Comparison of quetiapine and risperidone in the treatment of schizophrenia: A randomized, double-blind, flexible-dose, 8-week study

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.     

Neurocognitive effectiveness of quetiapine,olanzapine, risperidone,and ziprasidone: A pragmatic,randomized trial

PurposeCognitive effects of second generation antipsychotics (SGAs) are indicated in efficacy studies but the generalizability of the results may be limited by rigid designs and selected samples. The aim of this naturalistic, industry-independent study is to investigate whether differential neurocognitive effectiveness can be found among olanzapine, quetiapine, risperidone, and ziprasidone in a clinically relevant sample with psychosis.Subjects and methodsAdult patients acutely admitted to an emergency ward for psychosis were randomized to risperidone, olanzapine, quetiapine or ziprasidone and followed for up to 2 years. Participants were assessed repeatedly using the Positive and Negative Syndrome Scale and a repeatable neurocognitive test battery.ResultsA total of 226 patients were included and 171 patients underwent neurocognitive assessments. The sample had a global cognitive performance score at baseline about one standard deviation below that of the general population. The ziprasidone group had the fastest increase in global functioning which was significantly superior to that of the olanzapine group for the entire follow-up period. Before 90 days, the quetiapine group had the fastest increase which was statistically superior to the olanzapine group.DiscussionZiprasidone and quetiapine demonstrated superiority to olanzapine in increasing global neurocognitive performance in this naturalistic sample.     

An open-label randomized comparison of olanzapine versus risperidone in the treatment of childhood-onset schizophrenia

BACKGROUND AND PURPOSE: Childhood-onset schizophrenia (COS) is a clinically severe form of schizophrenia, which causes severe impairment to cognitive, linguistic, and social development. There are few prospective and retrospective open clinical trials of risperidone and olanzapine in COS. In this open-label, randomized, prospective study, we compared the tolerability and effectiveness of risperidone versus olanzapine in the treatment of COS patients. METHODS: The study population consisted of 25 children with COS (mean age 11.09 +/- 1.55 years). After an evaluation, patients received risperidone (0.25-4.5 mg/day, mean dose 1.62 +/- 1.02 mg/day) or olanzapine (2.5-20 mg/day, mean dose 8.18 +/- 4.41 mg/day) for 12 weeks, with weekly evaluations. RESULTS: Both groups showed comparable significant (p < 0.001) within-group improvement from baseline to endpoint (LOCF) in Positive and Negative Symptoms Scale (PANSS) total and subscale scores. Of the olanzapine-treated children, 11 (91.7%) completed the 12 weeks of the study, whereas in the risperidone-treated children only 9 (69.2%) did. No significant differences between risperidone-treated children and olanzapine-treated children were observed on Barnes Akathisia Rating Scale (BAS) and Simpson-Angus Scale (SAS) rating scales. Both treatment groups showed significant (p < 0.001) increase in weight from baseline to endpoint. CONCLUSION: Our open-label, small-scale comparative study suggests that both risperidone and olanzapine appear to be efficacious antipsychotic medications in COS, with a slight nonsignificant advantage of olanzapine in the dropout rate.     

Effectiveness of antipsychotic maintenance therapy with quetiapine in comparison with risperidone and olanzapine in routine schizophrenia treatment: results of a prospective observational trial

Objective of this observational trial is to examine the effects of quetiapine in comparison with olanzapine and risperidone on clinical outcomes and quality of life in patients with schizophrenia and schizoaffective disorder in routine care. 374 adult persons with schizophrenia or schizoaffective disorder prescribed antipsychotic maintenance therapy with quetiapine, olanzapine, or risperidone at discharge from inpatient treatment were included. Clinical and psychosocial outcomes were assessed before discharge and at 6, 12, 18, and 24?months. Statistical analyses were conducted by mixed-effects regression models for longitudinal data. The propensity score method was used to control for selection bias. Patients discharged on olanzapine had significantly lower hospital readmissions than those receiving quetiapine or risperidone. The average chlorpromazine equivalent dose of quetiapine was higher than in patients treated with olanzapine or risperidone. No further significant differences between treatment groups were found. Quetiapine and risperidone are less effective in preventing the need for psychiatric inpatient care than olanzapine, and higher chlorpromazine equivalent doses of quetiapine are needed to obtain clinical effects similar to those of olanzapine and risperidone.     

Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics

OBJECTIVE: In many parts of the world, second-generation antipsychotics have largely replaced typical antipsychotics as the treatment of choice for schizophrenia. Consequently, trials comparing two drugs of this class--so-called head-to-head studies--are gaining in relevance. The authors reviewed results of head-to-head studies of second-generation antipsychotics funded by pharmaceutical companies to determine if a relationship existed between the sponsor of the trial and the drug favored in the study's overall outcome. METHOD: The authors identified head-to-head comparison studies of second-generation antipsychotics through a MEDLINE search for the period from 1966 to September 2003 and identified additional head-to-head studies from selected conference proceedings for the period from 1999 to February 2004. The abstracts of all studies fully or partly funded by pharmaceutical companies were modified to mask the names and doses of the drugs used in the trial, and two physicians blinded to the study sponsor reviewed the abstracts and independently rated which drug was favored by the overall outcome measures. Two authors who were not blinded to the study sponsor reviewed the entire report of each study for sources of bias that could have affected the results in favor of the sponsor's drug. RESULTS: Of the 42 reports identified by the authors, 33 were sponsored by a pharmaceutical company. In 90.0% of the studies, the reported overall outcome was in favor of the sponsor's drug. This pattern resulted in contradictory conclusions across studies when the findings of studies of the same drugs but with different sponsors were compared. Potential sources of bias occurred in the areas of doses and dose escalation, study entry criteria and study populations, statistics and methods, and reporting of results and wording of findings. CONCLUSIONS: Some sources of bias may limit the validity of head-to-head comparison studies of second-generation antipsychotics. Because most of the sources of bias identified in this review were subtle rather than compelling, the clinical usefulness of future trials may benefit from minor modifications to help avoid bias. The authors make a number of concrete suggestions for ways in which potential sources of bias can be addressed by study initiators, peer reviewers of studies under consideration for publication, and readers of published studies.     

Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind 52-week comparison

OBJECTIVE: This 52-week randomized, double-blind, flexible-dose, multicenter study evaluated the overall effectiveness (as measured by treatment discontinuation rates) of olanzapine, quetiapine, and risperidone in patients early in the course of psychotic illness. METHOD: Patients were randomly assigned to treatment with olanzapine (2.5-20 mg/day), quetiapine (100-800 mg/day), or risperidone (0.5-4 mg/day) administered in twice-daily doses. Statistical analyses tested for noninferiority in all-cause treatment discontinuation rates up to 52 weeks (primary outcome measure) based on a prespecified noninferiority margin of 20%. RESULTS: A total of 400 patients were randomly assigned to treatment with olanzapine (N=133), quetiapine (N=134), or risperidone (N=133). The mean modal prescribed daily doses were 11.7 mg for olanzapine, 506 mg for quetiapine, and 2.4 mg for risperidone. At week 52, all-cause treatment discontinuation rates were 68.4%, 70.9%, and 71.4% for olanzapine, quetiapine, and risperidone, respectively. Reductions in total score on the Positive and Negative Syndrome Scale (PANSS) were similar for the three treatment groups, but reductions in PANSS positive subscale scores were greater in the olanzapine group (at 12 weeks and at 52 weeks or withdrawal from study) and the risperidone group (at 12 weeks). The most common elicited adverse events for olanzapine were drowsiness (53%), weight gain (51%), and insomnia (38%); for quetiapine, drowsiness (58%), increased sleep hours (42%), and weight gain (40%); and for risperidone, drowsiness (50%), menstrual irregularities in women (47%), and weight gain (41%). CONCLUSIONS: Olanzapine, quetiapine, and risperidone demonstrated comparable effectiveness in early-psychosis patients, as indicated by similar rates of all-cause treatment discontinuation.     

Cognition, functioning and quality of life in schizophrenia treatment: results of a one-year randomized controlled trial of olanzapine and quetiapine

BACKGROUND: Cognitive deficits are recognized as a critical determinant of functional outcomes in schizophrenia; and second generation antipsychotic drugs have been touted for their potential to enhance cognitive functioning and community tenure. OBJECTIVES: The study examined the relative merits of olanzapine and quetiapine in improving cognitive deficits and enhancing psychosocial functioning in a sample of community dwelling adults previously treated with first generation antipsychotic drugs for schizophrenia. METHODS: In a prospective, rater-blinded study, 86 participants were randomized to receive either olanzapine or quetiapine, and assessed at baseline and after 3, 6, 9 and 12 months. Outcome measures included, besides symptoms and side effects rating scales, the subjective scale to investigate cognition in schizophrenia (SSTICS), a computer-assisted cognitive test battery (COGLAB), the sickness impact profile (SIP), the global assessment of functioning (GAF) scale, and the drug attitude inventory (DAI). RESULTS: Both olanzapine and quetiapine were equally effective in improving symptom severity and decreasing the neurological side effects. Quetiapine was significantly better tolerated (p=0.002), improved self-rated cognitive dysfunction (p=0.002) and subjects' performance on selected neurocognitive tasks (p=0.01). Olanzapine use was associated with greater symptom stability, fewer drop outs (p=0.01) and frequent metabolic aberrations (p=0.001). The accrued benefits of drug therapy, however, were not reflected as significant gains in daily functioning and quality of life. CONCLUSIONS: Quetiapine is noted to have specific cognition enhancing properties in schizophrenia that warrants further exploration. The observed clinical and cognitive benefits associated with quetiapine may likely be attributable to its loose binding to, and fast dissociation from the dopamine receptors. Olanzapine has proved to be a reliable antipsychotic drug with a greater liability to cause metabolic abnormalities.     

奥氮平与利培酮治疗首发精神分裂症对照研究

目的 比较奥氮平与利培酮治疗首发精神分裂症的疗效及不良反应。方法 随机将符合CCMD-2R精神分裂症的诊断标准70例患者进入奥氮平或利培酮组接受治疗,分别在治疗0、1、2、4、6、8周评定PANSS和TESS量表,在0、4、8周检查心脑电图和肝肾功能,在0、8周检查血催乳素和空腹血糖。结果 奥氮平与利培酮疗效相当,奥氮平能迅速减轻精神症状,其产生的不良反应少、严重程度轻,很少引起血催乳素变化;利培酮会显著提高血催乳素水平。结论 奥氮平对首发精神分裂症治疗安全有效。     

A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder

OBJECTIVE: The safety and efficacy of risperidone and olanzapine were compared in a double-blind trial that used doses widely accepted in clinical practice. METHOD: Subjects (N=377) who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomly assigned to receive 2-6 mg/day of risperidone (mean modal dose=4.8 mg/day) or 5-20 mg/day of olanzapine (mean modal dose=12.4 mg/day) for 8 weeks. RESULTS: The two study groups were similar at baseline except that the olanzapine group was slightly younger than the risperidone group. Seventy-five percent of the participants completed the trial, with no between-treatment differences in the proportion of dropouts. Similar proportions of the risperidone and olanzapine groups reported extrapyramidal symptoms (24% and 20%, respectively). Severity of extrapyramidal symptoms was low in both groups, with no between-group differences. Total Positive and Negative Syndrome Scale scores and scores on the five Positive and Negative Syndrome Scale factors were improved in both groups at week 8 (subjects who completed the study) and endpoint (all subjects, including dropouts). There were overall between-treatment differences in efficacy. Comparison of individual factors found no significant differences at endpoint; at week 8, however, improvements on Positive and Negative Syndrome Scale factors for positive symptoms and anxiety/depression were greater with risperidone than olanzapine. An increase in body weight of > or =7% was seen in 27% of olanzapine participants and 12% of risperidone participants. CONCLUSIONS: Both treatments were well tolerated and efficacious. The frequency and severity of extrapyramidal symptoms were similar in the two treatment groups. Greater reductions in severity of positive and affective symptoms were seen with risperidone than with olanzapine treatment among study completers. There was no measure on which olanzapine was superior. Greater weight gain was associated with olanzapine than with risperidone treatment.     

奎硫平与利培酮治疗精神分裂症的对照研究

目的验正奎硫平治疗精神分裂症的疗效及安全性。方法将121例精神分裂症患者随机分为奎硫平组（61例）与利培酮组（60例）,并进行对照研究,两药治疗剂量分别为200—800mg／d,2～5mg／d,疗程8周。采用阳性和阴性症状量表（PANSS）、简明精神病评定量表（BPRS）、治疗中出现的症状量表（TESS）进行评定及有关实验室检查。结果治疗结束时,两组PANSS和BPRS评分较入组时均显著减低（P〈0．01）,PANSS减分率奎硫平组为（65．7±28．1）,利培酮组为（66．4±27．3）,临床总有效率奎硫平组为70．5％,利培酮组为73．3％;两组疗效差异无显著性。奎硫平组的不良反应较利培酮组少,其中活动减少、震颤、扭转痉挛、静坐不能、口干、视物模糊、便秘、头晕的发生率显著少于利培酮组（P〈0．01或0．05）。结论国产奎硫平治疗精神分裂症的疗效与利培酮相当,部分不良反应较利培酮轻而少,是一种有效、耐受性较好的新型抗精神病药。     

Effects of olanzapine, quetiapine, and risperidone on neurocognitive function in early psychosis: a randomized, double-blind 52-week comparison

OBJECTIVE: The authors sought to compare the effects of olanzapine, quetiapine, and risperidone on neurocognitive function in patients with early psychosis. METHOD: In a 52-week double-blind, multicenter study, 400 patients early in the course of psychotic illness (<5 years) were randomly assigned to treatment with olanzapine (2.5-20 mg/day), quetiapine (100-800 mg/day), or risperidone (0.5-4 mg/day). The mean modal daily dose was 11.7 mg (SD=5.3) for olanzapine, 506 mg (SD=215) for quetiapine, and 2.4 mg (SD=1.0) for risperidone. A total of 224 patients completed neurocognitive assessments at baseline and at 12 weeks, and 81 patients also completed them at 52 weeks. Neurocognitive composite scores were calculated from the neurocognitive battery used in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and from the Brief Assessment of Cognition in Schizophrenia. RESULTS: At week 12, there was significant improvement in neurocognition for each treatment (p<0.01), but no significant overall difference between treatments. Composite z score improvements on the CATIE neurocognitive battery were 0.17 for olanzapine, 0.33 for quetiapine, and 0.32 for risperidone. Composite z score improvements on the Brief Assessment of Cognition in Schizophrenia were 0.19 for olanzapine, 0.34 for quetiapine, and 0.22 for risperidone. Statistically significant relationships between improvements in neurocognition and functional outcome were observed at weeks 12 and 52. CONCLUSIONS: Olanzapine, quetiapine, and risperidone all produced significant improvements in neurocognition in early-psychosis patients. Although cognitive improvements were modest, their clinical importance was suggested by relationships with improvements in functional outcome.     

奎的平与利培酮对精神分裂症认知功能的影响

目的 比较奎的平与利培酮对精神分裂症患者认知功能的影响。方法 将60例精神分裂症住院患者随机分为两组，并给予奎的平与利培酮治疗6周，于入组前及治疗结束时测查数字划销测验(CT)，修订韦氏记忆测验(WMS-RC)，威斯康星卡片分类测验(WCST)，分析两药对认知功能的影响。结果 两组治疗后WMS-RC测验的记忆商数均显著提高；奎的平组CT、WCST测验仅有部分项目成绩改善，利培酮组CT、WCST测验所有项目均改善显著。结论 两药对精神分裂症认知损害均有显著疗效，利培酮对注意、执行功能改善效果更明显。     

奎硫平与利培酮治疗精神分裂症对照研究

目的：评价奎硫平与利培酮治疗精神分裂症阴性症状的临床疗效与安全性。方法：对64例首次住院的以阴性症状为主的精神分裂症患者，随机分为两组，分别选用奎硫平或利培酮进行8周治疗，采用阳性症状与阴性症状量表(PANSS)评定疗效，用副反应量表(TESS)评定不良反应。结果：两药对精神分裂症阴性症状疗效相当，不良反应发生率及严重程度均相仿。结论：奎硫平与利培酮对精神分裂症阴性症状均有肯定的疗效，且安全性较高。     

Effects of olanzapine, risperidone and haloperidol on prepulse inhibition in schizophrenia patients: a double-blind, randomized controlled trial

Prepulse inhibition (PPI), whereby the startle eyeblink response is inhibited by a relatively weak non-startling stimulus preceding the powerful startle eliciting stimulus, is a measure of sensorimotor gating and has been shown to be deficient in schizophrenia patients. There is considerable interest in whether conventional and/or atypical antipsychotic medications can "normalize" PPI deficits in schizophrenia patients. 51 schizophrenia patients participated in a randomized, double-blind controlled trial on the effects of three commonly-prescribed antipsychotic medications (risperidone, olanzapine, or haloperidol) on PPI, startle habituation, and startle reactivity. Patients were tested at baseline, Week 4 and Week 8. Mixed model regression analyses revealed that olanzapine significantly improved PPI from Week 4 to Week 8, and that at Week 8 patients receiving olanzapine produced significantly greater PPI than those receiving risperidone, but not haloperidol. There were no effects of medication on startle habituation or startle reactivity. These results support the conclusion that olanzapine effectively increased PPI in schizophrenia patients, but that risperidone and haloperidol had no such effects. The results are discussed in terms of animal models, neural substrates, and treatment implications.     

奎硫平与利培酮治疗慢性精神分裂症研究

目的：比较奎硫平与利培酮对慢性精神分裂症的疗效和安全性。方法：将70例慢性精神分裂症患者随机分为两组,分别选用奎硫平或利培酮治疗,疗程8周。采用阳性与阴性症状量表（PANSS）及治疗中出现的症状量表（TESS）评定疗效和不良反应。结果：2药对慢性精神分裂症的疗效相当,不良反应发生率及严重程度均相仿。结论：奎硫平与利培酮治疗慢性精神分裂症均有肯定的疗效,且安全性高。     

奥氮平和利培酮治疗精神分裂症临床对照研究

目的比较奥氮平和利培酮对精神分裂症的治疗效果和安全性。方法以奥氮平与利培酮对120例精神分裂症患者进行为期6周的对照治疗,采用阳性和阴性症状量表（PANSS）评定疗效,用副反应量表（TESS）评定副反应。结果奥氮平组显效率76．7％,有效率95％;利培酮组显效率76．7％。有效率93％。奥氮平的主要副反应为嗜睡,利培酮的主要副反应为锥体外系反应。结论两药治疗精神分裂痘均有良好疗效．且安全性较高。     

奥氮平与利培酮治疗精神分裂症对照研究

目的:比较奥氮平与利培酮治疗精神分裂症的疗效和安全性。方法:将60例精神分裂症随机分两组,分别给予奥氮平与利培酮治疗8周。用阳性与阴性症状量表(PANSS)、治疗中出现的症状量表(TESS)评定疗效及不良反应。结果:奥氮平与利培酮的疗效差异无显著性。奥氮平主要不良反应是嗜睡、体质量增加,利培酮主要是锥外系反应、失眠。结论:奥氮平与利培酮均是治疗精神分裂症安全有效的非典型抗精神病药,可根据患者的情况分别选择。     

Switching to risperidone after unsuccessful treatment of olanzapine in the first-episode schizophrenia: an open trial

The purpose of this study was to assess the effect of switching to risperidone in the treatment of first-episode schizophrenia who had failed to respond to an initial-prescribed antipsychotic, olanzapine. Fifty-one patients with first-episode schizophrenia after unsuccessful treatment of olanzapine (the mean (S.D.) dosage: 16.4 (4.4) mg/day) were included in this switching study. Of the 51 patients, 43 (84.3%) completed the full 12-week trial and 8 (15.7%) dropped out. The mean dosage of risperidone at the endpoint (last observation) was 3.1 (2.0) mg/day. The total scores of Brief Psychiatric Rating Scales (BPRS) were significantly reduced from baseline to endpoint, especially in the positive and excitement factors (p<0.001). Responder rate (at least 20% decrease in BPRS total score plus final Clinical Global Impression score of 3 or less) was 35.3%. These findings indicate that the switching to risperidone could be one of the useful treatment options in this population.     

Double-blind, randomized comparison of olanzapine versus fluphenazine in the long-term treatment of schizophrenia

This study was undertaken to evaluate the efficacy and safety of olanzapine compared with fluphenazine in the treatment of patients who met the Diagnostic and Statistical Manual, fourth edition (DSM-IV) diagnostic criteria for schizophrenia or schizoaffective disorder. This was a long-term (22-week), randomized, double-blind, parallel clinical trial. Sixty patients (mean age, 35.4 years) were randomly assigned to either olanzapine (n=30) or fluphenazine (n=30). They received treatment at three centers in Croatia during a 22-week study period and were assessed weekly for the first 6 weeks and monthly thereafter. Efficacy was measured using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Rating Scale (PANSS) and the Clinical Global Impression (CGI) Severity and Improvement scores. The Hillside Akathisia Scale (HAS), Simpson-Angus Scale (SAS), Abnormal Involuntary Movement Scale (AIMS), vital signs, laboratory tests, and treatment-emergent adverse events were assessed to evaluate safety. The olanzapine group showed significantly greater mean decreases from baseline to endpoint for BPRS total (-25.8 vs. -16.5, P=.035), PANSS total (-45.7 vs. -29.5, P=.037), PANSS positive (-13.0 vs. -7.9, P=.034), and CGI Severity (-2.2 vs. -1.3, P=.031) scores. The olanzapine group showed greater mean decreases on all measures of extrapyramidal symptoms, significantly so for the SAS (-2.1 vs. 1.9, P=.004) and HAS (-3.4 vs. 2.6, P=.028). Patients in the fluphenazine group experienced a higher incidence of treatment-emergent adverse events (76.7% vs. 50.0%, P=.032). Weight gain was the most frequently reported adverse event in the olanzapine group (16.7% vs. 0.0%, P=.020). Akathisia (30.0% vs. 10.0%, P=.053) and insomnia (20.0% vs. 0.0%, P=.010) appeared most frequent in the fluphenazine group. Daily use of anticholinergics and benzodiazepines were both significantly greater for the fluphenazine group (P=.003 and.04, respectively). No significant changes were observed in vital signs, ECG, or clinical chemistry. The study indicates that olanzapine has advantages in both efficacy and safety compared to fluphenazine; however, the small sample size limits our ability to draw definitive conclusions.