Ethnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia.

OBJECTIVE: Atypical antipsychotics induce weight gain and are linked to increased diabetes risk, but their relative impact on factors that elevate disease risk are unknown. METHODS: We performed a 6-month, randomized, double-blind study to evaluate the effects of risperidone and olanzapine in patients with schizophrenia. At baseline and weeks 6 and 24, we quantified: (1) total adiposity by DEXA, (2) visceral adiposity by abdominal CT, and (3) insulin sensitivity (SI) and (4) pancreatic function ("disposition index", DI) by intravenous glucose tolerance test. RESULTS: At baseline, groups (risperidone: n=28; olanzapine: n=31) were overweight or obese by body mass index (risperidone: 28.4+/-5.4, olanzapine: 30.6+/-7.0kg/m2). Both drugs induced weight gain (p<0.004). Total adiposity was increased by olanzapine at 6 weeks (p=0.0006) and by both treatments at 24 weeks (p<0.003). Visceral adiposity was increased by olanzapine and risperidone by 24 weeks (p<0.003). S(I) did not deteriorate appreciably, although a downward trend was observed with risperidone. Given known ethnic differences in adiposity and S(I), we performed secondary analysis in African American and Hispanic subjects. In this subset, olanzapine expanded both total and visceral adiposity (p<0.02); no increase was observed with risperidone. There were modest downward trends for SI with both treatments. By week 24, olanzapine-treated subjects exhibited diminished DI (p=0.033), indicating inadequate pancreatic compensation for insulin resistance. CONCLUSIONS: This is the first prospective study in psychiatric patients that quantified antipsychotic effects on the multiple metabolic processes that increase diabetes risk. Results indicate that ethnic minorities may have greater susceptibility to antipsychotic-induced glucoregulatory complications.

Risperidone and cognitive function in children with disruptive behavior disorders.

BACKGROUND: Effects of risperidone on cognitive function in children with disruptive behavior disorders (DBDs) and subaverage intelligence quotient (IQ) were assessed. METHODS: Data from two 6-week, double-blind, placebo-controlled studies (n = 228) were combined, as were three 1-year, open-label studies (n = 688). Patients with DBDs and subaverage IQ, 5 to14 years, received placebo or risperidone .02 to .06 mg/kg/day. Cognitive measures included the Continuous Performance Task (CPT) and Verbal Learning Test for Children (VLT-C). Efficacy was assessed using the Nisonger Child Behavior Rating Form (NCBRF). Adverse events were collected via spontaneous report; sedation was assessed using visual analog scale. RESULTS: Improvements on the NCBRF Conduct Problem subscale were significantly greater for risperidone- versus placebo-treated patients (-15.8 vs. -6.4, p < .0001) in short-term studies; significant reductions were observed in long-term studies (-16.3, p < .0001). No overall decline and some significant improvement in attention (CPT) and memory (VLT-C) were noted regardless of treatment in short-term studies. VLT-C improved significantly (p < .0001) for both groups, with no difference between treatment groups. Improvements in memory (VLT-C) and attention (CPT) were noted in long-term studies. Somnolence/sedation did not affect cognitive function. CONCLUSIONS: Cognitive function was not altered by risperidone in short-term studies and was maintained or improved with one year of treatment in children with DBDs and subaverage IQ, potentially representing age-appropriate gains.

Patient-based and clinician-based support for the remission criteria in schizophrenia.

This analysis characterizes patients with schizophrenia or schizoaffective disorder treated with risperidone who met remission criteria. In a 50-week, open-label trial, stable patients received long-acting injectable risperidone every 2 weeks. Remission criteria included severity (absent-mild ratings on core symptoms of the Positive and Negative Syndrome Scale) and duration (> or =6 months) components. The patients not remitted (severity component only) at baseline (n=394) are the subjects of this report. Measures applied included the PANSS, Clinical Global Impressions-Severity, patient-rated mental health status (Short Form-36), and Drug Attitude Inventory. Among patients who met remission criteria during the study (n=82), mean scores for all 30 PANSS items reflected absent-mild ratings at endpoint. The highest items represented an 'interpersonal' cluster, although mean ratings were still minimal to mild. Remitted patients experienced substantial improvements in Short Form-36 and Drug Attitude Inventory scores at endpoint. Although improvement occurred, it was less robust in patients who remained nonremitted (n=312). Logistic regression analysis found that remission (severity component only) was associated with a 97.1% probability of a 'not ill' rating on the Clinical Global Impressions-Severity. These remission criteria identified patients who differed from the nonremitted population on symptoms of psychopathology, medication attitude, health status, and overall clinical status, supporting the clinical validity of the remission criteria.

The impact of insight on functioning in patients with schizophrenia or schizoaffective disorder receiving risperidone long-acting injectable.

This post hoc analysis explored the role of insight as a mediator of functioning in a 52-week, double-blind, international trial of 323 patients with schizophrenia or schizoaffective disorder receiving risperidone long-acting injectable. Measures included the Positive and Negative Syndrome Scale (PANSS) insight item, PANSS factors, Clinical Global Impressions-Severity (CGI-S), Strauss-Carpenter Levels of Functioning (LOF), Personal and Social Performance (PSP) scale, and a cognitive test battery. Correlation/regression analyses examined associations between demographic and clinical characteristics, including insight, and functional measures. Insight scores correlated significantly with CGI-S, PANSS subscales, PSP, LOF, and several cognitive measures. Regression models demonstrated that changes in insight, changes in negative symptoms, and study duration were significantly associated with PSP and LOF total change scores. Findings identified important variables to consider for intervention to improve functioning in schizophrenia.

Maintenance therapy with once-monthly administration of long-acting injectable risperidone in patients with schizophrenia or schizoaffective disorder: a pilot study of an extended dosing interval.

BACKGROUND: Several clinical studies have established the efficacy, safety, and tolerability of long-acting risperidone administered once every 2 weeks in patients with schizophrenia or schizoaffective disorder. This report evaluates preliminary efficacy, safety, tolerability, and pharmacokinetic data for a novel (once-monthly) administration of long-acting injectable risperidone 50 mg in patients with schizophrenia or schizoaffective disorder. METHODS: Clinically stable patients participated in a 1-year, open-label, single-arm, multicenter pilot study. During the 4-week lead-in phase, patients received long-acting risperidone 50 mg injections every 2 weeks, with 2 weeks of oral risperidone supplementation. Injections of long-acting risperidone 50 mg every 4 weeks followed for up to 48 weeks, without oral supplementation. The primary endpoint was relapse; other assessments included PANSS, CGI-S, adverse event reports, and determination of risperidone and 9-hydroxyrisperidone plasma concentrations. RESULTS: Twelve patients in the intent-to-treat population (n = 67) met relapse criteria (17.9%). Relapse risk at 1 year was estimated as 22.4%. Non-statistically significant improvements in symptoms (PANSS) and clinical status (CGI-S) at endpoint were observed. The most common adverse events included schizophrenia aggravated not otherwise specified (19.5%), anxiety (16.1%), insomnia (16.1%), and headache (11.5%). There were no unexpected safety and tolerability findings. Mean plasma concentrations for risperidone and 9-hydroxyrisperidone were generally stable during the study. CONCLUSION: Once-monthly dosing of long-acting risperidone was well tolerated, associated with a relatively low relapse rate (similar to that reported with other antipsychotics), and maintained the clinically stable baseline status of most patients. Although the results suggest that some symptomatically stable patients with schizophrenia or schizoaffective disorder might be safely managed with long-acting risperidone 50 mg once monthly, these findings alone do not identify which patients will have a sufficient therapeutic benefit nor do they quantify comparative effects of standard and altered dosing. Study limitations (the open-label pilot study design, small sample size, and lack of a concurrent biweekly treatment arm) prevent broad interpretations and extrapolations of results. Controlled studies would be required to support a recommendation for alternative dosing regimens.

Effects of risperidone augmentation in patients with treatment-resistant depression: Results of open-label treatment followed by double-blind continuation.

Approximately one-third of persons with depression do not respond to antidepressant monotherapy. Studies suggest that atypical antipsychotic augmentation may benefit these patients. We investigated the longer-term efficacy of risperidone augmentation of serotonin-selective reuptake inhibitor treatment for resistant depression. In 57 in- and outpatient centers in three countries, we conducted a three-phase study with 4-6 weeks of open-label citalopram monotherapy, 4-6 weeks of open-label risperidone augmentation, and a 24-week double-blind, placebo-controlled discontinuation phase. A total of 489 patients with major depressive disorder and 1-3 documented treatment failures entered the citalopram monotherapy phase (20-60 mg/day). Patients with <50% reduction in HAM-D-17 scores entered the risperidone augmentation phase (0.25-2.0 mg/day). Patients with HAM-D-17< or =7 or CGI-S < or = 2 were randomized to risperidone or placebo augmentation. The primary outcome was time to relapse during the double-blind phase. During citalopram monotherapy, 434 patients had <50% HAM-D-17 reduction; 299 (68.9%) were fully nonresponsive (<25% reduction) and 135 were partially nonresponsive (25-49% reduction). Of the 386 nonresponders who entered the augmentation phase, 243 remitted and 241 entered the double-blind phase. Median time to relapse was 102 days with risperidone augmentation and 85 days with placebo (NS); relapse rates were 53.3 and 54.6%, respectively. In a post hoc analysis of patients fully nonresponsive to citalopram monotherapy, median time to relapse was 97 days with risperidone augmentation and 56 with placebo (p = 0.05); relapse rates were 56.1 and 64.1%, respectively (p < or = 0.05). Open-label risperidone augmentation substantially enhanced response in treatment-resistant patients, but the longer-term benefits of augmentation were not demonstrated in this study.

A 1-year double-blind study of 2 doses of long-acting risperidone in stable patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: This study examined the effects of 2 doses of long-acting risperidone injection in patients with schizophrenia or schizoaffective disorder. METHOD: This 52-week, prospective, randomized, double-blind, multicenter, international study included clinically stable outpatients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Settings included physicians' offices and clinics. Patients received a fixed dose of long-acting risperidone (25 or 50 mg) every 2 weeks. Primary outcome was time to relapse, defined as either re-hospitalization or other exacerbation criteria. Other assessments included the Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity of Illness scale, and functional and quality-of-life measures. Safety was assessed via treatment-emergent adverse events, laboratory tests, and movement disorder rating scales. Data were collected from December 2002 to September 2004. RESULTS: A total of 324 patients were randomized to 25 mg (N = 163) or 50 mg (N = 161) of long-acting risperidone. Time to relapse was comparable (p = .131) for both groups. Projected median time to relapse was 161.8 weeks (95% CI = 103.0 to 254.2) with 25 mg and 259.0 weeks (95% CI = 153.6 to 436.8) with 50 mg. One-year incidences of relapse were 21.6% (N = 35) and 14.9% (N = 24), respectively (p = .059). Psychiatric hospitalization was the reason for relapse for 16 (10%) in the 25-mg group and 10 (6%) in the 50-mg group. Patients experienced statistically significant but modest improvements at endpoint in most measures (i.e., psychotic symptoms, functioning, movement disorder severity) with both doses, with no significant between-group differences. CONCLUSION: In this 1-year study, long-acting risperidone was associated with low relapse and rehospitalization rates, indicating that doses of 25 to 50 mg are appropriate for long-term treatment in schizophrenia.

A model of anticholinergic activity of atypical antipsychotic medications.

BACKGROUND: Atypical antipsychotics clozapine, olanzapine, and quetiapine have significant affinity for the muscarinic receptors in vitro, while aripiprazole, risperidone, and ziprasidone do not. Dissimilarity in binding profiles may contribute to the reported differences in the anticholinergic effects of these antipsychotics. However, it is difficult with the available data to predict the likelihood of anticholinergic effects occurring with various doses of an atypical antipsychotic. METHODS: We developed a model to assess the potential anticholinergic activity (AA) of atypical antipsychotics at therapeutic doses. A radioreceptor assay was used to measure in vitro AA at 6 clinically relevant concentrations of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone. Using published pharmacokinetic data, in combination with the measured in vitro AA, dose-AA curves were generated. RESULTS: Clozapine, and to a lesser extent olanzapine and quetiapine showed dose-dependent increases in AA. At therapeutic doses, the AA (in pmol/mL of atropine equivalents) was estimated to range from 27-250, 1-15, and 0-5.4 pmol/mL for clozapine, olanzapine, and quetiapine, respectively. Aripiprazole, risperidone, and ziprasidone did not demonstrate AA at any of the concentrations studied. CONCLUSIONS: Therapeutic doses of clozapine, olanzapine, and, to a lesser extent, quetiapine are associated with clinically relevant AA.

A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization.

OBJECTIVE: This study compared the effects of atypical antipsychotics (risperidone or quetiapine) with placebo and with each other in recently exacerbated patients with schizophrenia requiring hospitalization. METHODS: This international, randomized, double-blind study included a 2-week monotherapy phase followed by a 4-week additive therapy phase. Recently exacerbated patients with schizophrenia or schizoaffective disorder (DSM-IV) were randomized (2:2:1) to risperidone (n = 153), quetiapine (n = 156), or placebo (n = 73). Target doses were 4 or 6 mg/day of risperidone and 400 or 600 mg/day of quetiapine by day 5, with the ability to increase to 600 or 800 mg/day of quetiapine on day 8. The main outcome measures were the total Positive and Negative Syndrome Scale (PANSS) and need for additional psychotropic medications. RESULTS: Monotherapy Phase: The combined atypical antipsychotic group (n = 308) reached borderline superiority to placebo (n = 71) at the 2-week endpoint on mean change in total PANSS score (-24.1 +/- 1.2 and -20.2 +/- 2.0, respectively; p = 0.067). The change in the atypical group was driven by the improvement with risperidone (-27.7 +/- 1.5 vs. -20.2 +/- 2.0 with placebo, p < 0.01; and vs. -20.5 +/- 1.5 with quetiapine, p < 0.01); the improvement with quetiapine was similar to placebo, p = 0.879. Results were similar on other efficacy endpoints. Additive Therapy Phase: Additional psychotropics were prescribed to fewer (p < 0.01) risperidone (36%) than quetiapine (53%) or placebo patients (59%). The overall discontinuation rate was 18%, 26%, and 38%, respectively. Risperidone, compared with placebo, was associated with more parkinsonism, akathisia, plasma prolactin changes, and weight gain; while quetiapine was associated with more somnolence, sedation, dizziness, constipation, tachycardia, thyroid dysregulation, and weight gain. CONCLUSION: While the combined atypical antipsychotic group did not experience greater improvements than the placebo group, risperidone, but not quetiapine, was significantly superior in all measured domains to placebo in the management of recently exacerbated hospitalized patients with schizophrenia or schizoaffective disorder, with no unexpected tolerability findings.

Insight and its relationship to clinical outcomes in patients with schizophrenia or schizoaffective disorder receiving long-acting risperidone.

Poor insight is common in schizophrenia, predictive of non-compliance, and an impediment to effective patient management. We hypothesized that long-acting risperidone would be associated with enhanced insight, contributing to improved quality of life measures. In an international, open-label 50-week study, stable patients received long-acting risperidone every 2 weeks. Assessments included the Positive and Negative Syndrome Scale [PANSS; item G12 rated 'impaired insight and judgment' from 1 (no impairment) to 7 (severe impairment)]; Clinical Global Impressions-Severity (CGI-S); and the Medical Outcomes Study Short-form 36-item Health Survey (SF-36) (patient-rated quality of life). Correlation and regression post-hoc analyses examined associations between insight and other measures. At baseline, 314 (51.1%; N=614) patients had impaired insight (G12=3-7) and 83 (26.4%) achieved normal or near normal ratings at endpoint (G12=1-2). Symptom severity corresponded with insight: baseline mean+/-SD PANSS total scores were 56.0+/-14.4 in patients without impaired insight (G12=1-2); 73.4+/-15.7 with mild-moderate impairment (G12=3-4); and 86.0+/-17.4 with severe impairment (G12=5-7). These scores improved significantly in each group at endpoint (P<0.001). Improved insight ratings correlated with improvements in CGI-S (r=0.37); PANSS disorganized thought (r=0.46); negative symptoms (r=0.32); and anxiety/depression (r=0.24; P<0.001 all comparisons), but not quality of life ratings. The change in insight did not contribute significantly to the variance in SF-36 scores; however, changes in negative symptoms, anxiety/depression and CGI-S scores did contribute significantly. Long-acting risperidone was associated with improvements in insight, symptom domains, clinical status and quality of life measures. Associations were noted between patient-rated quality of life and specific symptom domains, but not insight.

Reduction in psychotic symptoms as a predictor of patient satisfaction with antipsychotic medication in schizophrenia: data from a randomized double-blind trial.

BACKGROUND: Patient satisfaction with antipsychotic treatment is important. Limited evidence suggests that satisfaction is associated with symptom improvement and compliance. Predictors of patient satisfaction with antipsychotic medication were examined in a study of patients with a recent exacerbation of schizophrenia. METHODS: Data are from a randomized, double-blind trial comparing risperidone (n = 152), quetiapine (n = 156), and placebo (n = 73). Medication Satisfaction Questionnaire (MSQ) was completed after 14 days of treatment and after 6 weeks at last study visit. RESULTS: Medication satisfaction at both time points was significantly associated in multiple regression analysis with improvement on 3 Positive and Negative Syndrome Scale (PANSS) factor scores (positive symptoms p < .01; uncontrolled hostility/excitement, p < .0005; anxiety/depression, p < .04) and treatment with risperidone (p < .03); at day 14, significant association was also found with older age (p = .01). At both time points, predictor variables explained over 30% of the variance in medication satisfaction. Change in Hamilton Depression Scale, prolactin levels, sex, and reported adverse events of extrapyramidal symptoms, sedation, and movement disorders were not significant predictors of satisfaction. Lower level of medication satisfaction at day 14 was associated with earlier discontinuation in the trial at week 6 end point. A focused principal components analysis of PANSS factors and MSQ suggested that medication satisfaction relates to 3 groups of factors in descending order of magnitude: lower levels of (a) uncontrolled hostility/excitement, (b) positive symptoms, and (c) negative symptoms, disorganized thoughts, and anxiety/depression. CONCLUSION: Results give further support that treatment satisfaction is positively associated with symptom improvement, particularly psychotic symptoms, and suggest that satisfaction may also be related to compliance, as those who were more satisfied remained in the trial for a longer period of time.

An assessment of emergent tardive dyskinesia and existing dyskinesia in patients receiving long-acting, injectable risperidone: results from a long-term study.

INTRODUCTION: Treatment-emergent tardive dyskinesia (TD) can be a serious side effect of antipsychotic treatment. Atypical antipsychotics are associated with a lower risk for TD than are conventional agents. A long-acting atypical antipsychotic, with more stable blood levels and lower peak blood levels than an oral formulation, may provide differential benefit regarding side effects, including movement disorders. This analysis assessed TD by defined research criteria in patients receiving long-acting, injectable risperidone. METHODS: Clinically stable subjects with schizophrenia or schizoaffective disorder participated in a 50-week, open-label trial of long-acting, injectable risperidone. TD was studied by defined research criteria (Schooler, N.R., Kane, J.M., 1982. Research diagnosis for tardive dyskinesia. Arch. Gen. Psychiatry. 39, 486-487; Americal Psychiatric Association, 2000. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Association, Washington, DC). The severity of dyskinesia and other movement disorders were rated by the Extrapyramidal Symptom Rating Scale (ESRS). RESULTS: ESRS dyskinesia data were available for 662 patients. Five of 530 subjects without dyskinesia at baseline (0.94%) met the predefined criteria for emergent persistent TD during therapy. Based on either exposure to study medication or Kaplan-Meier analysis, the 1-year rate was 1.19%. Among the 132 subjects with dyskinesia at baseline, the mean score on the ESRS physician's exam for dyskinesia improved significantly at endpoint (-2.77; P<0.0001), regardless of anticholinergic drug use. (P=0.243 for patients with versus without anticholinergic drug use.) CONCLUSIONS: In this open-label study, treatment with long-acting risperidone was associated with a low rate of emergent persistent TD. Significant improvement in existing dyskinesias was noted. The TD rate reported here is consistent with other reports of atypical antipsychotics and substantially lower than with conventional antipsychotics.

Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS): cross-scale comparison in assessing tardive dyskinesia.

Assessing tardive dyskinesia (TD) has been complicated by the use of different research criteria and rating scales. We studied concordance between two commonly used scales, the Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS), to study interscale concordance and criteria to define TD. Patients with schizophrenia or schizoaffective disorder (N = 374) were rated at baseline with both scales. Linear and logistic regression models explored relationships between scale ratings and mapped scores for corresponding items. TD was defined as at least mild in > or = 2 anatomical areas, or moderate or greater symptoms in > or = 1 area at baseline. Logistic regression was used to find simplified criteria for predicting AIMS-defined TD by ESRS scores. There was a strong association on corresponding item ratings. "Mild" was defined as AIMS score of 2 and ESRS 2 or 3, and "moderate or greater" as AIMS score > or = 3 and ESRS > or = 4. Using these criteria, there was 96.0% (359/374) agreement between AIMS- and ESRS-defined TD cases. The ESRS Clinical Global Impressions of severity of dyskinesia (CGI-SD) best predicted AIMS-defined TD. An ESRS CGI-SD > or = 4 (95% CI: 3.61, 4.76) was associated with > or = 95% probability of AIMS-defined TD. High concordance between the scales for dyskinesia scores was found. Findings suggest that the ESRS CGI-SD score can serve as a simplified criterion for identifying AIMS-defined TD, and may be a useful tool for future research-based TD analyses, when occurring in the context of a full movement disorder assessment.

Remission in schizophrenia: Results from a 1-year study of long-acting risperidone injection.

PURPOSE: Although treatment advances have improved outcomes in schizophrenia, definitions of remission and recovery are still evolving. Recently proposed criteria for remission (mild or less on multiple core-symptom ratings for at least 6 months) have been applied to a 1-year study of long-acting risperidone injection. METHODS: In a 50-week, open-label trial, stable patients with schizophrenia or schizoaffective disorder who received long-acting risperidone injection every 2 weeks were assessed using the Positive and Negative Syndrome Scale (PANSS). Remission criteria for the PANSS were applied; global illness severity (Clinical Global Impressions) and patient-rated health status (36-Item Short-form Health Survey) were measured. RESULTS: Groups were identified by initial remission status (excluding the time component). Although considered clinically "stable," 68.2% (394/578) did not meet the symptom-severity component of remission criteria at baseline. Following long-acting, injectable risperidone treatment, 20.8% (82) of nonremitted patients achieved symptom remission for at least 6 months, with significant decreases in mean PANSS total and cluster scores (P < 0.0001) and significantly improved patient-rated health status (P < 0.0001). Percentages rated as not ill, very mild, or mild increased from 39% to 88%. Among 31.8% (184/578) of patients meeting the symptom-severity component of remission criteria at baseline, 84.8% (156) maintained these criteria at endpoint. CONCLUSIONS: Among previously "stable," nonremitted patients, many achieved symptom remission after long-acting, injectable risperidone treatment, with significant improvements in multiple symptom domains and patient-rated health status. These results warrant further study as these remission criteria may represent a meaningful clinical endpoint and an important step towards functional recovery.

Psychometric evaluation of the Readiness for Discharge Questionnaire.

OBJECTIVE: The Readiness for Discharge Questionnaire (RDQ) was developed as an easy to use tool for assessing readiness for discharge, independent of socio-economic factors, for inpatients with schizophrenia. The psychometric properties of the RDQ are described. METHODS: The RDQ consists of 6 items assessing suicidality/homicidality, control of aggression/impulsivity, activities of daily living, medication-taking, delusions/hallucinations interfering with functioning and global status. A final yes/no question assesses readiness for discharge. Data derived from 3 studies (500 patients in 3 countries) were used in analyzing inter-rater and test-retest reliability, content and construct validity, and sensitivity to change. RESULTS: The inter-rater reliability was high for all items of the RDQ (reliability coefficients >0.9) and moderate to high for the readiness for discharge status (Session I: 84% agreement, kappa 0.39, polychoric correlation r=0.81; Session II: 89% agreement, kappa 0.63, polychoric correlation r=0.81. Test-retest reliability was also high for all items of the RDQ (reliability coefficients >0.9) and the readiness for discharge status (kappa=0.743; tetrachoric correlation r=0.819). Overall, 84% of the raters agreed (mean score=5.0 of possible 6.0) that the RDQ was useful in assessing a patient's readiness for discharge from the hospital. Evidence of good construct validity included significant correlations with PANSS total and factor scores, and a significant relationship with actual discharge. Significantly more patients with symptom improvement were judged ready for discharge (compared to those without symptom improvement), indicating that the RDQ was sensitive to change over time. CONCLUSIONS: The RDQ has favorable reliability and validity properties, and is an easy to use instrument in research studies for assessing readiness for discharge of inpatients with schizophrenia. Additional work in naturalistic settings is required to further validate the instrument for routine clinical use.

Treatment of behavior disorders in mental retardation: report on transitioning to atypical antipsychotics, with an emphasis on risperidone.

BACKGROUND: Mental illnesses are more common in people with mental retardation and developmental disabilities than in the general population. Due to the difficulty of making specific psychiatric diagnoses in these patients, the target of medication is often a behavioral symptom. For many symptoms, antipsychotic medications are effective, but the serious side effect profile of conventional antipsychotics renders their use problematic. Recent findings concerning the safety and efficacy of atypical antipsychotics for control of certain disruptive behaviors in adults and children led a Special Topic Advisory Panel to draw up guidelines for transitioning patients with specific symptoms from classical antipsychotics to risperidone and, by extrapolation, to other atypical agents. PARTICIPANTS: Participants were chosen by Janssen Pharmaceutica, based on individual achievements and lifetime experience. The Special Topic Advisory Panel on Transitioning to Risperidone Therapy in Patients With Mental Retardation and Developmental Disabilities comprised academic clinicians with at least 10 years' experience in the field of mental retardation and developmental disabilities. It included a clinical pharmacist, consultant pharmacists, a certified developmental disabilities nurse, psychiatrists, a family physician, and a psychologist. EVIDENCE: The Panel considered recent studies of the efficacy and tolerability of risperidone and other atypical antipsychotics in adults and children with mental retardation and developmental disabilities. MEDLINE searches were conducted using the name of each atypical antipsychotic and the following terms: mental retardation, developmental disabilities, and behavior disorders. Searches were conducted starting in July 2002 and done periodically through April 2004 to capture new additions to the literature. Searches were confined to English. GUIDELINES PROCESS: The Panel reviewed the available evidence, identified optimal doses and titration schedules, considered instruments and rating scales for assessing symptoms, and developed guidelines. CONCLUSIONS: The guidelines set forth initial and target doses and titration schedules of risperidone therapy for some behavioral symptoms and provide recommendations concerning withdrawal of previous medications and for procedures and rating scales for assessing symptoms. In patients with severe retardation, the goal is often to identify specific target behaviors rather than to pursue an exact diagnosis, which may be unattainable.

Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam.

BACKGROUND: Standard treatment for acute psychotic agitation often involves intramuscular administration of the benzodiazepine lorazepam and the antipsychotic haloperidol. This study compared the efficacy and safety of oral treatment with the atypical antipsychotic risperidone plus lorazepam with those of standard intramuscular treatment. We hypothesized that the efficacy and speed of action of both treatments would be similar. METHOD: In a prospective, parallel-group, randomized, rater-blinded noninferiority study conducted at 24 sites in the United States, 162 patients exhibiting agitation associated with active psychosis were randomly assigned to receive either oral treatment with 2 mg of risperidone plus 2 mg of lorazepam (N = 83) or intramuscular treatment with 5 mg of haloperidol plus 2 mg of lorazepam (N = 79). The change scores on a 5-item acute-agitation cluster from the Positive and Negative Syndrome Scale (hallucinatory behavior, excitement, hostility, uncooperativeness, and poor impulse control) were the main outcome measure. The study was conducted from January 8 to August 8, 2001. RESULTS: Mean acute-agitation cluster scores were similar in the 2 groups at baseline. Mean score improvements at 30, 60, and 120 minutes after dosing were significant at each timepoint in both groups (p <.0001) and were similar in both groups (p >.05). Both treatments were well tolerated. CONCLUSION: A single oral dose of risperidone plus lorazepam was as effective as parenterally administered haloperidol plus lorazepam for the rapid control of agitation and psychosis. These findings suggest that this oral regimen is an acceptable alternative to the current intramuscular treatment for acute psychotic agitation.

Correlates of anticholinergic activity in patients with dementia and psychosis treated with risperidone or olanzapine.

BACKGROUND: Older individuals with dementia are highly sensitive to the effects of muscarinic receptor blockade. STUDY DESIGN: This was a 6-week multisite, randomized clinical trial. SUBJECTS: Eighty-six patients with probable Alzheimer's disease, vascular dementia, or mixed-etiology dementia (DSM-IV criteria) were randomly assigned to treatment with olanzapine or risperidone. ASSESSMENTS: Anticholinergic activity was measured with a radioreceptor assay, and plasma levels of antipsychotic medications were determined. Primary outcomes were assessed with the Udvalg for Kliniske Undersogelser (UKU) scale and somnolence adverse events; secondary outcome measures included scores on the Neuropsychiatric Inventory (NPI) and other scales. RESULTS: There were no between-treatment differences in the UKU scale or in somnolence adverse events. Statistically significant improvements (p < .001) from baseline were found for the NPI measures, with no between-treatment group differences. Olanzapine was associated with significant increases from baseline in anticholinergic activity, while risperidone was not; the between-treatment group differences were not statistically significant. Increase in anticholinergic activity was associated with an increase in anticholinergic side effects and slower performance on the Trail Making Test Part A. Higher endpoint anticholinergic activity was associated with higher endpoint scores on several items from the NPI, including delusions, anxiety, and aberrant motor behavior. IMPLICATIONS: Efficacious doses of olanzapine increased anticholinergic activity in older patients with dementia, while similarly efficacious doses of risperidone did not. Patients whose anticholinergic activity increased were more likely to experience anticholinergic side effects and to have worsening in certain cognitive domains. These data suggest that certain patients may be vulnerable to the anticholinergic activity associated with antipsychotic treatment.

Smokers and nonsmokers equally affected by olanzapine-induced weight gain: metabolic implications.

OBJECTIVE: To examine the impact of smoking status on antipsychotic-associated weight gain. METHOD: In two double-blind studies, 552 adult and elderly patients with schizophrenia or schizoaffective disorder were randomly assigned to risperidone or olanzapine treatment for 8 weeks. Smoking status at baseline was recorded together with other background characteristics. RESULTS: In both adult and elderly patients, olanzapine-treated smokers and nonsmokers gained weight at a similar rate, whereas risperidone-treated smokers gained less weight than did nonsmokers. Olanzapine was associated with significantly greater weight gain than was risperidone across all measures in both adult and elderly patients. CONCLUSION: These findings support a quantitatively or qualitatively different effect of risperidone and olanzapine on the metabolic changes underlying antipsychotic-associated weight gain. Mechanisms responsible for olanzapine's effect on weight appear to counteract smokers' physiologic bias toward weight loss, an effect not seen among risperidone-treated patients.

Efficacy and safety of long-acting risperidone in stable patients with schizoaffective disorder.

BACKGROUND: The treatment of schizoaffective disorder is often complicated by the variety of symptoms that contribute to its pathology. Data from a large study (n=725), which included schizoaffective patients to assess the effect of long-acting risperidone, are presented. METHOD: A multicenter, open-label study enrolled non-acute, clinically stable patients with schizoaffective disorder (n=110). Patients on a stable dose of antipsychotic for at least 4 weeks at study entry were switched to long-acting risperidone every 2 weeks for 50 weeks. RESULTS: Mean Positive and Negative Syndrome Scale (PANSS) total scores (+/-S.E.) improved significantly (p<0.001) at each measured time point, including endpoint (-9.0+/-1.6), compared with baseline. Significant reductions were observed on mean PANSS cluster scores for both anxiety/depression (-1.3+/-0.4, p<0.001) and uncontrolled hostility/excitement (-0.7+/-0.3, p<0.05). In addition, scores improved significantly for positive symptoms (-2.2+/-0.5, p<0.001), negative symptoms (-3.1+/-0.5, p<0.001), and disorganized thoughts (-1.7+/-0.4, p<0.001). The overall subjective score of movement disorders was low at baseline (3.6+/-4.1) and had significantly decreased at endpoint (2.75; p<0.05). Patients were previously treated with antipsychotics for 398+/-790 days before being switched to long-acting risperidone. LIMITATIONS: Although this was a 50-week study, which included over 100 patients with schizoaffective disorder, limitations include the open-label design and that it was not designed specifically to assess patients with this disorder. PANSS symptom domains previously defined by factor analytic methods were used for mood symptom measures. No specific mood symptom scales were administered in this study. CONCLUSION: Patients with schizoaffective disorder, considered stable on their antipsychotic medication at study entry, experienced additional significant clinical improvements and minimal side effects with injections of long-acting risperidone over a 50-week study period.