M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats.
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In a recent study using Wistar rats, the serotonergic 5-HT2 receptor antagonists ketanserin and risperidone reduced the disruptive effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine on prepulse inhibition (PPI), suggesting that there is an interaction between serotonin and glutamate in the modulation of PPI. In contrast, studies using the noncompetitive NMDA antagonist phencyclidine (PCP) in Sprague-Dawley rats found no effect with 5-HT2 antagonists. To test the hypothesis that strain differences might explain the discrepancy in these findings, risperidone was tested for its ability to reduce the PPI-disruptive effects of dizocilpine in Wistar and Sprague-Dawley rats. Furthermore, to determine which serotonergic receptor subtype may mediate this effect, the 5-HT2A receptor antagonist M100907 (formerly MDL 100,907) and the 5-HT2C receptor antagonist SDZ SER 082 were tested against dizocilpine. Recent studies have found that the PPI-disruptive effects of PCP are reduced by the alpha 1 adrenergic receptor antagonist prazosin. Furthermore, the alpha 1 receptor agonist cirazoline disrupts PPI. As risperidone and M100907 have affinity at the alpha 1 receptor, a final study examined whether M100907 would block the effects of cirazoline on PPI. Risperidone partially, but nonsignificantly, reduced the effects of dizocilpine in Wistar rats, although this effect was smaller than previously reported. Consistent with previous studies, risperidone did not alter the effects of dizocilpine in Sprague-Dawley rats. Most importantly, M100907 pretreatment fully blocked the effect of dizocilpine in both strains; whereas SDZ SER 082 had no effect. M100907 had no influence on PPI by itself and did not reduce the effects of cirazoline on PPI. These studies confirm the suggestion that serotonin and glutamate interact in modulating PPI and indicate that the 5-HT2A receptor subtype mediates this interaction. Furthermore, this interaction occurs in at least two rat strains. (+info)
Effects of atypical antipsychotic drug treatment on amphetamine-induced striatal dopamine release in patients with psychotic disorders.
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Clozapine, risperidone, and other new "atypical" antipsychotic agents are distinguished from traditional neuroleptic drugs by having clinical efficacy with either no or low levels of extrapyramidal symptoms (EPS). Preclinical models have focused on striatal dopamine systems to account for their atypical profile. In this study, we examined the effects of clozapine and risperidone on amphetamine-induced striatal dopamine release in patients with psychotic disorders. A novel 11C-raclopride/PET paradigm was used to derive estimates of amphetamine-induced changes in striatal synaptic dopamine concentrations and patients were scanned while antipsychotic drug-free and during chronic treatment with either clozapine or risperidone. We found that amphetamine produced significant reductions in striatal 11C-raclopride binding during the drug-free and antipsychotic drug treatment phases of the study which reflects enhanced dopamine release in both conditions. There were no significant differences in % 11C-raclopride changes between the two conditions indicating that these atypical agents do not effect amphetamine-related striatal dopamine release. The implications for these data for antipsychotic drug action are discussed. (+info)
A cost-effectiveness clinical decision analysis model for schizophrenia.
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A model was developed to estimate the medical costs and effectiveness outcomes of three antipsychotic treatments (olanzapine, haloperidol, and risperidone) for patients with schizophrenia. A decision analytic Markov model was used to determine the cost-effectiveness of treatments and outcomes that patients treated for schizophrenia may experience over a 5-year period. Model parameter estimates were based on clinical trial data, published medical literature, and, when needed, clinician judgment. Direct medical costs were incorporated into the model, and outcomes were expressed by using three effectiveness indicators: the Brief Psychiatric Rating Scale, quality-adjusted life years, and lack of relapse. Over a 5-year period, patients on olanzapine had an additional 6.8 months in a disability-free health state based on Brief Psychiatric Rating Scale scores and more than 2 additional months in a disability-free health state based on quality-adjusted life years, and they experienced 13% fewer relapses compared with patients on haloperidol. The estimated 5-year medical cost associated with olanzapine therapy was $1,539 less than that for haloperidol therapy. Compared with risperidone therapy, olanzapine therapy cost $1,875 less over a 5-year period. Patients on olanzapine had approximately 1.6 weeks more time in a disability-free health state (based on Brief Psychiatric Rating Scale scores) and 2% fewer relapses compared with patients on risperidone. Sensitivity analyses indicated the model was sensitive to changes in drug costs and shortened hospital stay. Compared with both haloperidol and risperidone therapy, olanzapine therapy was less expensive and provided superior effectiveness outcomes even with conservative values for key parameters such as relapse and discontinuation rates. (+info)
Economic outcomes associated with the use of risperidone in a naturalistic group practice setting.
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The purpose of this cohort pilot study was to compare the resource utilization and economic outcomes associated with the use of risperidone versus haloperidol in a naturalistic setting. Patient charts from a large psychiatric group practice were reviewed, and hospital billing data were obtained. Patients meeting the inclusion criteria were placed into one of two cohorts depending on their medication history. Thirty patients treated with risperidone met the selection criteria, and a random quota sampling technique was used to allow for a matched control cohort of 30 patients treated with haloperidol. In the haloperidol and risperidone cohorts, 24 and 28 patients, respectively, were evaluated statistically. Mean utilization rates and costs per patient per month for each service were estimated by using regression analysis. Patients in the risperidone cohort had significantly fewer hospitalizations than did those in the haloperidol cohort (P = 0.004). Likewise, risperidone patients had significantly lower hospitalization costs than haloperidol patients (P = 0.005). Conversely, patients treated with risperidone visited the physician more frequently than did those treated with haloperidol (P = 0.0005). Estimated mean total monthly costs were $123.34 lower (95% confidence interval = $464, $217) per patient in the risperidone cohort than in the haloperidol cohort ($1,636.11 vs $1759.45; P = 0.4693). Significant reductions in hospital costs in the risperidone cohort offset higher medication and physician costs. Overall, total monthly costs were similar for the two cohorts. (+info)
Looking beyond the formulary budget in cost-benefit analysis.
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With the introduction of newer, more expensive psychotropic medications, healthcare providers and managed care administrators must consider whether these drugs offer "value for the money." A true picture of the benefits of these drugs emerges only when all the costs of treatment are considered. Focusing exclusively on the acquisition cost of the drug can result in a misleading impression of the drug's worth. Although the medication costs associated with treating a patient with a newer drug increase, use of these agents may actually result in an overall decrease in healthcare costs, through reductions in hospitalization and length of stay, use of mental health services, and prescriptions for adjunctive drugs. In one study of the newer antipsychotic agent risperidone, the overall annual costs of treating a patient with schizophrenia were reduced by nearly $8,000 (Canadian dollars), even though medication costs increased by approximately $1,200 (Canadian dollars). Retrospective and prospective pharmacoeconomic studies can provide valuable data on the cost effectiveness of treatment with newer psychotropic medications. (+info)
Risperidone versus haloperidol on secondary memory: can newer medications aid learning?
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The introduction of the new generation of antipsychotic medications for the treatment of schizophrenia has been accompanied by a growing interest in the neurocognitive effects of these drugs. The present study compared the effects of risperidone and haloperidol on secondary memory in a group of treatment-resistant schizophrenia patients. The study design included a baseline phase and two double-blind phases in which patients were randomly assigned to medication under two different dose conditions (fixed dose and flexible dose). Secondary memory was assessed at baseline, fixed-dose, and flexible-dose phases, using the California Verbal Learning Test (CVLT). Six measures were selected, which formed three factors (general verbal learning ability, retention, and learning strategy). Risperidone-treated patients showed greater improvement than haloperidol-treated patients in general verbal learning ability, a finding characterized by significant treatment effects on CVLT measures of learning acquisition, recall consistency, and recognition memory. After controlling for benztropine status, differences on the measures of learning acquisition and recall consistency remained significant, and differences in recognition memory weakened slightly (p = 0.07). No significant treatment effects were noted on retention or learning strategy. These findings suggest that risperidone may exert a facilitating effect on the acquisition of new verbal information, an effect that does not appear to be due to the activation of semantic encoding strategies. (+info)
The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.
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Cognitive function is markedly impaired in most patients with schizophrenia. Antecedents of this impairment are evident in childhood. The cognitive disability is nearly fully developed at the first episode of psychosis in most patients. The contribution of cognitive impairment to outcome in schizophrenia, especially work function, has been established. Preliminary results indicate that cognitive function, along with disorganization symptoms, discriminate schizophrenia patients who are able to work full-time from those who are not. Typical neuroleptic drugs lack the ability to improve the various domains of cognitive function impaired in schizophrenia. Atypical antipsychotic drugs pharmacologically related to clozapine-quetiapine, olanzapine, risperidone, sertindole, and ziprasidone--share the ability to produce fewer extrapyramidal symptoms than typical neuroleptic drugs and more potent antagonism of serotonin2a relative to dopamine2 receptors. However, they have a number of different clinical effects. We have identified all the studies of clozapine, olanzapine, and risperidone that provide data on their effects on cognition in schizophrenia. Data for each drug are reviewed separately in order to identify differences among them in their effects on cognition. Twelve studies that report cognitive effects of clozapine are reviewed. These studies provide (1) strong evidence that clozapine improves attention and verbal fluency and (2) moderate evidence that clozapine improves some types of executive function. However, results of the effects of clozapine on working memory and secondary verbal and spatial memory were inconclusive. Risperidone has relatively consistent positive effects on working memory, executive functioning, and attention, whereas improvement in verbal learning and memory was inconsistent. Preliminary evidence presented here suggests that olanzapine improves verbal learning and memory, verbal fluency, and executive function, but not attention, working memory, or visual learning and memory. Thus, atypical antipsychotic drugs as a group appear to be superior to typical neuroleptics with regard to cognitive function. However, available data suggest that these drugs produce significant differences in specific cognitive functions. These differences may be valuable adjunctive guides for their use in clinical practice if cognitive improvements reach clinical significance. The effects of the atypical antipsychotic drugs on cholinergic and 5-HT2a-mediated neurotransmission as the possible basis for their ability to improve cognition are discussed. It is suggested that the development of drugs for schizophrenia should focus on improving the key cognitive deficits in schizophrenia: executive function, verbal fluency, working memory, verbal and visual learning and memory, and attention. (+info)
Electroencephalographic and psychomotor effects of chlorpromazine and risperidone relative to placebo in normal healthy volunteers.
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AIMS: To investigate the effects of single oral doses of chlorpromazine (50 mg) and risperidone (2 mg) relative to placebo on topographical electroencephalometry (CATEEMTM ) and psychomotor tests in 12 healthy male volunteers. METHODS: A double-blind, placebo-controlled, three-way crossover design using a double dummy blinding technique was utilized. Chlorpromazine was selected as representative of the 'typical' neuroleptics, being also highly sedative. Risperidone has been suggested as representative of the newer 'atypical' neuroleptics and is claimed to be only minimally sedative. Volunteers were dosed on 3 separate days with a minimum of 7 days interval between trial days. On each trial day volunteers were dosed twice. Dose 1 consisting of either chlorpromazine 50 mg or placebo to chlorpromazine, and dose 2 either risperidone 2 mg or placebo to risperidone. The volunteers were randomized so that each received either chlorpromazine or risperidone (or neither), but not both on an individual trial day. A 17 electrode quantitative topographical electroencephalograph (EEG) recording was taken for each volunteer before and after each dosing period. Seven psychomotor function tests were used to determine the effects of each treatment on psychomotor performance. RESULTS: The data confirm the cited reports of sedation following single oral doses of chlorpromazine 50 mg. However, 7 of the 12 volunteers dosed with risperidone 2 mg also reported drowsiness/lethargy which was of greater severity and duration than 5 of the 12 volunteers who reported somnolence following dosing with chlorpromazine 50 mg. Objective assessment of psychomotor impairment using a short battery of psychomotor function tests mirrored the subjective reports of somnolence in that the impairment in volunteers dosed with risperidone 2 mg was greater in extent and magnitude than in volunteers dosed with chlorpromazine 50 mg. With respect to the cortical quantitative electroencephalogram, both chlorpromazine (50 mg) and risperidone (2 mg) increased power (4.75-6.75 Hz) in keeping with cited effects of other neuroleptics on the quantitative EEG. In addition, there was a statistically significant increase (P<0.05) in alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.5 Hz) wavebands in volunteers dosed with risperidone 2 mg. Furthermore, based on estimates of variability, we propose that a 3 min eyes open and 3 min eyes closed quantitative EEG recording is sufficient to maintain adequate power for this technique, whilst allowing its application to early volunteer trials of novel neuroleptic agents. CONCLUSIONS: This study demonstrates that quantitative EEG can be utilized in the profiling of neuroleptic agents, and could be readily applied to the early profiling of novel neuroleptics in limited numbers of volunteers, early in drug development. The chosen battery of psychomotor tests has clearly demonstrable sensitivity to the quantification of the subjective reports of somnolence secondary to both chlorpromazine and risperidone. (+info)