5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.

Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.

Multisensory perceptual and causal inference is largely preserved in medicated post-acute individuals with schizophrenia.

Hallucinations and perceptual abnormalities in psychosis are thought to arise from imbalanced integration of prior information and sensory inputs. We combined psychophysics, Bayesian modeling, and electroencephalography (EEG) to investigate potential changes in perceptual and causal inference in response to audiovisual flash-beep sequences in medicated individuals with schizophrenia who exhibited limited psychotic symptoms. Seventeen participants with schizophrenia and 23 healthy controls reported either the number of flashes or the number of beeps of audiovisual sequences that varied in their audiovisual numeric disparity across trials. Both groups balanced sensory integration and segregation in line with Bayesian causal inference rather than resorting to simpler heuristics. Both also showed comparable weighting of prior information regarding the signals' causal structure, although the schizophrenia group slightly overweighted prior information about the number of flashes or beeps. At the neural level, both groups computed Bayesian causal inference through dynamic encoding of independent estimates of the flash and beep counts, followed by estimates that flexibly combine audiovisual inputs. Our results demonstrate that the core neurocomputational mechanisms for audiovisual perceptual and causal inference in number estimation tasks are largely preserved in our limited sample of medicated post-acute individuals with schizophrenia. Future research should explore whether these findings generalize to unmedicated patients with acute psychotic symptoms.

Cognitive Impairment Associated with Schizophrenia: From Pathophysiology to Treatment.

Cognitive impairment is a core feature of schizophrenia and a major contributor to poor functional outcomes. Methods for assessment of cognitive dysfunction in schizophrenia are now well established. In addition, there has been increasing appreciation in recent years of the additional role of social cognitive impairment in driving functional outcomes and of the contributions of sensory-level dysfunction to higher-order impairments. At the neurochemical level, acute administration of N-methyl-d-aspartate receptor (NMDAR) antagonists reproduces the pattern of neurocognitive dysfunction associated with schizophrenia, encouraging the development of treatments targeted at both NMDAR and its interactome. At the local-circuit level, an auditory neurophysiological measure, mismatch negativity, has emerged both as a veridical index of NMDAR dysfunction and excitatory/inhibitory imbalance in schizophrenia and as a critical biomarker for early-stage translational drug development. Although no compounds have yet been approved for treatment of cognitive impairment associated with schizophrenia, several candidates are showing promise in early-phase testing.

MiRAGE: mining relationships for advanced generative evaluation in drug repositioning.

MOTIVATION: Drug repositioning, the identification of new therapeutic uses for existing drugs, is crucial for accelerating drug discovery and reducing development costs. Some methods rely on heterogeneous networks, which may not fully capture the complex relationships between drugs and diseases. However, integrating diverse biological data sources offers promise for discovering new drug-disease associations (DDAs). Previous evidence indicates that the combination of information would be conducive to the discovery of new DDAs. However, the challenge lies in effectively integrating different biological data sources to identify the most effective drugs for a certain disease based on drug-disease coupled mechanisms. RESULTS: In response to this challenge, we present MiRAGE, a novel computational method for drug repositioning. MiRAGE leverages a three-step framework, comprising negative sampling using hard negative mining, classification employing random forest models, and feature selection based on feature importance. We evaluate MiRAGE on multiple benchmark datasets, demonstrating its superiority over state-of-the-art algorithms across various metrics. Notably, MiRAGE consistently outperforms other methods in uncovering novel DDAs. Case studies focusing on Parkinson's disease and schizophrenia showcase MiRAGE's ability to identify top candidate drugs supported by previous studies. Overall, our study underscores MiRAGE's efficacy and versatility as a computational tool for drug repositioning, offering valuable insights for therapeutic discoveries and addressing unmet medical needs.

Genetics-informed precision treatment formulation in schizophrenia and bipolar disorder.

Genetically informed drug development and repurposing is an attractive prospect for improving patient outcomes in psychiatry; however, the effectiveness of these endeavors is confounded by heterogeneity. We propose an approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritize individual "directional anchor" genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, which we call a pharmagenic enrichment score (PES), identify individuals with a higher burden of genetic risk, localized in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial.

BACKGROUND: New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis. METHODS: EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161). FINDINGS: From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]). INTERPRETATION: In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia. FUNDING: Karuna Therapeutics.

Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment.

BACKGROUND: Treatment resistant schizophrenia (TRS) is broadly defined as inadequate response to adequate treatment and is associated with a substantial increase in disease burden. Clozapine is the only approved treatment for TRS, showing superior clinical effect on overall symptomatology compared to other drugs, and is the prototype of atypical antipsychotics. Risperidone, another atypical antipsychotic with a more distinctive dopamine 2 antagonism, is commonly used in treatment of schizophrenia. Here, we conducted a genome-wide association study on patients treated with clozapine (TRS) vs. risperidone (non-TRS) and investigated whether single variants and/or polygenic risk score for schizophrenia are associated with TRS status. We hypothesized that patients who are treated with clozapine and risperidone might exhibit distinct neurobiological phenotypes that match pharmacological profiles of these drugs and can be explained by genetic differences. The study population (n = 1286) was recruited from a routine therapeutic drug monitoring (TDM) service between 2005 and 2022. History of a detectable serum concentration of clozapine and risperidone (without TDM history of clozapine) defined the TRS (n = 478) and non-TRS (n = 808) group, respectively. RESULTS: We identified a suggestive association between TRS and a common variant within the LINC00523 gene with a significance just below the genome-wide threshold (rs79229764 C > T, OR = 4.89; p = 1.8 × 10-7). Polygenic risk score for schizophrenia was significantly associated with TRS (OR = 1.4, p = 2.1 × 10-6). In a large post-mortem brain sample from schizophrenia donors (n = 214; CommonMind Consortium), gene expression analysis indicated that the rs79229764 variant allele might be involved in the regulation of GPR88 and PUDP, which plays a role in striatal neurotransmission and intellectual disability, respectively. CONCLUSIONS: We report a suggestive genetic association at the rs79229764 locus with TRS and show that genetic liability for schizophrenia is positively associated with TRS. These results suggest a candidate locus for future follow-up studies to elucidate the molecular underpinnings of TRS. Our findings further demonstrate the value of both single variant and polygenic association analyses for TRS prediction.

The relationship between familial-genetic risk and pharmacological treatment in a Swedish national sample of patients with major depression, bipolar disorder, and schizophrenia.

Using Swedish registers, we examine whether the prescription of and the response to antidepressants (AD), mood stabilizers (MS), and antipsychotics (AP) in the treatment of, respectively, major depression (MD), bipolar disorder (BD), and schizophrenia (SZ), are influenced by familial-genetic risk. We examined individuals born in Sweden 1960-1995 with a first diagnosis of MD (n = 257,177), BD (n = 23,032), and SZ (n = 4248) from 2006 to 2018. Drug classes and Defined Daily Dose (DDD) were obtained from the Pharmacy register using the Anatomical Therapeutic Chemical system. We utilized the Familial Genetic Risk Scores (FGRS) calculated from morbidity risks in first- through fifth degree relatives. Treatment with antidepressants (AD) in MD, mood-stabilizers (MS) in BD, and antipsychotics (AP) in SZ were associated with significantly higher disorder-specific familial-genetic risks. Using dosage trajectory analysis of AD, MS, and AP treatment for MD, BD, and SZ, respectively, familial-genetic risk was positively associated with higher and/or increasing drug dosages over time. For MD and BD, examining cases started on the most common pharmacologic treatment class (SSRIs for MD and "other anti-epileptics" for BD), familial-genetic risks were significantly lower in those who did not versus did later receive treatment from other AD and MS classes, respectively. Higher familial-genetic risk for BD predicted switching AD medication in cases of MD. Among pharmacologically treated cases of BD, familial-genetic risk was significantly higher for those treated with lithium. In a large population-based patient cohort, we found evidence of a wide-spread association between higher familial-genetic risk and i) increased likelihood of receiving pharmacologic treatment but 2) responding more poorly to it-as indicated by a switching of medications -- and/or requiring higher doses. Further investigations into the clinical utility of genetic risk scores in the clinical managements of MD, BD, and SZ are warranted.

Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

Pharmacological fingerprint of antipsychotic drugs at the serotonin 5-HT2A receptor.

The intricate involvement of the serotonin 5-HT2A receptor (5-HT2AR) both in schizophrenia and in the activity of antipsychotic drugs is widely acknowledged. The currently marketed antipsychotic drugs, although effective in managing the symptoms of schizophrenia to a certain extent, are not without their repertoire of serious side effects. There is a need for better therapeutics to treat schizophrenia for which understanding the mechanism of action of the current antipsychotic drugs is imperative. With bioluminescence resonance energy transfer (BRET) assays, we trace the signaling signature of six antipsychotic drugs belonging to three generations at the 5-HT2AR for the entire spectrum of signaling pathways activated by serotonin (5-HT). The antipsychotic drugs display previously unidentified pathway preference at the level of the individual Gα subunits and ß-arrestins. In particular, risperidone, clozapine, olanzapine and haloperidol showed G protein-selective inverse agonist activity. In addition, G protein-selective partial agonism was found for aripiprazole and cariprazine. Pathway-specific apparent dissociation constants determined from functional analyses revealed distinct coupling-modulating capacities of the tested antipsychotics at the different 5-HT-activated pathways. Computational analyses of the pharmacological and structural fingerprints support a mechanistically based clustering that recapitulate the clinical classification (typical/first generation, atypical/second generation, third generation) of the antipsychotic drugs. The study provides a new framework to functionally classify antipsychotics that should represent a useful tool for the identification of better and safer neuropsychiatric drugs and allows formulating hypotheses on the links between specific signaling cascades and in the clinical outcomes of the existing drugs.

Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation.

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

Using normative modeling to assess pharmacological treatment effect on brain state in patients with schizophrenia.

Quantifying individual differences in neuroimaging metrics is attracting interest in clinical studies with mental disorders. Schizophrenia is diagnosed exclusively based on symptoms, and the biological heterogeneity makes it difficult to accurately assess pharmacological treatment effects on the brain state. Using the Cambridge Centre for Ageing and Neuroscience data set, we built normative models of brain states and mapped the deviations of the brain characteristics of each patient, to test whether deviations were related to symptoms, and further investigated the pharmacological treatment effect on deviation distributions. Specifically, we found that the patients can be divided into 2 groups: the normalized group had a normalization trend and milder symptoms at baseline, and the other group showed a more severe deviation trend. The baseline severity of the depression as well as the overall symptoms could predict the deviation of the static characteristics for the dorsal and ventral attention networks after treatment. In contrast, the positive symptoms could predict the deviations of the dynamic fluctuations for the default mode and dorsal attention networks after treatment. This work evaluates the effect of pharmacological treatment on static and dynamic brain states using an individualized approach, which may assist in understanding the heterogeneity of the illness pathology as well as the treatment response.

Sex-related cortical asymmetry in antipsychotic-naïve first-episode schizophrenia.

Schizophrenia has been considered to exhibit sex-related clinical differences that might be associated with distinctly abnormal brain asymmetries between sexes. One hundred and thirty-two antipsychotic-naïve first-episode patients with schizophrenia and 150 healthy participants were recruited in this study to investigate whether cortical asymmetry would exhibit sex-related abnormalities in schizophrenia. After a 1-yr follow-up, patients were rescanned to obtain the effect of antipsychotic treatment on cortical asymmetry. Male patients were found to show increased lateralization index while female patients were found to exhibit decreased lateralization index in widespread regions when compared with healthy participants of the corresponding sex. Specifically, the cortical asymmetry of male and female patients showed contrary trends in the cingulate, orbitofrontal, parietal, temporal, occipital, and insular cortices. This result suggested male patients showed a leftward shift of asymmetry while female patients showed a rightward shift of asymmetry in these above regions that related to language, vision, emotion, and cognition. Notably, abnormal lateralization indices remained stable after antipsychotic treatment. The contrary trends in asymmetry between female and male patients with schizophrenia together with the persistent abnormalities after antipsychotic treatment suggested the altered brain asymmetries in schizophrenia might be sex-related disturbances, intrinsic, and resistant to the effect of antipsychotic therapy.

Multilayer network analysis reveals instability of brain dynamics in untreated first-episode schizophrenia.

Although aberrant static functional brain network activity has been reported in schizophrenia, little is known about how the dynamics of neural function are altered in first-episode schizophrenia and are modulated by antipsychotic treatment. The baseline resting-state functional magnetic resonance imaging data were acquired from 122 first-episode drug-naïve schizophrenia patients and 128 healthy controls (HCs), and 44 patients were rescanned after 1-year of antipsychotic treatment. Multilayer network analysis was applied to calculate the network switching rates between brain states. Compared to HCs, schizophrenia patients at baseline showed significantly increased network switching rates. This effect was observed mainly in the sensorimotor (SMN) and dorsal attention networks (DAN), and in temporal and parietal regions at the nodal level. Switching rates were reduced after 1-year of antipsychotic treatment at the global level and in DAN. Switching rates at baseline at the global level and in the inferior parietal lobule were correlated with the treatment-related reduction of negative symptoms. These findings suggest that instability of functional network activity plays an important role in the pathophysiology of acute psychosis in early-stage schizophrenia. The normalization of network stability after antipsychotic medication suggests that this effect may represent a systems-level mechanism for their therapeutic efficacy.

Beyond dopamine: Novel strategies for schizophrenia treatment.

Despite extensive research efforts aimed at discovering novel antipsychotic compounds, a satisfactory pharmacological strategy for schizophrenia treatment remains elusive. All the currently available drugs act by modulating dopaminergic neurotransmission, leading to insufficient management of the negative and cognitive symptoms of the disorder. Due to these challenges, several attempts have been made to design agents with innovative, non-dopaminergic mechanisms of action. Consequently, a number of promising compounds are currently progressing through phases 2 and 3 of clinical trials. This review aims to examine the rationale behind the most promising of these strategies while simultaneously providing a comprehensive survey of study results. We describe the versatility behind the cholinergic neurotransmission modulation through the activation of M1 and M4 receptors, exemplified by the prospective drug candidate KarXT. Our discussion extends to the innovative approach of activating TAAR1 receptors via ulotaront, along with the promising outcomes of iclepertin, a GlyT-1 inhibitor with the potential to become the first treatment option for cognitive impairment associated with schizophrenia. Finally, we evaluate the 5-HT2A antagonist paradigm, assessing two recently developed serotonergic agents, pimavanserin and roluperidone. We present the latest advancements in developing novel solutions to the complex challenges posed by schizophrenia, offering an additional perspective on the diverse investigated drug candidates.

Cardiovascular risk management among individuals with type 2 diabetes and severe mental illness: a cohort study.

AIMS/HYPOTHESIS: The aim of this study was to compare cardiovascular risk management among people with type 2 diabetes according to severe mental illness (SMI) status. METHODS: We used linked electronic data to perform a retrospective cohort study of adults diagnosed with type 2 diabetes in Scotland between 2004 and 2020, ascertaining their history of SMI from hospital admission records. We compared total cholesterol, systolic BP and HbA1c target level achievement 1 year after diabetes diagnosis, and receipt of a statin prescription at diagnosis and 1 year thereafter, by SMI status using logistic regression, adjusting for sociodemographic factors and clinical history. RESULTS: We included 291,644 individuals with type 2 diabetes, of whom 1.0% had schizophrenia, 0.5% had bipolar disorder and 3.3% had major depression. People with SMI were less likely to achieve cholesterol targets, although this difference did not reach statistical significance for all disorders. However, people with SMI were more likely to achieve systolic BP targets compared to those without SMI, with effect estimates being largest for schizophrenia (men: adjusted OR 1.72; 95% CI 1.49, 1.98; women: OR 1.64; 95% CI 1.38, 1.96). HbA1c target achievement differed by SMI disorder and sex. Among people without previous CVD, statin prescribing was similar or better in those with vs those without SMI at diabetes diagnosis and 1 year later. In people with prior CVD, SMI was associated with lower odds of statin prescribing at diabetes diagnosis (schizophrenia: OR 0.54; 95% CI 0.43, 0.68, bipolar disorder: OR 0.75; 95% CI 0.56, 1.01, major depression: OR 0.92; 95% CI 0.83, 1.01), with this difference generally persisting 1 year later. CONCLUSIONS/INTERPRETATION: We found disparities in cholesterol target achievement and statin prescribing by SMI status. This reinforces the importance of clinical review of statin prescribing for secondary prevention of CVD, particularly among people with SMI.

Inhibition of reactive oxygen species production accompanying alternatively activated microglia by risperidone in a mouse ketamine model of schizophrenia.

Recent studies have highlighted the potential involvement of reactive oxygen species (ROS) and microglia, a major source of ROS, in the pathophysiology of schizophrenia. In our study, we explored how the second-generation antipsychotic risperidone (RIS) affects ROS regulation and microglial activation in the hippocampus using a mouse ketamine (KET) model of schizophrenia. KET administration resulted in schizophrenia-like behaviors in male C57BL/6J mice, such as impaired prepulse inhibition (PPI) of the acoustic startle response and hyper-locomotion. These behaviors were mitigated by RIS. We found that the gene expression level of an enzyme responsible for ROS production (Nox2), which is primarily associated with activated microglia, was lower in KET/RIS-treated mice than in KET-treated mice. Conversely, the levels of antioxidant enzymes (Ho-1 and Gclc) were higher in KET/RIS-treated mice. The microglial density in the hippocampus was increased in KET-treated mice, which was counteracted by RIS. Hierarchical cluster analysis revealed three morphological subtypes of microglia. In control mice, most microglia were resting-ramified (type I, 89.7%). KET administration shifted the microglial composition to moderately ramified (type II, 44.4%) and hyper-ramified (type III, 25.0%). In KET/RIS-treated mice, type II decreased to 32.0%, while type III increased to 34.0%. An in vitro ROS assay showed that KET increased ROS production in dissociated hippocampal microglia, and this effect was mitigated by RIS. Furthermore, we discovered that a NOX2 inhibitor could counteract KET-induced behavioral deficits. These findings suggest that pharmacological inhibition of ROS production by RIS may play a crucial role in ameliorating schizophrenia-related symptoms. Moreover, modulating microglial activation to regulate ROS production has emerged as a novel avenue for developing innovative treatments for schizophrenia.

Antipsychotic drugs in first-episode psychosis: a target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in first-episode psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts, to emulate a target trial comparing antipsychotics, with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from the European First Episode Schizophrenia Trial, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse-probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone were 61.5% (95% CI, 52.5-70.6), 73.5% (95% CI, 60.5-84.9), 76.8% (95% CI, 67.2-85.3), 58.4% (95% CI, 40.4-77.4), 76.5% (95% CI, 62.1-88.5), and 74.4% (95% CI, 67.0-81.2), respectively. Compared with aripiprazole, the 12-month risk differences were -15.3% (95% CI, -30.0 to 0.0) for olanzapine, -12.8% (95% CI, -25.7 to -1.0) for risperidone, and 3.0% (95% CI, -21.5 to 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration sufficed to remove confounding for these clinical questions. This article is part of a Special Collection on Mental Health.

Putative neural mechanisms underlying release-mode-specific abnormalities in dopamine neural activity in a schizophrenia-like model: The distinct roles of glutamate and serotonin in the impaired regulation of dopamine neurons.

Abnormalities in dopamine function might be related to psychiatric disorders such as schizophrenia. Even at the same concentration, dopamine exerts opposite effects on information processing in the prefrontal cortex depending on independent dopamine release modes known as tonic and phasic releases. This duality of dopamine prevents a blanket interpretation of the implications of dopamine abnormalities for diseases on the basis of absolute dopamine levels. Moreover, the mechanisms underlying the mode-specific dopamine abnormalities are not clearly understood. Here, I show that the two modes of dopamine release in the prefrontal cortex of a schizophrenia-like model are disrupted by different mechanisms. In the schizophrenia-like model established by perinatal exposure to inflammatory cytokine, epidermal growth factor, tonic release was enhanced and phasic release was decreased in the prefrontal cortex. I examined the activity of dopamine neurons in the ventral tegmental area (VTA), which sends dopamine projections to the prefrontal cortex, under anaesthesia. The activation of VTA dopamine neurons during excitatory stimulation (local application of glutamate or N-methyl-d-aspartic acid [NMDA]), which is associated with phasic activity, was blunt in this model. Dopaminergic neuronal activity in the resting state related to tonic release was increased by disinhibition of the dopamine neurons due to the impairment of 5HT2 (5HT2A) receptor-regulated GABAergic inputs. Moreover, chronic administration of risperidone ameliorated this disinhibition of dopaminergic neurons. These results provide an idea about the mechanism of dopamine disturbance in schizophrenia and may be informative in explaining the effects of atypical antipsychotics as distinct from those of typical drugs.