentiation with little agonist activity in a high-throughput screen using a calcium influx assay in cultured hippocampal primary neurons. In rats, compound 7k had better pharmacokinetic properties and oral bioavailability (F = 67.19%); it also exhibited an acceptable safety profile in vital internal organs based on hematoxylin and eosin staining. We found that 7k produced a rapid antidepressant-like effect in chronic restraint stress-induced mice 1 h after intraperitoneal administration. Our study presented a series of novel AMPAR potentiators and identified 7k as a promising drug-like candidate against major depressive disorders.

Association of the plasma complement system with brain volume deficits in bipolar and major depressive disorders.

BACKGROUND: Inflammation plays a crucial role in the pathogenesis of major depressive disorder (MDD) and bipolar disorder (BD). This study aimed to examine whether the dysregulation of complement components contributes to brain structural defects in patients with mood disorders. METHODS: A total of 52 BD patients, 35 MDD patients, and 53 controls were recruited. The human complement immunology assay was used to measure the levels of complement factors. Whole brain-based analysis was performed to investigate differences in gray matter volume (GMV) and cortical thickness (CT) among the BD, MDD, and control groups, and relationships were explored between neuroanatomical differences and levels of complement components. RESULTS: GMV in the medial orbital frontal cortex (mOFC) and middle cingulum was lower in both patient groups than in controls, while the CT of the left precentral gyrus and left superior frontal gyrus were affected differently in the two disorders. Concentrations of C1q, C4, factor B, factor H, and properdin were higher in both patient groups than in controls, while concentrations of C3, C4 and factor H were significantly higher in BD than in MDD. Concentrations of C1q, factor H, and properdin showed a significant negative correlation with GMV in the mOFC at the voxel-wise level. CONCLUSIONS: BD and MDD are associated with shared and different alterations in levels of complement factors and structural impairment in the brain. Structural defects in mOFC may be associated with elevated levels of certain complement factors, providing insight into the shared neuro-inflammatory pathogenesis of mood disorders.

Fingolimod ameliorates schizophrenia-like cognitive impairments induced by phencyclidine in male rats.

BACKGROUND AND PURPOSE: Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis. KEY RESULTS: Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1ß pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the ERK signalling pathway. CONCLUSION AND IMPLICATIONS: This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.

From cells to insights: the power of human pluripotent stem cell-derived cortical interneurons in psychiatric disorder modeling.

Psychiatric disorders, such as schizophrenia (SCZ) and autism spectrum disorders (ASD), represent a global health challenge with their poorly understood and complex etiologies. Cortical interneurons (cINs) are the primary inhibitory neurons in the cortex and their subtypes, especially those that are generated from the medial ganglionic emission (MGE) region, have been shown to play an important role in the pathogenesis of these psychiatric disorders. Recent advances in induced pluripotent stem cell (iPSC) technologies provide exciting opportunities to model and study these disorders using human iPSC-derived cINs. In this review, we present a comprehensive overview of various methods employed to generate MGE-type cINs from human iPSCs, which are mainly categorized into induction by signaling molecules vs. direct genetic manipulation. We discuss their advantages, limitations, and potential applications in psychiatric disorder modeling to aid researchers in choosing the appropriate methods based on their research goals. We also provide examples of how these methods have been applied to study the pathogenesis of psychiatric disorders. In addition, we discuss ongoing challenges and future directions in the field. Overall, iPSC-derived cINs provide a powerful tool to model the developmental pathogenesis of psychiatric disorders, thus aiding in uncovering disease mechanisms and potential therapeutic targets. This review article will provide valuable resources for researchers seeking to navigate the complexities of cIN generation methods and their applications in the study of psychiatric disorders.

Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway.

Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder (BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex (mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206 (40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania. Furthermore, selective knockdown of AKT via AAV-AKT-shRNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly, pharmacological activation of AKT signaling by SC79 (40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002 (25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin (mTOR) signaling with rapamycin (10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.

A combination of neuroimaging and plasma metabolomic analysis suggests inflammation is associated with white matter structural connectivity in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a common mental disorder with unknown pathophysiology. The abnormality of white matter structural connectivity and dysregulation of metabolome in MDD had been widely reported previously. Exploration of the relationship between white matter structural connectivity and plasma metabolites would be helpful for explanation of molecular mechanism for the findings from neuroimaging researches in MDD. METHODS: The diffusion spectrum imaging data were collected for identification of difference of white matter structural connectivity between MDD (n = 49) and HC (n = 68). The plasma metabolite profiles were acquired by liquid chromatography-mass spectrometry analysis and clustered as co-expression modules. The correlation analysis was performed to identify structural connectivity associated metabolite. RESULTS: We identified two structural connectivity related metabolite modules. One module was correlated with fractional anisotropy (FA) value between left middle temporal gyrus and left inferior temporal gyrus, which were enriched in tryptophan metabolism pathway; another module was correlated with fiber numbers (FN) between right fusiform gyrus and right inferior temporal gyrus, which was enriched in lysophosphatidylcholine (LPC), lysophosphatidylinositol (LPI) and lysophosphatidylglycerol (LPG) lipid sets. l-Kynurenine in tryptophan metabolism pathway was negatively correlated with FN between right fusiform gyrus and right inferior temporal gyrus, and LPC was positively correlated with FA value between left middle temporal gyrus and left inferior temporal gyrus in MDD. LIMITATIONS: First, the sample size was relatively small. Second, the long-term effects of antidepressants were not excluded. CONCLUSION: The results suggested inflammation-related mechanism was associated with white matter structural connectivity in MDD.

Mitochondrial dysfunction in psychiatric disorders.

Psychiatric disorders are a heterogeneous group of mental disorders with abnormal mental or behavioral patterns, which severely distress or disable affected individuals and can have a grave socioeconomic burden. Growing evidence indicates that mitochondrial function plays an important role in developing psychiatric disorders. This review discusses the neuropsychiatric consequences of mitochondrial abnormalities in both animal models and patients. We also discuss recent studies associated with compromised mitochondrial function in various psychiatric disorders, such as schizophrenia (SCZ), major depressive disorder (MD), and bipolar disorders (BD). These studies employ various approaches including postmortem studies, imaging studies, genetic studies, and induced pluripotent stem cells (iPSCs) studies. We also summarize the evidence from animal models and clinical trials to support mitochondrial function as a potential therapeutic target to treat various psychiatric disorders. This review will contribute to furthering our understanding of the metabolic etiology of various psychiatric disorders, and help guide the development of optimal therapies.

Generation and characterization of human-derived iPSC lines from two cousins with schizophrenia and bipolar disorder and their unaffected cousin.

Schizophrenia (SCZ) and bipolar disorder (BD) are debilitating neurodevelopmental disorders with high heritability. In this study, peripheral blood mononuclear cells (PBMCs) were donated by three females. An adolescent female was clinically diagnosed as first-episode SCZ. One of her cousins was clinically diagnosed as BD and another one was unaffected control. Induced pluripotent stem cells (iPSCs) were established with reprograming factors Oct4, Sox2, Nanog, Lin28, c-myc, Klf4, and SV40LT. All lines presented normal karyotype and highly expressed pluripotency markers in vitro. All iPSCs were capable to differentiate into derivatives of three germ layers in vivo.

Correlation between reduced telomere length and behavioural and emotional problems in left-behind children in a rural area in China.

Evidence shows that being left behind experience (LBE) during childhood may increase the risks of poor psychopathological outcomes. However, it is unclear to what extent the mental health is affected by the LBE. Telomere length (TL), one of the most extensively studied biological markers of cellular ageing, provides a valuable tool for exploring the potential effects of parent-child separation on psychological problems by integrating genetic and environmental factors. In this study, a total of 613 children (mean age = 10.77, SD = 1.92) were recruited from the rural area of Deyang, Sichuan Province, China. We used a self-designed questionnaire to assess LBE, and collected psychopathological outcomes by using the Piers-Harris Children's Self-concept Scale, the Teacher's Report Form 6/18 and the Youth Self-Report 11/18. Terminal restriction fragment analysis was used to measure TL in peripheral blood leukocytes. Analyses revealed that 342 out of 613 participants (55.79%) were Left-behind children. LBE was observed to associated with shorter TL, lower self-esteem, and increased behavioural and emotional problems. The cumulative effects of LBE may be reflected by greater altered telomere homeostasis, decreased self-esteem, and worsened behavioural and emotional problems. The association of the total time of being left behind with self-esteem and behavioural and emotional problems was significantly mediated by altered telomere homeostasis, with estimated effects of 14.19%, 47.95% and 45.13%, respectively. The LBE in childhood, especially prolonged parent-child separation, increases the risk of mental health problems in childhood and adolescence.

Generation and characterization of human-derived iPSC lines from one pair of dizygotic twins discordant for schizophrenia.

Schizophrenia (SCZ) is a debilitating neurodevelopmental disorder with a high heritability. In this study, peripheral blood mononuclear cells (PBMCs) were donated by a pair of dizygotic twins. The female was clinically diagnosed as SCZ by Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria, and her unaffected male sibling was healthy control. Induced pluripotent stem cells (iPSCs) were established using Episomal vectors carrying reprograming factors OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT. These lines with normal karyotype highly expressed pluripotency markers and are capable to differentiate into derivatives of three germ layers. Both lines are negative of mycoplasma.

Alterations in CRY2 and PER3 gene expression associated with thalamic-limbic community structural abnormalities in patients with bipolar depression or unipolar depression.

Objectives The current study aimed to identify shared and distinct brain structure abnormalities and their relationships with the expression of circadian genes in patients with bipolar or unipolar depression. Method A total of 93 subjects participated in this study, including 32 patients with bipolar depression (BDP), 26 patients with unipolar depression (UDP) and 35 age- and sex-matched healthy controls. Brain structural magnetic resonance imaging scans were obtained, and optimized voxel-based morphometry was used to explore group differences in regional gray matter volume (GMV). The mRNA expression levels of circadian genes in peripheral blood were measured using reverse transcription quantitative real-time polymerase chain reaction. Results Our results showed that the GMV in brain regions in the thalamus-limbic pathways had significantly increased in the BDP patients compared to controls, while the increased GMV in UDP patients compared to controls was limited to the thalamus. The mRNA expression levels of circadian-related genes decreased significantly in patients with BDP, but increased in patients with UDP, compared to controls. In addition, the GMV in the right thalamus in the patients with UDP was positively associated with mRNA levels of CRY2, while the GMV in the right hippocampus in the patients with BDP was negatively associated with mRNA levels of PER3. Conclusion Our study suggested that patients with BDP or MDD shared GMV abnormalities in the right thalamus. The PER3 and CRY2 genes might be critical to right hippocampal dysfunction in BDP and right thalamic dysfunction in UDP, respectively. The result provided potentially important molecular targets for the treatment of mood disorders.

Migratory cortical interneuron-specific transcriptome abnormalities in schizophrenia.

Cortical interneurons (cINs) are substantially affected in Schizophrenia (SCZ) and enriched for SCZ heritability during development. To understand SCZ-specific changes in these cells during development, we isolated migratory cINs from cIN spheres derived from 5 healthy control (HC) and 5 SCZ induced pluripotent stem cell lines (iPSCs). Transcriptome analyses show dysregulation in extracellular matrix pathways as the major disturbances in SCZ migratory cINs, whereas sphere cINs show dysregulation in immune pathways. This result suggests the importance of using homogeneous cell populations to identify stage-specific abnormalities and provides a platform to further study the biology of schizophrenia pathogenesis during early development.

Association Analysis Between Catechol-O-Methyltransferase Expression and Cognitive Function in Patients with Schizophrenia, Bipolar Disorder, or Major Depression.

INTRODUCTION: Schizophrenia, bipolar disorder (BD), and major depressive disorder are three common mental disorders. Although their diagnosis and treatment differ, they partially overlap. METHODS: To explore the similarities and characteristics of these three psychiatric diseases, an intelligence quotient (IQ) assessment was performed to evaluate cognitive deficits. Relative catechol-O-methyltransferase (COMT) expression in peripheral blood mononuclear cells was examined in all three groups compared with healthy controls (HCs). RESULTS: The results indicated that patients with any of the three psychiatric diseases presented IQ deficits, and that the first-episode schizophrenia (FES) group had even lower cognitive function than the other two groups. The relative COMT expression decreased in the FES group and increased in the BD group compared with the HC group. The correlation analysis of COMT expression level and IQ scores showed a positive correlation between relative COMT expression and full-scale IQ in the HC group. However, this correlation disappeared in all three psychiatric diseases studied. CONCLUSION: In conclusion, this cross-disease strategy provided important clues to explain lower IQ scores and dysregulated COMT expression among three common mental illnesses.