New Drug Treatments for Schizophrenia: A Review of Approaches to Target Circuit Dysfunction

Biological Psychiatry, Journal Year: 2024, Volume and Issue: 96(8), P. 638 - 650

Published: May 28, 2024

Schizophrenia is a leading cause of global disease burden. Current drug treatments are associated with significant side effects and have limited efficacy for many patients, highlighting the need to develop new approaches that target other aspects neurobiology schizophrenia. Preclinical, in vivo imaging, postmortem, genetic, pharmacological studies highlighted key role cortical GABAergic (gamma-aminobutyric acidergic)-glutamatergic microcircuits their projections subcortical dopaminergic circuits pathoetiology negative, cognitive, psychotic symptoms. Antipsychotics primarily act downstream component this circuit. However, multiple drugs currently development could elements circuit treat These include or glutamatergic targets, including glycine transporters, D-amino acid oxidase, sodium channels, potassium channels. Other likely on pathways regulate system, such as muscarinic trace amine receptors 5-HT

Language: Английский

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Urolithin A ameliorates schizophrenia-like behaviors and cognitive impairments in female rats by modulating NLRP3 signaling

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 151, P. 114336 - 114336

Published: Feb. 22, 2025

Language: Английский

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Neuroimaging epicenters as potential sites of onset of the neuroanatomical pathology in schizophrenia

Science Advances, Journal Year: 2024, Volume and Issue: 10(24)

Published: June 12, 2024

Schizophrenia lacks a clear definition at the neuroanatomical level, capturing sites of origin and progress this disorder. Using network-theory approach called epicenter mapping on cross-sectional magnetic resonance imaging from 1124 individuals with schizophrenia, we identified most likely "source origin" structural pathology. Our results suggest that Broca's area adjacent frontoinsular cortex may be epicenters pathophysiology in schizophrenia. These can predict an individual's response to treatment for psychosis. In addition, cross-diagnostic similarities based over 4000 diagnosed neurological, neurodevelopmental, or psychiatric disorders appear limited. When present, these are restricted bipolar disorder, major depressive obsessive-compulsive We provide comprehensive framework linking schizophrenia-specific multiple levels neurobiology, including cognitive processes, neurotransmitter receptors transporters, human brain gene expression. Epicenter reliable tool identifying potential onset neural

Language: Английский

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What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia

Biomolecules, Journal Year: 2024, Volume and Issue: 14(8), P. 906 - 906

Published: July 25, 2024

Schizophrenia is a frequently debilitating and complex mental disorder affecting approximately 1% of the global population, characterized by symptoms such as hallucinations, delusions, disorganized thoughts behaviors, cognitive dysfunction, negative symptoms. Traditional treatment has centered on postsynaptic dopamine antagonists, commonly known antipsychotic drugs, which aim to alleviate improve functioning quality life. Despite availability these medications, significant challenges remain in schizophrenia therapeutics, including incomplete symptom relief, resistance, medication side effects. This opinion article explores advancements treatment, emphasizing molecular mechanisms, novel drug targets, innovative delivery methods. One promising approach strategies that target neural networks circuits rather than single neurotransmitters, acknowledging complexity brain region interconnections involved schizophrenia. Another development biased agonists, selectively activate specific signaling pathways downstream receptors, offering potential for more precise pharmacological interventions with fewer The concept polypharmacy, where targets multiple pathways, exemplified KarXT, combining xanomeline trospium address both psychosis dysfunction. represents comprehensive strategy potentially improving outcomes patients. In conclusion, advancing understanding exploring therapeutic hold promise addressing unmet needs aiming effective tailored interventions. Future research should focus approaches achieve better clinical functional level life individuals

Language: Английский

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Clinical Characteristics and Prognostic Clinical Factors of Anti-Gamma-Aminobutyric Acid-B Receptor (Gabab-R) Encephalitis in Turkiye: A Multicenter Study

Published: Jan. 1, 2025

IntroductionGABAB-R encephalitis is a rare and newly recognized autoimmune disease. This study investigates the clinical laboratory features, treatment response, prognosis, malignancy associations in GABAB-R encephalitis.MethodsWe included consecutive patients with autoantibodies retrospectively analyzed their data, neuroimaging, EEG findings, seizure characteristics, responses, cancer presence. Prognosis was classified using final Modified Rankin Score (mRS), mRS>2 indicating poor prognosis.ResultsThere were 17 antibodies (12 males). The mean age at onset 61.29 (range: 37-86), follow-up 20.3 months 6-60). most common findings seizures, observed 10 (58.8%), which increased to 13 (76.5%) during follow-up, psychiatric symptoms 35.3%, hyponatremia 35.3%. Ten required intensive care unit (ICU) admission, 11 had an underlying malignancy, predominantly lung cancer. Additionally, one patient CASPR2 antibodies, another AMPA-R antibodies. Lesion probability map analysis revealed predominant involvement of bilateral mesiotemporal regions. Patients modified Scale greater than 2 (n=10) exhibited higher prevalence symptoms, ICU hyponatremia. Of 12 on anti-seizure medications, only 8 achieved seizure-free status follow-up. Those paraneoplastic etiology more likely present symptoms. Mortality, occurred 7 patients, associated persistent seizures admission.DiscussionMale gender are encephalitis, also displays high mortality rates. Remarkable prognostic factors include A significant number GABA-B receptor antibody experience

Language: Английский

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Haloperidol dopamine receptor occupancy and antagonism correspond to delirium agitation scores and EPS risk: A PBPK-PD modeling analysis

Journal of Psychopharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

Background: Delirium is a severe neuropsychiatric disorder associated with increased morbidity and mortality. Numerous precipitating factors etiologies merge into the pathophysiology of this condition which can be marked by agitation psychosis. Judicious use antipsychotic medications such as intravenous haloperidol reduces these symptoms distress in critically ill individuals. Aims: This study aimed to develop physiologically-based pharmacokinetic (PBPK) model for medication haloperidol; estimate plasma unbound interstitial brain concentrations repetitive administrations used hyperactive delirium treatment; determine dopamine receptor occupancy antagonism under conditions; correlate results Richmond Agitation-Sedation Scale (RASS) scores risk developing extrapyramidal (EPSs). Methods: The PBPK single peroral was developed PK-Sim software. pharmacodynamic (PD) RASS concentration passed regressor MonolixSuite 2021R platform. Results: Peak following 2 mg dose are 32 ± 5 nM 2.4 0.4 nM. With administrations, 70%–83% D2 L R 1%–10%. Variations changes individuals delirium. There linear association between odds ratio EPS peak functions occupancy. Conclusions: Haloperidol time course parallel score risk, respectively.

Language: Английский

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Research Progress on MECT Combined with Second-Generation Antipsychotic Drugs in the Treatment of Schizophrenia

Advances in Clinical Medicine, Journal Year: 2025, Volume and Issue: 15(01), P. 871 - 877

Published: Jan. 1, 2025

Language: Английский

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Striatal dopamine D2/D3 receptor regulation of human reward processing and behaviour

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 21, 2025

Abstract Signalling at dopamine D2/D3 receptors is thought to underlie motivated behaviour, pleasure experiences and emotional expression based on animal studies, but it unclear if this the case in humans or how relates neural processing of reward stimuli. Using a randomised, double-blind, placebo-controlled, crossover neuroimaging study, we show healthy that sustained receptor antagonism for 7 days results negative symptoms (impairments hedonic experience, verbal expression) related blunted striatal response In contrast, partial agonism does not disrupt signalling, behaviour experience. Both induce motor impairments, which are response. These findings identify central role signalling mechanism underlying responses humans, with implications understanding neuropsychiatric disorders such as schizophrenia Parkinson’s disease.

Language: Английский

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Single-subject network analysis of FDOPA PET in Parkinson’s disease and Psychosis spectrum

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Greater understanding of individual biological differences is essential for developing more targeted treatment approaches to complex brain disorders. Traditional analysis methods in molecular imaging studies have primarily focused on quantifying tracer binding specific regions, often neglecting inter-regional functional relationships. In this study, we propose a statistical framework that combines data with perturbation covariance construct single-subject networks and investigate patterns alterations. This was tested [18F]-DOPA PET as marker the dopamine system patients Parkinson's Disease (PD) schizophrenia evaluate its ability classify characterize their disease severity. Our results show effectively capture alterations, differentiate individuals heterogeneous conditions, account within-group variability. Moreover, approach successfully distinguishes between preclinical clinical stages psychosis identifies corresponding connectivity changes response antipsychotic medications. Mapping presents new powerful method characterizing individualized trajectories well evaluating effectiveness future research.

Language: Английский

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The Relationship of glutamate signaling to cannabis use and schizophrenia

Current Opinion in Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Purpose of review This examines the literature associating cannabis with schizophrenia, glutamate dysregulation in and involvement pathways. Cannabis use is widespread among adolescents world-wide sold legally many countries for recreational a variety forms. Most people it without lasting effects, but portion individuals have negative reactions that manifest acute psychotic symptoms, some, symptoms continue even after has ceased. To date, there huge gap our understanding why this occurs. Recent findings studies focused on abnormalities pathway effect system, role brain Default Mode Network. Summary Given these observations, we hypothesize perturbance neuronal connectivity by brains genetically at high risk psychosis will initiate schizophrenia-like psychosis. Future may tie together diverse observations combining magnetic resonance spectroscopy (MRS) functional imaging (fMRI) default resting state network patients new onset schizophrenia who do not compared nonpsychotic cannabis.

Language: Английский

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