Risperidone Research Articles (Page 1)

Modulation of tramadol-induced hyperthermia by risperidone and ambient temperature in rats.

Risperidone induces osteoporosis and neuropsychiatric treatment resistance via SMPD1-lysosome-mediated ferroptosis: dual rescue by active vitamin D analog ED-71.

The superior clinical efficacy of clozapine (CLO) in treatment-resistant schizophrenia remains incompletely understood. To elucidate these mechanisms, we employed a multi-platform proteomic strategy-combining data-dependent acquisition (DDA) with fractionation, data-independent acquisition (DIA) and targeted parallel reaction monitoring (PRM)-to analyse chronic drug-induced proteomic changes in the prefrontal cortex (PFC) and remaining cerebral cortex (CX) of rats. This approach enabled unbiased analysis of over 6300 proteins per group in DDA and over 8700 in DIA. Consistent across all analytical methods, chronic CLO administration induced robust downregulation of the serotonin 5-HT2A receptor (5HTR2A) in both PFC and CX, whereas risperidone (RIS) exhibited no significant effect on 5-HTR2A levels at clinically relevant doses. Despite sharing high affinity for this receptor, CLO and RIS elicited markedly distinct signalling profiles. In the PFC, CLO inhibited serotonergic, G-protein (Gαq and Gβγ), calcium, and cytoskeletal signalling pathways, accompanied by strong downregulation of phospholipase C delta 4 (PLCδ4), an isoform implicated in suicidal behaviour. Concurrently, CLO upregulated calcium-independent phospholipase A2γ (iPLA2γ) and guanylyl cyclase C (GUCY2C), suggesting potential modulation of docosahexaenoic acid (DHA) signalling and cGMP-driven synaptic plasticity. In contrast, RIS predominantly activated Gαi, Gαz, and Gβγ signalling in the CX and enhanced mitochondrial function. RIS also upregulated GUCY2C. Both drugs differentially modulated protein networks associated with potential heteromeric complexes involving 5HTR2As, including interactions with 5-HT1A, 5-HT2C, dopamine D2, oxytocin and cannabinoid CB1 receptors, highlighting their impact on complex serotonergic modulation. Notably, despite CLO's suppression of Gαq signalling, compensatory upregulation of Gαi was not observed, indicating a net attenuation of 5HTR2A-mediated output rather than a simple G-protein coupling switch. These findings advance our understanding of serotonergic, metabolic and receptor-level adaptations induced by atypical antipsychotics and suggest that CLO's superior efficacy may derive from its unique ability to downregulate 5HTR2A and remodel signalling networks beyond classical dopaminergic mechanisms.

Ultrahigh antipsychotics selective accumulation and efficient photocatalytic degradation using a novel 2D BiOIO3-based molecularly imprinted photocatalyst.

Autism spectrum disorder (ASD) is characterized by persistent problems in speech, social interaction, restricted and repetitive behavior patterns, lack of interest, and intellectual disabilities. Currently, there is no effective treatment available for the core symptoms of ASD. Among various treatments, herbal pharmacological treatments have shown promising results with fewer side effects, especially cannabidiol (CBD) treatment for the core symptoms and co-morbidities of ASD. The current study was performed to explore the therapeutic potential of CBD oil supplementation against the valproic acid (VPA)-induced autism mouse model. The autism mouse model was developed by exposing albino BALB/c mouse fetuses to VPA (600mg/kg) on gestational day 13. On postnatal day (PND)-21, the male pups from both control and diseased groups were further divided into the following treatment groups: (I) control saline group, (II) VPA-exposed group, (III) VPA+CBD oil (100mg/kg/day/orally) group, and (IV) standard group of VPA+risperidone (RISP) (0.5mg/kg/day/orally) for 3 consecutive weeks. VPA mice displayed autistic behaviors upon delivery, such as increased anxiety levels, delayed response to painful stimuli, and impaired social interaction. VPA mice also showed depletion of glutathione and other antioxidant levels. CBD oil improved these dysfunctions, as seen through biochemical analysis and morphological staining of the hippocampal region, prefrontal cortex, and Purkinje cells. These findings showed that CBD oil treatment significantly improved behavioral abnormalities and lowered the oxidative stress in the autistic mouse model by acting as an antioxidant.

Risperidone (RIS) is one of the most prescribed atypical antipsychotics approved for the treatment of various neuropsychiatric diseases. For the correlation of serum concentration and pharmacological effects of RIS, therapeutic drug monitoring is considered a fundamental concept for clinical application. This paper is provided to develop an electrochemical probe for the determination of RIS in biological samples by modification of glassy carbon electrode (GCE) using gold nanoparticles (AuNPs) and iron metal-organic-frameworks (FeMOFs). This probe fabrication process was characterized with various techniques including Fourier transform infrared (FTIR), emission scanning electron microscopy (FESEM), energy dispersive X-ray (EDX), atomic force microscopy (AFM), and dynamic light scattering (DLS) to confirm the proper synthesis of materials and the sensors designing. The developed probe square-wave voltammetry (SWV) signal was linear upon RIS concentration from 0.02 to 50 µg/mL with a low limit of quantification (LOQ) of 0.02 µg/mL. Based on the validated method, high accuracy and precision, good specificity, and suitable stability of fabricated probes were achieved. As the ultimate step, this method was successfully applied for the quantification of RIS in patients’ plasma samples with regular RIS consumption. The fabricated electrochemical demonstrates favorable clinical applicability due to its simplicity, high sensitivity, low sample pretreatment time, and rapid analysis time, making it a promising probe as an alternative to current separation-based methods. Also, the developed probe is cost-effective, as it uses a low amount of materials, decreases sample processing time, and utilizes inexpensive materials, which could remarkably reduce the overall cost of RIS concentration detection in clinical samples. The obtained results showed the potential of the developed probe for fast and reliable detection of RIS in plasma samples.

Ketamine challenge is a suitable animal model for evaluating cognitive, positive and negative symptoms of schizophrenia, besides oxidative stress, cholinergic, dopaminergic, GABAergic and nitrergic dysfunctions observed in the disease. Effects of Ficus platyphylla (FP) methanol extract on behavioral alterations triggered by ketamine were investigated in forced swim, open field, and new object identification tests. To examine the part played by nitrergic, cholinergic, and oxidative pathways in the antipsychotic properties of FP, acetylcholinesterase activity, levels of oxidative stress biomarkers, and nitrite in the brain were also evaluated. In silico molecular docking analysis was conducted to predict the interactions between bioactive compounds from FP and potential drug targets for the treatment of schizophrenia. FP administered alone or in conjunction with risperidone (RIS) significantly reversed ketamine-induced schizophrenic-like behaviors in rats; the increased brain levels of glutathione, catalase and superoxide dismutase activities, the decreased acetylcholinesterase activity, levels of nitrite and malonyladehyde in ketamine-treated rats. The bioactive compounds from FP demonstrated binding affinities for the recognized drug targets for pharmacotherapy of schizophrenia, including dopamine, serotonin and metabotropic glutamate receptors, and phosphodiestrases. Our findings revealed that cholinergic, nitrergic, and oxidative pathways were modulated by FP alone or in conjunction with RIS to reverse symptoms akin to schizophrenia triggered by ketamine. These findings further suggest that co-administration of Ficus platyphylla extracts and risperidone may improve the ameliorative effects of risperidone on cognitive, negative, and positive symptoms of schizophrenia.

To evaluate the role of diffusion process dimensionality in drug absorption following subcutaneous or intramuscular administration. The diffusion dimensionality model is based on analytical solutions of the 1-, 2- or 3-dimensional diffusion equations for a bolus input linked to a central compartment with first-order elimination. The model equations were reparameterized to contain three parameters for the time needed for the drug diffusion from the administration site, drug absorption into the central compartment, and the elimination rate constant. The diffusion dimensionality models were challenged with previously published subcutaneous absorption data for 13 antibody drugs and insulin lispro, and the long-acting injectable antipsychotic drugs: subcutaneous Perseris™, intramuscular Invega Sustenna®, Risperdal Consta®, and olanzapine. The Bayesian information criterion was used for model selection. The solution to the diffusion equation for a bolus dose administration is strongly dependent on the number of dimensions. The maximal concentration is lowest for the 3-dimensional diffusion equation. The pharmacokinetic profiles of all 13 antibodies were satisfactorily approximated by a diffusion dimensionality model. Three antibodies (CNTO5825, ACE910 and ustekinumab) were best described by the 2-dimensional diffusion equation. The 2- and 3-dimensional diffusion equations were equivalent for ABT981, guselkumab, adalimumab, nemolizumab, omalizumab, and secukinumab. Golimumab, DX2930, AMG139, and mepolizumab were best described by the 3-dimensional diffusion equation. All the long-acting antipsychotic dosage forms except Risperdal Consta were modeled satisfactorily. Diffusion dimensionality models are a parsimonious and effective approach for modeling drug absorption profiles of subcutaneously and intramuscularly administered small molecule and protein drugs and their dosage forms.

Psychosis is usually a substantial global burden with a prevalence of 0.4–2%. On the other hand, 50 million people are suffering from dementia, with dementia-related psychosis affecting approximately 25% of them. The current experiment aimed to investigate the effect of the anti-dementia drug memantine (MEM) on testicular damage and insulin resistance induced by the chronic administration of risperidone (RIS) in rats. Six groups of Wistar albino rats were designated as follows: control, MEM-5 (rats received MEM at 5 mg/kg/day, orally, for 4 weeks), MEM-10 (rats received MEM at 10 mg/kg/day, orally, for 4 weeks), RIS (rats were administered RIS at 2.5 mg/kg/day, orally, for 4 weeks), RIS + MEM-5 (rats received MEM at 5 mg/kg/day, orally, co-administered with RIS as in the RIS group for 4 weeks), and RIS + MEM-10 (rats received MEM at 10 mg/kg/day, orally, co-administered with RIS as in the RIS group for 4 weeks). The duration of the study was 28 days. Serum testosterone, resistin, and adiponectin concentrations were determined. The homeostatic model assessment of insulin resistance (HOMA-IR) was also evaluated. Oxidative stress, inflammatory markers, and immunoblotting of ERK1/2, and Nrf2 were quantified in testicular tissue together with histopathological evaluation and a caspase-3 immunohistochemical study. MEM co-administration increased adiponectin, serum testosterone, GSH, SOD, CAT, and Nrf2 expression while decreasing HOMA-IR, resistin, MDA, NOx, ERK1/2, IL-6, TNF-α, NFĸB, and caspase-3 expression. Furthermore, MEM ameliorated all measured parameters and histopathological changes that occurred in the RIS group in a dose-dependent manner. The primary outcomes were attained by attenuating oxidative stress, inflammation, and apoptosis in the testis caused by chronic RIS administration via regulation of the ERK1/2-Nrf2 signaling pathway. Targeting the ERK1/2-Nrf2 pathway is a potential strategy for addressing testicular injury.

Cannabidiol reverses myeloperoxidase hyperactivity in the prefrontal cortex and striatum, and reduces protein carbonyls in the hippocampus in a ketamine-induced schizophrenia rat model.

Schizophrenia is one of the most severe mental disorders,affectingapproximately 24 million people worldwide. Conventional treatments,such as drug-loaded implants and intramuscular injections, have severallimitations, including pain during administration and the need formedical professionals to perform the procedure. In this study, a poly(lactic-co-glycolic) acid (PLGA)-based implantable microneedle patch(IMN) was developed for the transdermal delivery of risperidone (RIS)as a treatment for schizophrenia. RIS IMNs were prepared by sequentiallycasting gel-based formulations into microneedle (MN) molds. The patcheswere then characterized using microscopy, differential scanning calorimetry,and infrared spectroscopy, as well as through evaluations of MN insertionand RIS release. A selected formulation was further tested by evaluatingits cytocompatibility and its ability to deliver RIS in a rat animalmodel. The RIS IMN demonstrated excellent mechanical properties, successfullyinserting up to 378 nm into model skin, which is crucial for effectivetransdermal drug delivery. A biocompatibility study using human dermalfibroblasts showed no cytotoxicity, with cell viability and proliferationbeing close to 100%. The optimized formulation achieved a sustained in vitro release over 7 days, while ex vivo skin deposition and permeation studies showed over 65% RIS deliveryefficiency. In vivo animal studies confirmed thatRIS IMNs maintained therapeutic plasma concentrations throughout thenine-day experiment, with Cmax valuesof RIS and 9-OH RIS reaching 387.96 ± 194.02 and 139.89 ±47.68 ng/mL at 6 and 96 h, respectively. In contrast, intramuscularinjection showed a Cmax of 1756.70 ±246.06 and 1377.38 ± 160.78 ng/mL at 2 and 6 h but lost therapeuticeffect after just 24 h. These findings suggest that RIS IMNs offersignificant clinical benefits for patients with schizophrenia, providingprolonged therapeutic effects with a simple, self-administering drugdelivery system, reducing the need for frequent medical interventions.

This study evaluated behavioral phenotypes and superoxide dismutase (SOD) enzymatic activity in a repeated sub-anesthetic dose of ketamine (KET) administered to model schizophrenia in an animal study. The animals were divided into three (3) experimental groups. The KET alone group received sub-anesthetic dose of KET (20 mg/kg) for 14 consecutive days. The control group vehicle (VEH) received distilled water (10 mL/kg) as a VEH, while the KET and risperidone (RISP) group (KET + RISP) received a sub-anesthetic dose of KET (20 mg/kg) alone for 7 consecutive days, followed by RISP (0.5 mg/kg) administered 1-h post-KET treatment from days 8 to 14. All treatments were administered intraperitoneally (i.p.). Twenty-four hours after the last treatment, behavioral phenotypes (locomotor activity and cognition) were assessed using the locomotor activity cage and the elevated plus maze (EPM). Thereafter, SOD enzymatic activity was evaluated in homogenized brain tissue from each mouse using spectrophotometric analysis. Animals that received KET (20 mg/kg i.p) alone showed a significant (P < 0.05) increase in movement counts and rearing events in the locomotor activity test. It also prolonged the latency to enter the open arms during the anxiety-induced cognitive assessment in the EPM, compared to animals that received distilled water or those that received KET and RISP. SOD enzymatic activity was significantly elevated in the KET group compared to the VEH and KET + RISP groups. The elevated SOD enzymatic activity may represent a compensatory response to the oxidative stress induced by repeated sub-anesthetic doses of KET.

Atypical antipsychotics improve dendritic spine pathology in temporal lobe cortex neurons in a developmental rodent model of schizophrenia.

BackgroundFerroptosis is an iron-dependent regulatory cell death, which plays an essential role in bone loss. This study investigated whether the mechanism of risperidone (RIS)-induced bone loss is related to ferroptosis.MethodsThe schizophrenia mice were induced by administering MK-801. Subsequently, RIS were injected, or ferroptosis inhibitor Ferrostatin-1 (Fer-1) co-injected for 8 weeks. Bone loss of schizophrenia mice were assessed using microCT, H&E staining, ALP staining, ARS staining and WB, respectively. Ferroptosis of schizophrenia mice were detected by Iron Colorimetric Assay Kit and WB, respectively. In addition, ALP staining, ARS staining, and WB were performed to reveal the role of RIS in osteogenic differentiation of MC3T3-E1 and BMSCs cells.ResultsRIS treatment facilitates bone loss in schizophrenia mice and inhibit osteogenic differentiation of MC3T3-E1 and BMSCs cells. Moreover, up-regulated ferroptosis was found in vivo and in vitro after RIS treatment. Interesting, the bone loss and inhibition of osteogenic differentiation induced by RIS in schizophrenia mice were reversed by ferroptosis inhibitor Fer-1.ConclusionFerroptosis induced by RIS aggravates the bone loss of schizophrenia mice via inhibiting osteogenic differentiation.

Implantable drug delivery systems are crucial for achieving sustained delivery of active compounds to specific sites or systemic circulation. In this study, a novel reservoir‐type implant combining a biodegradable rate‐controlling membrane with a drug‐containing core prepared using direct compression techniques is developed. The membrane is composed of poly(caprolactone) (PCL), and risperidone (RIS) served as the model drug. Characterization of both membranes and direct compressed pellets includes hardness testing, optical coherence tomography, mercury intrusion porosimetry, and surface morphology observation. In vitro release studies of RIS reveal that higher drug loading in the pellets extended‐release duration up to 70 days when incorporated into membranes with four layers. Increasing the number of membrane layers slows the release rate further, ranging from 70 to 170 days depending on membrane thickness. Biocompatibility studies demonstrate that these implantable devices are non‐toxic and biocompatible with cells in vitro. In vivo studies conduct in male Wistar rats demonstrate sustained release of RIS, with plasma levels showing a significant increase post‐implantation at a relatively constant rate for up to 49 days. These results indicate that the developed implants have the potential to provide long‐acting drug delivery to the systemic circulation.

Implementing therapeutic deep eutectic systems (THDESs) in various drug delivery systems (DDSs) has expanded enormously. THDESs offer eco-friendly alternatives to conventional organic solvents, featuring adaptable and simple preparation methods with high-yield products. Previously, the solubility of risperidone (RISP) was immensely enhanced by forming a hydrophobic THDES of RISP with capric acid (CA). To build upon the previous findings and utilize the hydrophobic properties of THDES, a self-emulsifying drug delivery system (SEDDS) was developed. A stable SEDDS formulation was successfully developed using the THDES as the nonpolar phase, a nonionic surfactant, Tween 20, and a co-surfactant, PEG 400. By employing a pseudo-ternary phase diagram, the ideal ratio of Tween 20 to PEG 400 was determined to be 3:1. The developed SEDDS demonstrated robust stability in thermal stability tests, dispersity evaluations, and dilution tests, exhibiting no instances of phase separation or precipitation. Gratifyingly, the in vitro dissolution of RISP through the developed SEDDS showed a higher release by 3-fold after 5 min and achieved 90% release within 2 hours. More interestingly, the plasma profile of RISP and the SEDDS were compared in rats, which revealed an improved drug bioavailability, as indicated by the attained higher AUC0–∞ (3907.06 versus 3426.28 h µg/ml) and a significantly higher Cmax (68.97 versus 50.35 µg/ml) with the SEDDS formulation when compared to RISP.

This study explores the prospective of risperidone-loaded β-cyclodextrin nanosponges as a therapeutic strategy for managing altered mental status (AMS) and delirium in cancer patients. Almost 87% of patients with advanced cancer experience AMS or delirium, significantly impacting prognosis and quality of life. The present study aims to enhance the solubility, bioavailability, and therapeutic effectiveness of second-generation antipsychotic medication risperidone (RSP), with poor aqueous solubility, it was encapsulated in β-cyclodextrin nanosponges. The nanosponges prepared by fusion technique using different β-CD: DPC molar ratios, were tested for their ability to encapsulation efficiency, drug loading, and dissolutions kinetics. Batch 1, (1:1 molar ratio) exhibits RSP loading capacity (454.2 µg/mg) and encapsulation efficiency (90.84%) along with DSC and FTIR also confirmed that the RSP was successfully encapsulated and without any chemical interactions. In vitro dissolution studies demonstrated a biphasic release profile, with an initial burst followed by sustained release, governed by Fickian diffusion as confirmed by release kinetics modeling. The improved solubility and dissolution profile of the nanosponges will be significant to improve risperidone delivery, ensuring better symptom management in a vulnerable population. These findings highlight the potential of β-cyclodextrin nanosponges as an innovative and adaptable platform for enhancing antipsychotic drug delivery.

The aim of this study was to develop a long-acting injectable formulation of risperidone using polylactic acid (PLA) or poly (lactic-co-glycolic acid) (PLGA), a biodegradable and biocompatible polymer. Risperidone microspheres (RMs) were prepared by creating an O/W emulsion using dichloromethane (DCM) as a solvent and then employing the solvent evaporation method. The RMs were prepared with four different risperidone-to-PLGA ratios (1:1, 1:1.3, 1:2, and 1:3 (w/w)), and each ratio was subjected to the same manufacturing process. The physicochemical properties of the prepared RMs, such as their shape, particle size, drug loading ratio, encapsulation efficiency, and in vitro degradation profile, were evaluated. The particle size of the RMs ranged from 30 to 100 μm, with larger PLGA ratios resulting in larger RM sizes. The drug loading ratio was inversely proportional to the increase in the PLGA ratio in the RMs, and all the formulations showed improved release profiles compared to the reference drug, Risperdal Consta®. The release data modeling results showed that the RM-3 formulation with a 1:1 (w/w) ratio of risperidone and PLGA exhibited a release pattern close to zero-order kinetics. The manufactured RMs were confirmed to have the potential to be used as a long-acting risperidone injection with sustained and stable release as well as an extended dosing interval.

Autism spectrum disorder (ASD) is characterized by deficits in communication, social interaction, and repetitive and stereotyped behaviors, with no specific drug therapy available. Studies have found that cannabidiol (CBD) can improve hyperactive and cognitive symptoms in children with ASD. However, little is known about the effect of CBD in combination with other medications, such as risperidone (RISP). This study aimed to evaluate the behavioral and biochemical effects of CBD in animals using a valproic acid (VPA)-induced ASD animal model. VPA was administered in pregnant Wistar rats on Day 12.5 of gestation to induce the ASD model. From the 10th to the 16th postnatal day (PND), the neurodevelopment of the animals was assessed through eye-opening, olfactory discrimination, and negative geotaxis behavioral tests. From PNDs 9 to 54, the animals were weighed. They were treated for 21 days with CBD alone (100mg/kg, by gavage, twice a day) or in combination with RISP (0.1mg/kg, by gavage, once a day). At PND 55, the animals were evaluated in social interaction and locomotor activity experiments. Finally, after behavioral assessment, the animals were euthanized, the brain was isolated, and oxidative stress parameters were evaluated in the hippocampus and cortex posterior. Animals exposed to VPA showed neurodevelopmental delays in opening their eyes, difficulties in turning around their axis, and took longer time to find the original nest when compared to control animals. They also exhibited impaired sociability and reduced exploratory activity, which indicates model impairments. Interestingly, animals exposed to VPA treated with CBD+RISP significantly improved sociability parameters, whereas isolated CBD did not affect this parameter. In the biochemical analysis, a significant decrease in the hippocampal sulfhydryl content was noted in the CT+CBD group and an increase in the VPA+CBD group. In conclusion, these results suggest that CBD, in combination with RISP, may be an interesting pharmacological approach to reducing ASD-related symptoms. Summary: Besides the increased prevalence of ASD cases in recent years, there are no medications to improve the central symptoms of autism. Numerous studies discuss CBD as an important medication for improving ASD symptoms; however, it is not known how CBD interacts with commonly used drugs in ASD individuals, such as RISP. This study demonstrated that CBD therapy, only when combined with RISP, improved sociability in a VPA-induced ASD animal model.

A new insight into the mechanism of loading of Granisetron, Naltrexone and Risperidone in poly(ortho ester) and poly (lactic-co-glycolic acid) as the controlled release drug delivery systems using a computational molecular approach