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Objectives: To describe clinical consequences of risperidone medication errors in children of less than 13 years and to estimate a clinically relevant toxic dose., Methods: All cases of risperidone medication errors managed by French Poison Centres from 2001 to 2012 were analyzed. Inclusion criteria were a delay of at least 2 hours between ingestion and request to the FPC in asymptomatic children, an ingested dose above two-fold the maximal daily dose for children above 5 years or any symptomatic patient at the time of first contact., Results: One hundred and sixty cases met our criteria. Median age was 8 years (range 0.9-12) and 28.1% were aged 5 years or less. Causes of the error were an incorrect dose in treated children (84.2%) or a dose given to a wrong child (15.8%). The median ingested dose was 0.1 mg/kg or 3.3-fold the maximum recommended dose. Overall, 59 children had no symptoms, 95 experienced minor symptoms and six moderate symptoms. Somnolence/sedation was the most common (73.3%). Of the 17 children who developed extrapyramidal disorders, all had minor or moderate symptoms and only five required a symptomatic treatment., Conclusions: Risperidone medication errors in children cause minimal effects. Somnolence and mild to moderate extrapyramidal reactions were the main features of toxicity, and significant cardiac or other neurological features were not observed. No case with severe toxicity was noted. At home surveillance can be proposed for children exposed to a dose ≤0.15 mg/kg.

Extrapyramidal symptoms (EPS) are the major constraint in the use of antipsychotic agents. It is usually forewarned whenever therapy with these agents is considered. In this case, we present a child diagnosed with relapsed Wilm's tumour, who developed EPS just after a short duration of initiation of risperidone prescribed as an appetite stimulant. The patient became symptom free after management and risperidone was discontinued. Although risperidone has been approved to treat different indications in adolescents and children, scarce scientific evidence and our case report, are suggestive of further studies to establish safety of risperidone use in preschool children.

Objectives: To describe a cohort of young users of risperidone and quetiapine in the province of Manitoba (Canada) and assess the risk for movement disorders in the two treatments., Methods: This was a population-based study conducted on all residents of the province of 19 years of age and younger who received prescriptions for risperidone or quetiapine between April 1, 1996, and March 31, 2011. Incident rates of antipsychotic use were reported. The risk for movement disorders in patients treated with quetiapine compared with those treated with risperidone was assessed by time-to-event analysis using Cox proportional hazards models., Results: Between April 1, 1996, and March 31, 2011, 23,888 youth (age ≤19 years) were prescribed an antipsychotic agent. Among them, 8756 were identified as new incident users. After applying exclusion criteria, 2594 individuals comprised the cohort of users of risperidone and quetiapine. The use of quetiapine was associated with a lower risk of extrapyramidal symptoms (EPSs) adverse events. The unadjusted and adjusted hazard ratios (95% confidence interval [CI]) for quetiapine versus risperidone were 0.83 (0.56-1.25) and 0.53 (0.34-0.83), respectively., Conclusion: EPS diagnoses have been detected in children treated with quetiapine; however, the risk of movement disorders appears to be higher with treatment with risperidone. Clinicians should always take into consideration the risk-benefit before treating children with antipsychotic medications and should be vigilant of the onset of drug-induced adverse events.

Antipsychotic drugs can induce various undesirable adverse motor reactions, such as extrapyramidal side effects (EPS). A widely accepted pharmacodynamic mechanism underlying EPS includes an increase in striatal D2-receptor occupancy. However, less is known about the pharmacokinetic background of EPS. The aim of this study was to analyze in-vivo possible pharmacokinetic patterns underlying biperiden-treated EPS in risperidone (RIS)-medicated patients. A large therapeutic drug monitoring database containing plasma concentrations of RIS and its metabolite 9-hydroxyrisperidone (9-OH-RIS) of 2293 adult inpatients and outpatients was analyzed. Two groups were compared: a group receiving RIS (n=772) and a group comedicated with biperiden (n=68). Plasma concentrations, dose-adjusted plasma concentrations (C/D) of RIS, 9-OH-RIS, and active moiety (AM) (RIS+9-OH-RIS) as well as ratios of concentrations for metabolite to parent drug (9-OH-RIS/RIS) were computed. We compared the plasma concentrations of the different compounds between the two groups considering the prescription of biperiden as an indirect report of EPS. The daily dosage of RIS did not differ between groups. No differences were detected in case of plasma concentrations and C/D of RIS and active metabolite between the groups. However, plasma concentrations of the AM were significantly higher in the comedicated group (P=0.032) and showed a trend in terms of the active metabolite 9-OH-RIS (P=0.053). Data indicate enhanced AM plasma concentrations of RIS in patients comedicated with biperiden as an EPS treatment. This might underscore an association between higher plasma concentrations of the AM and treatment-requiring EPS.

Objectives: To compare rates of specific adverse outcomes between patients starting quetiapine, olanzapine, or risperidone use in the Netherlands., Methods: Observational study using the PHARMO Database Network, including patients starting quetiapine (4658), olanzapine (5856), or risperidone (7229) in 2000-2009, comparing rates of all-cause mortality, failed suicide attempts, extrapyrimidal symptoms (EPS), diabetes mellitus (DM), hypothyroidism, and acute myocardial infarction (AMI)., Key Findings: Median follow-up until discontinuation/end of follow-up was 0.6 years. Prescribed doses were generally lower than the approved defined daily doses, especially for quetiapine. Quetiapine was significantly associated with lower EPS rates (HR 0.18; 95% CI 0.13-0.24), but higher failed suicide attempt rates (HR 2.07; 95% CI 1.35-3.16) compared to risperidone. Quetiapine was significantly associated with lower EPS rates (HR 0.59; 95% CI 0.42-0.84) and DM rates (HR 0.66; 95% CI 0.44-0.97) compared to olanzapine. Rates for all-cause mortality, hypothyroidism, and stroke were similar between groups. AMI events were too infrequent to draw conclusions., Conclusions: Quetiapine was associated with lower EPS, but higher failed suicide attempt rates compared to risperidone. Quetiapine was associated with lower EPS and DM rates compared to olanzapine. The results should be interpreted with caution because of possible channelling and residual confounding. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

To identify potential candidate genes for future pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we used gene expression arrays to analyze changes induced by risperidone in mice strains with different susceptibility to EPS. We proposed a systems biology analytical approach that combined the identification of gene co-expression modules related to AP treatment, the construction of protein-protein interaction networks with genes included in identified modules and finally, gene set enrichment analysis of constructed networks. In response to risperidone, mice strain with susceptibility to develop EPS showed downregulation of genes involved in the mammalian target of rapamycin (mTOR) pathway and biological processes related to this pathway. Moreover, we also showed differences in the phosphorylation pattern of the ribosomal protein S6 (rpS6), which is a major downstream effector of mTOR. The present study provides new evidence of the involvement of the mTOR pathway in AP-induced EPS and offers new and valuable markers for pharmacogenetic studies.

Background: Iron deficiency disrupts dopaminergic signaling in rodents, resulting in cognitive deficits that may be reversed with psychostimulants. In humans, iron deficiency with or without anemia has similarly been found to cause neuropsychological and behavioral impairments. However, the clinical effects of low body iron stores in antipsychotic-treated children have not been examined., Methods: Medically healthy, 5- to 17-year-old boys treated with risperidone for at least 1 year were enrolled between February 2009 and November 2013 in a multiphase study, examining the skeletal effects of calcium and vitamin D supplementation in risperidone-induced hyperprolactinemia. Anthropometric measures were collected and medical and pharmacy records were reviewed to obtain treatment history. Psychiatric diagnoses were based on clinical interviews, structured interviews, rating scales, and a review of their medical records. Extrapyramidal symptoms were assessed, and a food frequency questionnaire was completed in a subsample. Laboratory tests, including ferritin concentration (a marker of body iron status), were obtained upon study entry., Results: A total of 114 participants (mean age: 11.0 ± 2.6 years) were included, the vast majority (>90%) having attention-deficit/hyperactivity disorder and/or disruptive behavior disorder. They had taken risperidone for an average 3.1 ± 2.0 years. Their serum ferritin concentration was 37.3 ± 25.6 μg/L with 21% of the sample having a level <20 μg/L, despite appropriate daily dietary iron intake. Ferritin concentration was inversely associated with weight gain following risperidone treatment onset but was not significantly associated with prolactin. After adjusting for the weight-adjusted dose of psychostimulants and risperidone and the daily dose of selective serotonin reuptake inhibitors, ferritin was inversely associated with the severity of disruptive behavior and positively associated (albeit marginally) with prosocial behavior. No association was found between ferritin concentration and extrapyramidal symptoms., Conclusions: Body iron stores are inversely related to risperidone-induced weight gain, even after extended treatment and despite adequate iron intake. Low iron stores are associated with poorer treatment response. Future research should examine iron absorption during antipsychotic treatment and whether repleting iron stores would facilitate clinical response.

The risperidone maintenance treatment in schizophrenia study was designed to identify the duration of maintenance treatment required with an initial therapeutic dose in contrast to reducing the dose over time. This study investigated extrapyramidal symptoms (EPSs) in different risperidone maintenance treatment paradigms over 1 year. Clinically stabilized patients with schizophrenia (n = 374) were randomized to a no-dose-reduction group and 4-week and 26-week reduction groups, in which the dose was gradually reduced by 50% over 8 weeks and maintained. Extrapyramidal symptoms were assessed at baseline and monthly for 6 months, followed by every 2 months. The Simpson-Angus Scale of Extrapyramidal Symptoms-Chinese version assessed EPS severity. Data were analyzed by a generalized linear mixed model (GLMM). The frequency of EPS at baseline was 23.2%, 20.0%, and 21.3% in the 4-week, 26-week, and no-dose-reduction groups, respectively. Risperidone dosage, positive symptoms, and disorganized thoughts at baseline predicted development of EPS. The GLMM indicated that a significant decrease in EPS was maintained, and different trajectories occurred over time across groups. In the 235 patients who continued treatment after 1 year, the incidence of EPS decreased to 4.1%, 2.8%, and 10.0% in the 4-week, 26-week, and no-dose-reduction groups, respectively, whereas the numbers of dropouts because of intolerable EPS were not significantly different (4.8%, 6.7%, and 6.2%, respectively). These novel findings indicate EPSs were tolerable and differentially decreased depending on the dose paradigm during the 1-year treatment period. Future studies should implement a GLMM to investigate antipsychotic adverse effects during long-term treatment.

To identify the candidate genes for pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we propose a systems biology analytical approach, based on protein-protein interaction network construction and functional annotation analysis, of changes in gene expression (Human Genome U219 Array Plate) induced by treatment with risperidone or paliperidone in peripheral blood. 12 AP-naïve patients with first-episode psychosis participated in the present study. Our analysis revealed that, in response to AP treatment, constructed networks were enriched for different biological processes in patients without EPS (ubiquitination, protein folding and adenosine triphosphate (ATP) metabolism) compared with those presenting EPS (insulin receptor signaling, lipid modification, regulation of autophagy and immune response). Moreover, the observed differences also involved specific pathways, such as anaphase promoting complex /cdc20, prefoldin/CCT/triC and ATP synthesis in no-EPS patients, and mammalian target of rapamycin and NF-κB kinases in patients with EPS. Our results showing different patterns of gene expression in EPS patients, offer new and valuable markers for pharmacogenetic studies.

Importance: Patients with late-life schizophrenia (LLS) are highly susceptible to antipsychotic adverse effects. Treatment guidelines endorse lower antipsychotic doses. However, the optimal dose of antipsychotics and associated dopamine D2/3 receptor (D2/3R) occupancies remain largely unexplored in patients with LLS., Objective: To evaluate effects of antipsychotic dose reduction on striatal dopamine D2/3R occupancies, clinical variables, and blood pharmacokinetic measures in patients with LLS., Design, Setting, and Participants: An open-label, single-arm prospective study with a 3- to 6-month follow-up period (January 10, 2007, to October 21, 2013) was conducted at an academic tertiary care center with practice for ambulatory care. Participants included 35 outpatients with clinically stable LLS (patients aged ≥ 50 years receiving olanzapine or risperidone monotherapy at the same dose for 6 to 12 months). Follow-up was completed on October 21, 2013, and analysis was conducted from October 22, 2014, to February 2, 2015., Interventions: Carbon 11-labeled raclopride positron emission tomography, clinical measures, and blood pharmacokinetic measures performed before and after gradual dose reduction by up to 40% from the baseline dose and at least 3 months after dose reduction., Main Outcomes and Measures: Striatal dopamine D2/3R occupancies with antipsychotics, clinical measures (Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Targeted Inventory on Problems in Schizophrenia, Simpson-Angus Scale, Barnes Rating Scale for Drug-Induced Akathisia, Udvalg for Kliniske Undersøgelser Side Effect Rating Scale), and blood pharmacokinetic measures (prolactin and antipsychotic blood levels)., Results: Dopamine D2/3R occupancy of the entire sample decreased by a mean (SD) of 6.2% (8.2%) following dose reduction (from 70% [12%] to 64% [12%]; P < .001). The lowest D2/3R occupancy associated with clinical stability was 50%. Extrapyramidal symptoms (EPSs) were more likely to occur with D2/3R occupancies higher than 60%: 90.5% (19 of 21) of the participants with baseline EPSs and 76.9% (10 of 13) of the participants with postreduction EPSs had striatal D2/3R occupancies higher than 60%. The baseline D2/3R occupancies were lower in patients with clinical deterioration (n = 5) than in those whose condition remained stable (n = 29) (58% [15%] vs 72% [10%]; P = .03). Following dose reduction, Targeted Inventory on Problems in Schizophrenia score increased (P = .046) and Positive and Negative Syndrome Scale (P = .02), Brief Psychiatric Rating Scale (P = .03), Simpson-Angus Scale (P < .001), Barnes Rating Scale for Drug-Induced Akathisia (P = .03), and Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (P < .001) scores and prolactin (P < .001) and blood antipsychotic (olanzapine, P < .001; risperidone plus the metabolite 9-hydroxyrisperidone, P = .02) levels all decreased., Conclusions and Relevance: Antipsychotic dose reduction is feasible in patients with stable LLS, decreasing adverse effects and improving illness severity measures. The results of the present study suggest a lower therapeutic window of D2/3R occupancy in patients with LLS (50%-60%) than previously reported in younger patients (65%-80%).

Antipsychotic (AP) treatment-emergent extrapyramidal symptoms (EPS) are acute adverse reactions of APs. The aim of the present study is to analyze gene-gene interactions in nine genes related to the mTOR pathway, in order to develop genetic predictors of the appearance of EPS. 243 subjects (78 presenting EPS: 165 not) from three cohorts participated in the present study: Cohort 1, patients treated with risperidone, (n=114); Cohort 2, patients treated with APs other than risperidone (n=102); Cohort 3, AP-naïve patients with first-episode psychosis treated with risperidone, paliperidone or amisulpride, n=27. We analyzed gene-gene interactions by multifactor dimensionality reduction assay (MDR). In Cohort 1, we identified a four-way interaction, including the rs1130214 (AKT1), rs456998 (FCHSD1), rs7211818 (Raptor) and rs1053639 (DDIT4), that correctly predicted 97 of the 114 patients (85% accuracy). We validated the predictive power of the four-way interaction in Cohort 2 and in Cohort 3 with 86% and 88% accuracy respectively. We develop and validate a powerful pharmacogenetic predictor of AP-induced EPS. For the first time, the mTOR pathway has been related to EPS susceptibility and AP response. However, validation in larger and independent populations will be necessary for optimal generalization., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

We investigated the relationship between basal ganglia volume and treatment response to the atypical antipsychotic medication risperidone in unmedicated patients with schizophrenia. Basal ganglia volumes included the bilateral caudate, putamen, and pallidum and were measured using the Freesurfer automated segmentation pipeline in 23 subjects. Also, baseline symptom severity, duration of illness, age, gender, time off medication, and exposure to previous antipsychotic were measured. Treatment response was significantly correlated with all three regions of the bilateral basal ganglia (caudate, putamen, and pallidum), baseline symptom severity, duration of illness, and age but not gender, time off antipsychotic medication, or exposure to previous antipsychotic medication. The caudate volume was the basal ganglia region that demonstrated the strongest correlation with treatment response and was significantly negatively correlated with patient age. Caudate volume was not significantly correlated with any other measure. We demonstrated a novel finding that the caudate volume explains a significant amount of the variance in treatment response over the course of 6 weeks of risperidone pharmacotherapy even when controlling for baseline symptom severity and duration of illness., (© 2013 Published by Elsevier Ireland Ltd.)

Aim: To elucidate the relationship between CYP2D6 genotype and risperidone pharmacokinetics and extrapyramidal symptoms we propose the APSEP pharmacogenetic clinical trial., Materials & Methods: Twenty-five healthy subjects were included in this randomized, placebo-controlled, single dose (risperidone 2.5 mg) crossover and double-blind clinical trial. Subjects were selected according to their CYP2D6 genotype and classified as: poor metabolizers (n = 8), extensive metabolizers (n = 10) and ultrarapid metabolizers (n = 7)., Results & Conclusion: Our study demonstrates that CYP2D6 predicted 65% of the risperidone metabolism variability. Moreover, its ability to predict actigraphy records is similar to the predictive power of pharmacokinetic parameters (24%). Our results also highlight the need for the development of pharmacogenetic predictors that take into account the complexity of pharmacokinetic and pharmacodynamic relationships.

The descriptive term behavioral and psychological symptoms of dementia (BPSD) is used to cover a range of noncognitive disturbances including anxiety, depression, irritability, aggression, agitation, eating disorders, and inappropriate social or sexual behaviors. Behavioral and psychological symptoms of dementia are seen in about 90% of patients with dementia. We aimed to compare the efficacy and tolerability of risperidone, yokukansan, and fluvoxamine used for BPSD in elderly patients with dementia. Ninety inpatients with dementia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria were investigated in Sato Hospital, Koutokukai. We conducted an 8-week, rater-blinded, randomized trial, administering flexibly dosed risperidone, yokukansan, or fluvoxamine. Primary outcome measures were Neuropsychiatric Inventory in Nursing Home Version total score and its items. Secondary outcome measures were cognitive function measured by Mini-Mental State Examination and daily life function measured by Functional Independence Measure (FIM). Neurological adverse effects were measured by the Drug-Induced Extra-Pyramidal Symptoms Scale. At the end of the study, we analyzed 76 patients (92.7%). Mean Neuropsychiatric Inventory in Nursing Home Version total score decreased in all 3 drug groups, with no significant between-group differences. Mini-Mental State Examination and Functional Independence Measure scores did not change significantly. Drug-Induced Extra-Pyramidal Symptoms Scale scores did not change in the yokukansan and fluvoxamine groups, but increased significantly in the risperidone group. Risperidone, yokukansan, and fluvoxamine were equally effective in the treatment of BPSD in elderly patients. However, yokukansan or fluvoxamine for BPSD showed a more favorable profile in tolerability compared with risperidone. This trial is registered at UMIN Clinical Trials Registry (identifier: UMIN000006146).

Background: Depot formulations of antipsychotics provide a potential solution to the poor adherence to oral therapies in schizophrenia. However, there have been few comparative studies on the effectiveness and tolerability of first and second generation depot antipsychotics in a real clinical practice setting. The objectives of the present study were to compare safety and outcomes in patients with schizophrenia initiated on risperidone long-acting injection (RLAI) or first generation antipsychotic injections (FGAI) at a Mental Health Centre in British Columbia., Methods: Data were collected by retrospective chart review of all active patients starting depot therapy who were ≥ 18 years of age, had received at least 3 injections of depot antipsychotic and had no prior clozapine treatment. Kaplan Meier survival curves were used to estimate probability of treatment discontinuation and hospitalization., Results: A total of 70 RLAI and 102 FGAI patient charts were reviewed. At baseline patients in both groups had similar ages (39.7 and 42.7 years for RLAI and FGAI patients (p = 0.09), respectively) but FGAI patients had a longer time since diagnosis (13.6 vs. 9.85 years (p = 0.003)). Treatment retention at 18 months was 77% for RLAI and 86% for FGAI patients (p = 0.22) and 82% and 88% of patients, respectively (p = 0.28), had not been hospitalized. However, RLAI analyses were compromised by lack of long-term patient data. Concomitant medication utilization was similar in both groups except for anticholinergics which were used less frequently in RLAI patients (5.7% vs. 35.3%, p < 0.001). Adverse event frequency was also similar except for extrapyramidal symptoms (EPS) which were more common in FGAI patients (52.9% vs. 17.0% for RLAI (p < 0.001))., Conclusions: There was no apparent difference in treatment discontinuation or hospitalization between RLAI and FGAI treated patients, although analysis was compromised by low patient numbers. However, decreased EPS with RLAI may offer a significant clinical benefit to patients with schizophrenia.

Rabbit syndrome is an antipsychotic-induced rhythmic motion of the mouth and lips, resembling the chewing motion of a rabbit. The motion consists of vertical movement; the tongue is not involved. The reported prevalence of rabbit syndrome ranges from 2.3% to 4.4% of patients treated with typical antipsychotic drugs. There have been isolated reports of rabbit syndrome in patients treated with atypical antipsychotics. Rabbit syndrome needs to be closely differentiated from tardive dyskinesia, the tongue-involving movement disorder. Treatment of rabbit syndrome is empirical, reflecting poor understanding of this syndrome. The striking aspect of this syndrome is its specificity. The etiology of rabbit syndrome focuses attention on the basal ganglia, which is also implicated in oral dyskinesia. Continuing neuro-physiological research of the basal ganglia probably holds the key to better understanding of this syndrome. The aim of this article is to create awareness of rabbit syndrome and its implications in clinical dentistry.

Rationale: It has previously been shown that impairment of postural stability is a side effect of typical antipsychotic drugs, which are largely administered to control psychosis and behavioral symptoms in elderly patients. Surprisingly, no study has yet addressed this problem with second-generation antipsychotics., Objective: The objective of this study was to determine the extent to which risperidone at low doses altered balance control in healthy participants., Methods: Twelve healthy young adults received, following a randomized double-blind crossover design, a single oral dose of placebo, 1 and 3 mg of risperidone on separate days at least 14 days apart. Evaluation of extrapyramidal symptoms using the Extrapyramidal Symptom Rating Scale-abbreviated scoring form (ESRS-A) and measures of postural sway using a force platform were assessed over 9 h following drug ingestion., Results: There is a significant increase in the postural stability item of the ESRS-A parkinsonism subscale at 3 and 6 h following 3 mg of risperidone only when compared to placebo. With regard to balance control, body sway measures were increased at 1 mg of risperidone but more pronounced at 3 mg. The peak effects were observed at 3 h after administration of the drug and had not completely returned to baseline after 9 h., Conclusions: Risperidone administered at low doses did not elicit clinically detectable EPS but had significant effects on balance control. A dose-response effect on impairment of balance was observed that followed the expected time course of the drug pharmacokinetics. These results are likely to apply to older or demented individuals who have pre-existing balance control deficit.

Background: The aim of this randomized, parallel-arm trial was to study the effect of treating subsyndromal delirium with risperidone on the incidence of clinical delirium in elderly patients who underwent on-pump cardiac surgery., Methods: One hundred one patients aged 65 yr or older who experienced subsyndromal delirium after on-pump cardiac surgery were randomized using a computer-generated list to receive 0.5 mg risperidone (n = 51) or placebo (n = 50) every 12 h by mouth. Patients were assessed at 8 h by a blinded observer using the Intensive Care Delirium Screening Checklist, and those scoring more than 3 were evaluated by a blinded psychiatrist to confirm delirium. Patients in either group who experienced delirium were treated according to the same algorithm. Initially, risperidone was administered and if symptoms were not controlled, haloperidol was administered. The primary outcome was the proportion of patients who experienced delirium in either group., Results: Seven (13.7%) patients in the risperidone group experienced delirium versus 17 (34%) in the placebo group (P = 0.031) Competing-risks regression analysis showed that failure to treat subsyndromal delirium with risperidone was an independent risk factor for delirium (subhazard ratio, 3.83; 95% CI, 1.63-8.98; P = 0.002). Two (3.9%) patients in the risperidone group experienced extrapyramidal manifestations versus one (2%) in the placebo group (P = 1.0)., Conclusion: Administration of risperidone to elderly patients who experienced subsyndromal delirium after on-pump cardiac surgery was associated with significantly lower incidence of delirium. Larger studies are required to determine whether early administration of risperidone during the subsyndromal phase of delirium would influence the clinical course of such patients.

Increase in use of atypical antipsychotics has been paralleled by an increase in the incidence of intentional and nonintentional overdose. Pediatric cases are uncommon, but may be severe. We describe a case of a child presenting with severe extrapiramidal symptoms, initially interpreted as seizures, caused by a nonintentional intoxication with risperidone, and review management options and the literature.

Introduction: Atypical antipsychotics or antipsychotics of second generation are still recommended by guidelines for primary use in the treatment of psychotic disorders because of their better neurologic safety and efficacy. However, they require daily dosing, thus compromising their overall efficacy whereas conventional depot neuroleptics provide constant pharmacologic treatment but induce extrapyramidal adverse effects and poor efficacy on negative symptoms. Long acting injectable risperidone (LAIR) is the first long-acting second-generation antipsychotic. Registered in October 2003 and launched in March 2005 in France thanks to Kane et al.'s and Fleischhacker et al.'s reference studies, it was supposed to provide the advantages of conventional long acting formulations of antipsychotics over those of an atypical agent., Objectives and Methods: The aims of this study, with the description of the prescription practices of LAIR in naturalistic conditions, were to assess the place of this new drug in psychotic medication, with the efficiency value measured by treatment discontinuation rate and analysis of the reasons for discontinuation, and to assess whether the prescriptions practices are or not in adequacy with guidelines and reglementation. In June 2005, we conducted a one-year naturalistic non-randomised open-label study in nine French psychiatric hospitals, members of the PIC network: were included all the patients who received LAIR every 2 weeks, between July 1st 2005 and November 30th 2005., Results: Prescriptions of 216 patients were examined for 1 year. LAIR was used off label for 15% of the patients. Ninety-two percent of patients were hospitalized at the beginning of the treatment while 72% of the treated patients had dropped out one year after the first injection. Regarding the nature of previous antipsychotic treatments prescribed in the last three months before the first injection of LAIR: 31% patients had received a first generation antipsychotic, half of which had received a depot antipsychotic of first generation and 69% had received a second-generation antipsychotic, among which half had received oral risperidone. The principal reason noted by the clinicians for starting the new formulation was non-observance with anterior treatments. However, oral antipsychotic treatment preceding the first injection was used less than 4 weeks for one third of the patients. When this treatment was oral risperidone, average posology at the first injection was 6.7 ± 2.4 mg per day; it was 7.4 ± 2.1 mg per day for the patients who received the higher dose of LAIR (50 mg/2 weeks). So, it seems that some patients were not sufficiently stabilized by their antipsychotic before the beginning of the long acting treatment. The result was a significant rate of treatment discontinuations (53%) in the following year, principally caused by the withdrawal of the patient's consent and an insufficient response to treatment., Conclusion: This investigation provided the opportunity to analyze the prescriptions of a new formulation drug in routine clinical practice. It confirms the need for respecting the authorized indications and the recommendations of good use of a drug to avoid the failures of treatment and also the importance of the role of the pharmacist in recalling it to the physicians., (Copyright © 2010 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Previously one intronic DRD3 SNP, rs167771, was associated with risperidone-induced extrapyramidal side-effects (EPS). The aim of the present study was to search hitherto unidentified common functional variants or rare variants, in DRD3 associated with risperidone-induced EPS. 126 subjects treated with risperidone participated in this study. We sequenced the seven exons of DRD3. After sequencing we localized five dbSNPs and four new rare variants. None of the dSNPs or rare variants seems to be functional after bioinformatics analysis. Our results suggest that, rather than exonic regions, regulatory regions and introns could be related to the associations reported for DRD3 and the incidence of locomotor side-effects., (Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.)

Objective: The aim of this study was to describe the clinical and electrocardiographic features of risperidone overdose, including the frequency of dystonic reactions., Methods: A consecutive series of admissions for risperidone overdose (>6 mg) were identified from a prospective database of poisoning admissions to a regional toxicology service. Data extracted included patient demographics, details of ingestion, clinical features including neurological findings and evidence of dystonias, electrocardiographic parameters (heart rate [HR], QRS, and QT intervals), complications, and medical outcomes including intensive care unit admission. In addition to descriptive statistics, visual inspection of plots of QT-HR pairs compared with the QT nomogram was performed., Results: There were 107 patients with 157 presentations, including 38 patients with 45 risperidone-alone overdoses. Of the 38 patients who ingested risperidone alone, the median age was 25 years (interquartile range [IQR],16-31 years), and 19 (50%) were female. The median dose ingested was 33 mg (IQR, 15-75 mg; range, 8-248 mg). Median length of stay was 16 hours (IQR, 8-18 hours), and none was ventilated or admitted to the intensive care unit. There were 5 cases (11%) with dystonic reactions, 26 (58%) with tachycardia (HR >or=100 beats/min), and no cases with hypotension (blood pressure <90 mm Hg). Only 1 patient (2%) recorded a decreased Glasgow Coma Scale score of 14, and there were no seizures or deaths. On review of electrocardiograms in 41 of the 45 cases where risperidone was ingested alone, there were no acute dysrhythmias. In 4 electrocardiograms (10%), there was an abnormal QT-HR pair, but all bar one were associated with an HR of greater than 110 beats/min. The median maximum QRS width was 80 milliseconds (IQR, 80-80 milliseconds; range, 40-120 milliseconds)., Conclusions: Risperidone taken alone in overdose causes minimal effects. Tachycardia and dystonic reactions were the main features of toxicity. Significant cardiac and other neurological features seem to be uncommon.

The use of antipsychotics in treatment of children and adolescents requires good knowledge of psychopathology, psychofarmacotherapy, developmental processes and family relations. It is necessary to have parental consent for the use of a medication in this age, with previous explanation of therapeutic goals, limitations and possible side effects of antipsychotics. The number of antipsychotics registered for use in children and adolescents is quite limited. The combination of clinical experience of those working with psychotic adolescents and a good collaboration with parents, creates a therapeutic space where good results in treatment can be achieved. Side effects, though rarely, can bring in question the course of treatment and disorder follow up. In this work we will present a 14-year old girl adolescent with psychotic symptoms, in which case the course of treatment and discontinuance of therapy was caused by a side effect - an oculogyric crisis.

We present a pharmacogenetic study of acute antipsychotic (AP)-induced extrapyramidal symptoms (EPS) using an extensive linkage disequilibrium mapping approach in seven-candidate genes with a well-established link to dopamine (DRD2, DRD3, ACE, COMT, DAT, MAO-A, MAO-B). From a cohort of 321 psychiatric inpatients, 81 cases presenting with EPS (Simpson-Angus > 3) and 189 controls presenting without EPS (Simpson-Angus < or = 3) took part. Eighty-four-tag single nucleotide polymorphisms (SNPs) in candidate genes were genotyped. After extensive data cleaning, 70 SNPs were analyzed for association of single markers and haplotypes. AP dosage, AP-DRD2 blockade potency and age were identified as susceptibility factors for AP-induced EPS. One SNP of the DRD3 gene, rs167771, achieved significant association with EPS risk after Bonferroni correction (nominal P-value 1.3 x 10(-4)) in the patients treated with risperidone (132 patients). AP-induced EPS remains a serious public health problem. Our finding of a common SNP (rs167771) in the DRD3 gene provides a strong new candidate gene for risperidone-induced EPS.

Aim: Perospirone is classified as a second-generation antipsychotic agent for the treatment of schizophrenia. Perospirone binds with high affinity to serotonin 5-HT2A receptors and dopamine D2 receptors. There are no reports of clinical comparisons of perospirone and risperidone in multicenter studies. To clarify the clinical traits of perospirone in the treatment of schizophrenia, the clinical efficacies and side-effects of perospirone and risperidone were compared in a randomized clinical multicenter trial., Methods: Sixty-six schizophrenia patients were enrolled in the trial. The Positive and Negative Syndrome Scale (PANSS) total, positive, negative and general symptoms scores and Drug-Induced Extra-Pyramidal Symptoms Scale (DIEPSS) scores were investigated at 0, 4, 8 and 12 weeks., Results: Significant reductions in the PANSS total and subscale scores were observed in both the perospirone and risperidone groups, with no significant between-group differences at 4 and 12 weeks. Risperidone improved the total scores and overall psychopathologic symptom total scores more effectively than perospirone at week 8. There were no significant differences in the DIEPSS scores at 0, 4, 8 and 12 weeks between the perospirone and risperidone groups. The numbers of patients who dropped out did not differ between the perospirone and risperidone groups., Conclusions: Perospirone was as effective as risperidone against positive and negative symptoms in patients with schizophrenia. Both antipsychotic agents were equally well-tolerated.

Objectives: This Schizophrenia Outcome Survey compared medical costs, psychopathology and adverse events in outpatients for 2 years following hospitalisation for an acute schizophrenic episode., Methods: Adults stabilised with haloperidol, olanzapine or risperidone entered this observational study or=1 EPS; 69% (p<0.013), 40 and 44%, respectively, had >or=1 sexual problem (NS). Mean weight gain was 0.4 (NS), 2.6 (p<0.05) and 2.6 kg (p<0.05), respectively., Conclusions: In this naturalistic study, treatment allocation might have introduced a bias in the interpretation of efficiency results, but olanzapine and risperidone caused less EPS than haloperidol during 2 years of outpatient follow-up.

Objective: It is generally held that the elderly are more sensitive to motor side effects of antipsychotics, although the mechanisms for such an effect are not fully understood. The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect., Design: Cross-sectional., Setting: Centre for Addiction and Mental Health, Toronto, Ontario, Canada., Participants: Thirteen subjects aged 50 (mean +/- standard deviation age: 62 +/- 9 years) with schizophrenia or schizoaffective disorder who were receiving risperidone., Measurements: Dopamine D2 binding potential in the striatum, using [C]raclopride positron emission tomography scan. D2 receptor occupancy was calculated, using age-corrected measure from healthy individuals and region of interest analysis., Results: The authors observed the expected nonlinear relationship between total risperidone and 9-hydroxyrisperidone plasma level and striatal D2 receptor occupancy. The estimated plasma level of risperidone plus 9-hydroxyrisperidone associated with 50% maximal receptor occupancy was 7.3 ng/mL, which is similar to what has been reported in younger patients. However, extrapyramidal side effects (EPS) were observed in seven subjects at D2 occupancy of 34%-79%, occupancy levels that are lower than previously reported for younger patients in whom EPS are rare at occupancies lower than 80%., Conclusion: The observation of greater functional effect (EPS in this case) for a given drug occupancy than the younger patients supports a pharmacodynamic mechanism for age-related antipsychotic drug sensitivity. This finding has important implications for dosing of antipsychotics in older patients with schizophrenia.

Background: Risperidone long-acting injectable (RLAI), the first second-generation depot antipsychotic, has extensively been studied before introduction. Thereafter, questions about the type of patients actually treated with RLAI in daily practice remain to be answered for making valid antipsychotic treatment comparisons involving RLAI in observational studies., Objective: We aimed to determine in chronic antipsychotic users who switched treatment, predictors for the prescription of (1) depot versus oral antipsychotics and (2) RLAI versus first-generation antipsychotics (FGAs) depot., Methods: We used pharmacy dispensing data from 53 community pharmacies in the northeast of the Netherlands containing approximately 500,000 persons. Chronic antipsychotic users were defined and followed up for a switch in antipsychotic treatment within the first period that RLAI was on the market. Multivariable analysis was performed to relate patient, prescriber, and medication characteristics to prescription of a new antipsychotic drug., Results: Predictors for switching to depot versus oral antipsychotics were male sex, previous use of depot antipsychotics, recent anticholinergic drug use, and a gap in antipsychotic dispensation history. Predictors for switching to RLAI versus FGA depot were previous use of depot and consulting a specialist., Conclusions: The results suggest that, compared with oral antipsychotics, patients receiving a depot are less compliant users, with more extrapyramidal side effects. Compared with FGA depot, patients receiving RLAI tend to be more severely ill patients. We conclude that RLAI may be partly channeled to patients as a last resort, which may have important consequences for the interpretation of observational effectiveness comparisons between RLAI and other antipsychotics in daily practice.

In a plural and multidisciplinary process of care, it would be fruitful to ally complementary, pharmacologic and psychodynamic approaches. We have done a review of the literature on the effectiveness and the cautions for prescription of risperidone, a second generation antipsychotic drug. Risperidone has proved helpful in treating children and adolescents with autism spectrum, conduct and bipolar disorders, Tourette's syndrome, and schizophrenia. The principal side effects are sedation, weight gain, and metabolic disturbances. Extrapyramidal symptoms, QTc prolongation, and hyperprolactemia with clinical signs are infrequent and not clinically significant. The benefit/risk is clearly in favor of the prescription when it is accompanied with the precautions and with the adequate monitoring.

Objective: The aim of this study was to determine the long-term safety of risperidone as maintenance therapy in children and adolescents with disruptive behavior disorders (DBDs) and normal intelligence., Method: An open-label, 1-year extension study was conducted from January, 2002, to July, 2004, in 232 subjects with DBDs (5-17 years) previously randomized to risperidone (RIS) (n = 115, RIS/RIS) or placebo (PLA) (n = 117, PLA/RIS) in a double-blind, 6-month withdrawal study. Adverse events (AEs) and clinical laboratory test results were recorded. Efficacy was assessed using Nisonger Child Behavior Rating Form. Safety and efficacy were evaluated in the intent-to-treat population., Results: A total of 169/232 (73%) subjects completed the study. Subjects were predominantly male, with a diagnosis of oppositional defiant disorder. Risperidone was generally well tolerated. Weight gain and extrapyramidal symptoms were each reported as AEs by 10 subjects (4.3%). Mean weight z-scores decreased for RIS/RIS subjects (-0.04 +/- 0.28) and increased for PLA/RIS subjects (0.11 +/- 0.43). No subject developed tardive dyskinesia. Prolactin tended to increase with risperidone, although this effect diminished with prolonged use and was infrequently associated with AEs. There were no clinically relevant changes in glucose or lipid metabolism. Clinical improvement in DBD symptoms was observed with flexible risperidone doses, regardless of previous treatment and whether subjects had experienced symptom recurrence., Conclusions: Risperidone reinitiated for DBD in children with normal intelligence quotients (IQ) was safe and well tolerated over an additional year of treatment. Patients demonstrated clinical benefits, including those who previously experienced symptom recurrence.

This multicentre, observational, prospective, nonrandomized study compared the effectiveness and tolerability of quetiapine and risperidone in the acute and long-term treatment of schizophrenia in a clinical setting. Patients admitted to an acute unit with schizophrenia, schizophreniform or schizoaffective disorder (DSM-IV), who were prescribed quetiapine or risperidone (3 : 1 ratio) within the first week of treatment, according to the physician's usual practice, were recruited. In total, 492 patients (quetiapine: 367; risperidone: 125) were followed up at weeks 1 and 2, discharge and 6 and 12 months thereafter. Mean doses at 12 months were: quetiapine 718.5 mg/day and risperidone 7.0 mg/day. Efficacy measures (Brief Psychiatric Rating Scale, Clinical Global Impression Severity of Illness and Improvement) indicated similar results for both agents. No difference was found in rehospitalization rate with either drug. In terms of tolerability, orthostatic hypotension was more frequent with quetiapine, but extrapyramidal symptoms and male sexual dysfunction were more frequent with risperidone. In conclusion, quetiapine and risperidone had comparable effectiveness, but there were differences between treatments in their side effect profile.

Objective: To describe six older patients who were treated with risperidone long-acting injection, and to discuss the role of this medication in a psychogeriatric setting., Method: Case series., Results: Of the six patients trialled on risperidone long-acting injection, two remain on this treatment. Of the other four, three required a change of treatment due to a combination of adverse side-effects and non-response, and one due to adverse side-effects alone., Conclusions: Risperidone long-acting injection may have a role to play in the management of older patients with psychotic disorders but further research is required.

Some evidence suggests that the pathophysiology of schizophrenia is associated with the abnormal immune system, and cytokines may be important in schizophrenia. Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib reduce the production of proinflammatory cytokines including Th1-like cytokines. Indeed, COX-2 inhibitors rebalance type-1 and type-2 immune response. The purpose of the present investigation was to assess the efficacy of celecoxib as an adjuvant agent in the treatment of chronic schizophrenia in an eight-week, double-blind and placebo-controlled trial. Eligible participants in this study were 60 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV criteria for schizophrenia. Patients were allocated in a random fashion, 30 to risperidone 6 mg/day plus celecoxib 400 mg/day (200 mg bid) (morning and evening) and 30 to risperidone 6 mg/day plus placebo. Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and celecoxib showed a significant superiority over risperidone alone in the treatment of positive symptoms, general psychopathology symptoms as well as PANSS total scores. The means Extrapyramidal Symptoms Rating Scale for the placebo group were higher than in the celecoxib group over the trial. However, the differences were not significant. The results of this study suggest that celecoxib may be an effective adjuvant agent in the management of patients with chronic schizophrenia and anti-inflammatory therapies should be further investigated.

Objective: The authors compared 4-month treatment outcomes for olanzapine versus risperidone in patients with first-episode schizophrenia spectrum disorders., Method: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with olanzapine (2.5-20 mg/day) or risperidone (1-6 mg/day)., Results: Response rates did not significantly differ between olanzapine (43.7%, 95% CI=28.8%-58.6%) and risperidone (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the olanzapine group (40.9%, 95% CI=16.8%-65.0%) than in the risperidone group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. Extrapyramidal symptom severity scores were 1.4 (95% CI=1.2-1.6) with risperidone and 1.2 (95% CI=1.0-1.4) with olanzapine. Significantly more weight gain occurred with olanzapine than with risperidone: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with olanzapine and 11.3% (95% CI=8.4%-14.3%) with risperidone. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with olanzapine and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with risperidone., Conclusions: Clinical outcomes with risperidone were equal to those with olanzapine, and response may be more stable. Olanzapine may have an advantage for motor side effects. Both medications caused substantial rapid weight gain, but weight gain was greater with olanzapine.

The therapeutic properties of typical antipsychotic drugs (APDs) such as haloperidol in schizophrenia treatment are mainly associated with their ability to block dopamine D2 receptors. This blockade is accompanied by side effects such as extrapyramidal symptoms (EPS). Atypical APDs such as risperidone have superior therapeutic efficacy possibly due to their activity at multiple receptors (in particular 5-HT2A receptors). Although the risk of EPS is significantly lower in atypical than in typical APDs, it is not negligible. To investigate and compare the behavioural profile and EPS-asssociated side effects of haloperidol and risperidone APD treatment we applied a multi-tiered, comprehensive behavioural phenotyping approach. Sprague-Dawley rats were treated chronically (28 days) with supratherapeutic EPS-inducing doses of haloperidol and risperidone using osmotic minipumps. Domains such as motor activity, exploration, memory, and anxiety were analysed together with EPS assessment ("early onset" vacuous chewing movements and catalepsy). Both APDs produced diminished motor activity and exploration, impaired working memory performances, and increased anxiety levels. These effects were more pronounced in haloperidol-treated animals. Chronic APD treatment also caused a time-course dependent elevation of EPS-like symptoms. Risperidone-treated animals showed a catalepsy-like phenotype, which differed to that of haloperidol-treated rats, indicating that processes other than the anticipated dopaminergic mechanisms are underlying this phenomenon. These EPS-related phenotypes are consistent with reported EPS-inducing D2 receptor occupancies of around 80%. Differences in the behavioural profile of haloperidol and risperidone, which were revealed by a comprehensive phenotyping strategy, are likely due to the unique receptor activation profiles of these APDs.

Objective: To compare the efficacy and tolerability of quetiapine and risperidone in the treatment of schizophrenia., Method: In this 8-week, double-blind, multicenter, flexible-dose study, patients with schizophrenia (DSM-IV diagnosis) were randomly assigned to quetiapine (200-800 mg/day) or risperidone (2-8 mg/day). The primary hypothesis was that quetiapine was not inferior to risperidone. The primary efficacy measure was change from baseline in Positive and Negative Syndrome Scale (PANSS) total scores; secondary outcomes included response rate (> or = 40% reduction in PANSS scores), Clinical Global Impression-Change (CGI-C), and cognitive and social functioning. Tolerability assessments included treatment-emergent adverse events and changes in weight, glucose, and prolactin. Patients were recruited from June 2001 to September 2002., Results: Patients (N = 673) were randomly assigned to quetiapine (N = 338, mean dose = 525 mg/day) or risperidone (N = 335, mean dose = 5.2 mg/day). The primary analysis demonstrated noninferiority between treatments (p < .05). Improvements with both treatments were comparable on PANSS total, negative, and general psychopathology subscales. Risperidone-treated patients had a significantly (p = .03) greater improvement in PANSS positive subscale score among all patients, but not among completers. Improvements in PANSS response rates, CGI-C, and cognitive function were similar between treatment groups. Changes in serum glucose and weight were minimal and comparable. The rate of extrapyramidal symptom (EPS)-related adverse events was significantly higher with risperidone (22%) than quetiapine (13%; p < .01). Somnolence was more common with quetiapine (26%) than risperidone (20%; p = .04). Prolactin levels increased with risperidone (+35.5 ng/mL), but decreased with quetiapine (-11.5 ng/mL; p < .001)., Conclusions: Quetiapine and risperidone had broadly comparable clinical efficacy. Both agents improved cognitive and social functioning, and neither had a clinically significant effect on weight or glucose. Somnolence was more common with quetiapine; EPS and elevated prolactin rates were significantly higher with risperidone.

Unlabelled: Extrapyramidal symptoms and Parkinsonism (PS) are side effects commonly observed with antipsychotic treatment. However, about 24% of never-treated schizophrenic patients may suffer from PS, which contrast with that 1% observed from the general population. 123I-FP-CIT SPECT has probe useful to differentiate degenerative from non-degenerative PS, so it could be interesting using it for establishing the functional state of presynaptic dopamine neurons of these patients., Aim: To determine the dopamine transporter binding (DAT) in a homogeneous group of first-episode schizophrenic patients., Methods: An open, transversal study. Thirty schizophrenic in-patients and 15 healthy subjects were recruited. Patients were treated with similar doses of risperidone and all subjects were scanned with 123I-FP-CIT. Extrapyramidal symptoms and psychopathological status was assessed by Simpson-Angus, CGI and PANSS. Semi-quantitative analyses of SPECT images were performed using ROIs placed in caudate nucleus, anterior, medium and posterior putamen and occipital cortex., Results: Whole striatum 123I-FP-CIT binding ratio was significantly lower in patients than healthy subjects (t = 2.56, p < 0.014). This was observed in whole putamen (t = 2.66, p < 0.011), anterior (t = 2.35, p < 0.023), medium (t = 2.38, p < 0.022) and posterior putamen (t = 2.09, p < 0.042). No differences were observed in caudate nucleus (t = 1.81, p = 0.076). Females obtained higher binding ratios than males (t = -3.13, p < 0.003). No correlation was observed between 123I-FP-CIT binding ratios and clinical scales., Conclusion: In our series, first episode schizophrenic patients treated with risperidone have a decrease striatal DAT binding assessed with 123I-FP-CIT SPECT. This alteration could be related to their own schizophrenia disease or be secondary to the antipsychotic treatment.

Objective: To examine clinical outcomes in Asian patients with schizophrenia receiving monotherapy with olanzapine, risperidone or typical antipsychotics in naturalistic settings., Method: In this report, data from the first 12 months of the prospective, observational, 3-year Intercontinental Schizophrenia Outpatient Health Outcomes study are presented for patients from participating Asian countries (Korea, Taiwan and Malaysia) who were started on, or switched to, monotherapy with olanzapine (n = 484), risperidone (n = 287) or a typical antipsychotic drug (n = 127) at baseline., Results: At 12 months, overall reduction in the score of Clinical Global Impressions-Severity of Illness rating scale was greatest with olanzapine (p < 0.001 vs typical agents), followed by risperidone (p = 0.007 vs typical agents) treatment. Olanzapine treatment was found to have significantly better effects than typical agents on negative and depressive symptom scores, and significantly greater improvements than risperidone on negative and cognitive symptoms. The occurrence of extrapyramidal symptoms was least likely with olanzapine (p < 0.001 vs typical agents, and p = 0.012 vs risperidone), while the estimated odds of tardive dyskinesia were greatest in the typical treatment group (p = 0.046 vs olanzapine, and p = 0.082 vs risperidone). Mean weight increase was greater for olanzapine-treated patients compared with the other agents (p = 0.030 vs typical agents and p < 0.001 vs risperidone). The risk of menstrual disturbance was relatively high with risperidone when compared with olanzapine treatment (p < 0.001)., Conclusions: The results of this observational study indicate that, in Asian patients with schizophrenia, olanzapine may offer benefits when compared with typical agents or risperidone. However, the significantly greater odds of weight gain should be considered in the clinical management of olanzapine-treated patients.

Objective: Long-acting injectable risperidone represents the first clinically available depot atypical antipsychotic. The present study used positron emission tomography (PET) to evaluate its dopamine D(2) binding profile at doses of 25, 50, or 75 mg administered every 2 weeks., Method: After achieving stabilization with one of the doses, nine patients with a diagnosis of schizophrenia or schizoaffective disorder underwent [(11)C]raclopride PET to measure D(2) occupancy. Participants were scanned twice during the 2-week injection interval: within 3 days after injection (postinjection) and within 5 days before the next injection (preinjection). At the same time, plasma was collected for measurements of risperidone plus 9-hydroxyrisperidone., Results: Mean post- and preinjection D(2) occupancy levels for the 25-, 50-, and 75-mg doses were 71.0% and 54.0%, 74.4% and 65.4%, and 81.5% and 75.0%, respectively. There was a significant correlation between dose and plasma concentrations of risperidone plus 9-hydroxyrisperidone, and the estimated plasma concentration associated with 50% D(2) occupancy (ED(50)) was 11.06 ng/ml. Prolactin levels were not correlated with drug levels or D(2) occupancy., Conclusions: All three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response; the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal symptoms. Doses of 25 or 50 mg should provide therapeutic efficacy while minimizing the risk of extrapyramidal symptoms.

Objective: Despite the clinical observation that antipsychotics can produce negative symptoms, no previous controlled study, to our knowledge, has evaluated this action in healthy subjects. The present study assessed observer-rated and self-rated negative symptoms produced by conventional and second-generation antipsychotics in healthy volunteers., Method: The authors used a double-blind, placebo-controlled trial of single doses of haloperidol (5 mg) and risperidone (2.5 mg) in normal subjects. Thirty-two subjects were administered haloperidol, risperidone, and placebo in a random order. Motor variables and observer-rated negative symptoms were assessed after 3-4 hours and subjective negative symptoms and drowsiness after 24 hours., Results: Neither of the active drugs caused significant motor extrapyramidal symptoms after administration. Haloperidol caused significantly more negative signs and symptoms than placebo on the Scale for the Assessment of Negative Symptoms (SANS) and two self-rated negative symptom scales: the Subjective Deficit Syndrome Scale total score and an analog scale that evaluates subjective negative symptoms. Risperidone caused significantly more negative signs and symptoms than placebo on the Brief Psychiatric Rating Scale (BPRS), the SANS, the Subjective Deficit Syndrome Scale total score, and the analog scale for subjective negative symptoms. After control for drowsiness, risperidone but not haloperidol produced more negative symptoms than placebo on the BPRS and the SANS. Significance was lost for the subjective negative symptoms with both drugs., Conclusions: Single doses of both haloperidol and risperidone produce negative symptoms in normal individuals. Drowsiness may be an important confounding factor in the assessment of negative symptoms in antipsychotic trials.

Objective: Asperger's disorder consists of negative symptoms similar to those seen in schizophrenia, autism, schizoid personality disorder, and schizotypal personality disorder. We investigated whether risperidone, which is effective in treating the negative symptoms of schizophrenia, would improve such symptoms observed in Asperger's disorder in a prospective, open-label trial., Method: Thirteen male patients aged 6 to 18 years who were diagnosed with Asperger's disorder by DSM-IV criteria were enrolled in a 12-week, prospective, open-label pilot study from March 13, 2002 to August 11, 2003. All subjects were started on risperidone 0.25 mg twice per day. Doses were increased based on clinical indication and tolerability. The primary efficacy variable was the Scale for the Assessment of Negative Symptoms (SANS). Each subject's baseline score served as his control. Secondary efficacy measures included the Positive and Negative Syndrome Scale, Brief Psychiatric Rating Scale, Montgomery-Asberg Depression Rating Scale, Global Assessment Scale, and a modified Asperger Syndrome Diagnostic Scale., Results: We found a statistically significant improvement from baseline for last-observation-carried-forward (LOCF) analyses as well as for analyses of 12-week completers (N = 9) in our primary outcome measure, SANS scores (F = 13.41, p < .0001 for 12-week completers; F = 9.64, p < .0001 for LOCF). We also found statistically significant improvement in all secondary efficacy measurements (F values range, 8.41 to 15.73, p values range, < .0001 to < .005 for 12-week completers; F values range, 6.53 to 7.75, all p < .0001 for LOCF)., Conclusions: Subjects' symptoms significantly improved after risperidone. The open-label nature of this small pilot study suggests caution in interpreting these data, but the results suggest that placebo-controlled trials should follow.

Background: Risperidone significantly improves behavioral and psychological symptoms of dementia (BPSD), including aggression, agitation and psychosis, as shown by randomized, placebo-controlled trials., Methods: An 8-week, multicenter, naturalistic, open-label study was carried out to examine whether the benefits of risperidone apply to clinical practice. A total of 4499 patients were treated with risperidone at flexible doses chosen by physicians, and were included in the safety evaluation. Of these, 3909 patients met the intended study criteria (at least 65 years of age, dementia, and the presence of BPSD) and were included in the efficacy analyses., Results: At the end of the study (after 8 weeks of treatment), risperidone (average final dose 1.6 mg/day) significantly improved all symptoms studied (agitation, aggressiveness, disturbance of the sleep-wake rhythm, social withdrawal, suspiciousness and delusions) as rated by physicians on a five-point scale of severity. On a four-point scale of global efficacy, more than 90% of patients were rated improved by both physicians and caregivers after 8 weeks of treatment. A significant improvement in sleep-wake cycle disturbances was also noted. A total of 422 adverse events were documented in 346 of the 4499 patients (7.7%); these included insufficient efficacy (2.6%), extrapyramidal symptoms (0.89%), deterioration of psychiatric symptoms (0.73%), sedation (0.56%), gastrointestinal disturbances (0.49%), cardiovascular disorders (0.38%), and cerebrovascular adverse events (0.36%)., Conclusions: Risperidone is an effective and well-tolerated treatment for BPSD in routine clinical practice.

Background: Dementia is associated with progressive cognitive impairment and behavioral and psychological symptoms. Sleep-wake cycle disturbances are common in patients with dementia. This study evaluated the efficacy and safety of risperidone in the treatment of the behavioral and psychological symptoms of dementia (BPSD) and associated sleep-wake cycle disturbances., Methods: In this open-label, 12-week, observational, prospective study, the effects of risperidone were assessed using the Neuropsychiatric Inventory (NPI) total and subscale scores. Sleep-wake cycle disturbances were rated by patients/caregivers using a newly developed sleep behavior questionnaire that included assessment of sleep duration, quality, awakenings, and effects on daily activities. Tolerability assessments included the Udvalg for Kliniske Undersogelser (UKU) subscale for extrapyramidal symptoms (EPS) and the recording of adverse events., Results: A total of 338 patients entered the study, with 321 patients completing. Following 12 weeks of risperidone treatment (mean dose 1.49 mg/day at end-point), the mean NPI score was reduced to 10.6 from a baseline score of 28.7. Compared with baseline, patients/caregivers reported significant improvements following 12 weeks of risperidone in total sleep hours at night (5.5 vs. 7.1 hours), hours awake in bed at night (2.3 vs. 1.2 hours), insomnia (40.1% vs. 8.4%), and other sleep-related variables. Six patients reported a total of 10 adverse events, including somnolence (n = 3) and sialorrhea (n = 2). Scores on the UKU subscale of EPS improved significantly (mean 4.0 at baseline vs. 1.7 at week 12)., Conclusions: Risperidone is effective and well tolerated in the treatment of BPSD and associated sleep disturbances.

This analysis used pooled data from three randomized, placebo-controlled trials that examined the efficacy and safety of risperidone for the treatment of agitation, aggression, and psychosis associated with dementia in elderly nursing home residents to assess the risk-benefit of the use of risperidone in this population. The efficacy data (risperidone n=722, placebo n=428) were obtained from the Cohen-Mansfield agitation inventory (CMAI) and behavioral pathology in Alzheimer's disease (BEHAVE-AD) total and subscales. Additionally, clinical global impression (CGI) assessments were performed. Subgroup analyses were performed by type of dementia, severity of dementia, presence or absence of somnolence as an adverse event, and presence or absence of psychosis at baseline. Safety assessments included evaluation of treatment emergent adverse events, Extrapyramidal Symptom Rating Scale, ECG and vital signs, and Mini-Mental State Examination (MMSE). The mean dose of risperidone at end point was 1.0 mg/day (0.02 S.E.). The observed mean change at end point was significantly higher for risperidone than for placebo on CMAI total score (-11.8 versus -6.4, respectively; p<0.001), total aggression score (-5.0 versus -1.8, respectively; p<0.001), BEHAVE-AD total score (-6.1 and -3.6, respectively; p<0.001), and psychotic symptoms score (-2.1 and -1.3, respectively; p=0.003). The main treatment effects of risperidone were similar in all subgroup analyses. Additionally, risperidone-treated patients scored significantly better than placebo-treated patients on the CGI scales at end point. The incidence of treatment-emergent adverse events was comparable between risperidone (84.3%) and placebo (83.9%). More patients discontinued due to adverse events in the risperidone-treated group (17.2%) than in the placebo group (11.2%). Differences in adverse event incidences between placebo and risperidone were observed for extrapyramidal symptoms (EPS), mild somnolence and the less common cerebrovascular adverse events (CAE). Risperidone induced neither orthostatic, nor anticholinergic side effects nor falls nor cognitive decline. Of all atypical antipsychotics, risperidone has the largest database of double-blind controlled trials to support its efficacy and safety in the treatment of agitation, aggression, and psychosis associated with dementia. At the recommended doses, risperidone displayed a favorable risk-benefit profile. Risperidone was well tolerated with respect to EPS, somnolence, and anticholinergic side effects in this elderly population. In view of the risk for CAEs, risperidone, should be targeted towards the treatment of those patients in whom psychotic and behavioral symptoms of dementia are prominent and associated with significant distress, functional impairment or danger to the patient.

Introduction: Assessment of the relation between oral risperidone dose, serum drug levels and clinical response may provide important information for rational treatment decisions. Inter-individual differences in the liver cytochrome P450 system, especially in the CYP2D6 subsystem, which account for a significant portion of risperidone metabolism, may also influence plasma drug levels and alter clinical response parameters. We thus prospectively investigated risperidone serum concentrations in relation to clinical efficacy and side-effects and genotyped major CYP2D6 polymorphisms to determine their effect upon these parameters., Methods: Neuroleptic monotherapy with risperidone was administered to schizophrenia patients in a 6-week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of risperidone and 9-OH-risperidone were carried out. In addition, major CYP2D6 polymorphisms including alleles *4, *6 and *14 were genotyped., Results: Eighty-two patients were recruited. Mean oral dose of risperidone was 4.3 +/- 0.9 mg. Mean plasma level of both risperidone and 9-OH-risperidone together ("active moiety") was 41.6 +/- 26.6 ng/ml. Significant improvements in PANSS scales and the various subscales ensued. There was a positive linear correlation between active moiety plasma levels and dose (r = 0.291, p = 0.015) and between risperidone and 9-OH-risperidone levels (r = 0.262; p = 0.016). Nonresponders to pharmacotherapy (PANSS-Improvement < 30%) showed significantly higher active moiety plasma levels (49.9 +/- 30.7 ng/ml) than responders (38.2 +/- 17.0 ng/ml; p = 0.045) without significantly higher oral doses (p = 0.601). Patients with longer illness duration (> or = 3 years) had significantly higher plasma drug levels than those with a shorter course (< 3 years; p = 0.039). Extrapyramidal side effects (EPS) and plasma levels were not correlated (r = 0.028; p = 0.843), but higher plasma levels at week 2 predicted an incidence for EPS (p < 0.050). Accordingly, patients initially receiving higher oral doses of risperidone were significantly more likely to respond with EPS in the trial course. Eight patients (9.8%) were heterozygous carriers of the CYP2D6 allele *4. CYP2D6 polymorphisms did not predict clinical response, but predicted a tendential increase in the plasma risperidone to 9-OH-risperidone ratio (0.5 +/- 0.6 vs. 1.9 +/- 1.8; p = 0.120)., Discussion: The major finding was that responders to risperidone treatment had significantly lower blood levels of risperidone and 9-OH risperidone than patients who did not respond to the treatment despite administration of similar oral doses. The observed CYP2D6 polymorphisms did not contribute to altered clinical efficacy, but affected risperidone to 9-OH-risperidone ratios. Increased plasma levels of the active moiety in patients with longer illness may represent general aging effects. Conversely, the observed higher plasma levels in nonresponders may derive from unaccounted genetic metabolism abnormalities or Phase II metabolism disturbances. Patients initially receiving higher oral risperidone doses were more likely to respond with extrapyramidal side effects which reaffirms the need for careful titration. The high inter-individual variability in risperidone and 9-OH-risperidone metabolization and the relationship between clinical outcome and plasma levels warrants regular plasma level monitoring of both compounds to assess for the clinically relevant active moiety.

Objective: The authors compared efficacy of olanzapine versus placebo and risperidone as measured by the Neuropsychiatric Inventory and Clinical Global Impression-Severity of Psychosis scale in patients with dementia-related psychosis., Methods: Patients with moderate-to-severe psychotic symptoms associated with dementia were recruited from outpatient or residential settings and randomly assigned to 10-week, double-blind, flexible-dose treatment with olanzapine (N=204; 2.5 mg-10 mg/day; mean: 5.2 mg/day), risperidone (N=196; 0.5 mg-2 mg/day; mean: 1.0 mg/day) or placebo (N=94)., Results: Most measures of neuropsychiatric functioning improved in all treatment groups, including the placebo group, and no significant treatment differences occurred. Overall discontinuation was lowest in the placebo group, and the olanzapine group had a significantly higher incidence of discontinuation due to adverse events (16.2%) relative to placebo (3.2%) and risperidone (8.7%) groups. Treatment-emergent extrapyramidal symptoms were more numerous for risperidone- than placebo- or olanzapine-treated patients. Abnormally high prolactin levels occurred in 78.0% of risperidone patients, compared with 16.7% for olanzapine and 5.0% for placebo. The incidence of weight gain greater than 7% from baseline was higher in the olanzapine group relative to risperidone, but neither active-treatment group showed a statistical difference from placebo (1.1%). No other statistically significant and clinically relevant differences were seen for any other vital sign, electrocardiographic measure, or laboratory hematology and chemistry, including glucose, except for cholesterol, which decreased from baseline to endpoint in both active-treatment groups., Conclusions: Patients' neuropsychiatric functioning improved with olanzapine, risperidone, and placebo treatment. There was a substantial response in the placebo group, and no significant differences emerged among treatments.