IUPHAR Review - Novel therapeutic targets for schizophrenia treatment: a translational perspective

Pharmacological Research, Journal Year: 2025, Volume and Issue: unknown, P. 107690 - 107690

Published: March 1, 2025

Schizophrenia is a severe and debilitating psychiatric disorder that profoundly impacts cognitive, emotional, social functioning. Despite its devastating personal societal toll, current treatments often provide only partial relief, underscoring the urgent need for innovative therapeutic strategies. This review explores emerging approaches target complex neurobiological underpinnings of schizophrenia, moving beyond traditional dopamine-centric models. Among these, some novel drugs still employ multimodal mechanisms, simultaneously targeting dopaminergic serotonergic systems to enhance efficacy tolerability. Given well-documented excitatory/inhibitory imbalance in significant efforts have been directed toward addressing NMDA receptor hypofunctionality. However, strategies this pathway yet demonstrate consistent clinical efficacy. In contrast, therapies cholinergic system shown greater promise. For instance, xanomeline-trospium combination, which modulates muscarinic receptors, has recently gained approval, other molecules with similar mechanisms are currently under development. Beyond these approaches, being explored pathways, including neuroplasticity, neuroinflammation, mitochondrial dysfunction. These designed as part combinatorial strategy available antipsychotic drugs. progress, challenges remain translating experimental discoveries into effective applications. Future research should prioritize biomarker-driven precision medicine optimize individualized treatment outcomes. By integrating targets, schizophrenia may evolve more comprehensive personalized approach, disorder's full spectrum symptoms improving patient quality life.

Language: Английский

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Why hasn’t genetics taught us more about schizophrenia?

The Transmitter, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Gene dosage architecture across complex traits

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

Copy number variants (CNVs) have large effects on complex traits, but they are rare and remain challenging to study. As a result, our understanding of biological functions linking gene dosage traits remains limited, whether these sensitive similar those underlying the single nucleotide (SNVs) common unknown. We developed FunBurd, functional burden analysis, test association CNVs aggregated within sets. applied this approach in 500,000 individuals from UK Biobank associate 43 with disrupting 172 sets across tissues cell types. compared CNV findings LoF (Loss Function) SNVs same cohort using All showed FDR significant associations CNVs. Brain tissue neuronal cell-types highest levels pleiotropy. Most set could, part, be explained by genetic constraint, except for brain related processes. Shared contributions between pairs were concordant types variants, average 2-fold higher, variants.Functional enrichment found limited overlap variants. Moreover, deletions duplications negatively correlated most traits.In conclusion, we present new methods separate constraint function traits. Overall, convergence different -even duplications- limited. limited.FunBurd (functional analysis) was UKBiobank tissues/cell type sets.All brain-related higher The Our provide insights

Language: Английский

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Does Cannabis Use Contribute to Schizophrenia? A Causation Analysis Based on Epidemiological Evidence

Biomolecules, Journal Year: 2025, Volume and Issue: 15(3), P. 368 - 368

Published: March 4, 2025

Cannabis abuse has been linked to acute psychotic symptoms as well the development of schizophrenia. Although association described, causation not yet investigated. Therefore, we investigated whether cannabis or cannabinoid use is causal for schizophrenia, conducting a systematic literature review according PRISM guidelines. Epidemiological studies and randomized clinical trials investigating links between psychosis-like events (PLE) schizophrenia were identified (according guidelines), relevant included in Forest plot analysis. Confounder analysis was performed using funnel plot, Hill causality criteria used estimate causation. A total 18 fulfilled search criteria; 10 forest plot. All reported an increased risk PLE nine ten studies, significant increase; overall OR calculated be 2.88 (CI 2.24 3.70), with twofold-higher during adolescence. effects indicated by The high likelihood contribution development. Cannabinoids likely contribute chronic especially if taken This effect increases THC concentration frequency use, stronger males than females. points possibility selective toxicity on synaptic plasticity adolescence, compared adult use. should regulated discouraged, prevention efforts strengthened, reference

Language: Английский

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Intergenerational transmission of complex traits and the offspring methylome

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Abstract The genetic makeup of parents can directly or indirectly affect their offspring phenome through transmission via the environment that is influenced by parental heritable traits. Our understanding mechanisms which indirect effects operate limited. Here, we hypothesize one mechanism methylome. To test this hypothesis, polygenic scores (PGSs) for schizophrenia, smoking initiation, educational attainment (EA), social deprivation, body mass index (BMI), and height were analyzed in a cohort 1528 (51.5% boys, mean [ SD ] age = 10 [2.8] years). We modelled parent PGSs on buccal-DNA methylation, accounting own PGS offspring, found significant associations between EA, BMI, height, buccal methylation sites, comprising 16, 2, 1, 6 respectively (alpha 2.7 × −5 ). More DNA sites associated with maternal than paternal PGSs, possibly reflecting pre- periconceptional stronger involvement shaping offspring’s during early childhood.

Language: Английский

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Cortical differences across psychiatric disorders and associated common and rare genetic variants

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

Genetic studies have identified common and rare variants increasing the risk for neurodevelopmental psychiatric disorders (NPDs). These also been shown to influence structure of cerebral cortex. However, it is unknown whether cortical differences associated with genetic are linked they confer NPDs. To answer this question, we analyzed thickness (CT) surface area (SA) NPDs, in ∼33000 individuals from general population clinical cohorts, as well ENIGMA summary statistics 8 Rare NPDs were preferentially total SA, while mean CT. Larger effects on CT, but not observed NPD medicated subgroups. At regional level, sensorimotor areas, showed higher association areas. We show that schizophrenia- bipolar-disorder- SNPs positive negative effect sizes SA suggesting their aggregated cancel out additive polygenic models. Overall, CT do relate those across individual may be critical non-genetic factors, such medication lived experience disorder.

Language: Английский

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A foundational neuronal protein network model unifying multimodal genetic, transcriptional, and proteomic perturbations in schizophrenia.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

Schizophrenia (SCZ) is a complex psychiatric disorder with diverse genetic landscape, involving common regulatory variants, rare protein-coding mutations, structural genomic rearrangements, and transcriptional dysregulation. A critical challenge in developing rationally designed therapeutics understanding how these various factors converge to disrupt cellular networks the human brain, ultimately contributing SCZ. Towards this aim, we generated multimodal data, including SCZ-specific protein-protein interactions stem-cell-derived neuronal models adult postmortem cortex, integrated transcriptomic datasets from individuals disorders. We identified three distinct neuron-specific SCZ protein networks, or modules, significantly enriched for perturbations associated The relevance of modules was validated through whole-cell proteomics patient-derived neurons, revealing their disruption 22q11.2 deletion carriers diagnosed demonstrated therapeutic potential by showing that are targets GSK3 inhibition using phosphoproteomics. Our findings present foundational model integrates genetic, transcriptional, proteomic This provides cohesive framework polygenic affect pathways as well data-driven pathway resource identifying drug reverse disruptions observed networks.

Language: Английский

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A mechanism of global gene expression regulation is disrupted by multiple disease states and drug treatments

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(5), P. e0317071 - e0317071

Published: May 8, 2025

Conventional expression studies quantify messenger RNA (mRNA) transcript levels gene-by-gene. We recently showed that protein is modulated at a global scale by amino acid availability, suggesting mRNA might be equivalently affected. Through re-analysis of public transcriptomic datasets, it was confirmed nucleobase supply interacts with the specific demands A + U:C G sequence composition to shape profile expression, which can quantified as gradient average change change. In mammals, each separate organ and cell-type displays distinct baseline expression. These profiles shift dynamically across circadian day menstrual cycle. They are also significantly distorted viral infection, multiple complex genetic disorders (including Alzheimer’s disease, schizophrenia, autoimmune disorders), after treatment 115 597 chemical entities analysed. included known toxins analogues, but many commonly prescribed medications such antibiotics proton pump inhibitors, thus revealing new mechanism drug action side-effect. As well key roles in disease susceptibility, mRNAs extreme compositions over-represented gene ontologies transcription cell division, making these processes particularly sensitive swings This may permit efficient, en bloc transcriptional reprogramming state through simple adjustment proportion supply. It proposed this helped mitigate loss essential synthesis higher organisms. summary, regulation invisible conventional analysis, its measurement allows useful distinction between active, promoter-mediated changes passive, state-dependent competence. Linking metabolism directly offers an entirely perspective on evolution, aetiopathology x environment - GxE interactions), nature pharmacological response.

Language: Английский

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Genomics of schizophrenia, bipolar disorder and major depressive disorder

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: May 12, 2025

Language: Английский

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Accounting for the impact of rare variants on causal inference with RARE: a novel multivariable Mendelian randomization method

Briefings in Bioinformatics, Journal Year: 2025, Volume and Issue: 26(3)

Published: May 1, 2025

Abstract Mendelian randomization (MR) method utilizes genetic variants as instrumental variables to infer the causal effect of an exposure on outcome. However, impact rare traits is often neglected, and traditional MR assumptions can be violated by correlated horizontal pleiotropy (CHP) uncorrelated (UHP). To address these issues, we propose a multivariable approach, extension standard framework: MVMR incorporating Rare Accounting for multiple Risk factors shared plEiotropy (RARE). In simulation studies, demonstrate that RARE effectively detects effects exposures outcome with accounting inference. Additionally, apply study high density lipoprotein low type 2 diabetes coronary atherosclerosis, respectively, thereby illustrating its robustness effectiveness in real data analysis.

Language: Английский

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