Risperidone Research Articles

In vitro-in vivo correlation of parenteral PLGA microspheres: Effect of variable burst release

Development of IVIVCs is a very complicated process, especially for complex drug products such as parenteral PLGA microspheres with multiphasic drug release characteristics. Specifically, microspheres that exhibit an initial burst release phase are even more challenging since the in vitro and in vivo burst release phases may not be comparable if drug absorption is rate-limiting at this stage. Therefore, the objectives of the present work were: 1) to investigate the predictability of developed IVIVCs for the in vivo burst release phase based on the in vitro burst release phase of the formulations; and 2) to evaluate the impact of variable burst release on the predictability of the developed IVIVCs for two different types of microsphere-based drug products. Accordingly, Risperdal Consta® (Risperidone) and Lupron Depot® (Leuprolide acetate, LA) were selected as model products. Compositionally equivalent risperidone and LA formulations with variable burst release phases were prepared with manufacturing process changes (such as solvent systems and mixing methods). The prepared microspheres exhibited differences in critical physicochemical properties (such as particle size, porosity, average pore diameter, and drug distribution) and hence differences in their in vitro release characteristics (such as variable burst release and release rate). The in vitro and in vivo (rabbit model (intramuscular injection) burst release were similar for the risperidone microspheres but were significantly different for the LA microspheres. This had an impact on the complexity of the developed IVIVC models. Level A IVIVCs with the ability to predict various types of burst release were developed using time scaling and shifting factors. Moreover, it was observed that IVIVCs developed using formulations with less variation in burst release had better predictability and vice-versa. Thus, the present research has provided a comprehensive understanding of the impact of the burst release phase on the development, complexity, and predictability of IVIVCs for complex parenteral microspheres containing a variety of therapeutic molecules.

Risperidone: A Commentary on Drug Profiling.

Risperidone: A Commentary on Drug Profiling.

Randomized controlled trial of adjunctive Valproate for cognitive remediation in early course schizophrenia

BackgroundSchizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically. MethodsUsing a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (N = 109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ. ResultsThere were no significant differences between Valproate and placebo (PLA) treated groups with respect to changes in cognitive functions, positive or negative symptom scores or daily function scores at the beginning and end of the study. No significant Valproate/PLA differences were noted on TOXO serostatus or TOXO-related cognitive dysfunction. ConclusionValproate treatment may not be beneficial for cognitive dysfunction in SZ or for TOXO infection.

Galactorrhea Induced by Risperidone

Galactorrhea Induced by Risperidone

Impact of a pharmacist‐administered long‐acting injectable antipsychotic service in a supermarket‐based community pharmacy on medication adherence

AbstractIntroductionLong‐acting injectable antipsychotic (LAIA) medications can improve medication adherence in patients with schizophrenia and bipolar disorder due to their 1‐ to 3‐month administration schedules.ObjectivesThe primary objective of this study was to examine the effect of a pharmacist‐administered LAIA service in a supermarket‐based community pharmacy on medication adherence rates.MethodsIn this descriptive study, service data from July 1, 2017 through February 28, 2018 were obtained from a national chain pharmacy. The study population included all patients utilizing the pharmacist‐administered LAIA service who received one of the following LAIA medications during the study period: aripiprazole, aripiprazole lauroxil, paliperidone palmitate, and risperidone. Patients under the age of 18 and those who received fewer than two pharmacist administrations of the same medication were excluded. Medication adherence was measured using the proportion of days covered (PDC) with ≥80% being considered adherent. Logistic regression analysis was performed to identify factors that affected PDC.ResultsA total of 78% (500/641) of patients enrolled in the service were determined to be adherent to their LAIA. Statistically significant differences were found between PDC rates based on medication selection. Using aripiprazole (Abilify Maintena) as a reference, patients on paliperidone palmitate (Invega Sustenna), paliperidone palmitate (Invega Trinza), and risperidone (Risperdal Consta) were 2.1 (95% CI 1.3‐3.3, P < .002), 4.4 (95% CI 1.8‐11.2, P < .002), and 4.3 (95% CI 1.6‐11.8, P < .004) times more likely to have a PDC ≥80%, respectively.ConclusionA majority of patients (78%) enrolled in a community pharmacy‐based service in which pharmacists‐administered LAIA medications were shown to be adherent to their medication. Specific LAIA medications were found to be associated with greater medication adherence. Findings from this study will provide insight into effective means of care delivery for other community‐based specialty pharmacy programs.

Persistent and transgenerational effects of risperidone in zebrafish

Since behavior is the connection between the internal physiological processes of an animal and its interaction with the environment, a complete behavioral repertoire is crucial for fish survival and fitness, at both the individual and population levels. Thus, unintended exposure of non-target organisms to antipsychotic residues in the environment can impact their normal behavior, and some of these behavioral changes can be seen during the entire life of the animal and passed to subsequent generations. Although there are some reports related to transgenerational toxicology, little is known of the long-term consequences of exposure to pharmaceutical compounds such as risperidone. Here, we show that zebrafish exposed to risperidone (RISP) during embryonic and larval stages presented impaired anti-predatory behavior during adulthood, characterizing a persistent effect. We also show that some of these behavioral changes are present in the following generation, characterizing a transgenerational effect. This suggests that even short exposures to environmentally relevant concentrations, at essential stages of development, can persist throughout the whole life of the zebrafish, including its offspring. From an environmental perspective, our results suggested possible risks and long-term consequences associated with drug residues in water, whichcan affect aquatic life and endanger species that depend on appropriate behavioral responses for survival.

Formulation and biopharmaceutical evaluation of risperidone-loaded chitosan nanoparticles for intranasal delivery

Objective: High lipophilicity and extensive hepatic metabolism limits the oral application of risperidone in the treatment of CNS disorders. In order address this limitation, risperidone (RS) loaded chitosan nanoparticles (CS-NPs) were processed for intranasal administration in the management of schizophrenia. Methods: RS loaded CS-NPs were prepared by ionic gelation of chitosan with tripolyphosphate and stabilized by tween 80/ poloxamer 188. The CS-NPs were characterized by FTIR, DSC, particle size, zeta potential and surface morphology. Entrapment efficiency, mucoadhesive strength, in vitro drug release, and release kinetics of CS-NPs were evaluated. Pharmacokinetics and pharmacodynamics of RS loaded CS-NPs were studied using Wistar rats. Stereotypy behavior and swimming normalization tests were conducted in amphetamine induced psychosis in animals.Results: Risperidone nanoparticles (RP12) were produced with an average size of 86 nm, polydispersity index of 0.287, zeta potential of +36.6 mV, mucoadhesion of 68.9% and entrapment efficiency of 77.96%. CS-NPs released the RS in controlled manner with Fickian diffusion mode. Maximum concentration of RS in plasma was 1240 ng/ml at 4 h for RP12, and 403.8 ng/ml at 2 h for RS sample. RS loaded CS-NPs significantly reduced the stereotypy score in experimental animals that indicated the efficiency of CS-NPs in delivery of RS at brain tissues and moreover amphetamine effect was reversed. Thus, RS loaded CS-NPs proved as potential delivery systems against induced psychotic disorders. Conclusion: Risperidone loaded chitosan nanoparticles were effective against schizophrenia via intranasal route.

The Antipsychotic Drug, Risperidone, Distributes to Bone Marrow: What is the Impact on Immune Function?

Antipsychotic medications are associated with serious side effects including obesity, dyslipidemia, diabetes, increased risk of fractures and bone loss. Additionally, it has been widely reported that schizophrenic patients are more susceptible to infections; however the role of antipsychotic medications (if any) in determining susceptibility to infectious disease is not understood. We have previously reported that risperidone (RIS) distributes to bone marrow of female mice following a single oral dose (Motyl et al., 2017, Bone 103:168–176).HypothesisThe bone marrow compartment may be a key target of risperidone action, resulting in altered immune function.MethodsTo test this hypothesis pre‐clinically, we treated male and female C57BL/6 mice with vehicle (VEH) or a low, clinically relevant dose of RIS (0.75 mg/kg, PO) for 5 days or 4 weeks. At the end of each treatment period, mice were sacrificed and plasma, bone marrow, and other tissues were collected for analysis. All animal study protocols were approved by the University of New England IACUC committee.ResultsConcentrations of drug and metabolites in plasma and bone marrow were determined by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) analysis. RIS and the active metabolite 9‐OH RIS (PAL) distributed to marrow of male mice following 5 days of dosing, and concentrations were higher in marrow than in plasma at 1 and 3 hours post‐dose (10–15 fold higher in marrow vs. plasma; P<0.05). Plasma concentrations of 40 cytokines or chemokines were measured in plasma from mice treated for 4 weeks with RIS or VEH using the Mouse Cytokine Array Panel (Proteome Profiler*TM Array, R&D Systems, Minneapolis, MN). Eight key immune mediators (IL‐17, INFγ, IL‐7, TIMP1, BCA‐1, IL‐13, IL‐1α, and I‐309) were significantly (P <0.5) downregulated in RIS‐treated mice. Hearts from VEH and RIS mice treated for 4 weeks were analyzed by RNASeq analysis and expression of 31 genes from immune/inflammatory pathways were significantly (2‐fold; P<0.05) altered (8 upregulated; 23 downregulated) in a manner consistent with global immunosuppression.ConclusionsThe highly prescribed antipsychotic, risperidone, distributes to bone marrow in mice and is associated with global immunosuppression as evidenced by reduced tissue (heart) and plasma concentrations of multiple cytokines and immune modulators. These data are consistent with increased susceptibility to infection, observed clinically. Future studies will explore the effect of RIS to modulate response to an immune challenge (in vivo).Support or Funding InformationFunding source: NIH grant DK095413 to KLHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Simultaneous determination of six antipsychotics, two of their metabolites and caffeine in human plasma by LC-MS/MS using a phospholipid-removal microelution-solid phase extraction method for sample preparation

A simple and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated in human plasma for the simultaneous determination of aripiprazole (ARI) and its metabolite dehydro-aripiprazole (DARI); olanzapine (OLA), risperidone (RIS), paliperidone (PAL), quetiapine (QUE), clozapine (CLO) and caffeine (CAF). CAF is included to the method because it can have an influence on drug metabolism due to competitive inhibition. The above mentioned compounds and their isotope-labeled internal standards were extracted from 200 µL human plasma samples by both, effective phospholipids-eliminating three-step microelution-solid-phase extraction (µ-SPE) and protein precipitation (PPT) for comparison. A combination of formic acid (0.2%)-acetonitrile (pH 3.0; 65:35, v/v) was used as mobile phase and the chromatogram was run under gradient conditions at a flow rate of 0.6 mL/min. Run time lasted 6 min, followed by a re-equilibration time of 3 min. All analytes were monitored by mass spectrometric detection operating in multiple reaction monitoring mode and the method was validated covering the corresponding therapeutic ranges: 0.18–120 ng/mL for ARI, 0.25–80 ng/mL for DARI, 1.00–100 ng/mL for OLA, 0.70–60 ng/mL for RIS, 0.20–30 ng/mL for PAL, 0.50–160 ng/mL for QUE, 0.50–1000 ng/mL for CLO, and finally 1200–3700 ng/mL for CAF. The method was validated based on the recommendations of regulatory agencies through tests of precision, accuracy, extraction recovery, identity confirmation, trueness, matrix effect, process efficiency, stability, selectivity, linearity and carry-over effect fulfilling the guideline requirements. Our µ-SPE method results in the elimination of more than 99% of early eluting and more than 92% of late-eluting phospholipids compared to PPT. Additionally, the method was successfully applied for quantifying ARI and OLA plasma concentrations from healthy volunteers.

Influence of drying processes on the structures, morphology and in vitro release profiles of risperidone-loaded PLGA microspheres

The purpose of this study was to investigate the influences of drying methods on the risperidone (RIS) release profiles of RIS-loaded PLGA microspheres. These microspheres were fabricated with an O/W emulsion solvent evaporation method. The wet microspheres were dried with freeze drying and vacuum drying methods. The microspheres were mono-dispersed spheres with an average diameter of 100 μm. Studies found that drying methods had great influence on the porosity, morphology, and release profiles of RIS-loaded PLGA microspheres. Specifically, the freeze-dried microspheres had higher porosity (78.46 ± 1.64%) than those vacuum-dried ones (52.45 ± 2.68%), and they showed higher RIS release rates (p < 0.05). In the accelerated release tests (45 °C), these microspheres dried under the pressures of 700 mmHg and 200 mmHg gave faster release rates than those ones dried under the pressure of 450 mmHg. Importantly, the accelerated release test (45 °C) had a high correlation with the real-time test (37 °C) (R2 > 0.99). These studies exhibited a significance in the precise preparation of RIS-loaded PLGA microspheres.

The protective effect of resveratrol against risperidone-induced brain damage and metabolic side effects

Purpose: The aim of this study was to investigate the protective effect of resveratrol (RSV) against risperidone (RIS) on weight gain/loss via of the expression of some various neurotransmitter receptors. Materials and Methods: Thirty five female Spraque-Dawley rats were divided into 5 groups (n=7): Control, RIS, RIS+RSV-1, RIS+RSV-2, RIS+RSV-3. Rats were treated orally with RIS (2 mg/kg/day) and RSV (20, 40 and 80 mg/kg/day) for 14 days. On treatment day 15, blood and brain tissues were removed for analysis. Results: The reduced neuropeptide Y1 expression levels in the RSV groups correlated with the RSV-induced weight loss. The Dopamine D1 receptor and seratonin 5-HT2c expression levels decreased significantly with RSV treatment. In addition, the RSV increased the glucose, triiodothyronine, tetraiodothyronine, and total antioxidant status, and decreased the cholesterol, triglyceride, high density lipoproteins, low density lipoproteins, thyroid-stimulating hormone, oxidative stress index, and total oxidant status levels significantly. Conclusion: The daily treatment with RSV increased the antioxidant capacity, protected the apoptotic cell injury, and the possibility of death. RSV could be an effective course of therapy to enhance therapeutic efficacy.

Clozapine versus risperidone for people with schizophrenia

Clozapine versus risperidone for people with schizophrenia

Comparison of the efficacy of sertraline combined with risperidone or quetiapine in the treatment of schizophrenia

Objective To compare the efficacy of sertraline hydrochloride combined with risperidone or quetiapine in the treatment of schizophrenia. Methods Eighty-six patients with schizophrenia in Ningbo Psychiatric Hospital were selected and divided into observation group and control group according to the order of admission.The observation group was treated with sertraline hydrochloride combined with quetiapine, and the control group was treated with sertraline hydrochloride combined with risperidone.The clinical symptoms score, clinical efficacy and adverse reactions were compared between the two groups. Results Before treatment, the negative symptoms, positive symptoms, psychopathology, total score between the two groups had no statistically significant differences(all P>0.05). After treatment, the negative symptoms, positive symptoms, psychopathology and total scores of the observation group were (13.43±1.27)points, (11.26±1.05)points, (13.54±1.84)points and(46.48±4.52)points, respectively, which were significantly lower than those of the control group[(16.87±1.98)points, (15.48±1.63)points, (18.35±2.04)points, (58.25±5.76)points](t=9.590, 14.272, 11.481, 10.541, all P 0.05). Conclusion Sertraline hydrochloride combined with quetiapine in the treatment of schizophrenia can improve the clinical symptoms of patients, the clinical efficacy is good, with mild adverse reactions. Key words: Schizophrenia; Risperidone; Quetiapine

Risperidone withdrawal

Risperidone withdrawal

Application of quality by design for optimization of spray drying process used in drying of Risperidone nanosuspension

The objective of present study was to optimize spray drying of Risperidone (RIS) nanosuspension for achieving lower particle size, higher yield and good compressibility of spray dried powder using Quality by design approach. RIS nanosuspension was prepared by anti-solvent precipitation technique using poloxamer 68 and Poloxamer 127 as stabilizers.3 level 2 factorial design was applied using two independent factor variables viz., X1: feed pump speed (RPM) and X2: inlet temperature (ºC) and their effect upon dependent variables viz., Y1: Size, and Y2: %Entrapment efficiency was determined at three different levels. Spray dried powder was further characterized for bulk level properties and formulated as an orally dispersible tablet (ODT). The developed ODT were characterized by various parameters like wetting time, disintegration time, hardness, friability, weight variation and dissolution for comparison. Size and PDI of formulated RIS Nanosuspension were found to be 200.00 ± 0.40 nm and 0.210 ± 0.03 respectively. Optimized process parameters for spray dryer were obtained from design space, which gave critical quality attributes (CQA) response of lowest size and highest yield of 214.21 ± 2.01 nm and 61.85 ± 1.02% respectively. FTIR, DSC, XRD and AFM studies of spray dried RIS nanosuspension revealed that crystallinity of RIS was altered during spray drying process. Bulk density, Tapped density, Hausner ratio, Compressibility index and Angle of repose of spray dried RIS was found to be 0.588 ± 0.12 g/mL, 0.641 ± 0.20 g/mL, 1.09 ± 0.26, 8.33 ± 0.32 and 32.40º ± 0.98º respectively. ODT formulated using optimized spray dried nanosuspension showed higher dissolution than marketed ODT formulation which may be due to increase in solubility of Risperidone during spray drying of nanosuspension.

Dependence of Heterogeneous Nucleation on Hydrogen Bonding Lifetime and Complementarity

The crystallization of seven active pharmaceutical ingredients (APIs) (acetaminophen (AAP), carbamazepine (CBMZ), caffeine (CAF), phenylbutazone (PBZ), risperidone (RIS), clozapine base (CPB), and fenofibrate (FF)) was studied in the absence and presence of microcrystalline cellulose (MCC) which acted as a heterosurface. Two of the active pharmaceutical ingredients (APIs), namely, AAP and CBMZ, possess hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) functionalities, whereas the other five possess HBA functionality only. Density functional theory (DFT) and molecular dynamics calculations complemented the experimental study. The smallest nucleation rate enhancement was observed for CBMZ at 1.4 times, and the largest was observed for FF at 16 times. For all the APIs studied, the interfacial energy was similar for crystallizations performed in the presence and absence of the heterosurface. By contrast, the pre-exponential factor was larger by a factor of ca. 2 and more for crystallizations carried ...

Effects on brain-derived neurotrophic factor signalling of chronic mild stress, chronic risperidone and acute intracranial dopamine receptor challenges.

We have previously reported the effects of intracranial injections of dopamine D1, D2 and D3 ligands in animals subjected to the Novel Object Recognition (NOR) test following exposure to chronic mild stress (CMS) and chronic treatment with risperidone (RSP). Here, we present some molecular biological data from the same animals. It was predicted that brain-derived neurotrophic factor (BDNF) signalling in the prefrontal cortex (PFC) would reflect behavioural performance, implying an increase following acute administration of a D2 agonist or a D3 antagonist, blockade of this effect by CMS and its restoration by chronic RSP. In separate cohorts, animals were injected within the PFC or the hippocampus (HPC) with either the D1 agonist SKF-81297, the D2 agonist quinpirole or the D3 antagonist SB-277,011, following exposure to control conditions or CMS and chronic treatment with saline or RSP. Intracranial injections followed an exposure trial in the NOR test, with a retention trial 24 h later. Immediately afterwards, the animals were killed and expression of BDNF and TRKβ protein, and their respective mRNAs, was measured in PFC and HPC samples. CMS decreased the expression of TRKβ in both PFC and HPC. Several effects associated with intracranial injection were noted, but they were inconsistent and unrelated to CMS exposure. The effects of CMS on TRKβ are consistent with a decrease in BDNF signalling, albeit that expression of BDNF itself did not change significantly. There was no evidence for an involvement of the BDNF-TRKβ system in responses to RSP or dopamine ligands in animals exposed to CMS. However, there was a 24 h delay between the intracranial injection and tissue harvesting, meaning that brief early drug effects could have been missed.

Pharmacokinetics and pharmacodynamics evaluation on risperidone-containing microsphere fabricated by ultra-fine particle processing system

Risperidone (RIS) is one of the first-line treatments for schizophrenia. However, its short half-life and adverse effects, which are induced by the fluctuation of the drug concentration, limited its wide application. The PLGA microsphere was a rapidly developing delivery system for sustained release, which can extend the releasing time of drugs and decrease the fluctuation of the drug concentration. In this study, series of in vivo evaluation were performed to verify the improved efficacy of RIS through PLGA microspheres. The RIS loaded PLGA microspheres (RIS-MS) were prepared by the ultra-fine particle processing system (UPPS) - a novel technique was self-developed to fabricate microspheres. A pharmacokinetic study was employed to verify the sustained release of RIS-MS, and the head-twitch test and pole-climbing test were performed to explore the pharmacodynamics of RIS-MS. Pharmacokinetics showed the a 10-day sustained drug release was achieved by RIS-MS, and the correlation between the in vitro dissolution profile and in vivo absorption of RIS-MS was established successfully (R2 = 0.9356). Moreover, the head-twitch test revealed a continuous release of RIS-MS for 5 d, and the pole-climbing test demonstrated that less adverse effects were caused by RIS-MS compared to the RIS solution. Briefly, RIS-MS prepared by UPPS successfully achieved the in vivo sustained release and amended the adverse effects of RIS.

Preparation of New Risperidone Depot Microspheres Based on Novel Biocompatible Poly(Alkylene Adipate) Polyesters as Long-Acting Injectable Formulations

Risperidone (RIS)-loaded microspheres based on poly(alkylene adipate)s derived from dicarboxylic acids and different aliphatic diols were prepared by the oil in water emulsion and solvent evaporation method. Specifically, 3 polyesters, namely poly(ethylene adipate), poly(propylene adipate), and poly(butylene adipate), were prepared with the aid of a 2-stage melt-polycondensation method and characterized by gel permeation chromatography, proton nuclear magnetic resonance (1H NMR), differential scanning calorimetry, and X-ray diffraction analysis. Results showed that the molecular weight of the polyesters increased as the diol molecular weight increased, while all polymers were of semi-crystalline nature and the melting temperature was varying from 49.1°C to 51.8°C and 65.9°C for poly(propylene adipate), poly(ethylene adipate), and poly(butylene adipate), respectively. The particle size of the RIS-loaded microspheres varied from 10 to 100 μm depending on the polyester type and the drug loading, while X-ray diffraction analysis revealed amorphous active pharmaceutical ingredient in the cases of high drug-loaded microspheres. In vitro drug release studies along with scanning electron microscopy images of microspheres after the completion of dissolution process showed that in all cases RIS release was controlled by the glass transition temperature of polyesters and physical state of active pharmaceutical ingredients via diffusion.

Pretreatment With Risperidone Ameliorates Systemic LPS-Induced Oxidative Stress in the Cortex and Hippocampus.

Risperidone (RIS), an atypical antipsychotic has been found to show anti-inflammatory effect against lipopolysaccharide (LPS)-induced inflammation. In vitro study has revealed that RIS inhibits the LPS-induced reactive oxygen species (ROS) formation. We investigated the antioxidant effects of RIS on LPS-induced oxidative stress markers in Swiss albino mice. Ten weeks old male Swiss albino mice (30 ± 2 g) were pretreated with either distilled water (control) or RIS (3 mg/kg) for 7 days. On day 8, animals were challenged with a single dose of LPS (0.8 mg/kg) while control animals received distilled water only. The animals were sacrificed after 24 h of LPS administration and tissue samples were collected. RIS administration significantly (p < 0.05) reduced the LPS-induced elevated levels of lipid peroxidation product malondialdehyde (MDA), advanced protein oxidation products, and nitric oxide (NO) in the cortex. Catalase (CAT) and superoxide dismutase (SOD) levels were also diminished while the level of glutathione (GSH) was enhanced. Hippocampus data showed that RIS significantly (p < 0.05) reduced the LPS-induced increased levels of MDA and NO, and SOD activity. Our results suggest that LPS-induced neuronal oxidative damage can be alleviated by the pretreatment with RIS and the effect is shown presumably by scavenging of the ROS by risperidone as an antioxidant.