Search Results (622)

Background/Objectives: Cariprazine (CAR), an atypical antipsychotic drug, exhibits potent anticancer activity; however, its mechanism of action remains unclear. Methods: We conducted a comparison of CAR-induced cell death mechanism in HeLa and HCT116 cancer cells and explored its potential role as a Qi-site inhibitor of cytochrome bc1 reductase (complex III). Results: CAR induced a dose-dependent cytotoxic effect and triggered apoptosis in both cell lines; however, the mitochondrial responses were distinctively different. HeLa cells exhibited significant mitochondrial membrane depolarization, significant cytochrome c release, a strong increase in the Bax/Bcl-2 ratio, elevated caspase-3 activation, and notable S phase arrest along with autophagy induction, indicating that mitochondria-driven apoptosis occurred rapidly. In contrast, HCT116 cells showed moderate mitochondrial dysfunction, moderate cytochrome c release, enhanced suppression of Akt signaling, and significant G0/G1 phase arrest, which are consistent with a slower and mixed apoptotic response. The findings from molecular docking studies predicted that CAR had stable binding at the Qi site and showed interactions at the Qi site that were comparable to those of antimycin A, thereby suggesting its possible inhibitory effect on complex III. Conclusions: The results from our study indicate the engagement of CAR-activated apoptotic pathways that are specific to different types of cancer cells, and hence suggest that CAR may act as a new anticancer drug by potentially directing its action towards the mitochondrial Qi-sites of complex III. Full article

This study evaluated long-term trends in the prevalence of use of atypical and typical antipsychotic drugs (APDs), both as classes of drugs and as individual drugs, among adult inpatients in the United States (US). The Health Facts^® database developed by Cerner Corporation was used to analyze the prevalence of APD use among adult inpatients aged 18 years or older who were administered at least one antipsychotic medication order during hospitalization between 1 January 2000 and 31 December 2016. The prevalence of APD use was standardized by age, sex, race, and census region. Typical and atypical antipsychotic treatment patterns in the US differed over this period. While the use of atypical APDs increased overall, the use of typical antipsychotic medications decreased, but remained more prevalent. Overall, haloperidol and prochlorperazine were the two most administered antipsychotic medications throughout the study period. From 2000 to 2011, prochlorperazine and haloperidol were the first- and second-most prescribed typical APDs, respectively; haloperidol became the most administered antipsychotic of this class as of 2012. Quetiapine was the most administered atypical antipsychotic medication, followed by risperidone and olanzapine until 2014, after which olanzapine was the second-most administered atypical APD. There was a notable decline in the use of atypical antipsychotics medications between 2005 and 2008, which may reflect the impact of the Food and Drug Administration’s warnings and the American Diabetes Association’s consensus position, but only for a short time. The usage patterns observed in this study support existing evidence of substantial off-label use of antipsychotic drugs in the US. Full article

Background/Objectives: Combination therapy for schizophrenia may exacerbate side effects mediated by multiple brain receptors. This study aimed to elucidate the pharmacodynamic and pharmacokinetic interactions between chlorpromazine and risperidone. We investigated dopamine 2 (D₂), serotonin 2A (5-HT_2A), histamine 1 (H₁), and muscarinic acetylcholine (mACh) receptor occupancy in the brain as well as pharmacokinetic interactions after oral administration of chlorpromazine and risperidone in rats. Methods: Rats were orally administered chlorpromazine, risperidone, or their combination. A tracer cocktail solution was injected intravenously to measure multiple receptor occupancies simultaneously. Tracer and drug concentrations in the brain tissue and plasma were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: Receptor occupancy increased in a dose-dependent manner. The doses required for 70% D₂ receptor occupancy were 4.5 mg/kg for chlorpromazine and 1.5 mg/kg for risperidone. Co-administration of chlorpromazine (4.5 mg/kg) and risperidone (1.5 mg/kg) resulted in an increase in D₂ and 5-HT_2A receptor occupancy to approximately 90%. Risperidone alone caused a transient increase in H₁ receptor occupancy to 80%, while co-administration increased mACh receptor occupancy to 60%. Co-administration with chlorpromazine significantly increased the plasma concentrations of risperidone and its metabolite, paliperidone, and decreased the oral clearance of risperidone by 5.9-fold. Conclusions: Co-administration of chlorpromazine and risperidone increases the occupancy of D₂, 5-HT_2A, and mACh receptors in the rat brain and increases the plasma concentrations of risperidone and paliperidone, suggesting a potential risk of enhanced adverse effects due to both pharmacokinetic and pharmacodynamic interactions involving target and non-target brain receptors. Full article

Substance use disorder (SUD) is a chronic and clinically complex condition, frequently complicated by significant organic and psychiatric comorbidities. Most patients are polymedicated and require opioid substitution programs (OSPs). This complexity is further exacerbated by drug–drug interactions, therapeutic duplication, and fragmentation of the healthcare system. This retrospective observational study analyses the prevalence of polypharmacy and associated pharmacotherapeutic risks in a cohort of 1050 patients with SUD treated at Drug Care Units (DCUs) in Tenerife (Canary Islands, Spain). Prescriptions were dominated by methadone (62%), antidepressants, and antipsychotics, often in combination with benzodiazepines. Significant polypharmacy (>10 active prescriptions) was observed in 2.3% of patients, while 8.1% received 6–10 medications and 37.2% were using 2–5 medications. Women showed a higher pharmacological burden, with 3.5% experiencing significant polypharmacy (>10 different prescriptions) compared with 1.1% of men. Overall, 31% of patients received antidepressants, 31% were treated with antipsychotics—frequently with concurrent use of multiple agents—and 6.4% received opioids outside the OSP. Therapeutic duplication was observed in 15.6% of patients for psycholeptics, 14.2% for psychoanaleptics, and 3.2% for antiepileptics. Additionally, 25.2% of patients reported self-medication, predominantly with benzodiazepines. These findings underscore the need for integrated pharmaceutical care programs incorporating individualized therapeutic review and deprescribing strategies to enhance the safety and efficacy of SUD treatment. Full article

Background: Anorexia nervosa (AN) and obsessive–compulsive disorder (OCD) share core features of cognitive rigidity, anxiety, and altered reward processing. Pharmacological options remain limited, and combined modulation of serotonergic and dopaminergic systems may provide new therapeutic directions. This naturalistic study explored the combined use of lurasidone and fluvoxamine in individuals with restrictive AN (AN-r) and comorbid OCD. Methods: Forty-five female inpatients with AN-r and OCD were followed for six months. Participants received either lurasidone + fluvoxamine (n = 14) or heterogeneous SSRI/antipsychotic regimens (n = 31). Primary outcomes were the Recovery Assessment Scale (RAS) and Body Uneasiness Test Global Severity Index (BUT-GSI). Secondary outcomes included the Eating Disorder Examination-Questionnaire (EDE-Q) and Eating Disorder Inventory-3 (EDI-3). Bayesian repeated-measures ANOVAs were conducted, reporting BF₁₀, BFInclusion, and P(M│data) values, with multiple imputation applied to manage missing data. Results: Analyses indicated time-related changes across primary outcomes (RAS and BUT-GSI), with moderate-to-strong evidence (BF¹⁰ = 4.2–18.6) supporting overall improvement during treatment. Secondary and exploratory measures showed weaker or inconsistent trends (BF₁₀ < 3). No evidence emerged for group-by-time interactions exceeding anecdotal strength. Conclusions: Within the constraints of this small, all-female inpatient cohort, the findings illustrate directional, time-related changes compatible with global rehabilitation effects rather than drug-specific efficacy. The study demonstrates the feasibility—and methodological challenges—of applying Bayesian longitudinal modeling to incomplete clinical datasets. Future randomized or adaptive trials incorporating objective endpoints and data-quality pipelines are warranted to test whether serotonergic–dopaminergic–σ-1 synergy provides genuine clinical benefit in the AN–OCD spectrum. Full article

Background/Objectives: This study aimed to repurpose aripiprazole (AR), an antipsychotic clinically approved by the FDA, as a novel antifungal drug and to potentiate its therapeutic efficacy through PEGylated terpesomes (PEG-TERs). Methods: PEG-TERs were prepared by thin-film hydration and optimized using a central composite design. The optimum PEG-TER formulation was characterized for entrapment efficiency (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP), and subsequently integrated into polylactic acid (PLA)-based 3D-printed ocuserts. Results: The optimized formulation exhibited spherical vesicles with high EE%, nanoscale PS, narrow PDI, and favorable ZP, alongside excellent stability and mucoadhesive properties. Ex vivo permeation demonstrated a sustained release profile of AR from PEG-TERs compared with an AR suspension, while confocal microscopy confirmed efficient corneal deposition of fluorescein-labeled PEG-TERs. In vivo, the optimum AR-loaded PEG-TERs ocusert exhibited a substantial therapeutic effect in a rabbit model of Candida albicans keratitis, while histopathological assessment confirmed its ocular safety and biocompatibility. Conclusions: In conclusion, AR-loaded PEG-TERs embedded in PLA-based 3D-printed ocuserts represent a promising, safe, and innovative therapeutic platform for the management of Candida albicans-induced corneal infections, offering both drug repurposing and emerging opportunities in advanced ocular drug delivery. Full article

Background and Objectives: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition characterized by social communication deficits, restricted interests, and repetitive behaviors. At present, there is no pharmacological intervention that reliably targets the core symptoms of ASD; instead, medications are primarily used to manage associated or concurrent symptoms such as irritability, aggression, anxiety, attention difficulties, and sleep disturbances. This review summarizes the current evidence for pharmacological treatments in ASD, emphasizing how these interventions are used in a symptom-focused, adjunctive manner, and highlighting efficacy, mechanisms, limitations, and emerging therapeutic targets. Methods: A comprehensive literature review was conducted across PubMed, Cochrane Library, and Embase to identify clinical trials, systematic reviews, meta-analyses, and preclinical studies on pharmacological interventions for ASD. Seventy-seven references were integrated to reflect the current state of evidence. Results: Established pharmacological strategies include atypical antipsychotics for severe irritability and aggression, as well as antidepressants, stimulants and non-stimulant agents, mood stabilizers, and anxiolytics for selected comorbid symptoms, although efficacy is often modest and variable, and side effects can be significant. Adjunctive and investigational approaches targeting glutamatergic and GABAergic neurotransmission, monoaminergic systems, and neuroinflammatory and oxidative stress pathways show preliminary promise but remain experimental. Across all categories, pharmacological treatments are most effective when embedded in individualized, multimodal care plans that integrate behavioral, rehabilitative, and psychological interventions. Conclusions: This review maps pharmacologic strategies in ASD onto their underlying neurobiological mechanisms and clarifies how evidence strength differs across drug classes and symptom domains. Ongoing advances in genetics, synaptic and circuit-level neuroscience, and neuroimmune signaling are expected to yield more specific, mechanism-based pharmacological approaches for autistic behaviors, with the potential to improve long-term functioning and quality of life when combined with comprehensive psychosocial care. Full article

Background: Clozapine remains the only antipsychotic with proven efficacy in treatment-resistant schizophrenia (TRS). However, it is effective in only about 40% of patients and is associated with numerous adverse drug reactions. Personalization of clozapine therapy is therefore of critical importance in clinical psychiatry. MiRNA expression may serve as a promising exploratory marker for understanding individual variability in clozapine efficacy and safety. Methods: In this study, we determined the complete miRNA expression profile in TRS patients before initiation of clozapine and after four weeks of treatment. Results: In 15 inpatients with TRS receiving 4-week clozapine monotherapy, PANSS total decreased from 98.8 ± 13.19 to 80.47 ± 14.63 (p = 0.001). The most frequent adverse drug reactions were hypersalivation (n = 13), drowsiness/sedation (n = 12), and prolonged sleep (n = 12). We detected 24 differentially expressed miRNAs after clozapine. Changes in hsa-miR-129-5p, hsa-miR-6068, and hsa-miR-6814-5p correlated with improvements in positive symptoms; hsa-miR-128-1-5p tracked general psychopathology; and hsa-miR-6814-5p aligned with global improvement (lower PANSS total, higher PSP). Safety signals included associations of hsa-miR-4472 with asthenia/fatigue and prolonged sleep, hsa-miR-4510 with prolonged sleep, hsa-miR-615-3p and hsa-miR-4715-3p with tachycardia, and hsa-miR-329-1-5p with weight gain. Conclusions: Because miRNAs regulate the expression of a wide range of genes, including those involved in clozapine’s efficacy and safety, these findings underscore the need for further studies integrating pharmacoepigenetic and pharmacogenetic biomarkers. Our preliminary findings suggest that specific miRNAs could be candidate biomarkers associated with clozapine response in TRS, although these results require validation in larger and controlled studies. Full article

Background: Patients presenting to the Emergency Department (ED) with amphetamine-type stimulant (ATS) use can exhibit a wide range of symptoms, ranging from mild agitation to life-threatening dysrhythmias. Early identification of patients at risk for more severe medical complications after ATS use is a key challenge in emergency care. Objective: To identify clinical and demographic predictors associated with a medical condition among patients presenting to the ED after ATS use. Methods: Retrospective cohort study of patients who presented to the ED with suspected ATS use at a large academic community hospital in Ontario from 1 September 2016 to 31 August 2017. Patients were screened using ICD-10 codes and included if they had a positive drug screen and clinical suspicion for ATS use. Our primary outcome was a composite of recognized complications of ATS toxicity. Predictor variables included age, sex, employment status, mental illness or substance use history, ED administration of benzodiazepines, antipsychotics, or physical restraints. Multivariable logistic regression was used to assess associations. Results: Of 1591 charts reviewed, 128 (8%) met the inclusion criteria. The median age was 29.5 years (interquartile range [IQR]: 23–36), and 50.8% were female. In adjusted analyses, benzodiazepine administration was significantly associated with a medical condition (Odds Ratio [OR] 3.33; 95% CI: 1.31–8.45; p = 0.011) as was employment status (OR 9.30; 95% CI: 1.00–86.03; p = 0.019). Conclusions: Benzodiazepine administration and unemployment were strong predictors of a medical condition among patients presenting to the ED after ATS use. These patients should undergo thorough physical examination and diagnostic testing to identify and manage potentially life-threatening conditions. Full article

Background: Penfluridol is a long-acting oral antipsychotic used for the treatment of schizophrenia. Although the prolonged half-life of penfluridol allows once-weekly dosing, improving patient compliance, its therapeutic potential is limited by low aqueous solubility and poor oral absorption. This study aimed to enhance the dissolution and oral bioavailability of penfluridol using solid dispersion technology. Methods: Ternary solid dispersions of penfluridol were prepared using a solvent evaporation method with various hydrophilic carriers. Following prescreening of polymeric carriers, the formulation composition was optimized using a random forest regression model. Structural characteristics and drug release behavior of the optimized formulation (PF-SD5) were evaluated through in vitro studies. Pharmacokinetic studies in rats were conducted to assess the effectiveness of PF-SD5 in enhancing oral bioavailability. Results: The optimized PF-SD5 formulation, comprising penfluridol, poloxamer 407, and polyvinylpyrrolidone K30 in a 1:3:1 ratio, exhibited a 117-fold increase in aqueous solubility compared with the pure drug. PF-SD5 achieved nearly complete drug release within 1 h across a pH range from acidic to neutral. Spectroscopic, microscopical, and thermal analyses confirmed that penfluridol transformed into an amorphous form and established molecular interactions within the carrier matrix. Pharmacokinetic studies in rats revealed approximately a 1.9-fold increase in oral bioavailability. Conclusions: Combining solid dispersion technology with machine learning-guided optimization provides an effective strategy for enhancing the oral absorption of poorly soluble penfluridol. Full article

Objectives: To evaluate reports of diabetic ketoacidosis (DKA) associated with antipsychotic drug (APD) use submitted to the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS). Methods: A retrospective pharmacovigilance analysis was conducted using FAERS data from January 2000 to December 2022. DKA cases were identified using the MedDRA preferred term “diabetic ketoacidosis” in reports listing antipsychotic drugs as suspect medications. Disproportionality analyses, including the proportional reporting ratio (PRR) and empirical Bayes geometric mean (EBGM), were used to assess reporting patterns. Multiple analyses were performed, including those restricted to primary suspect listed drugs only, expanded to incorporate secondary suspect drugs, and sensitivity analyses excluding reports submitted by legal professionals. Results: Among 19,961 DKA reports in FAERS, 2489 (12.5%) listed atypical antipsychotics as the primary suspect drug, whereas reports involving typical APDs were rare. The majority of reports were submitted by healthcare professionals (74.1%), and nearly half originated from the United States (45.4%). Hospitalization was a frequent outcome, reported in 74.3% of cases. Quetiapine and olanzapine were the most frequently reported atypical APDs, with disproportionality analyses demonstrating strong safety signals when compared to all other drugs in FAERS: olanzapine PRR 13.2 (95% CI: 12.4–14.2) and quetiapine PRR 11.8 (95% CI: 11.1–12.5). The findings remained consistent across multiple sensitivity analyses, including incorporating secondary suspect drugs, when the comparator group was restricted to only psychotropic drugs, and excluding reports submitted by lawyers. Conclusions: This pharmacovigilance analysis highlights a potential safety signal for DKA with atypical antipsychotic drugs, notably quetiapine and olanzapine. While these findings do not establish causality, they underscore the need for further investigation using clinical and epidemiological data. Full article

Background and Objectives: Schizophrenia is associated with a 15–20-year reduction in life expectancy, with cardiovascular disease as the leading cause. Sudden unexpected death is common in this population, often linked to structural heart disease, antipsychotic use, and overlapping cardiometabolic, autonomic, and drug-related factors. This study aimed to determine the incidence and causes of sudden unexpected death among schizophrenia inpatients between 2014 and 2024 and compare these findings with historical data from the same institution. Materials and Methods: We conducted a retrospective cohort study of schizophrenia inpatients admitted from January 2014 to December 2024. Hospital records were reviewed to identify sudden and unexpected deaths, verified by the Forensic Medicine Service Brașov. Sudden death was defined as death in an asymptomatic patient or within one hour of new symptom onset, excluding suicide, homicide, or accidental overdose. In accordance with Romanian legislation, an autopsy was performed in every case. Results: Over the 10-year period, six schizophrenia inpatients (mean age 53.2 ± 17.8 years) died suddenly. All had long-standing schizophrenia (mean illness duration 28.7 ± 17.7 years) and were receiving second-generation antipsychotics. Cardiovascular comorbidity was present in three cases. All patients received antipsychotic treatment within 24 h before death. No deaths occurred within the first 24 h of admission; one occurred within 48 h. Compared with the 1989–2013 cohort, which included 57 sudden deaths, the incidence during 2014–2024 declined substantially (0.27% vs. 0.79%). Conclusions: The incidence of sudden unexpected death among schizophrenia inpatients declined significantly over the past decade compared with the 1989–2013 cohort, reflecting improved multidisciplinary care, prompt transfer to general hospitals, and wider use of second-generation antipsychotics. Autopsy findings emphasize the continuing importance of cardiovascular disease and airway obstruction as preventable causes of sudden death in this population. Full article

Cancer remains a major global health challenge, with triple-negative breast cancer (TNBC) representing one of the most aggressive and difficult-to-treat subtypes, characterized by poor prognosis and limited therapeutic options. Current treatments, including chemotherapy, are hindered by high recurrence rates, drug resistance, and severe side effects, highlighting the urgent need for novel therapeutic strategies to address these challenges. Drug repurposing, which involves the application of existing FDA-approved (Food and administration) drugs for new oncological uses, offers a cost-effective and time-efficient alternative to traditional drug development. This review synthesizes recent findings on repurposed drugs, including antidiabetic, antiparasitic, antidepressant, antipsychotic, cardiovascular disease, and non-steroidal anti-inflammatory drugs (NSAIDs), and their potential to target TNBC through mechanisms such as immune modulation, interference with signaling pathways, and inhibition of cancer cell proliferation. Evidence suggests that these agents hold therapeutic promise across heterogeneous TNBC subtypes, although outcomes vary depending on the molecular context. Overall, drug repurposing has emerged as a promising avenue for expanding the treatment options for TNBC; however, further research and personalized approaches are essential to translate these findings into effective clinical applications. Full article

Radical drug therapy for schizophrenia is usually hard to achieve with one currently available antipsychotic agent. Indeed, it is the negative symptoms of this morbidity that are a dilemma to neutralize. Most of the first-generation agents can deal with the positive symptoms of the disease to a convincing degree, but not with its negative symptoms. The creation of so-called second-generation agents aimed to treat the negative symptoms, as these invisible barriers are the real reasons that isolate psychotic individuals and hinder their integration into society. Unfortunately, these newly designed drugs, including OLZ, turned out to induce different categories of undesired effects; the most embarrassing among them are the metabolic drawbacks, such as insulin resistance, weight gain, and other subcategories of metabolic consequences. Antagonism induced at certain receptors, particularly 5-HT2C and histamine H1 receptors, is implicated particularly in these metabolic adverse effects. The choice of antipsychotics (APCs) should be tailored separately for each case, as each patient responds variably to each neuroleptic. This possibility exists due to the abundant alternatives within the currently available APC medications. This work aims to discuss the reasons behind these undesired metabolic effects, how to deal with them, how to choose the appropriate agent for each psychotic case, and how to manage intoxication using olanzapine. To address these inquiries, we carefully selected 154 relevant studies, including robust meta-analyses, from the past 20 years and analyzed them in this work. Full article

Atypical antipsychotics (AAPs) remain the most effective treatment to control irritability associated with autism spectrum disorder (ASD). Although there is no pharmaceutical treatment to target the core symptoms of ASD, AAPs reduce their severity. However, AAPs have been reported to be associated with severe adverse drug reactions (ADRs) that may lead to long-term conditions such as diabetes mellitus and heart disease. Their prevalence varies depending on the type of AAP prescribed, age, ethnicity, gender, healthcare systems, and the severity of the ASD. Current ADR monitoring guidelines exist, but they are broad in scope and do not fully account for these factors. Therefore, the need to develop ADR monitoring guidelines considering these factors has increased with the expanded use of AAPs in paediatrics with ASD. This gap in knowledge and clinical practice highlights the ongoing need for research to explore these factors and how they can inform the creation of tailored guidelines for monitoring ADRs in this population. Full article