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Long‐term sample stability of five atypical antipsychoticdrugs risperidone, paliperidone, clozapine, quetiapine and olanzapine and the antidepressant drug mirtazapine in serum was studied by use of a newly developed and validated analytical method based on solid‐phase extraction and liquid chromatography–tandem mass spectrometry. Ascorbic acid was used as an antioxidative agent to stabilize olanzapine during storage and sample preparation.We assessed analyte stability on long‐term storage in serum samples at 25°C, 5°C, −20°C and −80°C, and during five freeze–thaw cycles. Analytes were stable for 23 days at room temperature except for olanzapine and mirtazapine (17 days). All analytes were stable for at least 30 days at 5°C. All analytes were stable for 270 days at −20°C, except for paliperidone and mirtazapine with 60 days and 180 days, respectively. All analytes were stable for 270 days at −80°C. Furthermore, all analytes were stable for five freeze–thaw cycles.We recommend storage at −80°C when samples drawn for analysis of antipsychotic drugs are stored for more than 60 days, whereas a temperature of −20°C is sufficient for storage less than 60 days. [ABSTRACT FROM AUTHOR]

Background: Antipsychotic medications are the primary treatment for schizophrenia, with olanzapine being an effective medication for schizophrenia. The economic cost for each individual with schizophrenia is high, with antipsychotic medication being a major expense. This study aims to develop an economic decision model that compares different treatment options for schizophrenia patients, including olanzapine Orally Dispersible Tablets (ODT), olanzapine [ODT + Standard Oral Tablet (SOT)], risperidone (ODT + SOT), and aripiprazole (ODT + SOT), to determine their cost-effectiveness with an objective to optimize healthcare resource allocation in Morocco. Methods: The study used published medical literature and a clinical expert panel to develop a decision analytic model. This model was designed to capture parameters such as adherence levels, treatment discontinuation, relapse with and without hospitalization, quality-adjusted life years (QALYs), treatment-related adverse events, healthcare resource utilization, and associated costs. The main outcomes of interest included the total annual direct cost per treatment, QALYs, and incremental cost-effectiveness ratio (ICER) per 1 QALY gained. One-way and probabilistic sensitivity analyses were employed to account for parameter uncertainty. Results: According to the simulation model, the ODT and ODT + SOT as a group form of olanzapine was the most effective treatment option in terms of the lowest percentages of inpatient relapse, and patients who remained stable (11% and 79% respectively) than risperidone (19% and 62% respectively) and aripiprazole ODT (26% and 50% respectively) and ODT + SOT formulation groups. Olanzapine (ODT + SOT) therapy group was cost-effective when compared to the combined group of ODT + SOT forms of risperidone [ICER: Moroccan Dirham (MAD) 103,907], and aripiprazole (ICER: MAD 65,047). Additionally, olanzapine ODT was found to be cost-effective compared to olanzapine SOT with an ICER of MAD 3921, risperidone ODT with an ICER of MAD 1,02,298, risperidone SOT with an ICER of MAD 31,088, and aripiprazole ODT or SOT formulations. All the above ICERs fall under the willingness-to-pay threshold in Morocco of MAD 250,832.40. Sensitivity analyses confirmed the reliability of the findings. Conclusions: The model concluded that olanzapine ODT is the most cost-effective first-line treatment option for schizophrenia in Morocco when compared to other atypical antipsychotic medications in ODT and SOT formulations. [ABSTRACT FROM AUTHOR]

Background: Risperidone is one of the most reliable and effective antipsychotics for schizophrenia treatment. However, the mechanism of action of risperidone is not yet fully understood. Traf2 and Nck-interacting protein kinase (TNIK), a schizophrenia susceptibility gene, is associated with risperidone treatment response. Our previous in vitro experiments confirmed that downregulated TNIK affected the effect of risperidone on downstream targets. However, the effect of downregulated TNIK on risperidone-induced molecular expression remains to be further explored. Methods: Transcriptome analysis was performed on U251 cells subjected to risperidone, TNIK siRNA, and no treatment, respectively. Compared to the notreatment group, two groups of DEGs were screened out and then intersected with the schizophrenia-related genes to screen the cross-talk genes. Those DEGs were analyzed using GO and KEGG. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network for the cross-talk gene. Results: The results showed that the parathyroid hormone synthesis, secretion, and action were significantly enriched after risperidone treatment. Downregulated TNIK could have an impact on the collagen-containing extracellular matrix, signaling receptor activator activity, and PI3K-Akt signaling pathway. Interestingly, bone mineralization function and calcium signaling pathway were enriched in the cross-talk genes. Additionally, FGFR2, FGF1, and FGFR might be the potential targets for TNIK affecting the effects of risperidone. Conclusion: The study indicated that risperidone primarily influences functions and/or pathways associated with bone metabolism, potentially contributing to the adverse effect of osteoporosis. Our study may offer a novel perspective on investigating the mechanisms underlying the adverse effects of risperidone. [ABSTRACT FROM AUTHOR]

Background: Chinese hamster ovarian (CHO) cells are widely employed in biotechnology for the production of recombinant proteins. Extending the life span of CHO cells and inhibiting the loss of producing cell population through the inhibition of apoptosis can benefit the productivity of those cells. In this study, we aimed to screen and evaluate the impact of some caspase-7 inhibitor candidates on the lifespan of CHO cells. Results: Through virtual screening and molecular docking, risperidone was screened and selected as a potential inhibitor of caspase-7 in CHO cells. The results of MTT assay revealed that the cytotoxicity of risperidone at all concentrations was lower than 50%, and thus it can be suggested as a safe treatment for CHO cells. Annexin V apoptosis and flow cytometry assays revealed that risperidone at 1, 25, and 50 lM concentrations inhibited apoptosis 72 h post-treatment through caspase-7 inhibition. Although gene expression analysis through qRT-PCR demonstrates that risperidone did not affect caspase-7 gene expression. Conclusions: This bioinformatics and experimental study suggests risperidone as a caspase-7 inhibitor with the potential to extend the lifespan of CHO cells and offers possible opportunities in biotechnology. [ABSTRACT FROM AUTHOR]

Many articles suggest that clozapine was strongly associated with a higher incidence of new-onset diabetes mellitus, and the issue has remained unsettled. Many articles have compared clozapine with FGAs, but few have compared clozapine with SGAs. We aimed to compare the risk of new-onset diabetes mellitus in adults with schizophrenia treated with clozapine and other SGAs. We conducted a comprehensive search of databases from their inception up until August 26, 2023. The specific databases include PubMed, Embase and others. We included non-randomized controlled trials involving the use of SGAs such as clozapine, olanzapine, risperidone, quetiapine, amisulpride, and zotepine, with a focus on new-onset diabetes mellitus as an outcome. We utilized odds ratio with 95 % credible intervals (95 % CI) as our effect size measures. The study protocol is registered with PROSPERO, number CRD42024511280. We included 7 studies with sufficient data to include in the meta-analysis. A total of eight studies with 641,48 participants met the eligibility criteria. The OR of the incidence rates of new-onset diabetes between clozapine and olanzapine was 0.95 (95 % CI:[0.82–1.09]), between clozapine and risperidone was 1.25 (95 % CI: [1.09–1.44]), between clozapine and quetiapine was 1.44 (95 % CI: [0.92–2.25]). In patients with schizophrenia, clozapine has been found to have a higher rate of new-onset diabetes mellitus compared to risperidone. However, there was no significant difference in incidence rate between clozapine versus olanzapine and quetiapine. These findings can assist clinicians in balancing the risks and benefits of those drugs. • Differences in the incidence of new-onset diabetes caused by second-generation antipsychotics were compared. • Clozapine and olanzapine cause a similar incidence of new-onset diabetes. • Clozapine is more likely to cause new-onset diabetes than risperidone. • Explored relationship between therapy duration and incidence [ABSTRACT FROM AUTHOR]

Introduction Conventional antipsychotic drugs that attenuate dopaminergic neural transmission are ineffective in approximately one-third of patients with schizophrenia. This necessitates the development of non-dopaminergic agents. Methods A systematic search was conducted for completed phase II and III trials of compounds for schizophrenia treatment using the US Clinical Trials Registry and the EU Clinical Trials Register. Compounds demonstrating significant superiority over placebo in the primary outcome measure in the latest phase II and III trials were identified. Collateral information on the included compounds was gathered through manual searches in PubMed and press releases. Results Sixteen compounds were identified; four compounds (ulotaront, xanomeline/trospium chloride, vabicaserin, and roluperidone) were investigated as monotherapy and the remaining 12 (pimavanserin, bitopertin, BI 425809, encenicline, tropisetron, pregnenolone, D-serine, estradiol, tolcapone, valacyclovir, cannabidiol, and rimonabant) were examined as add-on therapy. Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function. Discussion Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Aims: The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. Methods: A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. Results: The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one‐compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first‐order absorption processes and a combined zero‐order and first order process, with first‐order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness‐of‐fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data. Conclusions: The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once‐monthly gluteal injections of 100 mg and 75 mg. [ABSTRACT FROM AUTHOR]

According to certain findings, heroin addiction represents a significant medical as well as social problem. It is known that with opioid substitution treatment this disease can be overcome or alleviated. However, the application of this treatment does not always give the expected results, so it is necessary to apply additional neuroleptic therapy until the patients are fully stabilized. But the joint application of substitution and neuroleptic therapy can lead to a series of side effects, one of which is the appearance of hyperpolactinemia. The aim of this study is to observe the prevalence of symptoms of hyperprolactinemia in patients with poor response to methadone treatment, treated with neuroleptic therapy. Material and methods: The cross-sectional study evaluated 20 male patients with a mean age of ±24.13 years treated at the Skopje Psychiatric Hospital with high doses of Sol methadone 80-120 mg/day. All patients had a bad agreement on the methadone treatment, so additional therapy was included, tab. Risperidone with an average dose of 2 mg/day. Participants signed an informed consent to participate. Patients were assessed using a semi-structured questionnaire specifically designed for the study. Data consisted of age, sex, and symptoms of hyperprolactinemia: amenorrhea, loss of libido, erectile dysfunction, and gynecomastia. The results of this study were analyzed using descriptive methods, t-test and Pearson's correlation coefficient. The p value of statistical significance was set at p<0.05. Results: The results obtained in our study showed that a certain percentage of methadone patients who were on Risperidone therapy had symptoms of hyperprolactinemia, but the results were without statistical significance p>0.05. Conclusion: although in our study we obtained a small percentage of patients with symptoms of hyperprolactinemia, care must be taken in patients on methadone treatment who are also treated with neuroleptic therapy due to their synergistic effect, we should always keep in mind the possibility of developing hyperprolactinemia. [ABSTRACT FROM AUTHOR]

There is a significant variability in the prevalence of psychotropic medication use among young autistic persons worldwide and this is under-studied in Australia. Apart from risperidone, approved by the Therapeutic Goods Administration to manage challenging behaviour, the appropriateness of other psychotropic medications prescribed to young autistic persons warrants scrutiny. This retrospective study aims to gain initial insight into the magnitude, types and indications of psychotropic medication use in autistic children and adolescents in Western Australia. We analysed de-identified data from 239 autistic children and adolescents (⩽21 years) who participated in the Western Australian Autism Biological Registry between 2011 and 2015 and who completed a questionnaire regarding medication use. One-quarter (n = 66, 28%) of young autistic people reported using a total of 137 medications. Most (n = 46, 70%) of those medicated were under 12 years of age; half (n = 33) were 6–12 years and a fifth (n = 13) were under 6 years. The most used medications were stimulants (n = 35, 53.0%), followed by antidepressants (n = 24, 36.4%), antiepileptics (n = 21, 31.8%), sedatives (n = 15, 22.7%) and antipsychotics (n = 14, 21.2%). These medications were mainly to manage attention deficit hyperactivity disorder, challenging behaviours, seizures, insomnia, undefined anxiety, depression and mood instability. While most autistic young people in the Western Australian Autism Biological Registry did not report using psychotropic medication, over a quarter were prescribed medications, primarily stimulants, to manage symptoms of attention deficit hyperactivity disorder. Various medications, including risperidone, were used to help manage challenging behaviours. Medication use should be studied more comprehensively in a larger cohort of autistic persons to confirm our current preliminary observations. Further, future studies should monitor the effectiveness and safety outcomes of such medications due to a limited understanding of their effectiveness in managing the atypical presentation of co-occurring disorders in young autistic persons. Prescriptions and use of medications to treat mental health conditions in young autistic populations are inconsistent worldwide. This makes it hard to compare findings from international studies to the Australian autistic population, where there are limited relevant studies. Apart from risperidone, there are no other medications specified for direct use in autistic persons. This study aims to gain initial broad understanding of the use of medications, commonly prescribed for mental health conditions, specifically by autistics under the age of 21 years. We analysed data that were previously collected as part of the Western Australian Autism Biological Registry between 2011 and 2015 which amounted to 239 surveys completed on young persons with diagnosed autism. The questionnaires included information on co-occurring conditions, current or previous use of medications and reasons for use of the medications. Only one-quarter of the participants in this study reported using at least one mental health–related medication in their lifetime. The most reported medications were stimulants, antidepressants and antiepileptics. The reasons for using medication included managing attention deficit hyperactivity disorder, challenging behaviours, seizures, sleep difficulties and symptoms of anxiety and depression. The number of individuals reporting medication use in this study was lower compared to other developed countries. Nevertheless, these medications should be monitored due to limited understanding of their use to manage co-occurring symptoms in young autistic persons. The findings highlight the importance of ongoing research to better understand mental health–related medications and inform best practice. [ABSTRACT FROM AUTHOR]

Background: TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone that is approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. In the phase 3, randomized, double-blind RIsperidone Subcutaneous Extended-release (RISE) study, TV-46000 once monthly (q1m) and once every 2 months (q2m) significantly prolonged time to impending relapse compared with placebo [5.0-fold (q1m) and 2.7-fold (q2m)]. This phase 3, randomized, double-blind Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) study was designed to evaluate the long-term safety, tolerability, and exposure of TV-46000 in schizophrenia. Methods: Patients who completed RISE without relapse (rollover) or who were newly recruited (de novo) were eligible for the SHINE study. Patients were initially stabilized on oral risperidone for 12 weeks (completed in RISE for rollover, or in SHINE for de novo). Patients in the de novo cohort and patients who received placebo in RISE were randomized 1:1 in SHINE to receive TV-46000 q1m or q2m for up to 56 weeks. Primary endpoint for SHINE was frequency of reported adverse events (AEs); event rates [ER; events per 100 patient-years (PYs)] were calculated for each AE by patients upon general questioning. Results: Overall, 336 patients were randomized in SHINE [TV-46000 q1m, n = 174; TV-46000 q2m, n = 162; of these, de novo, n = 109 and rollover, n = 227 (n = 172 patients were treated and n = 55 received placebo)]. A total of 334 patients were evaluated for safety [q1m, n = 172 (PY = 97.8); q2m, n = 162 (PY = 104.5)]. Proportions of patients (ER) with ≥ 1 AE and ≥ 1 treatment-related AE were 37% (180.0) and 21% (84.9) for TV-46000 q1m and 46% (157.9) and 20% (70.8) for TV-46000 q2m, respectively. Frequent treatment-related AEs [≥ 3% of patients in either group; proportion of patients (ER)] were injection site pain [q1m, 5% (24.5); q2m, 4% (22.0)] and injection site nodule [q1m, 2% (9.2); q2m, 6% (12.4)]. The proportions of patients with serious AEs was 5% for TV-46000 q1m and 7% for TV-46000 q2m; serious AEs reported for ≥ 2 patients overall were worsening schizophrenia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 2 (1%; ER, 1.91)] and hyperglycemia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 1 (< 1%; ER, 0.96)]. Of three reported deaths, none were related to treatment. Overall, eight patients discontinued treatment because of AEs. Similar or somewhat lower rates of AEs were reported for patients who rolled over from TV-46000 treatment compared with those who had no prior TV-46000 treatment (de novo and placebo rollover). Most AEs related to injection site reactions were mild; no patient had a severe reaction. Conclusion: Results from this long-term safety study add to the favorable safety profiles of TV-46000 q1m and q2m, consistent with other formulations of risperidone and previous studies with TV-46000. Registration: ClinicalTrials.gov, NCT03893825; 27 March 2019. Plain language summary: The United States Food and Drug Administration approved TV-46000 in April 2023 for the treatment of schizophrenia in adults. TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) that uses technology that allows for the slow release of risperidone. TV-46000 is injected under the skin once monthly or once every 2 months. When people start taking TV-46000, they do not need an additional injection or oral risperidone. The Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) was a clinical study in which patients with schizophrenia received TV-46000. SHINE was conducted in patients who completed the RIsperidone Subcutaneous Extended-release (RISE) study and new patients. All patients (TV-46000 once monthly, n = 162; TV-46000 once every 2 months, n = 172) received TV-46000 in SHINE to see whether safety results were the same long term compared with RISE. The proportions with more than one adverse event were 37% for TV-46000 once monthly and 46% for TV-46000 once every 2 months. The proportions with more than one adverse event related to treatment were 21% for TV-46000 once monthly and 20% for TV-46000 once every 2 months. Common adverse events related to treatment were injection site pain and small swelling. Serious adverse events were rare. None of the three reported deaths were related to treatment. Similar or lower rates of adverse events were reported for those who received TV-46000 in RISE compared with those with no prior TV-46000 treatment. The long-term safety results in SHINE were consistent with other forms of risperidone and previous studies with TV-46000. [ABSTRACT FROM AUTHOR]

This study aims to describe the patterns and trends in antipsychotic prescription among Dutch youth before and during the corona virus disease 2019 (COVID-19) pandemic (between 2017 and 2022). The study specifically aims to determine whether there has been an increase or decrease in antipsychotic prescription among this population, and whether there are any differences in prescription patterns among different age and sex groups. The study utilized the IADB database, which is a pharmacy prescription database containing dispensing data from approximately 120 community pharmacies in the Netherlands, to analyze the monthly prevalence and incidence rates of antipsychotic prescription among Dutch youth before and during the pandemic. The study also examined the prescribing patterns of the five most commonly used antipsychotics and conducted an autoregressive integrated moving average (ARIMA) analysis using data prior to the pandemic, to predict the expected prevalence rate during the pandemic. The prescription rate of antipsychotics for Dutch youth was slightly affected by the pandemic, with a monthly prevalence of 4.56 [4.50–4.62] per 1000 youths before COVID-19 pandemic and 4.64 [4.59–4.69] during the pandemic. A significant increase in prevalence was observed among adolescent girls aged 13–19 years. The monthly incidence rate remained stable overall, but rose for adolescent girls aged 13–19 years. Aripiprazole, and Quetiapine had higher monthly prevalence rates during the pandemic, while Risperidone and Pipamperon had lower rates. Similarly, the monthly incidence rates of Aripiprazole and Olanzapine went up, while Risperidone went down. Furthermore, the results from the ARIMA analysis revealed that despite the pandemic, the monthly prevalence rate of antipsychotic prescription was within expectation. The findings of this study suggest that there has been a moderate increase in antipsychotic prescription among Dutch youth during the COVID-19 pandemic, particularly in adolescent females aged 13–19 years. However, the study also suggests that factors beyond the pandemic may be contributing to the rise in antipsychotic prescription in Dutch youth. [ABSTRACT FROM AUTHOR]

Gummy formulations are defined as gradually or slowly released solid oral dosage forms. Risperidone is an atypical antipsychotic medication used to treat schizophrenia and autism-related irritability. This study presents the development of visually appealing, patient-tailored medicated gummies that act as a novel pharmaceutical form of Risperidone for pediatrics. In this study, two gummy bases were used, one containing Glucomannan and the other containing Gelatin as a gelling agent, where these gummy bases were loaded with coated Risperidone pellets with a controlled release layer. The final products were evaluated for their pH, viscosity, content uniformity, drug content, and dissolution profile. Both formulas showed proper rheology and met content and weight uniformity standards. The release rates for F1 and F2 in the acidic media were 25% and 11%, respectively, after 2 h. At the same time, a full-release profile for Risperidone was noticed in both formulae at pH 6.8 where the release lasts for 24 h. It can be concluded that the chewable semi-solid dosages (gummies) filled with coated pellets are suitable for pediatric patients since pediatrics have drug-related problems which can be solved using high gastro-resistance coated pellets, which also shows a proper release profile for the drug. [ABSTRACT FROM AUTHOR]

Accurately measuring drug and its release kinetics in both in vitro and in vivo environments is crucial for enhancing therapeutic effectiveness while minimizing potential side effects. Nevertheless, the real-time visualization of drug release from microspheres to monitor potential overdoses remains a challenge. The primary objective of this investigation was to employ fluorescence imaging for the real-time monitoring of drug release from microspheres in vitro, thereby simplifying the laborious analysis associated with the detection of drug release. Two distinct varieties of microspheres were fabricated, each encapsulating different drugs within PLGA polymers. Cy5 was selected as the donor, and Cy7 was selected as the acceptor for visualization and quantification of the facilitated microsphere drug release through the application of the fluorescence resonance energy transfer (FRET) principle. The findings from the in vitro experiments indicate a correlation between the FRET fluorescence alterations and the drug release profiles of the microspheres. [ABSTRACT FROM AUTHOR]

Background: Second-generation antipsychotics (SGAs) are commonly prescribed medications used to treat a variety of mental health conditions. Recent data has correlated antipsychotic medications with venous thromboembolism (VTE). SGAs have diverse side effect profiles, which may contribute to differences in incidence of VTE. It is unknown which SGAs confer the most risk, and what the mechanism of increased risk is. Objective: Determine incidence of VTE in Veterans at Veterans Affairs North Texas Health Care System (VA-NTX HCS) between SGAs aripiprazole, olanzapine and risperidone. Methods: Retrospective chart review of adult Veterans at VA-NTX HCS between October 2015 to December 2019 prescribed aripiprazole, olanzapine, or risperidone. Results: Of 823 Veterans, incidence of VTE was lowest in aripiprazole group at.4%, increased to 1.7% in the olanzapine group, and was highest at 2.5% in the risperidone group. However, differences in incidence of VTE between SGAs were not statistically different, indicating no between-group differences. Conclusion: There was no difference in the incidence of VTE between risperidone, olanzapine, or aripiprazole. Given multiple limitations with this study, higher-powered studies should be conducted to investigate the possibility of differences in the incidence of VTE between the SGAs. [ABSTRACT FROM AUTHOR]

Objectives: Risperidone is commonly prescribed off-label in children and adolescents to manage disruptive behavior. This study aimed to investigate continued benefits of risperidone after at least 1 year of treatment and effects of discontinuation on physical health. Methods: Thirty-five youths (aged 6–18 years, intelligence quotient [IQ] >70) who were treated with risperidone for at least 1 year in regular clinical practice receiving outpatient care were randomly assigned to double-blind continuation of risperidone during 16 weeks or continuation for 2 weeks, gradual dose lowering over 6 weeks, and placebo for 8 weeks. Primary outcome was the total Disruptive Behavior (D-total) score of the parent-reported Nisonger Child Behavior Rating Form—Typical IQ (NCBRF-TIQ). Secondary outcome measures were the clinician-rated Clinical Global Impressions—Improvement scale (CGI-I), the parent, child, and teacher-rated Strengths and Difficulties Questionnaire (SDQ), the parent-rated Retrospective Modified Overt Aggression Scale (R-MOAS), and several health parameters (Udvalg for Kliniske Undersøgelser Side Effect Rating Scale [UKU-SERS], dyskinesia, akathisia, parkinsonism, body mass index (BMI), waist circumference, and laboratory outcomes). Mixed models for repeated measures were conducted for continuous outcomes and a chi-square test for the CGI-I. Results: Discontinuation of risperidone, as compared with continuation, was not associated with significant changes in parent-reported disruptive behaviors. However, discontinuation was related to significant deterioration in parent-rated verbal aggression, teacher-rated behavioral functioning, clinician-rated general functioning, and significant improvements in weight, BMI, waist circumference, and glucose, insulin, and prolactin levels. Although 56% of participants in the discontinuation group experienced relapse, causing premature withdrawal from the study, 44% was able to successfully discontinue risperidone. Conclusion: Discontinuation of risperidone was associated with deterioration on some, but not all behavioral measures according to this explorative study. Discontinuation was associated with important health gains. Despite long-term benefits of risperidone, attempts to withdraw risperidone should be undertaken in individual children. This is a crucial step in preventing harm and fostering health. [ABSTRACT FROM AUTHOR]

PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia. Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks. The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = −4.7 [95 % CI: −9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = −7.3 [95 % CI: −14.0,−0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: −4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = −2.2 [95 % CI: −3.8,−0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight. These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted. Clinicaltrials.gov identifier: NCT03055338 [ABSTRACT FROM AUTHOR]

Good adherence to antipsychotic therapy helps prevent relapses in first-episode psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts, to emulate a target trial comparing antipsychotics, with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from the European First Episode Schizophrenia Trial, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse-probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone were 61.5% (95% CI, 52.5-70.6), 73.5% (95% CI, 60.5-84.9), 76.8% (95% CI, 67.2-85.3), 58.4% (95% CI, 40.4-77.4), 76.5% (95% CI, 62.1-88.5), and 74.4% (95% CI, 67.0-81.2), respectively. Compared with aripiprazole, the 12-month risk differences were -15.3% (95% CI, -30.0 to 0.0) for olanzapine, -12.8% (95% CI, -25.7 to -1.0) for risperidone, and 3.0% (95% CI, -21.5 to 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration sufficed to remove confounding for these clinical questions. This article is part of a Special Collection on Mental Health. [ABSTRACT FROM AUTHOR]

In vitro-In vivo correlation (IVIVC) is a main focus of the pharmaceutical industry, academia and the regulatory sectors, as this is an effective modelling tool to predict drug product in vivo performance based on in vitro release data and serve as a surrogate for bioequivalence studies, significantly reducing the need for clinical studies. Till now, IVIVCs have not been successfully developed for in situ forming implants due to the significantly different in vitro and in vivo drug release profiles that are typically achieved for these dosage forms. This is not unexpected considering the unique complexity of the drug release mechanisms of these products. Using risperidone in situ forming implants as a model, the current work focuses on: 1) identification of critical attributes of in vitro release testing methods that may contribute to differences in in vitro and in vivo drug release from in situ forming implants; and 2) optimization of the in vitro release method, with the aim of developing Level A IVIVCs for risperidone implants. Dissolution methods based on a novel Teflon shape controlling adapter along with a water non-dissolvable glass fiber membrane (GF/F) instead of a water dissolvable PVA film (named as GF/F-Teflon adapter and PVA-Teflon adapter, respectively), and an in-house fabricated Glass slide adapter were used to investigate the impact of: the surface-to-volume ratio, water uptake ratio, phase separation rate (measured by NMP release in 24 h post injection in vitro or in vivo), and mechanical pressure on the drug release patterns. The surface-to-volume ratio and water uptake were shown to be more critical in vitro release testing method attributes compared to the phase separation rate and mechanical pressure. The Glass slide adapter-based dissolution method, which allowed for the formation of depots with bio-mimicking surface-to-volume ratios and sufficient water uptake, has the ability to generate bio-relevant degradation profiles as well as in vitro release profiles for risperidone implants. For the first time, a Level A IVIVC (rabbit model) has been successfully developed for in situ forming implants. Release data for implant formulations with slightly different PLGA molecular weights (MWs) were used to develop the IVIVC. The predictability of the model passed external validation using the reference listed drug (RLD), Perseris®. IVIVC could not be developed when formulations with different PLGA molar ratios of lactic acid to glycolic acid (L/G) were included. The present work provides a comprehensive understanding of the impact of the testing method attributes on drug release from in situ forming implants, which is a valuable practice for level A IVIVC development. [Display omitted] [ABSTRACT FROM AUTHOR]

Experimental evidence indicates that the noncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonists ketamine and MK‐801 induce schizophrenia‐like symptoms in rodents, including cognitive deficits. Crocins are among the active components of the plant Crocus sativus L. and were found to be effective in different models of psychiatric disorders comprising schizophrenia. The present study was designed to evaluate the efficacy of the joint administration of sub‐effective doses of crocins with those of the atypical antipsychotics clozapine and risperidone in alleviating nonspatial recognition and emotional memory deficits induced either by ketamine (3 mg/kg) or MK‐801 (0.1 mg/kg) in the rat. To this end, the object recognition and the step‐through passive avoidance tests were used. Co‐administration of sub‐effective doses of crocins (5 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted nonspatial recognition and emotional memory deficits induced by NMDA receptor antagonists. The current findings suggest that this combinatorial treatment was efficacious in attenuating cognitive impairments related to the blockade of the NMDA receptor. In addition, the present results support the potential of crocins as an adjunctive drug for the therapy of schizophrenia. [ABSTRACT FROM AUTHOR]

Long-acting injectable (LAI) antipsychotic medications can help improve treatment adherence in patients with schizophrenia and bipolar disorder. Despite this, they are underutilized. In 2003, intramuscular risperidone became the first available LAI atypical antipsychotic medication, and since then, a number of competing long-acting risperidone formulations have been brought to market, with additional options under active development. These include intramuscular, subcutaneous, long-acting oral, and implantable formulations. This review summarizes currently available and emerging long-acting risperidone formulations, including efficacy and safety data, and practical considerations aimed to help prescribers distinguish one formulation from another. There is an expanding number of currently available LAI antipsychotic medications giving patients and providers an opportunity to personalize and individualize care. Rates of adherence to treatment in patients with schizophrenia and bipolar disorder are low, and individualizing care can help improve this. The risperidone LAI treatment landscape includes five options approved by the U.S. Food and Drug Administration, with others under clinical development. These options differ in regard to mode of administration, approved indications, available dose strengths, injection intervals, needle size, injection volume, storage, and other variables. Prescribers should be familiar with these differing options to help patients find the best fit for their individual needs. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions Yokukansan is one of the most frequently used herbal medicines that can improve the behavioral and psychological symptoms of dementia. In this exploratory study, we investigated whether yokukansan affects the steady‐state blood concentrations of donepezil, risperidone, and the major metabolites of both drugs in a real‐world clinical setting.A non‐randomized, open‐label, single‐arm study examining drug–drug interactions was conducted. Fifteen dementia patients taking donepezil for at least 4 weeks and eight schizophrenia patients taking risperidone for at least 2 weeks were orally administered 2.5 g of yokukansan three times a day before or between meals, and blood samples were collected before and 8 weeks after starting co‐treatment with yokukansan. Plasma concentrations of donepezil, risperidone, and each metabolite were measured using high‐performance liquid chromatography–tandem mass spectrometry and compared before and after the 8‐week administration of yokukansan.The plasma concentrations of donepezil and its metabolites (6‐O‐desmethyl‐donepezil, 5‐O‐desmethyl‐donepezil, and donepezil‐N‐oxide), risperidone, and its metabolite paliperidone did not differ before and after the 8‐week treatment with yokukansan.The findings of this study show that the concomitant use of yokukansan may have little clinical impact on the steady‐state blood levels of donepezil and risperidone in patients with dementia or schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Schizophrenia is a debilitating condition that affects 1% of the global population. Understanding the prevalence and the factors predicting schizophrenia remission is crucial for healthcare providers. This study aimed to determine the prevalence of remission and factors affecting the remission. Cross-sectional study was conducted at the Amanuel Mental Specialized Hospital from 3 October, 2022, to 31 August, 2023, and included 271 participants. Remission was measured using Remission in Schizophrenia Working Group (RSWG) symptom severity-based criteria. Data analysis was done using SPSS V.25. Results: The mean age of participants was 34.2 with standard deviation (SD) of 10.5 years. Most were male (90%), unmarried (63.8%), lived with their relatives (91.9%), and were unemployed (56.5%). Fifty-two percent achieved symptomatic remission. Remission in patients with medication switched to SGAs increased by 1.9 times compared to patients without medication switch (AOR 1.9, 95% CI: 1.1, 1.2). Adherent patients had 2.7 times higher odds of symptomatic remission as compared to non-adherent patients (AOR 2.7, 95% CI: 1.5,4.9), and for each unit increase in body mass index (BMI), the odds of achieving symptomatic remission were increased by 13% (AOR 1.13, 95% CI: 1.04, 1.23). The odds of symptomatic remission decreased by 71% in patients experiencing moderate-to-severe side effects compared to their counterparts (AOR 0.29, 95% CI: 0.1, 0.6). Conclusions: Our study revealed a symptomatic remission was achieved in 141 (52%) of the subjects. There is a possibility to improve symptomatic remission with counseling on the importance of adherence, monitoring and managing side effects, and switching medication to either risperidone or olanzapine. Measuring remission using RSWG time-based criteria is recommended. [ABSTRACT FROM AUTHOR]

Many children with autism spectrum disorder (ASD) also have attention-deficit/hyperactivity disorder (ADHD). ADHD in children is associated with increased risk of negative outcomes, and early intervention is critical. Current guidelines recommend psychosocial interventions such as behavioral training as the first line of therapy in managing ADHD symptoms in children with or without ASD. Where symptoms are refractory to these interventions, medications such as stimulants, α2-adrenergic agonist inhibitors, selective norepinephrine reuptake inhibitors, and second-generation antipsychotics are recommended. However, these pharmacotherapies do not have regulatory approval for use in children of preschool age, and evidence on their safety and efficacy in this population has historically been very limited. Since publication of the current guidelines in 2020, several new randomized controlled trials and real-world studies have been published that have investigated the efficacy and tolerability of these medications in preschool children with ADHD, with or without comorbid ASD. Here, we provide a review of the key findings of these studies, which suggest that there is growing evidence to support the use of pharmacological interventions in the management of ADHD in preschool children with comorbid ASD. [ABSTRACT FROM AUTHOR]

Pharmacogenetic markers are current targets for the personalized treatment of psychosis. Limited data exist on COMT and NRG1 polymorphisms in relation to risperidone treatment. This study focuses on the impact of COMT rs4680 and NRG1 (rs35753505, rs3924999) polymorphisms on risperidone treatment in schizophrenia spectrum disorders (SSDs). This study included 103 subjects with SSD treated with risperidone monotherapy. COMT rs4680, NRG1 rs35753505, and rs3924999 were analyzed by RT-PCR. Participants were evaluated via the Positive and Negative Syndrome Scale (PANSS) after six weeks. Socio-demographic and clinical characteristics were collected. COMT rs4680 genotypes significantly differed in PANSS N scores at admission: AG>AA genotypes (p = 0.03). After six weeks of risperidone, PANSS G improvement was AA>GG (p = 0.05). The PANSS total score was as follows: AA>AG (p = 0.04), AA>GG (p = 0.02). NRG1 rs35753504 genotypes significantly differed across educational levels, with CC>CT (p = 0.02), and regarding the number of episodes, TT>CC, CT>CC (p = 0.01). The PANSS total score after six weeks of treatment showed a better improvement for TT

The interest in the development and therapeutic application of long-acting injectable products for chronic or long-term treatments has experienced exponential growth in recent decades. TV-46000 (Uzedy, Teva) is a long-acting subcutaneous (sc) injectable formulation of risperidone, approved for the treatment of schizophrenia in adults. Following sc injection, the copolymers together with risperidone precipitate to form a sc depot under the skin to deliver therapeutic levels of risperidone over a prolonged period of either 1 month or 2 months, depending upon the dose. This work presents the strategy and the results of the physiologically-based pharmacokinetic (PBPK) modeling and establishing of in vitro–in vivo correlation (IVIVC) for the prediction of TV-46000 pharmacokinetic profile in humans, using in vitro release, intravenous (iv), and sc single-dose pharmacokinetic data in beagle dogs. The resulting simulated TV-46000 PK profile in humans showed that the shape of the predicted risperidone and its active metabolite 9-OH-risperidone PK profiles was different from the observed one, thus suggesting that the TV-46000 release profile was species-dependent and cannot be directly extrapolated from dog to human. In conclusion, while level A IVIVC cannot be claimed, this work combining PBPK and IVIVC modeling represents an interesting alternative approach for complex injectable formulations where classical methods are not applicable. [ABSTRACT FROM AUTHOR]

This study investigated the usage patterns and impact of therapeutic drug monitoring (TDM) for risperidone and paliperidone in patients diagnosed with schizophrenia, utilizing retrospective real-world data sourced from a single center's Clinical Data Warehouse. Our study cohort comprised patients diagnosed with schizophrenia undergoing treatment with either risperidone or paliperidone. Data on demographic characteristics, comorbidities, medication utilization, and clinical outcomes were collected. Patients were categorized into two groups: those undergoing TDM and those not undergoing TDM. Additionally, within the TDM group, patients were further stratified based on their risperidone and paliperidone concentrations relative to the reference range. The findings revealed that patients in the TDM group received higher risperidone and paliperidone doses (320 mg/day and 252 mg/day, p = 0.0045) compared to their non-TDM counterparts. Nevertheless, no significant disparities were observed in hospitalization rates, duration of hospital stays, or compliance between the two groups (p = 0.9082, 0.5861, 0.7516, respectively). Subgroup analysis within the TDM cohort exhibited no notable distinctions in clinical outcomes between patients with concentrations within or surpassing the reference range. Despite the possibility of a selection bias in assigning patients to the groups, this study provides a comprehensive analysis of TDM utilization and its ramifications on schizophrenia treatment outcomes. [ABSTRACT FROM AUTHOR]

Antipsychotic medications are essential for managing severe mental illnesses like schizophrenia, which impacts about 1% of the global population. Despite efficacy, in some cases, they can induce hyperprolactinemia, affecting roughly half of the patients. The prevalence of this condition varies with the specific medication used. Although prolactinomas are rare among schizophrenia patients, treating them with dopamine agonists poses conflicts with antipsychotic medication, necessitating careful monitoring and adjustments. The aim of this study was to explore the presence of brain tumors, prolactinomas, and other structural brain changes in schizophrenia patients treated with second-generation antipsychotics using cerebral computed tomography (CT) scans. We conducted a cross-sectional study involving 152 hospitalized patients diagnosed between 1 January 2020 and 31 March 2024. Evaluations included cerebral CT scans, prolactin level assessments, and the monitoring of side effects. Patients, with an average age of 42.79 years and an illness duration of 17.89 years, predominantly received olanzapine (46.05%) and risperidone (36.84%). Side effects, reported by 61.78% of patients, included tremors, dizziness, and weight gain. Abnormal prolactin levels were observed in 53.95% of patients, more prevalent in females on risperidone and in both genders on olanzapine. No prolactinomas were detected on CT scans. Managing hyperprolactinemia in schizophrenia patients undergoing antipsychotic therapy is essential to prevent long-term complications and to ensure treatment compliance. [ABSTRACT FROM AUTHOR]

Several studies indicate the impact of antipsychotics like risperidone and paliperidone on oxidative stress parameters, yet data remain inconsistent. We investigated the link between these medications, hyperprolactinemia (HPRL), and oxidative stress. This study was conducted at the Psychiatry Clinic, University Clinical Center, Kragujevac, between November 2022 and August 2023. Inclusion criteria comprised diagnosed psychotic disorders from the ICD-10-based F20-F29 spectrum and clinical stability on risperidone/paliperidone for ≥12 weeks with no recent dose adjustments. Exclusion criteria included pregnancy, breastfeeding, relevant medical conditions, or co-therapy with prolactin-secreting drugs. Data encompassed drug choice, administration method, therapy duration, and daily dose. Prolactin (PRL) levels, oxidative stress parameters (TBARS, H2O2, O2−, NO2−), and antioxidant system (CAT, GSH, SOD) were assessed. Of 155 subjects, women exhibited significantly higher PRL levels (p < 0.001) and symptomatic HPRL (p < 0.001). Drug choice and regimen significantly influenced TBARS (p < 0.001), NO2− (p < 0.001), O2− (p = 0.002), CAT (p = 0.04), and GSH (p < 0.001) levels. NO2− levels were affected by drug dose (p = 0.038). TBARS (p < 0.001), O2− (p < 0.001), and SOD (p = 0.022) inversely correlated with PRL levels, suggesting PRL's protective role against oxidative stress. The female sex association with higher PRL levels implies additional factors influencing PRL's antioxidant role. Antipsychotic choice and dosage impact PRL and oxidative stress markers, necessitating further exploration. [ABSTRACT FROM AUTHOR]

Xiuli Yang,1 Xiaochun Zheng,1 Miaomiao Zhang,1,2 Jinlong Huang,1,2 Ping Huang,1,&ast; Jiangfeng Wang1,3,&ast; 1Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 2School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Pharmaceutical Services, Ipharmacare Ltd, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ping Huang; Jiangfeng Wang, Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, 158 Shangtang Road, Gongsu District, Hangzhou, Zhejiang, 310014, People’s Republic of China, Email huangpwly@sina.com; wangjfTP@126.comPurpose: Drug-induced gynecomastia significantly affects patient health and quality of life. This study aimed to perform an exploratory analysis of gynecomastia reports and the most commonly associated medications within the FAERS database.Patients and Methods: A comprehensive analysis of the FAERS from January 2004 to December 2023 was conducted. Disproportionality analysis and subsequent sensitivity analysis were performed to identify drugs potentially associated with gynecomastia, utilizing the reported odds ratio (ROR). Logistic regression analysis was employed to assess potential risk factors. The Weibull shape parameter (WSP) test was used to assess the time-to-onset characteristics of the top drugs associated with gynecomastia.Results: The study identified 30,265 cases of gynecomastia, primarily associated with nervous system drugs, accounting for 85.50% of cases. Notably, risperidone accounted for 80.81% of the total cases. Among the 165 agents with ≥ 5 cases of gynecomastia, the strongest signals were exhibited by risperidone (ROR 602.38, 95% CI 585.07– 620.20), dutasteride (ROR 17.18, 95% CI 15.55– 18.89), spironolactone (ROR 15.8, 95% CI 13.99– 17.83), and paliperidone (ROR 7.16, 95% CI 6.55– 7.84). In the sensitivity analysis of disproportionality, unexpected associations were observed, such as montelukast (n = 21, ROR 1.94, 95% CI 1.26– 2.98). The logistic regression analysis indicated that the risk of risperidone-induced gynecomastia was significantly lower in adults compared to pediatric patients (OR 0.12, 95% CI 0.09– 0.15) and in patients with higher body weight than in those with lower body weight (OR 5.24, 95% CI 3.62– 7.76). The WSP test showed that gynecomastia induced by most of the top 10 common agents tends to occur in an early failure mode.Conclusion: The rankings and signal strengths of drugs associated with gynecomastia were extracted from the FAERS. The age distribution and time-to-onset distribution of the top 10 drugs linked to gynecomastia were investigated, which can facilitate accurate clinical recognition of drug-induced gynecomastia.Keywords: drug-induced, gynecomastia, FAERS, risperidone, time-to-onset