Search Results (116)

Kynurenic acid (KYNA), a putative neuroprotective agent, modulates glutamatergic pathways in schizophrenia and Parkinson’s disease but is limited by acute motor activity impairments (e.g., ataxia). Research leveraging animal disease models explores its structure–activity relationship to enhance therapeutic efficacy while mitigating adverse effects, addressing global neuropsychiatric disorders affecting over 1 billion people. Structural analogs of KYNA (SZR-72, SZR-73, and SZR-81) were designed to uncouple therapeutic benefits from motor toxicity; yet, systematic comparisons of their acute behavioral profiles remain unexplored. Here, we assess the motor safety, time-dependent effects, and therapeutic potential of these analogs in mice. Using acute intracerebroventricular dosing, we evaluated motor coordination (rotarod), locomotor activity (open-field), and stereotypic behaviors. KYNA induced significant ataxia and stereotypic behaviors at 15 min, resolving by 45 min. In contrast, all analogs avoided acute motor deficits, with SZR-73 maintaining baseline rotarod performance and eliciting a delayed decrease in ambulation and inquisitiveness in open-field assays. These findings demonstrate that the structural optimization of KYNA successfully mitigates motor toxicity while retaining neuromodulatory activity. Here, we show that SZR-73 emerges as a lead candidate, combining transient therapeutic effects with preserved motor coordination. This study advances the development of safer neuroactive compounds, bridging a critical gap between preclinical innovation and clinical translation. Future work must validate chronic efficacy, disease relevance, and mechanistic targets to harness the full potential of KYNA analogs in treating complex neuropsychiatric disorders. Full article

Background/Objectives: The administration of parenteral medications is essential in managing acute arousal within the Behavioral Assessment Unit (BAU) of the emergency department (ED), where timely and effective intervention is critical. This study aims to evaluate current practices surrounding the use of parenteral medications for patients with acute agitation, focusing on adherence to protocols, medication safety, documentation accuracy, and patient outcomes. Methods: A retrospective analysis was conducted on 177 cases from December 2023 to February 2024. The study assessed the demographics, diagnoses, treatment protocols, and patient outcomes, with a particular emphasis on the use of parenteral medications such as benzodiazepines and antipsychotics. The relationship between medication administration and involuntary admission, mechanical restraint usage, and patient outcomes was also explored. Results: The majority of patients were aged between 21 and 30 years, and there was a predominance of male patients across both groups. Schizophrenia was the most common diagnosis, with a higher prevalence in the parenteral group (34%) compared to the oral-only group (24%), and personality disorders were more frequent in the parenteral group. Intramuscular (IM) medication administration was strongly associated with the use of mechanical restraint, with patients receiving IM medication being 35 times more likely to require restraint, emphasizing the link between more intensive treatment approaches and behavioral challenges. The most frequently administered medications were diazepam (40.6%) and olanzapine (36.5%), with olanzapine, droperidol, and diazepam most commonly used parenterally. Documentation of physical assessments prior to parenteral administration was present in most cases, though comprehensive evaluations such as ECGs were inconsistently performed. Conclusions: Parenteral medications, including benzodiazepines and antipsychotics, were effective in rapidly stabilizing patients, but the study emphasizes reducing dependency on mechanical restraints. Tailoring treatment to patient characteristics and employing alternative de-escalation strategies can improve safety and align with recovery-oriented care. This study highlights the need for evidence-based practices to optimize care and improve patient outcomes in ED settings. Further research is needed to explore long-term outcomes and refine non-coercive care approaches. Full article

Studies in animals and humans suggested that the tonic dopamine inhibition of prolactin release may be estimated by submaximal prolactin stimulation by thyrotropin-releasing hormone (TRH), the mini-TRH test. Because patients with schizophrenia may be more vulnerable to stress-induced elevations of prolactin, great care was taken to avoid stress-induced increases in prolactin, including applying local anaesthesia before blood extraction in our psychotic patients. Basal prolactin levels were in the reference range in all psychotic patients studied by us and were not higher in male patients than in normal men. Results of the mini-TRH test suggested that in acute patients with non-affective psychoses, everyday memory problems, non-paranoid delusions, and first-rank symptoms, but not other Comprehensive Psychopathological Rating Scale (CPRS) positive symptoms, could correlate with decreasing dopamine transmission in lactotrophs. In acute patients with first-episode schizophrenia, increasing negative disorganisation symptoms might correlate with increasing dopamine transmission. In first-episode patients, a hypersensitivity of the TRH response was detected, which could indicate that variability in the basal prolactin levels may confound the interpretation of the mini-TRH response. To avoid that, a smaller dose of TRH was recommended in first-episode patients. Studies using other estimates of basal dopamine release suggested that striatal dopamine transmission reflected delusions and hallucinations but not other Positive and Negative Symptom Scale (PANSS) positive symptoms. Including a wide range of symptoms in the PANSS positive scale may reduce its specificity for assessing basal dopamine transmission, although the scale remains useful for tracking treatment response. Full article

Background: Opioid Use Disorder (OUD) has claimed the lives of many Americans, with rates of overdose steadily rising over the past decade. Despite having highly effective medications to treat this condition, many providers still hesitate to prescribe them. Psychiatric inpatient facilities have a unique opportunity to engage patients with co-occurring disorders in the treatment of OUD; however, significant barriers exist. This study describes a novel OUD–buprenorphine (BUP) consultation service that provides such care to hospitalized psychiatric patients. Methods: This IRB-approved retrospective study reviewed the medical records of 123 hospitalized psychiatric patients who received consultations from the BUP consultation service. Descriptive and comparative statistics were performed. Results: The sample was predominantly male, with significant unemployment and housing instability. Patients were hospitalized for depressive, bipolar, and schizophrenia spectrum disorders. Over 90% of patients were discharged on buprenorphine, with over 50% being connected to specialized substance use services. No increase in the length of stay was found, and no difference in outcomes was observed based on diagnosis or BUP discharge status. Discussion/Conclusions: This novel service was effective in providing OUD treatment to patients with complex co-occurring psychiatric disorders without significantly increasing their length of stay. Despite acute exacerbations in psychiatric illness, patients were able to engage in discussions regarding BUP. While the study was limited in scope, it underscores the feasibility of integrating OUD treatment in the acute psychiatric inpatient setting. Full article

This article profiles 27 innovative advancements in small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) in 2024. These drugs target various therapeutic areas including non-small cell lung cancer, advanced or metastatic breast cancer, glioma, relapsed or refractory acute leukemia, urinary tract infection, Staphylococcus aureus bloodstream infections, nonalcoholic steatohepatitis, primary biliary cholangitis, Duchenne muscular dystrophy, hypertension, anemia due to chronic kidney disease, extravascular hemolysis, primary axillary hyperhidrosis, chronic obstructive pulmonary disease, severe alopecia areata, WHIM syndrome, Niemann–Pick disease type C, schizophrenia, supraventricular tachycardia, congenital adrenal hyperplasia, and cystic fibrosis. Among these approved small-molecule drugs, those with unique mechanisms of action and designated as breakthrough therapies by the FDA represent a significant proportion, highlighting ongoing innovation. Notably, eight of these drugs (including Rezdiffra^®, Voydeya^®, Iqirvo^®, Voranigo^®, Livdelzi^®, Miplyffa^®, Revuforj^®, and Crenessity^®) are classified as “first-in-class” and have received breakthrough therapy designation. These agents not only exhibit distinct mechanisms of action but also offer substantial improvements in efficacy for patients compared to prior therapeutic options. This article offers a comprehensive analysis of the mechanisms of action, clinical trials, drug design, and synthetic methodologies related to representative drugs, aiming to provide crucial insights for future pharmaceutical development. Full article

Psychiatric disorders are a major cause of illness in the world. Unfortunately, many patients are resistant to treatment and present serious complications. Schizophrenia is refractory to treatment in about one-third of patients. Antidepressants are effective in about half of patients. Suicidal ideation is an increasing issue in patients with mixed features in bipolar disorder (BD). Therefore, there is a need to develop and test new drugs or new indications of available medications for the treatment of psychiatric disorders through evidence-based investigations. This narrative review aims to present the molecules approved by the main drug agencies, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), from 2018 to date, along with new indications and new formulations of existing medications. We searched PubMed for new drugs approved for schizophrenia, BD, major depressive disorder (MDD), anxiety disorders, and obsessive-compulsive disorder (OCD). We evaluated their clinical benefits, safety, and tolerability profiles. Finally, we considered studies on the main molecules that have shown initial evidence of efficacy and are in the process of obtaining approval. Our search suggested that a new antipsychotic, lumateperone, and two drug combinations, olanzapine/samidorphan (OLZ/SAM) and xanomeline/trospium (KarXT), were approved for schizophrenia. In addition, some new methods of administration—monthly risperidone administration, subcutaneous risperidone administration, and transdermal asenapine administration—obtained approval from the main drug agencies. Lumateperone and OLZ/SAM were also approved in BD. Esketamine, a compound that modulates glutamatergic transmission, was approved to treat treatment-resistant depression and acute suicidal ideation. The dextromethorphan/bupropion combination was approved for MDD. Two new agents, brexanolone and zuranolone, were approved for treatment of postpartum depression. On the other hand, no new drugs received approval for anxiety disorders or OCD. In summary, some new psychotropic medications have been developed, in particular with the aim to improve the symptoms of resistant patients and to decrease the incidence of adverse effects. It is necessary to continue testing the effectiveness of new compounds in methodologically rigorous studies. Full article

Background: Agitation is a frequent and challenging symptom in schizophrenia and bipolar disorder, characterized by heightened motor activity, emotional distress, and potential aggression. This symptom is most observed during acute episodes, representing a significant burden on patients, caregivers, and healthcare systems. Agitation is a leading cause of emergency department visits and psychiatric hospitalizations, necessitating prompt and effective interventions to ensure safety and mitigate its far-reaching impact. Traditional treatments, including high-potency antipsychotics and benzodiazepines, remain first-line options but are associated with significant drawbacks such as sedation, extrapyramidal symptoms, tolerance, and limited applicability in certain patient populations, especially those with respiratory or cardiac depression and the elderly. Non-pharmacologic strategies like de-escalation techniques and environmental modifications are invaluable but may be impractical in acute care settings, as speed and efficiency are critical in emergent settings. These limitations, including the onset of extrapyramidal symptoms with high-dose antipsychotics and the development of tolerance with benzodiazepines, highlight gaps in care, including the need for faster-acting, safer, and more patient-friendly alternatives that reduce reliance on physical restraints and invasive interventions. Methods: This review explores the evolution of treatments for agitation, focusing on alternative and innovative approaches. To highlight these treatments, an extensive review of the literature was conducted utilizing PubMed, Google Scholar, Embase.com, and other search engines. Results: Key developments include sublingual dexmedetomidine, recently FDA-approved, which offers sedation without respiratory depression and a non-invasive administration route. Similarly, subcutaneous olanzapine provides a more convenient alternative to intramuscular injections, reducing injection-related complications. Other emerging treatments such as gabapentin, pregabalin, and ketamine show promise in addressing agitation in specific contexts, including comorbid conditions and treatment-resistant cases. A comparative analysis of these therapies highlights their mechanisms of action, clinical evidence, and practical challenges. Conclusions: Future directions emphasize intranasal delivery systems, novel pharmacologic agents, and potential roles for cannabinoids in managing agitation. These innovations aim to balance rapid symptom control with improved patient safety and experience. The set back with these emerging techniques is a lack of standardized dosing and protocols. They also face ethical concerns, including the chance of misuse or abuse, as well as regulatory barriers, as they lack FDA approval and their legality changes between states. This review underscores the clinical, practical, and ethical considerations in advancing care for agitated patients, paving the way for more effective and compassionate management strategies in psychiatric settings. Full article

As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer’s disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases. Full article

Background/Objectives: We aimed to evaluate asprosin and peptide tyrosine–tyrosine (PYY) levels in schizophrenia patients and the relationships between these levels and clinical severity, as well as whether these two hormones have a role in determining the disease and/or the phases of the disease. Methods: This study included 50 patients with schizophrenia in the remission phase, 50 in the acute phase, and 50 controls. The Positive and Negative Syndrome Scale (PANSS) was filled out for patients. The patients’ biochemical parameters and asprosin and PYY levels were measured. Results: Levels of asprosin and PYY were significantly different in all three groups (p < 0.001, p < 0.001). In the remission phase group, asprosin levels had a negative effect on PANSS general symptomatology scores (p: 0.002, p < 0.001). In the acute phase group, while PYY levels showed a negative effect on PANSS general symptomatology scores (p: 0.031), asprosin levels had a negative effect on all subscales of PANSS (p < 0.001). In the acute phase, a one-unit decrease in asprosin levels was associated with a 93% increase in PANSS total scores. The results of the receiver operating characteristic (ROC) analysis to distinguish the acute phase showed that PYY could not be used for diagnosis (p: 0.066), but asprosin was associated with the acute phase of schizophrenia (p < 0.001) and both asprosin and PYY were associated with the disease (p < 0.001, p < 0.001). Conclusions: We think that both asprosin and PYY can be used as potential biomarkers to identify schizophrenia, and only asprosin to identify the phases of the disease. PYY and asprosin levels may be markers that can be used to determine clinical severity. Full article

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

Background and Objectives: Research in this area focuses on acute schizophrenia-like psychotic disorder, as more than half of cases progress to a chronic course, manifesting as schizophrenia or schizoaffective disorder. Research has shown a link between viral infection and the onset of psychosis, and the influence of viruses on the clinical course of the disease is also being studied. Consequently, in cases where this type of psychosis co-occurs with a viral illness, there is a compelling rationale for identifying commonalities in both treatment and outcome. The ongoing global pandemic of COVID-19 provides a unique opportunity to assess these changes. The aim of this study is twofold: first, to examine the clinical characteristics of acute schizophrenia-like psychotic disorder in the context of the pandemic, and second, to analyze therapeutic interventions and outcomes. Materials and Methods: A non-invasive observational study was conducted in which 310 patients with acute schizophrenia-like psychotic disorder admitted as inpatients to a psychiatric hospital were divided into two groups according to the presence of COVID-19 (group I—F23.2 with COVID-19): 222 patients; Group II—F23.2 without COVID-19: 88 patients). After discharge, the patients in both groups were clinically followed in outpatient treatment for 36 months. Results: The results showed that acute schizophrenia-like psychotic disorder associated with COVID-19 was characterized by a greater severity of productive symptoms and the inclusion of the pandemic theme in psychotic symptoms. These patients were given higher doses of antipsychotic medication. Conclusions: The outcome of this type of psychosis is consistent, irrespective of the infection suffered at the onset of the disease, and is characterized by a chronic course with a predominant transition to the schizophrenic process. Full article

Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant due to their regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling, respectively, which are vital for learning, memory, and neuroprotection. This review synthesizes current evidence on the roles of PDE4 and PDE5 in neurological health and disease, focusing on their regulation of second messenger pathways and their implications for brain function. Elevated PDE4 activity impairs synaptic plasticity by reducing cAMP levels and protein kinase A (PKA) activity, contributing to cognitive decline, acute brain injuries, and neuropsychiatric conditions such as bipolar disorder and schizophrenia. Similarly, PDE5 dysregulation disrupts nitric oxide (NO) signaling and protein kinase G (PKG) pathways, which are involved in cerebrovascular homeostasis, recovery after ischemic events, and neurodegenerative processes in Alzheimer’s, Parkinson’s, and Huntington’s diseases. PDE4 and PDE5 are promising therapeutic targets for neurological disorders. Pharmacological modulation of these enzymes offers potential to enhance cognitive function and mitigate pathological mechanisms underlying brain injuries, neurodegenerative diseases, and psychiatric disorders. Further research into the regulation of PDE4 and PDE5 will advance therapeutic strategies for these conditions. Full article

The interplay between the cytokine network and antipsychotic treatment in schizophrenia remains poorly understood. This study aimed to investigate the impact of psychotropic medications on serum levels of IFN-γ, IL-4, TGF-β1, IL-17, and BAFF, and to explore their relationship with psychopathological features. We recruited 63 patients diagnosed with schizophrenia in the acute phase, all of whom were either drug-naïve or had been drug-free for at least three months. Serum levels of IL-4, IFN-γ, TGF-β1, IL-17, and BAFF were measured at baseline and after six months of antipsychotic treatment. The severity of symptoms was assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS), and the Scale for the Assessment of Negative Symptoms (SANS). Fifty-two patients completed the six-month follow-up for immunoassay analysis. Antipsychotic treatment led to a significant decrease in serum levels of IFN-γ, TGF-β1, and IL-17, alongside a significant increase in BAFF levels. Changes in IFN-γ were positively correlated with SANS scores and negatively correlated with Global Assessment of Functioning (GAF) scores. Changes in TGF-β1 were negatively correlated with GAF scores. Changes in BAFF were negatively correlated with SAPS scores. Multivariable regression models were used to explore the association between cytokine level changes (IL-17, BAFF, IFN-γ, and TGF-β1) and independent variables, including demographic (gender, age), behavioral (tobacco use), clinical (schizophrenia type, disease course, date of onset, prior treatment), and biological (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) factors, as well as standardized assessment scores. No significant associations were found, except for a significant negative correlation between TGF-β1 changes and GAF scores, as well as a positive correlation with age. Interestingly, advanced statistical analyses revealed that only changes in IL-17 and BAFF levels were significantly associated with antipsychotic treatment. Our findings suggest that antipsychotic drugs exert both pro- and anti-inflammatory effects on the cytokine network. The observed modulation of IL-17 and BAFF highlights their potential as future therapeutic targets in schizophrenia. Full article

Background/Objectives: Hypertriglyceridaemia and systemic inflammation are prevalent in patients with schizophrenia and contribute to an increased risk of cardiovascular disease. Although elevated triglycerides (TGs) and remnant cholesterol are linked to inflammation in the general population and individuals with metabolic syndrome, whether they are associated in patients with schizophrenia remains unclear. Methods: Fasting levels of TG, cholesterol (total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and remnant cholesterol)), and markers of systemic inflammation including high-sensitivity C-reactive protein (hsCRP), leukocyte counts and their differentials (neutrophils, monocytes and lymphocytes) were determined in 147 patients diagnosed with schizophrenia on long-term antipsychotic regimens and compared with 56 age- and sex-matched healthy controls. Apolipoprotein B and glycosylation of acute phase reactant (GlycA) signatures were assessed by NMR. Circulating cytokine levels were measured by a cytokine/chemokine multiplex assay. Results: Patients with schizophrenia had markedly elevated TG and remnant cholesterol relative to controls and had evidence of systemic inflammation with increased circulating hsCRP, GlycA, leukocyte, neutrophil counts and neutrophil-to-lymphocyte ratio (NLR). Unexpectedly TG and remnant cholesterol did not correlate with systemic inflammatory markers in patients with schizophrenia, and differences in inflammatory markers between controls and patients persisted after adjusting for the lipid profile. Interleukin (IL)-10 levels were increased in patients with schizophrenia, suggesting an anti-inflammatory signature. Conclusions: The discordance between TG, remnant cholesterol and systemic inflammation in patients with schizophrenia suggests these are likely independent contributors to cardiovascular risk in this population. Full article

Toxoplasma gondii is an Apicomplexan parasite that is estimated to infect at least one-third of the global human population. T. gondii infection may be transmitted horizontally or vertically. The main risk factors for transmission to humans are related to diet, especially the consumption of undercooked meat, along with soil contact. In immunocompetent persons, the acute infection may go undetected as it typically produces minor, non-specific symptoms that are self-limited. After infection is established, recurrent retinochoroiditis is the most common clinical disease. In contrast, severe systemic or cerebral toxoplasmosis may be life-threatening for immunocompromised individuals. Furthermore, congenital toxoplasmosis acquired in utero may have devastating consequences if not recognized and promptly treated. A growing body of research has identified associations between latent T. gondii infection, and personality traits and risk-taking behaviors. Other studies have documented associations between latent infection and psychiatric conditions that include schizophrenia and bipolar affective disorder. With no current treatment regimens being curative of T. gondii infection, effective prevention measures at both the public health and individual levels are vitally important. Full article