Neuromyelitis optica spectrum disorder (NMOSD) is a severe central nervous system disease primarily characterized by optic neuritis and myelitis, which can result in vision loss and limb paralysis. Current treatment options are limited in their ability to prevent relapses and mitigate disease progression, underscoring the urgent need for new drug targets to develop more effective therapies. The objective of this study is to identify potential drug targets associated with a reduced risk of NMOSD attacks or relapses through Mendelian randomization (MR) analysis, thereby addressing the limitations of existing treatment methods and providing better clinical options for patients. To identify therapeutic targets for NMOSD, a MR analysis was conducted. The cis-expression quantitative trait loci (cis-eQTL, exposure) data were sourced from the eQTLGen consortium, which included a sample size of 31,684. NMOSD (outcome) summary data were obtained from two of the largest independent cohorts: one cohort consisted of 86 NMOSD cases and 460 controls derived from whole-genome sequencing data, while the other cohort included 129 NMOSD patients and 784 controls. We performed a two-sample MR analysis to evaluate the association between single nucleotide polymorphisms (SNPs) and copy number variations with NMOSD. The MR analysis utilized the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to assess the presence of horizontal pleiotropy and heterogeneity. Colocalization analysis was employed to test whether NMOSD risk and gene expression are driven by common SNPs. Additionally, a phenome-wide association study (PheWAS) was performed to detect disease outcomes associated with NEU1. Supplementary analyses included single-nucleus RNA sequencing (snRNA-seq) data analysis, protein-protein interaction (PPI) networks, and drug feasibility assessments to prioritize potential therapeutic targets. Two drug targets, COL4A1 and NEU1, demonstrated significant MR results in two independent datasets. Notably, NEU1 showed substantial evidence of colocalization with NMOSD. Additionally, apart from the association between NEU1 and NMOSD, no other associations were observed between gene-proxied NEU1 inhibition and the increased risk of other NMOSD-related diseases. This study supports the potential of targeting NEU1 for drug inhibition to reduce the risk of NMOSD. Further preclinical research and drug development are warranted to validate the efficacy and safety of NEU1 as a therapeutic target and to explore its potential in NMOSD treatment.

Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the global population. Traditional antipsychotic treatments, while effective for positive symptoms, often have significant side effects and fail to address cognitive and negative symptoms. Novel pharmacological treatments targeting muscarinic receptors, TAAR1 agonists, serotonergic pathways, and glutamate modulation have emerged as promising alternatives.

This systematic literature review aims to critically evaluate the efficacy, safety, and mechanisms of action of novel pharmacological agents in the treatment of schizophrenia.

A comprehensive search was conducted across PubMed, Embase, Cochrane Library, Scopus, and Web of Science for randomized controlled trials (RCTs) and clinical trials published between April 2014 and March 2024. Studies evaluating novel treatments targeting muscarinic receptors, TAAR1 agonists, serotonergic agents, and glutamate modulation were included. Primary outcomes focused on symptom reduction and quality of life, while secondary outcomes included cognitive function and adverse events. The Joanna Briggs Institute (JBI) tool was used for quality assessment.

Eleven studies involving 4614 participants (mean age 37-43 years, predominantly male) were included. Drugs evaluated included xanomeline-trospium (KarXT), pimavanserin, ulotaront, emraclidine, and bitopertin. Significant improvements in PANSS and CGI-S scores were observed, with xanomeline-trospium showing a mean reduction of 17.4 points (p < 0.001). Adverse events were mostly mild and transient, with nausea, constipation, and somnolence being common.

Novel treatments for schizophrenia show promise in managing both positive and negative symptoms, with generally favorable safety profiles. Future studies should focus on large-scale, long-term trials to refine their efficacy, safety, and clinical applicability.

Glucuronic acid (GlcA) is crucial in the glucuronidation pathway, facilitating the metabolism and elimination of various substances and drugs. Recent studies have noted elevated GlcA levels in patients with schizophrenia (SCZ) compared with healthy individuals. However, it remains unclear whether this elevation contributes to SCZ pathophysiology or results from medication effects.

This study investigated the relationship between peripheral GlcA levels and clinical characteristics in patients with SCZ and assess whether these associations persist independently of psychotropic medication effects to provide insight into the potential role of GlcA in the pathophysiology of SCZ.

Plasma GlcA levels were analysed in 218 patients with SCZ, examining their association with clinical features. The correlation between GlcA levels and symptom severity, assessed using the Positive and Negative Syndrome Scale (PANSS), was analysed in 35 patients. In addition, multiple regression analysis was conducted to adjust for age and psychotropic medication effects.

Significant correlations were observed between GlcA levels and PANSS scores for negative symptoms, general psychopathology and total scores. After adjustment for age and psychotropic medications, significant correlations between GlcA levels and PANSS scores persisted for negative symptoms (adjusted β [95% CI], 13.926 [2.369, 25.483]) and general psychopathology (adjusted β [95% CI], 19.437 [3.884, 34.990]), while the total score was no longer significant (adjusted β [95% CI], 34.054 [-0.517, 68.626]).

Elevated GlcA levels in patients with SCZ are associated with specific symptom severity irrespective of the medication dose, suggesting a potential role of GlcA in SCZ pathophysiology.

Schizophrenia (SCZ) and bipolar disorder (BD) and are severe psychiatric conditions that contribute to disability and increased healthcare costs globally. Although first-, second-, and third-generation antipsychotics are available for treating BD and SCZ, most have various side effects unrelated to their unique functions. Many antipsychotics affect K+ channels (Kv, KCa, Kir, K2P, and other channels), which change the functions of various organs. This review summarizes the biological actions of antipsychotics, including off-target side effects involving K+ channels.

Clozapine exhibits significant therapeutic efficacy in schizophrenia, especially treatment-resistant schizophrenia. However, clozapine can cause agranulocytosis, a fatal adverse effect, and the aim of this study is to explore this mechanism based on network pharmacology and molecular docking.

Six and two databases were used to identify targets associated with clozapine and agranulocytosis, respectively. The bioinformatics online platform was used to identify overlaps between the drug and disease targets. The protein-protein interaction (PPI) network was characterized using Cystoscope 3.10.1 and STRING. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were analyzed using the DAVID online platform. A drug-target-pathway-disease network was constructed utilizing Cystoscope 3.10.1. The Auto Dock Vina and PyMOL software were used to verify the molecular docking of clozapine and core targets.

The analysis revealed 188 overlapping targets. The PPI and KEGG enrichment pathway analyses demonstrated that clozapine induces agranulocytosis by modulating the hematopoietic cell lineage and JAK-STAT signaling pathways via interleukin-3 (IL3), IL6, IL2 receptor subunit alpha (IL2RA), and granulocyte colony-stimulating factor. Binding energies between clozapine and core targets were favorable (< -7.0 kcal/mol).

Clozapine-induced agranulocytosis may be linked to the JAK-STAT inflammatory signaling pathway through inflammatory and hematopoietic-related cytokines. Our findings enhance our comprehension of the potential mechanisms underlying clozapine-induced agranulocytosis.

With the frequent use of antipsychotics, the metabolic disorder (MetD) caused by drugs has received increasing attention. However, the mechanism of drug-induced MetD is still unclear and is being explored. Keeping abreast of the progress and trending knowledge in this area is conducive to further work.

The aim of this study is to analyze the latest status and trends of research on antipsychoticinduced metabolic disorder (AIMetD) by bibliometric and visual analysis.

3478 publications of AIMetD from 2006 to 2021 were retrieved from the Web of Science Core Collection database. R-biblioshiny was used for descriptive analysis, CiteSpace for cooperative network, co-citation analysis and burst detection, and VOSviewer for co-occurrence keywords was used.

Since 2006, the publications have been growing fluctuantly. These studies have extensive cooperation among countries/regions. The most influential country/region, institution and author are the USA, King's College London and Christoph U Correll. Analysis of references shows the largest cluster of "antipsychotic-induced metabolic dysfunction", which is an important basis for MetD. The recent contents of the burst citation are related to "glucose homeostasis" and "cardiovascular metabolism". Several bursting keywords were discerned at the forefront, including "LC-MS/MS", "major depressive disorder", "expression", and "homeostasis".

The AIMetD study is in a state of sustained development. Close cooperation between countries/ regions has promoted progress. For grasping the foundation, development, and latest trends of AIMetD, it is recommended to focus on active institutions and authors. Based on AIMetD, subdivision areas such as "LC-MS/MS", "expression", and "homeostasis" are forefronts that deserve constant attention.

Despite research advances and progress in health care, schizophrenia remains a debilitating and costly disease. Onset occurs typically during youth and can lead to a relapsing and ultimately chronic course with persistent symptoms and functional impairment if not promptly and properly treated. Consequently, over time, schizophrenia causes substantial distress and disability for patients, their families and accrues to a collective burden to society. Recent research has revealed much about the pathophysiology that underlies the progressive nature of schizophrenia. Additionally, treatment strategies for disease management have been developed that have the potential to not just control psychotic symptoms but limit the cumulative morbidity of the illness. Given the evidence for their effectiveness and feasibility for their application, it is perplexing that this model of care has not yet become the standard of care and widely implemented to reduce the burden of illness on patients and society. This begs the question of whether the failure of implementation of a potentially disease-modifying strategy is due to the lack of evidence of efficacy (or belief in it) and readiness for implementation, or whether it's the lack of motivation and political will to support their utilization. To address this question, we reviewed and summarized the literature describing the natural history, pathophysiology and therapeutic strategies that can alleviate symptoms, prevent relapse, and potentially modify the course of schizophrenia. We conclude that, while we await further advances in mental health care from research, we must fully appreciate and take advantage of the effectiveness of existing treatments and overcome the attitudinal, policy, and infrastructural barriers to providing optimal mental health care capable of providing a disease-modifying treatment to patients with schizophrenia.

Glutamatergic system dysfunction contributes to a full spectrum of schizophrenia-like symptoms, including the cognitive and negative symptoms that are resistant to treatment with antipsychotic drugs (APDs). Aripiprazole, an atypical APD, acts as a dopamine partial agonist, and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia. Recently, an analog of aripiprazole, UNC9994, was developed. UNC9994 does not affect dopamine 2 receptor (D2R)-mediated Gi/o protein signaling but acts as a partial agonist for D2R/β-arrestin interactions. Hence, one of our objectives was to probe the behavioral effects of co-administrating haloperidol with UNC9994 in the N-methyl-D-aspartate receptor (NMDAR) mouse models of schizophrenia. The biochemical mechanisms underlying the neurobiological effects of dual haloperidol × UNC9994 action are currently missing. Hence, we aimed to explore D2R- and NMDAR-dependent signaling mechanisms that could underlie the effects of dual drug treatments.

NMDAR hypofunction was induced pharmacologically by acute injection of MK-801 (NMDAR pore blocker; 0.15 mg/kg) and genetically by knockdown of Grin1 gene expression in mice, which have a 90% reduction in NMDAR levels (Grin1 knockdown [Grin1-KD]). After intraperitoneal injections of vehicle, haloperidol (0.15 mg/kg), UNC9994 (0.25 mg/kg), or their combination, mice were tested in open field, prepulse inhibition (PPI), Y-maze, and Puzzle box. Biochemical effects on the phosphorylation of Akt, glycogen synthase kinase-3 (GSK-3), and CaMKII in the prefrontal cortex (PFC) and striatum of MK-801-treated mice were assessed by western blotting.

Our findings indicate that low dose co-administration of UNC9994 and haloperidol reduces hyperactivity in MK-801-treated animals and in Grin1-KD mice. Furthermore, this dual administration effectively reverses PPI deficits, repetitive/rigid behavior in the Y-maze, and deficient executive function in the Puzzle box in both animal models. Pharmacological inhibition of NMDAR by MK-801 induced the opposite effects in the PFC and striatum on pAkt-S473 and pGSK3β-Ser9. Dual injection of haloperidol with UNC9994 reversed MK-801-induced effects on pAkt-S473 but not on pGSK3β-Ser9 in both brain structures.

The dual administration of haloperidol with UNC9994 at low doses represents a promising approach to ameliorate symptoms of schizophrenia. The combined drug regimen elicits synergistic effects specifically on pAkt-S473, suggesting it as a potential biomarker for antipsychotic actions.

To examine the association between psychotropic medication usage and respiratory failure.

A systematic search of Embase, PubMed, CINAHL, PsycINFO, and the Cochrane Trial Registry databases for publications that evaluated the association between respiratory failure and the use of psychotropic medications in patients with chronic mental health disorders was performed.

Nine studies were included, with a total of 170,435 participants. There was no association between antidepressant use and respiratory failure reported in the antidepressant studies, however no formal odds ratio was reported in any of these studies. Three antipsychotic studies met inclusion criteria, which included a total of 169,919 participants. However, two of these studies were derived from overlapping datasets, and one of these studies was reported as an abstract. None controlled for the key confounder of smoking status. All three demonstrated an increased risk of respiratory failure with antipsychotic use (adjusted odds ratio ranged from 1.13 95% CI: 1.2-1.89; to 2.33 95% CI: 2.06-2.64). Two out of three antipsychotic studies had a low risk of bias.

No clear association between antidepressants and respiratory failure was identified. Three studies examining antipsychotic medications and respiratory failure indicated an increased risk for respiratory failure. However, studies demonstrated significant heterogeneity and confounding factors (e.g. smoking status) and strategies to deal with these were absent. Two studies were derived from overlapping datasets and one study was an abstract. Given the signal towards increased risk of respiratory failure with antipsychotic medications, further reporting on this association through large matched and independent datasets is required to allow meta-analysis to quantify the nature and extent of this increased risk.

Atypical antipsychotics are associated with several adverse effects including metabolic syndrome, weight gain, QTc interval prolongation, and extrapyramidal effects. This study aims to investigate the risk of renal impairment in patients receiving atypical antipsychotics.

A systematic literature search was conducted via PubMed and Ovid SP and Web of Science to retrieve studies reporting the risk of renal impairment in patients receiving atypical antipsychotic treatment. The pooled risk ratio (RR) of renal impairment and the subgroup analysis was calculated using the random-effects generic inverse variance method in Cochrane Review Manager.

A total of 4 studies involving 514,710 patients (221, 873 patients on atypical antipsychotics/CKD and 292, 837 controls) were included in this meta-analysis. Patients on atypical antipsychotics exhibited an increased risk of renal impairment, with a pooled risk ratio of 1.34 (95%CI 1.23-1.47). Subgroup analysis demonstrated that atypical antipsychotic use was associated with an increased risk of both acute kidney injury (AKI) (RR 1.51, 95%CI 1.34-1.71) and chronic kidney disease (CKD) (RR: 1.23, 95%CI 1.12-1.35).

Patients receiving atypical antipsychotics have an increased risk of renal impairment. Quetiapine carries the highest risk of renal impairment encompassing both AKI and CKD.

Lumateperone has been approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia in adults since 2019, however, there is still a lack of data report on adverse reactions in real-world settings. Conducting data mining on adverse events (AEs) associated with Lumateperone and investigating the risk factors for serious AEs can provide valuable insights for its clinical practice.

AE reports in the FDA Adverse Event Reporting System (FAERS) from 2019 Q4 (FDA approval of Lumateperone) to 2024 Q1 were collected and analyzed. Disproportionality in Lumateperone-associated AEs was evaluated using the following parameters: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Univariate and multivariate logistic regression analyses were conducted to identify the risk factors for Lumateperone-induced severe AEs.

A total of 2,644 reports defined Lumateperone as the primary suspected drug was collected, including 739 reports classified as severe AEs and 1905 reports as non-severe AEs. The analysis revealed that 130 preferred terms (PTs) with significant disproportionality were based on the four algorithms, 67 (51.53%) of which were not included in the product labeling, affecting 6 systems and organs. In addition, dizziness (81 cases) was the most reported Lumateperone-associated severe AEs, and tardive dyskinesia showed the strongest signal (ROR = 186.24). Logistic regression analysis indicated that gender, bipolar II disorder, and concomitant drug use are independent risk factors for Lumateperone-associated severe AEs. Specifically, female patients had a 1.811-fold increased risk compared with male patients (OR = 1.811 [1.302, 2.519], p = 0.000), while patients with bipolar II disorder had a 1.695-fold increased risk compared with patients diagnosed with bipolar disorder (OR = 1.695 [1.320, 2.178], p = 0.000). Conversely, concomitant use of CYP3A4 inhibitors or drugs metabolized by CYP3A4 was associated with a decreased risk of severe AEs (OR = 0.524 [0.434, 0.633], P = 0.000).

Collectively, this study provides critical insights into the safety profile of Lumateperone. It highlights the need for cautious use in high-risk populations, such as females and individuals with bipolar II disorder, and emphasizes the importance of monitoring for AEs, including dizziness and tardive dyskinesia. Healthcare also should remain alert to potential AEs not listed in the prescribing information to ensure medical safety.

Second-generation antipsychotics (SGAs) are often prescribed for patients with schizophrenia; however, SGAs are associated with the risk of metabolic syndrome (MetS). This study aimed to investigate the clinical and biochemical determinants of SGA-related MetS.

Patients with schizophrenia, aged between 20 and 65 years, and under clozapine or olanzapine treatment for at least 9 months, were recruited from a mental hospital. Demographic, comorbidity, clinical status, laboratory, and drug regimen data were collected through chart review. Circulating levels of adiponectin, thyroid hormone responsive protein, and fatty acid binding protein 4 (FABP4) were assayed. Multiple logistic regression was used to identify risk predictors of MetS.

A total of 176 participants were enrolled, including 138 (78.4 %) clozapine users and 38 (21.6 %) olanzapine users. Forty-five (25.6 %) patients were classified as having MetS. The duration of clozapine or olanzapine usage was significantly shorter in those with MetS (p=0.026) than those without MetS. Patients with MetS had a significantly higher serum FABP4 concentration than their counterparts (22.5 ± 8.8 ng/mL vs. 15.7 ± 6.7 ng/mL, p<0.001), and also a significantly lower adiponectin level (6.9 ±4.0 mg/mL vs. 11.6 ± 6.6 mg/mL, p<0.001). A FABP4 level ≥ 16.98 ng/mL (OR: 24.16, 95 % CI: 7.47-78.09, p<0.001) was positively correlated with MetS, whereas serum adiponectin level was inversely correlated with MetS (OR: 0.7980, 95 % CI: 0.70-0.90, p<0.001).

Adiponectin, FABP4, and certain clinical covariates and comedications were highly correlated with SGA-related MetS. Further studies are required to investigate the underlying mechanisms.

Traumatic brain injury (TBI) is linked with an increased risk of schizophrenia and other non-mood psychotic disorders (psychotic disorders), but the prevalence and contributing factors of these psychiatric conditions post-TBI remain unclear. This study explores this link to identify key risk factors in TBI patients.

We used the 2017 National Inpatient Sample dataset. Patients with a history of TBI (n = 26 187) were identified and matched 1:1 by age and gender to controls without TBI (n = 26 187). We compared clinical and demographic characteristics between groups. The association between TBI and psychotic disorders was explored using the logistic regression analysis, and results were presented as Odds ratio (OR) and 95% confidence interval (CI).

Psychotic disorders were significantly more prevalent in TBI patients (10.9%) vs controls (4.7%) (P < .001). Adjusted odds of psychotic disorders were 2.2 times higher for TBI patients (95% CI 2.05-2.43, P < .001). Male TBI patients had higher psychotic disorders prevalence than females (11.9% vs 8.4%). Younger age, bipolar disorder, anxiety disorders, substance abuse, personality disorders, and intellectual disability are associated with an increased risk of psychotic disorders in men.

Our study found that hospitalized TBI patients had 2.2 times higher odds of Schizophrenia non-mood psychotic disorder, indicating an association. This highlights the need for early screening of psychotic disorders and intervention in TBI patients, calling for more research.

In spite of major efforts and investment in development of psychiatric drugs, many clinical trials have failed in recent decades, and clinicians still prescribe drugs that were discovered many years ago. Although multiple reasons have been discussed for the drug development deadlock, we focus here on one of the major possible biological reasons: differences between the characteristics of drug targets in preclinical models and the corresponding targets in patients. Importantly, based on technological advances in single-cell analysis, we propose here a framework for the use of available and newly emerging knowledge from single-cell and spatial omics studies to evaluate and potentially improve the translational predictivity of preclinical models before commencing preclinical and, in particular, clinical studies. We believe that these recommendations will improve preclinical models and the ability to assess drugs in clinical trials, reducing failure rates in expensive late-stage trials and ultimately benefitting psychiatric drug discovery and development.

Hydrogels, formed from crosslinked hydrophilic macromolecules, provide a three-dimensional microenvironment that mimics the extracellular matrix. They served as scaffold materials in regenerative medicine with an ever-growing demand. However, hydrogels composed of only organic components may not fully meet the performance and functionalization requirements for various tissue defects. Composite hydrogels, containing inorganic components, have attracted tremendous attention due to their unique compositions and properties. Rigid inorganic particles, rods, fibers, etc., can form organic-inorganic composite hydrogels through physical interaction and chemical bonding with polymer chains, which can not only adjust strength and modulus, but also act as carriers of bioactive components, enhancing the properties and biological functions of the composite hydrogels. Notably, incorporating environmental or stimulus-responsive inorganic particles imparts smartness to hydrogels, hence providing a flexible diagnostic platform for in vitro cell culture and in vivo tissue regeneration. In this review, we discuss and compare a set of materials currently used for developing organic-inorganic composite hydrogels, including the modification strategies for organic and inorganic components and their unique contributions to regenerative medicine. Specific emphasis is placed on the interactions between the organic or inorganic components and the biological functions introduced by the inorganic components. The advantages of these composite hydrogels indicate their potential to offer adaptable and intelligent therapeutic solutions for diverse tissue repair demands within the realm of regenerative medicine.

Side effects are a very important aspect of antipsychotic treatments. Weight gain is an important side effect that jeopardizes the uninterrupted therapy administration, especially in patients with psychiatric conditions. This case-non-case pharmacovigilance study aims at investigating in a real-world adverse event reporting system whether several antipsychotics increase the risk of weight gain reporting, and the differences among men and women as far as weight gain as a reported adverse event is concerned.

Adverse event reports submitted to the FDA Adverse Event Reporting System of the Food and Drug Administration of the United States (FAERS) of 24 major antipsychotics were extracted, cleaned, and analyzed to determine which of these drugs were correlated with weight gain. The Reported Odds Ratio (ROR) and the adjusted Reported Odds Ratio (aROR) were calculated for each antipsychotic using logistic regression models. Demographics like age, gender, and concomitant insulin use were taken into consideration for each drug.

Women had a statistically significant increase in weight gain reporting compared to men, while the men's group was associated with a reduced weight gain reporting in every antipsychotics in the logistic regression analyses. Out of the 24 antipsychotics included in our analysis, Aripiprazole, Brexpiprazole, Olanzapine, and Haloperidol had statistically significantly more weight increase reporting compared to the others.

The use of adjunctive therapy for bipolar disorder is increasingly considered to increase the efficacy of standard treatments. In this randomized clinical trial, we evaluated the effect of vitamins B1 and B6 in separate treatment arms on mood symptoms, cognitive status, and sleep quality in hospitalized patients with bipolar disorder in manic episodes.

In addition to receiving standard lithium treatment, participants (N = 66) were randomized to one of three conditions: 100 mg of vitamin B1, 40 mg of vitamin B6, or placebo. Outcomes were assessed one and 8 weeks of daily treatment, including the Young Mania Rating Scale (YMRS), Pittsburgh Sleep Quality Scale (PSQI), and Mini-Mental State Examination (MMSE). This study was performed between December 2020 and September 2021 based on the registration code number IRCT20200307046712N1.

Vitamin B6 had a significant effect (P value < 0.025 as significant) on mood improvement compared to placebo (F (1, 27.42) = 30.25, P < 0.001, r = 0.72), but vitamin B1 had no significant effect on mood improvement compared to Placebo (F (1/35.68) = 4.76, P = 0.036, r = 0.34). The contrasts between groups on PSQI showed a significant effect (P value < 0.025 as significant) of vitamin B6 over placebo for sleep status improvement (F (1/32.91) = 16.24, P < 0.001, r = 0.57) and also a significant effect of vitamin B1 over placebo (F (1/41.21) = 13.32, P < 0.001, r = 0.49).

The use of vitamin B6 as an adjunctive therapy to lithium can be associated with the improvement of mood symptoms in patients with bipolar disorder in the midst of a manic episode.

Repetitive transcranial magnetic stimulation (rTMS) has been used in the treatment of patients with schizophrenia. The conventional targets of rTMS treatment are the dorsolateral prefrontal cortex (DLPFC) and temporoparietal cortex (TPC). However, the efficacy of these two treatment strategies was quite heterogeneous. Structural and functional abnormalities of the orbitofrontal cortex (OFC) in schizophrenia are closely related to negative symptoms. We sought to determine whether 1 Hz rTMS over the right OFC is effective in treating patients with first-episode schizophrenia. In this study, eighty-nine patients with drug-naïve, first-episode schizophrenia were randomly divided into the rTMS (n = 47) or sham stimulation (n = 42) groups, with both groups receiving twenty sessions of 1 Hz rTMS treatment. The PANSS was assessed at baseline, day 10, and day 20, and MATRICS Consensus Cognitive Battery (MCCB) was implemented to assess the cognitive impairment at baseline and day 20. Results showed that patients in the active rTMS group had more improvement in clinical symptoms and cognitive deficits than patients in sham group at day 20. In conclusion, 1 Hz rTMS over OFC can improve psychotic symptoms and cognitive functions in schizophrenic patients. Our study provides a new alternative for the treatment of negative symptoms and cognitive deficits in schizophrenia.

Schizophrenia is a debilitating condition necessitating more efficacious therapies. Previous studies suggested that schizophrenia development is associated with aberrant synaptic pruning by glial cells. We pursued an interdisciplinary approach to understand whether therapeutic reduction in glial cell-specifically astrocytic-phagocytosis might benefit neuropsychiatric patients. We discovered that beta-2 adrenergic receptor (ADRB2) agonists reduced phagocytosis using a high-throughput, phenotypic screen of over 3200 compounds in primary human fetal astrocytes. We used protein interaction pathways analysis to associate ADRB2, to schizophrenia and endocytosis. We demonstrated that patients with a pediatric exposure to salmeterol, an ADRB2 agonist, had reduced in-patient psychiatry visits using a novel observational study in the electronic health record. We used a mouse model of inflammatory neurodegenerative disease and measured changes in proteins associated with endocytosis and vesicle-mediated transport after ADRB2 agonism. These results provide substantial rationale for clinical consideration of ADRB2 agonists as possible therapies for patients with schizophrenia.

Despite accounting for significant disease morbidity in schizophrenia, the neuropathological basis of negative symptoms remains poorly understood and options for treatment limited. Our recent study identified robust associations between diminished auditory cortex (AC) dynamic range and social functioning impairments and negative symptoms in first episode psychosis (FESz). The current investigation examined the progression of these relationships 4-8 months from baseline testing.

Twenty-six FESz and 38 healthy controls (HC) were tested at baseline and follow-up. Magnetoencephalography (MEG) was recorded during binaural presentation of tones (75, 80, and 85 dB). Assessments included the MATRICS cognitive consensus battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS) and the Positive and Negative Syndrome Scale.

Overall, FESz exhibited a blunted response to increasing tone intensity relative to HC. While this deficit did not change over time at the group level, recovery of right hemisphere AC dynamic range (85-75 dB response) among FESz individuals was associated with reductions in negative symptoms (ρ = -0.50). Diminished dynamic range was also associated with impaired GFS (ρ = 0.65), GFR (ρ = 0.51), and MCCB (ρ = 0.49) at baseline and increased negative symptoms at baseline (ρ = -0.53) and follow-up (ρ = -0.51).

Despite persistent dynamic range impairment in FESz as a group, individual recovery of this AC response property was associated with significant reduction in negative symptoms. Identification of a functional neural deficit that tracts progression of negative symptoms during a critical period for disease modification is essential to the management of these devastating and historically treatment refractory symptoms.

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 < 0.001). The GMV and IL-6 reduction ratios correlated with each other in both groups (r = -0.17, P = 0.025). In the lithium group, the whole-brain GMV reduction ratio correlated with the working memory improvement ratio (r = -0.15, P = 0.030) and processing speed (r = -0.14, P = 0.036); the IL-6 reduction ratio correlated with the working memory (r = -0.21, P = 0.043) and verbal learning (r = -0.30, P = 0.031) improvement ratios. In the placebo group, the whole-brain GMV reduction ratio correlated only with the working memory improvement ratio (r = -0.24, P = 0.019); the IL-6 reduction ratio correlated with the working memory (r = -0.17, P = 0.022) and verbal learning (r = -0.15, P = 0.011) improvement ratios. Both treatments implemented in this study nearly improved the cognitive performance of patients with schizophrenia; relative to placebo, low-dose lithium had slightly greater effects on several aspects of cognition. The patterns of correlation among GMV reduction, IL-6 reduction, and cognitive performance improvement differed between groups.

Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.

Cognitive development after schizophrenia onset can be shaped by interventions such as cognitive remediation, yet no study to date has investigated whether patterns of early behavioral development may predict later cognitive changes following intervention. We therefore investigated the extent to which premorbid adjustment trajectories predict cognitive remediation gains in schizophrenia.

In a total sample of 215 participants (170 first-episode schizophrenia participants and 45 controls), we classified premorbid functioning trajectories from childhood through late adolescence using the Cannon-Spoor Premorbid Adjustment Scale. For the 62 schizophrenia participants who underwent 6 months of computer-assisted, bottom-up cognitive remediation interventions, we identified MATRICS Consensus Cognitive Battery scores for which participants demonstrated mean changes after intervention, then evaluated whether developmental trajectories predicted these changes.

Growth mixture models supported three premorbid functioning trajectories: stable-good, deteriorating, and stable-poor adjustment. Schizophrenia participants demonstrated significant cognitive remediation gains in processing speed, verbal learning, and overall cognition. Notably, participants with stable-poor trajectories demonstrated significantly greater improvements in processing speed compared to participants with deteriorating trajectories.

This is the first study to our knowledge to characterize the associations between premorbid functioning trajectories and cognitive remediation gains after schizophrenia onset, indicating that 6 months of bottom-up cognitive remediation appears to be sufficient to yield a full standard deviation gain in processing speed for individuals with early, enduring functioning difficulties. Our findings highlight the connection between trajectories of premorbid and postmorbid functioning in schizophrenia and emphasize the utility of considering the lifespan developmental course in personalizing therapeutic interventions.

Physical exercise programs are useful and necessary for the treatment of schizophrenia. The aim of this study was to assess the experiences of participants with schizophrenia in an out-of-hospital exercise program designed and supervised by qualified exercise professionals. Thirty-five individuals with schizophrenia from the intervention group of the CORTEX-SP study were interviewed. The interviews were transcribed verbatim and content analysis was performed using inductive coding. Two main categories emerged: the importance of the program being conducted out-of-hospital, and the individuals responsible for the program being qualified exercise professionals. The participants highlighted the importance of conducting the program outside the psychiatric center since it gave them greater satisfaction. They perceived greater seriousness and a greater number of resources and felt encouraged to repeat the program or prolong it. The success of the program, in addition to the space, was due to the personnel in charge of the program, i.e., the qualified exercise professionals, and the fact that the activities were designed and supervised. Participants emphasized the qualifications of the exercise professionals, key for this type of program, their social skills and the level of involvement with participants and their follow-up.

Psychedelics, also known as classical hallucinogens, have been investigated for decades due to their potential therapeutic effects in the treatment of neuropsychiatric and substance use disorders. The results from clinical trials have shown promise for the use of psychedelics to alleviate symptoms of depression and anxiety, as well as to promote substantial decreases in the use of nicotine and alcohol. While these studies provide compelling evidence for the powerful subjective experience and prolonged therapeutic adaptations, the underlying molecular reasons for these robust and clinically meaningful improvements are still poorly understood. Preclinical studies assessing the targets and circuitry of the post-acute effects of classical psychedelics are ongoing. Current literature is split between a serotonin 5-HT2A receptor (5-HT2AR)-dependent or -independent signaling pathway, as researchers are attempting to harness the mechanisms behind the sustained post-acute therapeutically relevant effects. A combination of molecular, behavioral, and genetic techniques in neuropharmacology has begun to show promise for elucidating these mechanisms. As the field progresses, increasing evidence points towards the importance of the subjective experience induced by psychedelic-assisted therapy, but without further cross validation between clinical and preclinical research, the why behind the experience and its translational validity may be lost.

A new generation of dual-target μ opioid receptor (MOR) agonist/dopamine D3 receptor (D3R) antagonist/partial agonists with optimized physicochemical properties was designed and synthesized. Combining in vitro cell-based on-target/off-target affinity screening, in silico computer-aided drug design, and BRET functional assays, we identified new structural scaffolds that achieved high affinity and agonist/antagonist potencies for MOR and D3R, respectively, improving the dopamine receptor subtype selectivity (e.g., D3R over D2R) and significantly enhancing central nervous system multiparameter optimization scores for predicted blood-brain barrier permeability. We identified the substituted trans-(2S,4R)-pyrrolidine and trans-phenylcyclopropyl amine as key dopaminergic moieties and tethered these to different opioid scaffolds, derived from the MOR agonists TRV130 (3) or loperamide (6). The lead compounds 46, 84, 114, and 121 have the potential of producing analgesic effects through MOR partial agonism with reduced opioid-misuse liability via D3R antagonism. Moreover, the peripherally limited derivatives could have therapeutic indications for inflammation and neuropathic pain.

The aim of this study was to investigate the subjective experiences of a concurrent exercise program designed to improve both physical and mental health, through participation, for people with schizophrenia. Participants diagnosed with schizophrenia (n = 35, 41.6 ± 10.3 years) received an intensive concurrent exercise program for a 5-month duration, three times a week, at out-of-hospital facilities. Qualitative data was collected via individual, semi-structured interviews, organized, and analyzed with thematic analysis. The findings highlight the participants' perspective in supporting an out-of-hospital exercise program as an acceptable and beneficial adjunct to usual treatment in people with schizophrenia for holistic health improvements.

The aim of this review is to appraise the data from available randomized clinical trials (RCT) regarding the possible combinations of neuroleptic and non-antipsychotic treatment which could enhance antipsychotic therapy efficacy whilst simultaneously addressing somatic symptoms in individuals with schizophrenia. A systematic search of the PubMed database up to February 2022 was conducted. Inclusion criteria: randomized controlled trials using augmentation therapy in chronic schizophrenia in adults, written in English, and only studies with psychometric assessments of schizophrenia were incorporated. Exclusion criteria: non-clinical, first episode of schizophrenia, patients on medication other than antipsychotics augmented, and not adjunctive therapy. Overall, 37 studies of 1931 patients with schizophrenia who received a combination of antipsychotic medication with other drugs were selected. A statistically significant reduction of negative and positive symptoms of schizophrenia, measured with the PANSS scale, when using a combination of antipsychotic treatment along with aspirin, simvastatin, N-acetylcysteine, or pioglitazone was found. A combination of antipsychotic medication with aspirin, simvastatin, N-acetylcysteine, or pioglitazone seems to be effective in the reduction of symptoms of schizophrenia in adults, but long-term studies are required to confirm this effect.

Schizophrenia is a severe brain disorder that usually produces a lifetime of disability. First generation or typical antipsychotics such as haloperidol and second generation or atypical antipsychotics such as clozapine and risperidone remain the current standard for schizophrenia treatment. In some patients with schizophrenia, antipsychotics produce complete remission of positive symptoms, such as hallucinations and delusions. However, antipsychotic drugs are ineffective against cognitive deficits and indeed treated schizophrenia patients have small improvements or even deterioration in several cognitive domains. This underlines the need for novel and more efficient therapeutic targets for schizophrenia treatment. Serotonin and glutamate have been identified as key parts of two neurotransmitter systems involved in fundamental brain processes. Serotonin (or 5-hydroxytryptamine) 5-HT2A receptor (5-HT2AR) and metabotropic glutamate 2 receptor (mGluR2) are G protein-coupled receptors (GPCRs) that interact at epigenetic and functional levels. These two receptors can form GPCR heteromeric complexes through which their pharmacology, function and trafficking becomes affected. Here we review past and current research on the 5-HT2AR-mGluR2 heterocomplex and its potential implication in schizophrenia and antipsychotic drug action. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".

Progressive brain structural MRI changes are described in schizophrenia and have been ascribed to both illness progression and antipsychotic treatment. We investigated treatment effects, in terms of total cumulative antipsychotic dose, efficacy and tolerability, on brain structural changes over the first 24 months of treatment in schizophrenia.

A prospective, 24-month, single-site cohort study in 99 minimally treated patients with first-episode schizophrenia, schizophreniform and schizoaffective disorder, and 98 matched healthy controls. We treated the patients according to a fixed protocol with flupenthixol decanoate, a long-acting injectable antipsychotic. We assessed psychopathology, cognition, extrapyramidal symptoms and BMI, and acquired MRI scans at months 0, 12 and 24. We selected global cortical thickness, white matter volume and basal ganglia volume as the regions of interest.

The only significant group × time interaction was for basal ganglia volumes. However, patients, but not controls, displayed cortical thickness reductions and increases in white matter and basal ganglia volumes. Cortical thickness reductions were unrelated to treatment. White matter volume increases were associated with lower cumulative antipsychotic dose, greater improvements in psychopathology and cognition, and more extrapyramidal symptoms. Basal ganglia volume increases were associated with greater improvements in psychopathology, greater increases in BMI and more extrapyramidal symptoms.

We provide evidence for plasticity in white matter and basal ganglia associated with antipsychotic treatment in schizophrenia, most likely linked to the dopamine blocking actions of these agents. Cortical changes may be more closely related to the neurodevelopmental, non-dopaminergic aspects of the illness.

Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A, encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disability [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients. Does loss of Grin2a or Akap11 in mice also result in EEG abnormalities? We monitored EEG in heterozygous and homozygous knockout Grin2a and Akap11 mutant mice compared with their wild-type littermates, at 3- and 6-months of age, across the sleep/wake cycle and during auditory stimulation protocols. Grin2a and Akap11 mutants exhibited increased resting gamma power, attenuated auditory steady-state responses (ASSR) at gamma frequencies, and reduced responses to unexpected auditory stimuli during mismatch negativity (MMN) tests. Sleep spindle density was reduced in a gene dose-dependent manner in Akap11 mutants, whereas Grin2a mutants showed increased sleep spindle density. The EEG phenotypes of Grin2a and Akap11 mutant mice show a variety of abnormal features that overlap considerably with human schizophrenia patients, reflecting systems-level changes caused by Grin2a and Akap11 deficiency. These neurophysiologic findings further substantiate Grin2a and Akap11 mutants as genetic models of schizophrenia and identify potential biomarkers for stratification of schizophrenia patients.

In the mammalian brain, glutamate is regarded to be the primary excitatory neurotransmitter due to its widespread distribution and wide range of metabolic functions. Glutamate plays key roles in regulating neurogenesis, synaptogenesis, neurite outgrowth, and neuron survival in the brain. Ionotropic and metabotropic glutamate receptors, neurotransmitters, neurotensin, neurosteroids, and others co-ordinately formulate a complex glutamatergic network in the brain that maintains optimal excitatory neurotransmission. Cognitive activities are potentially synchronized by the glutamatergic activities in the brain via restoring synaptic plasticity. Dysfunctional glutamate receptors and other glutamatergic components are responsible for the aberrant glutamatergic activity in the brain that cause cognitive impairments, loss of synaptic plasticity, and neuronal damage. Thus, controlling the brain's glutamatergic transmission and modifying glutamate receptor function could be a potential therapeutic strategy for cognitive disorders. Certain drugs that regulate glutamate receptor activities have shown therapeutic promise in improving cognitive functions in preclinical and clinical studies. However, several issues regarding precise functional information of glutamatergic activity are yet to be comprehensively understood. The present article discusses the scope of developing glutamatergic systems as prospective pharmacotherapeutic targets to treat cognitive disorders. Special attention has been given to recent developments, challenges, and future prospects.

Highly selective dopamine D3 receptor (D3R) partial agonists/antagonists have been developed for the treatment of psychostimulant use disorders (PSUD). However, none have reached the clinic due to insufficient potency/efficacy or potential cardiotoxicity. Cariprazine, an FDA-approved drug for the treatment of schizophrenia and bipolar disorder, is a high-affinity D3R partial agonist (Ki = 0.22 nM) with 3.6-fold selectivity over the homologous dopamine D2 receptor (D2R). We hypothesized that compounds that are moderately D3R/D2R-selective partial agonists/antagonists may be effective for the treatment of PSUD. By systematically modifying the parent molecule, we discovered partial agonists/antagonists, as measured in bioluminescence resonance energy transfer (BRET)-based assays, with high D3R affinities (Ki = 0.14-50 nM) and moderate selectivity (<100-fold) over D2R. Cariprazine and two lead analogues, 13a and 13e, decreased cocaine self-administration (FR2; 1-10 mg/kg, i.p.) in rats, suggesting that partial agonists/antagonists with modest D3R/D2R selectivity may be effective in treating PSUD and potentially comorbidities with other affective disorders.

Despite of multiple systematic studies of schizophrenia based on proteomics, metabolomics, and genome-wide significant loci, reconstruction of underlying mechanism is still a challenging task. Combination of the advanced data for quantitative proteomics, metabolomics, and genome-wide association study (GWAS) can enhance the current fundamental knowledge about molecular pathogenesis of schizophrenia. In this study, we utilized quantitative proteomic and metabolomic assay, and high throughput genotyping for the GWAS study. We identified 20 differently expressed proteins that were validated on an independent cohort of patients with schizophrenia, including ALS, A1AG1, PEDF, VTDB, CERU, APOB, APOH, FASN, GPX3, etc. and almost half of them are new for schizophrenia. The metabolomic survey revealed 18 group-specific compounds, most of which were the part of transformation of tyrosine and steroids with the prevalence to androgens (androsterone sulfate, thyroliberin, thyroxine, dihydrotestosterone, androstenedione, cholesterol sulfate, metanephrine, dopaquinone, etc.). The GWAS assay mostly failed to reveal significantly associated loci therefore 52 loci with the smoothened p < 10^-5 were fractionally integrated into proteome-metabolome data. We integrated three omics layers and powered them by the quantitative analysis to propose a map of molecular events associated with schizophrenia psychopathology. The resulting interplay between different molecular layers emphasizes a strict implication of lipids transport, oxidative stress, imbalance in steroidogenesis and associated impartments of thyroid hormones as key interconnected nodes essential for understanding of how the regulation of distinct metabolic axis is achieved and what happens in the conditioned proteome and metabolome to produce a schizophrenia-specific pattern.

NMDA-receptor hypofunction is increasingly considered to be an important pathomechanism in schizophrenia. However, to date, it has not been possible to identify patients with relevant NMDA-receptor hypofunction who would respond to glutamatergic treatments. Preclinical models, such as the ketamine model, could help identify biomarkers related to NMDA-receptor function that respond to glutamatergic modulation, for example, via activation of the glycine-binding site. We, therefore, aimed to investigate the effects of opposing modulation of the NMDA receptor on gamma activity (30-100 Hz) at rest, the genesis of which appears to be highly dependent on NMDA receptors. The effects of subanesthetic doses of S-ketamine and pretreatment with glycine on gamma activity at rest were examined in twenty-five healthy male participants using 64-channel electroencephalography. Psychometric scores were assessed using the PANSS and the 5D-ASC. While S-ketamine significantly increased psychometric scores and gamma activity at the scalp and in the source space, pretreatment with glycine did not significantly attenuate any of these effects when controlled for multiple comparisons. Our results question whether increased gamma activity at rest constitutes a suitable biomarker for the target engagement of glutamatergic drugs in the preclinical ketamine model. They might further point to a differential role of NMDA receptors in gamma activity generation.