Retrospective analysis of lithium treatment: examination of blood levels.

Introduction: Lithium is a key medication for treating various neuropsychiatric disorders, with a narrow therapeutic index and significant drug interactions. Monitoring lithium blood levels is crucial. This study aims to investigate the relationship between lithium blood levels and demographic characteristics such as age and gender, as well as possible drug interactions, in patients with a history of lithium use who applied to various services and outpatient clinics. Materials & methods: The files of 438 patients who were admitted to various services and outpatient clinics of Kirklareli Training and Research Hospital between January 1 and December 31, 2023, were retrospectively reviewed. Patients' blood lithium levels, gender, age, service/outpatient clinic they admitted to, other medications used, urea, creatinine, and eGFR values were recorded. Results: When the demographic characteristics of 438 patients were examined, 62% were female (270), 38% were male (168), and the average age was 46.3 ± 14.8 years, showing a normal distribution. It was found that 192 patients (71 males, 121 females) had therapeutic lithium blood levels, while 244 patients (97 males, 147 females) had levels below 0.6 mmol/L. Two female patients had blood levels above the therapeutic range (1.23 and 1.43 mmol/L). Among the clinics and services, the four most frequented were the psychiatry clinic (314 patients), internal medicine clinic (36 patients), emergency service (27 patients), and medical oncology clinic (17 patients). Of the 314 patients admitted to the psychiatry clinic, 168 had therapeutic drug levels; only 7 of the 36 admitted to internal medicine had therapeutic levels; 12 of the 27 patients in the emergency service had therapeutic levels; and all 17 patients in medical oncology had levels below therapeutic limits. Discussion: The data emphasize the importance of regular blood level monitoring to ensure lithium treatment's efficacy and patient safety. It is noteworthy that most patients in the psychiatry clinic had therapeutic drug levels, while those in other clinics had lower levels. Conclusion: In conclusion, this study highlights the importance of regular blood level monitoring to ensure the efficacy and safety of lithium treatment.

Fkbp5 gene deletion: Circadian rhythm profile and brain proteomics in aged mice.

FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub-anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel-running activity, but did offer protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal-cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51-focused therapeutics for stress-related disorders.

A Comprehensive Review of Low-Intensity Focused Ultrasound Parameters and Applications in Neurologic and Psychiatric Disorders.

OBJECTIVES: Low-intensity focused ultrasound (LIFU) is gaining increased interest as a potential therapeutic modality for a range of neuropsychiatric diseases. Current neuromodulation modalities often require a choice between high spatial fidelity or invasiveness. LIFU is unique in this regard because it provides high spatial acuity of both superficial and deep neural structures while remaining noninvasive. This new form of noninvasive brain stimulation may provide exciting potential treatment options for a variety of neuropsychiatric disorders involving aberrant neurocircuitry within deep brain structures, including pain and substance use disorders. Furthermore, LIFU is compatible with noninvasive neuroimaging techniques, such as functional magnetic resonance imaging and electroencephalography, making it a useful tool for more precise clinical neuroscience research to further understand the central nervous system. MATERIALS AND METHODS: In this study, we provide a review of the most recent LIFU literature covering three key domains: 1) the history of focused ultrasound technology, comparing it with other forms of neuromodulation, 2) the parameters and most up-to-date proposed mechanisms of LIFU, and finally, 3) a consolidation of the current literature to date surrounding the clinical research that has used LIFU for the modification or amelioration of several neuropsychiatric conditions. RESULTS: The impact of LIFU including poststroke motor changes, pain, mood disorders, disorders of consciousness, dementia, and substance abuse is discussed. CONCLUSIONS: Although still in its infancy, LIFU is a promising tool that has the potential to change the way we approach and treat neuropsychiatric disorders. In this quickly evolving field, this review serves as a snapshot of the current understanding of LIFU in neuropsychiatric research.

Reliability and validity of a newly developed PANDAS/PANS questionnaire.

OBJECTIVE: This study aimed to examine the reliability and validity of a newly developed questionnaire for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS). The aim was to contribute to future standardisation of screening methods for symptoms and comorbidity, as well as the measurement of symptom severity, daily life impairment, and treatment effectiveness in individuals diagnosed with PANDAS/PANS. METHODS: 27 items from the PANDAS/PANS questionnaire concerning symptoms and comorbidities associated with PANDAS/PANS were divided into ten domains. To assess the external validity, 119 PANDAS/PANS questionnaires from a cohort of 65 children with PANDAS/PANS were correlated with three well-known validated questionnaires: the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS), and the Strengths and Difficulties Questionnaire (SDQ). The internal validity of the PANDAS/PANS questionnaire was assessed by correlating the PANDAS/PANS items with the domains. RESULTS: Internal consistency of the PANDAS/PANS questionnaire was high, measuring moderate to very strong correlations. The external correlations for the PANDAS/PANS questionnaire showed a higher correlation with the ADHD-RS and CY-BOCS (rs ≥ 0.60) than with the SDQ (rs < 0.40). CONCLUSION: The validity and clinical feasibility of the PANDAS/PANS questionnaire were confirmed as an effective tool for screening symptoms, assessing symptom severity, and evaluating comorbidity and daily life impairment in individuals with PANDAS/PANS. These findings can potentially enhance the management of PANDAS/PANS patients in both clinical and research settings.

Sex-based differences in neuropsychiatric symptoms are due to estradiol/ERα-dependent transcriptional regulation via the modulation of steroid levels by sirolimus.

The sex of the patient often affects the prevalence, progression, and severity of many psychiatric disorders. The incidence, progression, and severity of Parkinson's disease and Alzheimer's disease, the most common neurodegenerative diseases, also differ between the sexes. Sex differences in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and anxiety are also observed in tuberous sclerosis complex (TSC). Neuropsychiatric symptoms are one of the most important manifestations of TSC, and the multiple neuropsychiatric symptoms are collectively referred to as TSC-associated neuropsychiatric disorders (TAND). We created TSC model mice (Tsc2 conditional knockout [cKO] mice) that developed epilepsy and TAND. Sex-based differences were observed for hyperactivity and cognitive dysfunctions in Tsc2 cKO mice with TAND, indicating more severe symptoms in female mice than in male mice. TSC is thought to be caused by the hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1), and mTORC1 inhibitors improve almost all TSC symptoms. Treatment with sirolimus, an mTORC1 inhibitor, improved TAND in Tsc2 cKO mice. We aimed to elucidate the mechanism underlying sex-based differences in TAND using Tsc2 cKO mice and sirolimus. We found that estradiol (E2) and estrogen receptor (ER)α are involved in sex differences in neuropsychiatric symptoms, and discovered a novel function of sirolimus. We showed that sirolimus ameliorated TAND by modulating brain steroid levels and regulating E2/ERα-dependent transcriptional activation. This indicates sirolimus may be beneficial for the treatment of TAND as well as diseases caused by sex-based differences and steroid levels.

Psychoactive substances for the treatment of neuropsychiatric disorders.

In the contemporary landscape of psychiatric medicine, critical advancements have been noted in the utilization of psychoactive substances such as hallucinogens, 3,4-methylenedioxymethamphetamine (MDMA), and ketamine for the treatment of severe mental health disorders. This review provides a detailed evaluation of these substances, focusing on their mechanisms of action and the profound clinical outcomes observed in controlled environments. Hallucinogens like lysergic acid diethylamide and psilocybin primarily target the 5-HT2A receptor agonist-2 (5-HT2AR), inducing substantial perceptual and cognitive shifts that facilitate deep psychological introspection and significant therapeutic advances, particularly in patients suffering from depression and anxiety disorders. MDMA, influencing multiple neurotransmitter systems including 5-Hydroxytryptamine (5-HT), dopamine, and norepinephrine, has been demonstrated to effectively alleviate symptoms of post-traumatic stress disorder, enhancing patients' emotional engagement and resilience during psychotherapy. Meanwhile, ketamine, a glutamate receptor antagonist, rapidly alleviates depressive symptoms, offering a lifeline for individuals with treatment-resistant depression through its fast-acting antidepressant properties. The integration of these substances into psychiatric practice has shown promising results, fundamentally changing the therapeutic landscape for patients unresponsive to traditional treatment modalities. However, the potent effects of these agents also necessitate a cautious approach in clinical application, ensuring careful dosage control, monitoring, and risk management to prevent potential abuse and mitigate adverse effects.

Unveiling the neurolipidome of obsessive-compulsive disorder: A scoping review navigating future diagnostic and therapeutic applications.

Obsessive-Compulsive Disorder (OCD) poses a multifaceted challenge in psychiatry, with various subtypes and severities greatly impacting well-being. Recent scientific attention has turned towards lipid metabolism, particularly the neurolipidome, in response to clinical demands for cost-effective diagnostics and therapies. This scoping review integrates recent animal, translational, and clinical studies to explore impaired neurolipid metabolism mechanisms in OCD's pathogenesis, aiming to enhance future diagnostics and therapeutics. Five key neurolipids - endocannabinoids, lipid peroxidation, phospholipids, cholesterol, and fatty acids - were identified as relevant. While the endocannabinoid system shows promise in animal models, its clinical application remains limited. Conversely, lipid peroxidation and disruptions in phospholipid metabolism exhibit significant impacts on OCD's pathophysiology based on robust clinical data. However, the role of cholesterol and fatty acids remains inconclusive. The review emphasises the importance of translational research in linking preclinical findings to real-world applications, highlighting the potential of the neurolipidome as a potential biomarker for OCD detection and monitoring. Further research is essential for advancing OCD understanding and treatment modalities.

Multi-Omics Integration Analysis Pinpoint Proteins Influencing Brain Structure and Function: Toward Drug Targets and Neuroimaging Biomarkers for Neuropsychiatric Disorders.

Integrating protein quantitative trait loci (pQTL) data and summary statistics from genome-wide association studies (GWAS) of brain image-derived phenotypes (IDPs) can benefit in identifying IDP-related proteins. Here, we developed a systematic omics-integration analytic framework by sequentially using proteome-wide association study (PWAS), Mendelian randomization (MR), and colocalization (COLOC) analyses to identify the potentially causal brain and plasma proteins for IDPs, followed by pleiotropy analysis, mediation analysis, and drug exploration analysis to investigate potential mediation pathways of pleiotropic proteins to neuropsychiatric disorders (NDs) as well as candidate drug targets. A total of 201 plasma proteins and 398 brain proteins were significantly associated with IDPs from PWAS analysis. Subsequent MR and COLOC analyses further identified 313 potentially causal IDP-related proteins, which were significantly enriched in neural-related phenotypes, among which 91 were further identified as pleiotropic proteins associated with both IDPs and NDs, including EGFR, TMEM106B, GPT, and HLA-B. Drug prioritization analysis showed that 6.33% of unique pleiotropic proteins had drug targets or interactions with medications for NDs. Nine potential mediation pathways were identified to illustrate the mediating roles of the IDPs in the causal effect of the pleiotropic proteins on NDs, including the indirect effect of TMEM106B on Alzheimer's disease (AD) risk via radial diffusivity (RD) of the posterior limb of the internal capsule (PLIC), with the mediation proportion being 11.18%, and the indirect effect of EGFR on AD through RD of PLIC, RD of splenium of corpus callosum (SCC), and fractional anisotropy (FA) of SCC, with the mediation proportion being 18.99%, 22.79%, and 19.91%, respectively. These findings provide novel insights into pathogenesis, drug targets, and neuroimaging biomarkers of NDs.

Can infliximab serve as a new therapy for neuropsychiatric symptoms?

Neuropsychiatric disorders present a global challenge to public health. Mechanisms associated with neuropsychiatric disorders etiology include apoptosis, oxidative stress, and neuroinflammation. Tumor necrosis factor alpha, an inflammatory cytokine, mediates pathophysiology of neuropsychiatric disorders. Therefore, its inhibition by infliximab might afford a valuable target for intervention. Infliximab is commonly used to treat inflammatory diseases, including ulcerative colitis, Crohn's disease, and rheumatoid arthritis. Recently, it has been shown that infliximab improves cognitive dysfunction, depression, anxiety, and life quality. Here, we review contemporary knowledge supporting the need to further characterize infliximab as a potential treatment for neuropsychiatric disorders.

New insights into potential biomarkers and their roles in biological processes associated with hepatitis C-related liver cirrhosis by hepatic RNA-seq-based transcriptome profiling.

Chronic hepatitis C virus infection is a major cause of mortality due to liver cirrhosis globally. Despite the advances in recent therapeutic strategies, there is yet a high burden of HCV-related cirrhosis worldwide concerning low coverage of newly developed antiviral therapies, insufficient validity of the current diagnostic methods for cirrhosis, and incomplete understanding of the pathogenesis in this stage of liver disease. Hence we aimed to clarify the molecular events in HCV-related cirrhosis and identify a liver-specific gene signature to potentially improve diagnosis and prognosis of the disease. Through RNA-seq transcriptome profiling of liver samples of Iranian patients with HCV-related cirrhosis, the differentially expressed genes (DEGs) were identified and subjected to functional annotation including biological process (BP) and molecular function (MF) analysis and also KEGG pathway enrichment analysis. Furthermore, the validation of RNA-seq data was investigated for seven candidate genes using qRT-PCR. Moreover, the diagnostic and prognostic power of validated DEGs were analyzed in both forms of individual DEG and combined biomarkers through receiver operating characteristic (ROC) analysis. Finally, we explored the pair-wise correlation of these six validated DEGs in a new approach. We identified 838 significant DEGs (padj ˂0.05) enriching 375 and 15 significant terms subjected to BP and MF, respectively (false discovery rate ˂ 0.01) and 46 significant pathways (p-value ˂ 0.05). Most of these biological processes and pathways were related to inflammation, immune responses, and cellular processes participating somewhat in the pathogenesis of liver disease. Interestingly, some neurological-associated genes and pathways were involved in HCV cirrhosis-related neuropsychiatric disorders. Out of seven candidate genes, six DEGs, including inflammation-related genes ISLR, LTB, ZAP70, KLRB1, and neuronal-related genes MOXD1 and Slitrk3 were significantly confirmed by qRT-PCR. There was a close agreement in the expression change results between RNA-seq and qRT-PCR for our candidate genes except for SAA2-SAA4 (P= 0.8). High validity and reproducibility of six novel DEGs as diagnostic and prognostic biomarkers were observed. We also found several pair-wise correlations between validated DEGs. Our findings indicate that the six genes LTB, ZAP70, KLRB1, ISLR, MOXD1, and Slitrk3 could stand as promising biomarkers for diagnosing of HCV-related cirrhosis. However, further studies are recommended to validate the diagnostic potential of these biomarkers and evaluate their capability as targets for the prevention and treatment of cirrhosis disease.

COVID-19 and Mental Health: A "Pandemic Within a Pandemic".

The COVID-19 pandemic has brought significant changes in daily life for humanity and has had a profound impact on mental health. As widely acknowledged, the pandemic has led to notable increases in rates of anxiety, depression, distress, and other mental health-related issues, affecting both infected patients and non-infected individuals. COVID-19 patients and survivors face heightened risks for various neurological and psychiatric disorders and complications. Vulnerable populations, including those with pre-existing mental health conditions and individuals living in poverty or frailty, may encounter additional challenges. Tragically, suicide rates have also risen, particularly among young people, due to factors such as unemployment, financial crises, domestic violence, substance abuse, and social isolation. Efforts are underway to address these mental health issues, with healthcare professionals urged to regularly screen both COVID-19 and post-COVID-19 patients and survivors for psychological distress, ensuring rapid and appropriate interventions. Ongoing periodic follow-up and multidimensional, interdisciplinary approaches are essential for individuals experiencing long-term psychiatric sequelae. Preventive strategies must be developed to mitigate mental health problems during both the acute and recovery phases of COVID-19 infection. Vaccination efforts continue to prioritize vulnerable populations, including those with mental health conditions, to prevent future complications. Given the profound implications of mental health problems, including shorter life expectancy, diminished quality of life, heightened distress among caregivers, and substantial economic burden, it is imperative that political and health authorities prioritize the mental well-being of all individuals affected by COVID-19, including infected individuals, non-infected individuals, survivors, and caregivers.

Microglia and Microbiome-Gut-Brain Axis.

The mammalian gut contains a community of microorganisms called gut microbiome. The gut microbiome is integrated into mammalian physiology, contributing to metabolism, production of metabolites, and promoting immunomodulatory actions. Microglia, the brain's resident innate immune cells, play an essential role in homeostatic neurogenesis, synaptic remodeling, and glial maturation. Microglial dysfunction has been implicated in the pathogenesis of several neuropsychiatric disorders. Recent findings indicate that microglia are influenced by the gut microbiome and their derived metabolites throughout life. The pathways by which microbiota regulate microglia have only started to be understood, but this discovery has the potential to provide valuable insights into the pathogenesis of brain disorders associated with an altered microbiome. Here, we discuss the recent literature on the role of the gut microbiome in modulating microglia during development and adulthood and summarize the key findings on this bidirectional crosstalk in selected examples of neuropsychiatric and neurodegenerative disorders. We also highlight some current caveats and perspectives for the field.

[Adverse effects of the tezacaftor/ivacaftor/elexacaftor combination that may lead to discontinuation: About a series of 10 cases]. / Effets indésirables de l'association tezacaftor/ivacaftor/elexacaftor pouvant mener à un arrêt de traitement : à propos d'une série de 10 cas.

INTRODUCTION: Cystic fibrosis transmembrane regulator (CFTR) channel modulators (ivacaftor, lumacaftor, tezacaftor and elexacaftor) represent a major advance in the management of cystic fibrosis. However, few data are available on the real-life safety profile of these medications, in particular on adverse events that may lead to their discontinuation. The aim of this study is to describe the characteristics and evolution of adverse reactions to the tezacaftor/ivacaftor/elexacaftor combination that led to discontinuation and were reported to the Centre régional de pharmacovigilance (CRPV) in Rennes (France). MATERIALS AND METHODS: A retrospective study was conducted from December 2021 to May 2023, focusing on cases of discontinuation of the tezacaftor/ivacaftor/elexacaftor combination due to the occurrence of one or more adverse effects, and reported to the CRPV of Rennes, France. RESULTS: Ten cases of drug discontinuation were reported to the Rennes CRPV (6 women/4 men). Adverse effects mainly involved neuropsychiatric disorders (n=6), followed by liver disorders (n=2), ear, nose and throat disorders (n=1), and digestive disorders (n=1). The average duration of treatment at discontinuation was 339.8 [39-668] days. The drug was reintroduced in 7 patients on average 48.7 [7-123] days after discontinuation, with a dosage adjustments (n=4) consisting of changes in dosing times or a reduction in daily doses, with varying success in alleviating adverse symptoms depending on the case. CONCLUSION: This small case series suggests that neuropsychiatric adverse effects may occur more frequently than initially described after initiation of tezacaftor/ivacaftor/elexacaftor, and should be carefully screened and monitored. Dosage or administration schedule modifications may be considered for patients experiencing these adverse effects. Further pharmacovigilance studies are needed to better understand the adverse effect profiles of "caftors", their possible risk factors, and the impact of adjusting dosing modalities.

Wolfram Syndrome 1: A Neuropsychiatric Perspective on a Rare Disease.

Wolfram syndrome 1 (WS1) is an uncommon autosomal recessive neurological disorder that is characterized by diabetes insipidus, early-onset non-autoimmune diabetes mellitus, optic atrophy, and deafness (DIDMOAD). Other clinical manifestations are neuropsychiatric symptoms, urinary tract alterations, and endocrinological disorders. The rapid clinical course of WS1 results in death by the age of 30. Severe brain atrophy leads to central respiratory failure, which is the main cause of death in WS1 patients. Mutations in the WFS1 gene, located on chromosome 4p16, account for approximately 90% of WS1 cases. The gene produces wolframin, a transmembrane glycoprotein widely distributed and highly expressed in retinal, neural, and muscular tissues. Wolframin plays a crucial role in the regulation of apoptosis, insulin signaling, and ER calcium homeostasis, as well as the ER stress response. WS1 has been designated as a neurodegenerative and neurodevelopmental disorder due to the numerous abnormalities in the ER stress-mediated system. WS1 is a devastating neurodegenerative disease that affects patients and their families. Early diagnosis and recognition of the initial clinical signs may slow the disease's progression and improve symptomatology. Moreover, genetic counseling should be provided to the patient's relatives to extend multidisciplinary care to their first-degree family members. Regrettably, there are currently no specific drugs for the therapy of this fatal disease. A better understanding of the etiology of WS1 will make possible the development of new therapeutic approaches that may enhance the life expectancy of patients. This review will examine the pathogenetic mechanisms, development, and progression of neuropsychiatric symptoms commonly associated with WS1. A thorough understanding of WS1's neurophysiopathology is critical for achieving the goal of improving patients' quality of life and life expectancy.

Neoprzewaquinone A alters the migration, phagocytosis and energy metabolism of IL-15-induced HMC3 cells.

Microglia play a major role in the immune defense system of the central nervous system and are activated in many neurological diseases. The immunomodulatory cytokine interleukin (IL)-15 is known to be involved in microglia response and inflammatory factors release. Neoprzewaquinone A (NEO) is an active compound isolated from Salvia miltiorrhiza Bunge. Our previous study has shown that NEO significantly inhibit the proliferation of IL-15-treated Mo7e cells. However, the role of NEO in the structure and function of IL-15-treated human microglial cells (HMC3) remains unclear. Thus, our study aimed to quantitatively analyze the beneficial effects of NEO on HMC3 cells following IL-15 treatment. The cell viability, phagocytosis, migration and energy metabolism were evaluated by Cell Counting Kit-8 (CCK8), scratch assay, pHrodo™ Red Zymosan BioParticles™ Conjugate, and Agilent Seahorse XF Cell Mito Test. Cephalothin (CEP) was selected as a positive drug because it has obvious inhibitory effect on IL-15 and IL-15Rɑ. Our results showed that IL-15 stimulated the proliferation, migration and phagocytosis of HMC3 cells in a time-dependent manner. Interestingly, NEO exhibited significant suppressive effects on these IL-15-induced changes, which were even superior to those observed with the CEP. Moreover, IL-15 treatment did not significantly alter energy metabolism, including glycolysis and mitochondrial respiration. NEO and CEP alone effectively reduced glycolysis, non-mitochondrial respiration, basal respiration, ATP turnover, respiration capacity, and H+ leak in HMC3 cells. Furthermore, NEO displayed a partial regulatory effect on mitochondrial function in IL-15-treated HMC3 cells. Our study confirms the effectively inhibition of NEO on IL-15-induced microglial activation and provides valuable insights into the therapeutic prospects of NEO in neuropsychiatric disorders associated with IL-15 and microglia.

Recent Advances in representative small-molecule DRD2 inhibitors: Synthetic Routes and clinical applications.

The dopamine D2 receptor (DRD2) represents a pivotal target for therapeutic intervention in the treatment of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and Parkinson's disease. The successful discovery of numerous effective DRD2 inhibitors has led to their clinical application and ongoing evaluation in various clinical trials. This review explores the synthetic approaches and clinical applications of prototypical small-molecule DRD2 inhibitors that have received approval or are currently undergoing clinical trials, highlighting their therapeutic potential and challenges. The synthesis of these inhibitors employs various chemical strategies, including modifications of phenothiazine and butyrophenone structures, which have yielded significant antipsychotic agents like chlorpromazine and haloperidol. Additionally, newer classes of inhibitors, such as aripiprazole, exhibit partial agonist activity at DRD2, offering a unique therapeutic profile. Clinically, DRD2 inhibitors demonstrate efficacy in managing positive symptoms of schizophrenia, manic episodes in bipolar disorder, and dopaminergic imbalance in Parkinson's disease. However, the emergence of adverse effects, including tardive dyskinesia, extrapyramidal symptoms and metabolic syndrome, presents substantial challenges. Advances in the development of second-generation antipsychotics aim to balance efficacy with a better side effect profile by targeting additional neurotransmitter receptors. This review aims to deliver an overview of the synthesis and clinical applications of representative small-molecule DRD2 inhibitors across various clinical phases, thereby offering strategic insights for the advancement of DRD2 inhibitor development.

An Unusual Case of GRIN2A Mutation Presenting as Progressive Limbic Encephalopathy in an Adult.

The glutamate ionotropic receptor NMDA (N-methyl-D-aspartate) type subunit 2A gene (GRIN2A) encodes the GluN2A subunit of NMDA receptors, which are essential for synaptic plasticity and memory consolidation. Mutations in GRIN2A can disrupt these processes, often affecting the pediatric population and causing various neurological disorders characterized by epilepsy, intellectual disability, and aphasia, among other neuropsychiatric findings. We report an unusual presentation of adult-onset GRIN2A mutation-associated progressive limbic encephalopathy (LE), characterized by rapidly progressive cortical atrophy, seizures, aphasia, and neuropsychiatric abnormalities, which ultimately led to the patient's sudden demise. Further research into GRIN2A mutations will improve our understanding of such presentations, guiding enhancements in diagnostic methods and therapeutic approaches.

Association in Toxoplasma gondii and Related Psychotic Disorders: A Primary Report.

Background: Implication of infection in etiology of psychotic disorders is an area of interest. Aim: We aimed to explore the relationship between Toxoplasma gondii and psychotic disorders in a preliminary study. Materials and methods: T. gondii immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies were measured in a sample of patients with psychotic disorders, first-degree relatives (FDR), and healthy volunteers (HV) and compared. Data were analyzed by descriptive statistics in the forms of frequency and percentage using Statistical Package for the Social Sciences (SPSS). Results: Sample size was 10. Men and women were equal. All were from rural background. One patient with psychotic disorder out of the four had anti-T. gondii IgG antibodies in comparison to none among the three each of the FDR and HV. The patient with positive Toxoplasma IgG antibody status had the diagnosis of acute and transient psychotic disorder (ATPD). Conclusion: This pioneering pilot project from this part of the globe highlights a pertinent area for further work in the future in order to have a newer understanding in proper management of psychotic disorder.