Young Zhu

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.

Randomized, Double-Blind, Placebo-Controlled Study of Paliperidone Extended-Release and Quetiapine in Inpatients With Recently Exacerbated Schizophrenia

OBJECTIVE The authors compared paliperidone extended-release and quetiapine in patients with recently exacerbated schizophrenia requiring hospitalization. METHOD In a 6-week double-blind study, inpatients with a recent exacerbation of schizophrenia were randomly assigned to treatment with paliperidone extended-release, quetiapine, or placebo. A 2-week monotherapy phase was followed by a 4-week additive-therapy phase. Target doses were at the upper end of recommended ranges: paliperidone extended-release, 9 or 12 mg/day, and quetiapine, 600 or 800 mg/day. The primary endpoint was the difference in mean total change score on the Positive and Negative Syndrome Scale (PANSS) between paliperidone extended-release and quetiapine at the 2-week monotherapy phase endpoint. RESULTS Six-week completion rates were 77.5% (124/160) with paliperidone extended-release, 66.7% (106/159) quetiapine, and 63.8% (51/80) placebo. Improvement in mean PANSS total change score was greater with paliperidone extended-release than with quetiapine from day 5 (-11.4 versus -8.2) through the monotherapy phase endpoint (-23.4 versus -17.1). Only paliperidone extended-release showed significantly greater PANSS improvement compared with placebo at 2 weeks. At the 6-week study endpoint, there was a significantly greater improvement with paliperidone extended-release compared with quetiapine despite similar use of additive therapy (predominantly other antipsychotics). Common adverse events with paliperidone extended-release, quetiapine, and placebo, respectively, were tremor (13.9%, 5.0%, 7.5%), somnolence (8.9%, 11.9%, 1.3%), insomnia (10.1%, 9.4%, 11.3%), and headache (12.0%, 7.5%, 13.8%). Six-week adverse event-related discontinuation rates were 6.3%, 10.1%, and 6.3%, respectively, in the paliperidone extended-release, quetiapine, and placebo groups. CONCLUSIONS Compared with quetiapine, paliperidone extended-release improved symptoms earlier and to a greater degree in patients with recently exacerbated schizophrenia requiring hospitalization, 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.

Minimal injection site pain and high patient satisfaction during treatment with long-acting risperidone.

Long-acting injectable antipsychotic formulations of conventional antipsychotics were developed to address the problem of partial adherence among patients with schizophrenia. Injection site pain, other skin reactions and patient satisfaction with treatment were assessed in two large, multicentre studies of long-acting injectable risperidone (Risperdal CONSTA™, Janssen Pharmaceutica Products, Titusville, New Jersey, USA), the first available long-acting atypical antipsychotic agent. Patients rated injection site pain using a 100-mm Visual Analogue Scale (VAS), and investigators rated injection site pain, redness, swelling and induration. Patient satisfaction with treatment was assessed with the Drug Attitude Inventory (DAI). VAS pain ratings were low at all visits across all doses in both studies, and decreased from first to final injection. In the 12-week, double-blind study, mean±SD VAS scores at the first and final injections were 15.6±20.7 and 12.5±18.3 for placebo-treated patients, and 11.8±14.4 (first) and 10.0±12.4 (final) for 25 mg; 16.3±21.9 (first) and 13.6±21.7 (final) for 50 mg; and 16.0±17.9 (first) and 9.6±16.0 (final, P<0.01) for 75 mg of long-acting risperidone. Mean VAS scores in the 50-week, open-label study at the first and final injection were: 17.9±22.2 (first) and 9.5±16.7 (final, P<0.0001) for 25 mg; 18.1±19.7 (first) and 10.4±14.8 (final, P<0.0001) for 50 mg; and 18.5±21.6 (first) and 13.6±19.9 (final, P=0.0001) for 75 mg of long-acting risperidone. Overall, there was no or minimal injection site pain and skin reactions were rare. Mean DAI ratings were available for the 50-week study and indicated high patient satisfaction throughout the trial (baseline=7.30; endpoint=7.70; P<0.0001 versus baseline). These findings may positively affect patient and clinician attitudes towards long-term therapy with long-acting injectable risperidone.

Long-Term Outcomes of Galantamine Treatment in Patients With Alzheimer Disease

OBJECTIVE The authors evaluated the long-term safety, efficacy, and tolerability of galantamine 24 mg/day in the treatment of Alzheimer disease by means of a 12-month, open-label extension of an earlier 5-month, double-blind, placebo-controlled trial with a 6-week withdrawal phase. METHODS Patients completing two double-blind, placebo-controlled trials (N=699) were escalated to a 24-mg dose (12 mg bid) of galantamine during a period of 2 weeks and treated for 12 months beyond the initial 6.5-month, double-blind period (total treatment duration: 18.5 months). The primary efficacy measure was the change from baseline in the Alzheimers Disease Assessment Scale (ADAS-Cog/11) score at 18.5 months; secondary endpoints included total scores on the Alzheimers Disease Cooperative Study of Activities of Daily Living and the Neuropsychiatric Inventory. Standard safety evaluations, including adverse-event monitoring, were performed. RESULTS Patients taking galantamine continuously throughout the double-blind and open-label studies (N=288) showed sustained cognitive benefits on ADAS-Cog/11 scores at 18.5 months. Patients were maintained close to baseline cognitive ability for 12 months, and safety was as expected and documented in other large studies of galantamine. Analysis of the subgroup of patients (N=113) who completed the entire 18.5 months of galantamine treatment showed that cognitive function was maintained up to 14 months. CONCLUSIONS Results of this open-label extension support the findings from previous galantamine studies and demonstrate the safety and tolerability of galantamine for up to 18.5 months.

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

BackgroundPatient 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.MethodsData 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.ResultsMedication 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.ConclusionResults 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.Trial registration numberTrial registration number NCT00061802

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 physicians 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.

Dimensions of Psychosis in Patients with Bipolar Mania as Measured by the Positive and Negative Syndrome Scale

Background: Psychosis is present in 50% or more of patients with bipolar mania and is commonly evaluated in clinical research by means of the Positive and Negative Syndrome Scale (PANSS). The aim of the present analysis was to investigate the psychotic dimensions of bipolar disorder and its contributing symptoms based on a factor analysis of baseline PANSS scores and to compare them with those identified in studies of patients with schizophrenia and bipolar disorder. Sampling and Methods: Baseline data were analyzed from two 3-week, double-blind, placebo-controlled studies of risperidone monotherapy for acute mania associated with bipolar I disorder (n = 535). Inclusion criteria were a DSM-IV diagnosis of bipolar I disorder with manic features, with or without psychotic features, age ≧18 years, and mean baseline Young Mania Rating Scale scores ≧20. A principal component analysis of the 30 PANSS item scores of the 535 patients with a diagnosis of a manic episode at baseline was conducted. Results: Five factors were extracted by the analysis: anxiety (13.4% of the variance), negative symptoms (12.3%), depression (10.5%), excitement (10.3%), and positive symptoms (8.7%). Similar factors, in particular the negative, excitement, and positive factors, have been identified in patients with schizophrenia. There was an absence of a cognitive factor supporting the notion that bipolar patients may present fewer cognitive symptoms. Conclusion: The results of the present analysis and those of other studies indicate similarities in psychotic symptom domains, as measured by the PANSS, in patients with bipolar mania and schizophrenia. Future analyses will address the effects of treatment on the identified factors.

Effects of Galantamine on Measures of Attention : Results From 2 Clinical Trials in Alzheimer Disease Patients With Comparisons to Donepezil

Deficits in attention are present early in the course of Alzheimer disease (AD). Acetylcholine receptors are appealing molecular targets for intervention as cholinergic pathways are involved in the neurobiology of attention. For this reason, measures of attention were included in 2 independent, multicenter, randomized, parallel, controlled trials in subjects with AD comparing the effects of galantamine, an acetylcholinesterase inhibitor and postulated nicotinic receptor modulator, and donepezil, an acetylcholinesterase inhibitor. The attention battery of the Cognitive Drug Research computerized assessment system was used in both trials. Small magnitude, positive signals were observed for simple and choice reaction times for both compounds. Attention task performance tended to improve early for galantamine-treated subjects. A consistent temporal pattern of improvement was not observed in donepezil-treated subjects. Quantitative findings appeared more pronounced in subjects with moderate AD. Galantamines proposed action as a nicotinic receptor modulator may bear on these findings. Improved attention may have positive effects on cognitive and functional outcomes for AD patients, although this hypothesis requires further study and validation.

Psychotic symptoms in patients with bipolar mania.

BACKGROUND Psychosis has been identified in as many as 68% of patients with bipolar mania. This analysis identified psychotic symptoms in these patients. METHODS Data were from two placebo-controlled, 3-week studies in patients with an acute episode of bipolar mania. Symptoms were identified by the 30-item Positive and Negative Syndrome Scale (PANSS; item ratings, 1 = absent to 7 = extremely severe), the Young Mania Rating Scale, and the Global Assessment Scale. RESULTS Psychotic features at study entry were diagnosed in 264 (51.3%) of the 515 patients. At baseline, these patients had significantly more severe scores on the PANSS, Young Mania Rating Scale, and Global Assessment Scale than patients without psychotic features. Patients with psychotic features had mean (+/-SD) scores of mild (3) or greater on six PANSS items: grandiosity (4.5+/-1.4), delusions (4.4+/-1.4), lack of judgment/insight (4.1+/-1.5), excitement (3.9+/-1.3), suspiciousness/persecution (3.1+/-1.6), and hostility (3.1+/-1.5). Grandiosity symptoms of delusional proportions (scores > or = 4) were noted in 205 (78%) of patients with a diagnosis of psychotic features and in 113 (45%) patients without the diagnosis. LIMITATIONS The study was not specifically designed to assess patients with psychotic features and the PANSS was developed to evaluate symptoms of schizophrenia. CONCLUSIONS These findings support prior reports indicating high rates of psychosis in patients with bipolar mania and identify the most prominent symptoms in these patients.