Search Results (203)

The dopamine D₂ receptor (D2R) is one of the principal therapeutic targets for the treatment of schizophrenia and other neuropsychiatric disorders. Understanding how ligands with different pharmacological profiles interact with D2R is essential for the rational design of safer and more effective antipsychotic drugs. In this work, Molecular Dynamics (MD) simulations combined with Quantum Theory of Atoms in Molecules (QTAIM) analysis were employed to investigate the electronic nature of protein–ligand interactions in D2R embedded in a neuronal membrane environment. Representative agonists (dopamine and rotigotine) and antipsychotics from different generations (haloperidol, risperidone, and aripiprazole) were analyzed to identify interaction patterns associated with distinct pharmacological activities. The agonist-bound simulations revealed recurrent interactions involving the serine-rich region, whereas the antipsychotic-bound systems exhibited more persistent contacts within the central aromatic region of the binding pocket. These observations suggest ligand-associated interaction tendencies rather than universal determinants of agonism or antagonism. Furthermore, aripiprazole displayed a unique interaction profile characterized by enhanced coupling with the PIF connector, suggesting a distinct modulation of the TM6 toggle switch compared with other antipsychotics. The integration of MD and electron density topology revealed ligand-specific interaction networks associated with distinct pharmacological profiles at D2R. The interaction patterns identified in this study highlight characteristic interaction motifs associated with ligand-specific pharmacological profiles and provide mechanistic insights that may support the rational design of novel dopaminergic therapeutics. Full article

Background/Objectives: Antipsychotic drug utilization has changed substantially over recent decades, reflecting evolving prescribing practices, drug availability, and treatment guidelines. Methods: This study analyzed national antipsychotic consumption in Serbia from 2006 to 2024 using official data from the Medicines and Medical Devices Agency of Serbia. Utilization was expressed as defined daily doses per 1000 inhabitants per day, and trends were assessed using linear and joinpoint regression analyses. Results: Total antipsychotic utilization increased from 4.35 to 14.42 DDD/1000 inhabitants/day, representing a 231.5% increase. This growth was predominantly driven by atypical antipsychotics, whose utilization increased from 1.16 to 10.91 DDD/1000 inhabitants/day (+840.2%). In contrast, typical antipsychotic utilization remained relatively stable in absolute terms. The share of atypical antipsychotics increased from 26.7% in 2006 to 75.6% in 2024, while the atypical: typical utilization ratio increased from 0.36 to 3.10. Atypical antipsychotics surpassed typical agents in 2013. Marked increases were observed for olanzapine, quetiapine, aripiprazole, paliperidone, risperidone, and clozapine, while chlorpromazine and fluphenazine declined. Conclusions: These findings demonstrate a substantial increase in overall antipsychotic utilization in Serbia and a pronounced structural shift toward atypical agents, highlighting the need for continued monitoring of prescribing trends, safety outcomes, and population-level treatment patterns. Full article

Background/Objectives: Sex-specific differences in the pharmacokinetics of psychotropic drugs are gaining increasing clinical relevance, but only limited data are currently available on sex-specific effects within genetically defined metabolizer phenotype categories. The objective of this study was to assess genotype-dependent sex differences in the metabolic capacity of the drug-metabolizing enzymes CYP2D6 and CYP2C19. Methods: Statistical analyses were performed using linear mixed-effects models with subject-level random intercepts to account for repeated therapeutic drug monitoring (TDM) measurements. Venlafaxine and risperidone were used as probe drugs to find differences in the metabolic capacity of CYP2D6 and escitalopram for CYP2C19. Pharmacokinetic surrogate parameters were the metabolite-to-parent ratio (MPR) for venlafaxine and risperidone and the dose-corrected serum concentration (CD) for escitalopram. Models included sex, metabolizer phenotype, and their interaction, adjusted for age and creatinine production rate (CPR). Sex-specific differences within phenotype groups were assessed using estimated marginal means. Results: Among venlafaxine samples (N = 117) and risperidone samples (N = 73), no significant sex-specific differences in MPR were observed within CYP2D6 metabolizer groups. For escitalopram samples (N = 51), a significant sex difference was observed among CYP2C19 normal metabolizers (NMs), with higher CD in males compared to females. Conclusions: Exploratory analyses suggested a higher metabolic capacity in CYP2C19 NM females treated with escitalopram. Due to the limited sample size, however, this finding should be considered hypothesis-generating. Future studies in larger samples are needed to corroborate whether sex and other factors modulate the metabolic capacity of CYP2C19, e.g., by epigenetic mechanisms. Full article

Background/Objectives: Risperidone oral solution (RIS-OS) is an easy-to-administer treatment for schizophrenia designed to improve medication adherence and rapid onset of effect. Mixing RIS-OS with beverages such as black tea is prohibited due to reduced RIS concentrations observed in vitro, despite the absence of pharmacokinetic data. In this study, we evaluated the pharmacokinetics of RIS and its active metabolite 9-OH-RIS in rats following oral administration with black tea. Methods: Male Wistar rats received RIS-OS intravenously or orally as a water or Dimbula black tea mixture; serial tail-vein blood samples were collected as dried blood spots, RIS and 9-OH-RIS were quantified using HPLC/ESI-MS/MS, and pharmacokinetic parameters were calculated and compared using Welch’s t-test. Results: Compared with the water mixture, the black tea mixture significantly reduced RIS C_max, while T_max and AUC remained unchanged. Furthermore, AUMC and MRT were significantly higher. The results were similar for 9-OH-RIS. Despite reduced RIS content in vitro, no difference in absolute bioavailability was observed in vivo. Although only one black tea variety was tested, evaluating additional varieties may help identify the components responsible for reducing RIS content. Conclusions: Mixing RIS-OS with black tea may delay absorption without reducing overall exposure, providing evidence that may contribute to safer guidance regarding beverage coadministration. Full article

Background: The increasing consumption of psychoactive pharmaceuticals has led to their continuous release into aquatic environments. Methods: This study assessed the ecotoxicological responses, phytoremediation capacity, and ecological risk of seven psychoactive pharmaceuticals—citalopram (CIT), sertraline (SER), fluoxetine (FLU), alprazolam (ALP), clonazepam (CLO), risperidone (RIS), and topiramate (TOP)—using Lemna minor under controlled exposure conditions. Plants were exposed to a concentration gradient, and physiological endpoints, including relative growth rate, chlorophyll content, and maximum photosystem II efficiency (Fv/Fm), were evaluated alongside compound removal and abiotic degradation. Results: Dose–response modeling revealed substantial variability in toxicity, with TOP (EC₅₀ = 74.11 ng L⁻¹), CLO (104.8 ng L⁻¹), and RIS (138.5 ng L⁻¹) exhibiting the highest potency, whereas FLU (1751 ng L⁻¹), CIT (89,941 ng L⁻¹), and ALP (465,351 ng L⁻¹) were less toxic. Relative growth rate was the most sensitive endpoint. Mixture exposure did not result in additional toxicity compared to the most responsive individual compounds. Abiotic degradation was negligible for most compounds (<3%), except for SER (~42%) and FLU (~22%). In contrast, L. minor achieved net removal efficiencies of up to 81%, although reductions occurred under mixed conditions. Probabilistic risk assessment indicated a high ecological risk (msPAFtotal = 1.0), with RIS as the dominant contributor. Full article

Background: Autonomic side effects are a major determinant of tolerability for many psychotherapeutic drugs. While often attributed to receptor-mediated mechanisms, the potential contribution of direct modulation of smooth muscle excitability remains poorly characterized at a comparative pharmacological level. Methods: A systematic comparative pharmacological profiling of a broad panel of psychotherapeutic drugs (antidepressants, antipsychotics, and anxiolytics) was conducted using a standardized ex vivo model. Potassium chloride (KCl, 105 mM) was used to induce depolarization-dependent contraction in three isolated smooth muscle preparations (rat uterus, rat vas deferens, and guinea-pig ileum). Inhibitory potency (IC₅₀), dose-dependency, and tissue consistency were integrated to define functional inhibitory profiles. Results: Psychotherapeutic drugs exhibited marked heterogeneity in their ability to inhibit K⁺-induced smooth muscle contraction. Integrative analysis stratified compounds into four distinct functional profiles: (i) High Inhibitory Liability (e.g., nortriptyline, paroxetine), characterized by low micromolar IC₅₀ values and dose-dependent inhibition across multiple tissues; (ii) Non-Selective Inhibition (e.g., flunarizine, cinnarizine), showing consistent but dose-independent inhibition; (iii) Tissue-Dependent Inhibition (e.g., risperidone, reboxetine); and (iv) Minimal Inhibition (e.g., moclobemide). Agents classified within the High Inhibitory Liability profile correspond to drugs known to carry a higher clinical burden of autonomic adverse effects. Conclusions: This study reveals a previously underrecognized pharmacodynamic dimension of psychotherapeutic drugs and establishes a comparative functional taxonomy based on their direct, non-receptor-mediated inhibition of smooth muscle excitability. The identified profiles provide a mechanism-informed framework for contextualizing autonomic side-effect liability and may support improved safety evaluation in psychotherapeutic drug development. Full article

Background: Biological sex contributes to variability in drug metabolism, receptor sensitivity, and susceptibility to adverse drug reactions (ADRs). Despite this, dosing recommendations for selective serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotics (SGAs) are still largely sex-neutral. This systematic review examines sex-related differences in pharmacokinetics (PK), pharmacodynamics (PD), and safety outcomes, with the aim of clarifying their potential implications for personalized psychopharmacology. Methods: A systematic search of PubMed was conducted for studies published between January 2010 and March 2026. The strategy combined MeSH terms and free-text keywords related to SSRIs, SGAs, sex differences, pharmacokinetics, pharmacodynamics, and ADRs. Two independent reviewers performed study selection and data extraction. Studies reporting sex-stratified PK, PD, or safety outcomes in humans were included. Owing to methodological heterogeneity, results were synthesized narratively. Results: Twenty-seven studies met the inclusion criteria. Overall, the evidence indicates clinically meaningful sex-related differences in psychotropic drug exposure and response. Women more frequently exhibited higher dose-adjusted serum concentrations, particularly for risperidone and some SSRIs, with age-related increases more evident in females. Pharmacodynamic findings suggest that women may reach comparable dopamine D2 receptor occupancy at lower olanzapine doses. Pharmacovigilance analyses revealed sex-specific adverse event patterns, including greater reporting of endocrine-related effects and QT prolongation in women. Conclusions: Sex influences psychotropic drug exposure, pharmacodynamic sensitivity, and safety profiles in ways that may be clinically relevant. Integrating sex-aware considerations into dosing strategies could improve therapeutic precision and reduce adverse outcomes, reinforcing the importance of sex as a key variable in personalized psychiatric care. Full article

Obsessive-compulsive disorder (OCD) is a chronic mental disorder characterized by distressing thoughts and repetitive behaviors that significantly impair daily functioning and quality of life. Many patients fail to achieve sufficient symptom relief with first-line treatments, such as cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs). Dopaminergic dysregulation has been implicated in the pathophysiology of OCD, providing a rationale for pharmacological augmentation strategies. This article presents a narrative review of the evidence regarding the efficacy, safety, and clinical applicability of antipsychotic agents and emerging pharmacological augmentation approaches, including extended-release methylphenidate (MPH-ER), in SSRI-resistant OCD. A literature search was conducted using PubMed, EBSCO, and Embase databases, with an additional search of Google Scholar, focusing on studies examining pharmacological augmentation in treatment-resistant OCD. Overall, the evidence base is limited by small sample sizes, short follow-up durations, heterogeneous response criteria, and a lack of head-to-head comparisons versus CBT augmentation, which constrains the generalizability of conclusions. Dopamine receptor antagonists, particularly risperidone, as well as the partial agonist aripiprazole, remain the most consistently supported augmentation strategies, while olanzapine and quetiapine may be considered in selected cases. Evidence for MPH-ER is currently limited—supported by one small RCT and two recent case series—and may be considered in carefully selected adults with comorbid ADHD or marked executive dysfunction, although larger controlled studies and long-term safety data are required before firm clinical recommendations can be made. Full article

Parkinson’s disease (PD) is one of the most prevalent and extensively studied neurodegenerative conditions. One of its most challenging clinical manifestations is the emergence of dyskinesias, characterized by involuntary movements that significantly impair patients’ quality of life. Meanwhile, boron, as a trace element, and boron-containing compounds have emerged as active modulators of neurotransmitter systems. To evaluate the effect of aryl-boroxazolidones on parkinsonism, the in vitro neurotoxicity of three boroxazolidones was assessed, along with the effects of two of them in mice with parkinsonism induced by MPTP administration. Two novel compounds demonstrated a limitation of parkinsonism, whereas risperidone reduced the beneficial effect of the tested boroxazolidones. The three boroxazolidones did not induce toxicity in neurons or glial cells at concentrations up to 100 µM. In silico analyses support the ability of BCC to act as ligands of dopamine and serotonin receptors. Taken together, these results suggest that the tested boroxazolidones are promising candidate agents, warranting further exploration for the treatment of PD. Full article

Background and Clinical Significance: Withdrawal symptoms from an abrupt discontinuation or rapid dose reduction in amantadine has been documented as early as 1987. Symptoms can align with several diagnoses, including but not limited to infection, fever, worsening of Parkinson’s disease, seizures, and an altered mental status. In the case described, the timely diagnosis of amantadine withdrawal was delayed due to its nonspecific presentation. Case Presentation: A man in his 60s presented with lethargy, confusion, and delayed responses. His past medical history included parkinsonism, a seizure, type 2 diabetes, and schizoaffective disorder. Outpatient medications included amantadine, benztropine, divalproex, levetiracetam, paliperidone, risperidone, and semaglutide. He was admitted for an altered mental status, and home medications were held when he became NPO. A nasogastric tube was placed, and amantadine was restarted. Following the amantadine reinitiation, the patient returned to baseline and, after ruling out other causes, was diagnosed with amantadine withdrawal. He ultimately completed a 20-day admission and was discharged to a nursing home. Conclusions: The timely diagnosis of amantadine withdrawal was delayed due to its nonspecific presentation. For patients taking amantadine, clinicians should include amantadine withdrawal in their list of differential diagnoses, and in cases of altered mentation, a careful review of the medication list is essential. Full article

Background/Objectives: Aggressive behaviour is commonly associated with neurodevelopmental disorders, such as autism spectrum disorder (ASD), and could be understood as a response to daily stress routines, which negatively impacts patients’ quality of life. Oxytocin (OT), a neuropeptide involved in social bonding and socio-affective regulation, has emerged as a promising candidate to enrich, rather than replace, current pharmacological approaches in managing ASD-associated aggressive behaviour. In this study, we examined the potential of OT to modulate aggressive behaviour frequency in a VPA-based animal model of ASD. Methods: Sixty adult zebrafish (1:1 sex ratio) were divided into six groups (n = 10/group) and received the following treatment for 7 consecutive days: CTR—control (no treatment); VPA (28.8 mg/L valproic acid); OT (33.2 ng/mL oxytocin); RIS (170 μg/L risperidone); VPA + OT (28.8 mg/L valproic acid and 33.2 ng/mL oxytocin); and VPA + RIS (28.8 mg/L valproic acid and 170 μg/L risperidone). The locomotor performance, and socio-affective and aggressive behaviours, were measured in the Novel Tank and Mirror Biting tests at the end of the treatments. Results: We observed that the VPA treatment led to locomotion and socio-affective impairments, as well as aggressive behaviour. Also, we found that OT and RIS had comparable potential to modulate the frequency of aggressive and anxiety-like behaviours. Conclusions: Our preliminary data showed that OT has the potential to modulate the frequency of anxiety-like and aggressive behaviours, similarly to the atypical antipsychotic, RIS, in our VPA zebrafish model. However, further studies are needed to investigate the mechanisms of action and their potential synergistic effects. 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: Children and adolescents with autism spectrum disorder (ASD) frequently receive antipsychotics and are considered at increased risk for weight gain. Few studies have compared longitudinal weight trajectories between youth with ASD and those with other psychiatric disorders. Methods: This naturalistic, registry-based study used data from the SENTIA cohort, which prospectively monitors antipsychotic safety in individuals under 18 years at a university hospital in Spain. Clinical characteristics were compared between participants with and without ASD. Longitudinal body mass index (BMI) z-score trajectories were analysed using linear mixed-effects models. Results: The sample included 266 participants, of whom 113 (42.5%) had ASD. Individuals with ASD were more often male and initiated antipsychotic treatment at a younger age. Of the 26 participants prescribed an antipsychotic before age 6, 88.5% had ASD. Comorbidity profiles were similar across groups. Risperidone and aripiprazole were the most frequently prescribed antipsychotics. BMI z-scores increased over time (β = 0.130, p = 0.017), and baseline BMI z-score was the strongest predictor. ASD diagnosis did not modify the average linear rate of BMI z-score change (time × ASD: p = 0.251); however, a significant quadratic time × ASD interaction (β = −0.016, p = 0.041) was consistent with a more pronounced early increase followed by earlier attenuation of BMI z-scores in the ASD group. Conclusions: Although antipsychotic treatment was initiated earlier in youth with ASD, no clear difference was observed in the rate of BMI z-score change. Differences in weight trajectories underscore the need for metabolic monitoring in antipsychotic-treated youth. 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