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.     

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.     

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.     

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.     

The clinical course of depressive symptoms in schizophrenia

A sample of 31 schizophrenic patients free of anti-psychotic drugs was examined on admission to hospital. 14 (45%) exhibited depressed mood. The course of depressive symptoms and psychotic symptoms was followed weekly while the patients received increasing doses of haloperidol in a standardised regime. In 11 of the 14 patients there was a close correspondence between the course of depressive and psychotic symptoms, suggesting that in these cases, depression was an integral part of the schizophrenic illness. In the other three cases, clinical course of the various symptoms gave some support to the concepts of 'pharmacogenic' and 'post-psychotic depression', although it was not possible to choose between them.     

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.     

One-year double-blind study of the neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia

Neurocognitive deficits in schizophrenia can reach 1 to 2 standard deviations below healthy controls. The comparative effect of typical and atypical antipsychotic medications on neurocognition is controversial, and based primarily on studies with small samples and large doses of typical comparator medications. The present study assessed neurocognitive efficacy. It was hypothesized that olanzapine treatment would improve neurocognitive deficits to a greater degree than either risperidone or haloperidol treatment. This was a double-blind, randomized, controlled, parallel study with neurocognition assessed at baseline, and 8, 24, and 52 weeks. Per protocol, the haloperidol arm was discontinued. Four hundred and fourteen inpatients or outpatients with schizophrenia and schizoaffective disorder were treated with oral olanzapine (n = 159), risperidone (n = 158), or haloperidol (n = 97). Individual domains (executive function, learning and memory, processing speed, attention/vigilance, verbal working memory, verbal fluency, motor function, and visuospatial ability) were transformed into composite scores and compared between treatment groups. At the 52-week endpoint, neurocognition significantly improved in each group (p < 0.01 for olanzapine and risperidone, p = 0.04 for haloperidol), with no significant differences between groups. Olanzapine- and risperidone-treated patients significantly (p < 0.05) improved on domains of executive function, learning/memory, processing speed, attention/vigilance, verbal working memory, and motor functions. Additionally, risperidone-treated patients improved on domains of visuospatial memory. Haloperidol-treated patients improved only on domains of learning/memory. However, patients able to remain in treatment for the entire 52 weeks benefited more from olanzapine or risperidone treatment than haloperidol treatment.     

Weight gain over 4 months in schizophrenia patients: a comparison of olanzapine and risperidone

Weight gain frequently accompanies treatment with antipsychotics. In order to determine whether newer antipsychotic agents differ from each other with respect to weight gain, we compared two cohorts of patients with DSM-IV schizophrenia who had newly started treatment with either risperidone or olanzapine. After obtaining informed consent, data regarding body weight and height were culled from existing medical records of 100 patients (50 patients in each treatment group). Baseline body weight, close to the time of starting the new medication, and body mass index [BMI = weight (kg)/height (m) squared] were compared to the body weight and BMI following 4 months of treatment. There was no significant change in mean body weight or BMI in the group treated with risperidone (baseline weight = 83.1 kg +/- 20.5, follow-up = 82.8 kg +/- 19.9; matched pair t = 0.66, P = n.s.; baseline BMI = 29.6 +/- 9.4, follow-up = 29.5 +/- 9.1; matched pair t = 0.79, P = n.s.). However, in the group treated with olanzapine, there was a significant increase in both mean body weight and BMI (baseline weight = 84.9 kg +/- 25.0, follow-up = 87.1 kg +/- 25.1; matched pair t = 4.62, P < 0.001; baseline BMI = 29.5 +/- 7.4, follow-up = 30.3 +/- 7.5; matched pair t = 4.43, P < 0.001). In this naturalistic study, treatment with olanzapine was associated with a mean weight gain of about 2 kg from baseline, in patients with schizophrenia, while treatment with risperidone was associated with no mean weight change.     

Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison

BACKGROUND: Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant. The psychiatrist has a limited evidence base to guide treatment, particularly as there are no trials in children comparing atypical antipsychotics, the mainstay of current treatment. OBJECTIVE: To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious. DESIGN: Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up. SETTING: National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge. PATIENTS: Children and adolescents recruited nationally, aged 7 to 16 years, meeting unmodified DSM-IV criteria for schizophrenia, and resistant to treatment with at least 2 antipsychotics. INTERVENTIONS: After drug washout and a 1- to 3-week antipsychotic-free period, patients were randomized to treatment with clozapine (n = 12) or olanzapine (n = 13). MAIN OUTCOME MEASURES: The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms. RESULTS: Clozapine was associated with a significant reduction in all outcome measures, whereas olanzapine showed a less consistent profile of clinical improvement. While there were moderate to large differential treatment effects in favor of clozapine, these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline (P = .04; effect size, 0.89). Clozapine was associated with more overall adverse events. At 2-year follow-up, 15 patients were receiving clozapine with evidence of sustained clinical improvement, but additional adverse events emerged, including lipid anomalies (n = 6) and seizures (n = 1). CONCLUSIONS: While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia, the study suggests that clozapine has a more favorable profile of clinical response, which is balanced against more associated adverse events.     

Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: The authors evaluated the efficacy and safety of augmenting clozapine with risperidone in patients with treatment-resistant schizophrenia. METHOD: In a randomized, double-blind, placebo-controlled 12-week trial, 40 patients unresponsive or partially responsive to clozapine monotherapy received a steady dose of clozapine combined with either placebo (N=20) or up to 6 mg/day of risperidone (N=20). Patient psychopathology was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS), among other measures. Movement disorders were assessed with the Simpson-Angus Rating Scale. RESULTS: From baseline to week 6 and week 12, mean BPRS total and positive symptom subscale scores were reduced significantly in both groups, but the reductions were significantly greater with clozapine/risperidone treatment. Reductions in SANS scores were also significantly greater with clozapine/risperidone treatment than with clozapine/placebo. The adverse event profile for clozapine/risperidone treatment was similar to that for clozapine/placebo. Simpson-Angus Rating Scale scores were lower with clozapine/risperidone treatment throughout the trial but increased to approach those of clozapine/placebo treatment at week 12. Clozapine/risperidone treatment did not induce additional weight gain, agranulocytosis, or seizures compared with clozapine/placebo treatment. CONCLUSIONS: In patients with a suboptimal response to clozapine, the addition of risperidone improved overall symptoms and positive and negative symptoms of schizophrenia. The combination appears to be safe and well tolerated. Augmentation of clozapine with risperidone may provide additional clinical benefit for patients who are nonresponsive or only partially responsive to clozapine alone.     

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, flexible-dose, quasi-naturalistic comparison of quetiapine, risperidone, and olanzapine in the short-term treatment of schizophrenia: the QUERISOLA trial

This was a randomized, flexible-dose, rater-blind, parallel-group, quasi-naturalistic trial comparing the efficacy, safety, and tolerability of quetiapine, risperidone, and olanzapine in patients with schizophrenia hospitalized for severe psychotic symptoms. Seventy-five patients were randomized to quetiapine (n=25), risperidone (n=25), or olanzapine (n=25). Mean doses at Week 8 were: 590.0 mg/day quetiapine; 5.1 mg/day risperidone; 15.1 mg/day olanzapine. Four quetiapine, five risperidone, and five olanzapine patients discontinued prior to Week 8. There were no significant differences between groups in the primary efficacy measures of improvement from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 8 in the per protocol (PP) population and the number of completers who experienced >or=40% improvement on the same scale. PP and intent-to-treat analyses showed significant improvement from baseline in each component of a PANSS-derived battery, without significant differences between treatments. No quetiapine patients, one risperidone, and four olanzapine patients reported an adverse event (AE) of moderate intensity; no severe AEs were reported. A linear mixed model for repeated measures showed an effect of treatment on body weight, with significant differences favoring quetiapine over risperidone and olanzapine. Simpson-Angus Scale scores were significantly worse with risperidone compared with both olanzapine and quetiapine at Week 3 and compared with quetiapine thereafter. Use of concomitant medications for anxiety or tension was significantly less frequent with quetiapine. In conclusion, quetiapine, risperidone, and olanzapine have similar efficacy in schizophrenia, but there are drug-specific differences for some AEs and in the use of concomitant medication that differentiate these agents.     

The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.

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.     

米诺环素辅助治疗早期精神分裂症阴性症状的双盲、随机、对照研究

目的探讨米诺环素辅助治疗精神分裂症患者阴性症状的效果及耐受性。方法将92例符合《精神疾病诊断与统计手册》(DSM-IV)诊断标准、以阴性症状为主且单一利培酮治疗的精神分裂症患者随机分为米诺环素组(n=46)和安慰剂对照组(n=46),治疗周期为16周。于入组及出组时以阴性症状评定量表(SANS)、阳性和阴性症状量表(PANSS)评定疗效,使用静坐不能量表(Barnes)和锥体外系副反应量表(SAS)评定不良反应。结果米诺环素组在SANS分、PANSS阴性症状分、PANSS总分较安慰剂组相比,减分差异有统计学意义(P0.01);两组间在副反应发生率及脱落率比较差异无统计学意义(P0.05)。结论米诺环素可能有助于改善精神分裂症的阴性症状,且耐受性良好。     

米诺环素辅助治疗精神分裂症阴性症状的效果及对免疫因子的影响

目的探讨米诺环素辅助治疗精神分裂症阴性症状的效果及免疫学机制。方法将92例符合美国《精神疾病诊断与统计手册(第4版)》(DSM-IV)诊断标准、以阴性症状为主且单一利培酮治疗的精神分裂症患者随机分为米诺环素组(n=46)或安慰剂对照组(n=46),治疗周期为16周。于入组及出组时以阴性症状评定量表(SANS)、阳性和阴性症状量表(PANSS)评定疗效,测定治疗前后白介素1-β(IL-1β)、肿瘤坏死因子-α(TNF-α)、一氧化氮(NO)浓度变化。结果 PANSS阴性症状评分和总评分与安慰剂组相比,减分差异有统计学意义(P0.01);两组治疗前后除NO外其余两个因子的浓度变化均无统计学意义(P0.05)。结论米诺环素辅助治疗精神分裂症的阴性症状有效,但作用机制仍不明,是否通过抑制NO浓度的变化尚需进一步的研究。     

Effect of olanzapine and risperidone on subjective well-being and craving for cannabis in patients with schizophrenia or related disorders: a double-blind randomized controlled trial

OBJECTIVE: To examine whether subjective well-being and craving for cannabis were different in patients with schizophrenia or related disorders treated with either olanzapine or risperidone. METHOD: A 6-week, double-blind, randomized trial of olanzapine and risperidone was carried out in 128 young adults with recent onset schizophrenia or related disorders. Primary efficacy measures were the mean baseline-to-endpoint change in total scores on the Subjective Well-Being under Neuroleptics scale, the Obsessive-Compulsive Drug Use Scale, the Drug Desire Questionnaire, and the cannabis use self-report. An analysis of covariance was used to test between-group differences. RESULTS: Estimated D(2) receptor occupancy did not differ between olanzapine (n = 63) and risperidone (n = 65). Similar improvements in subjective well-being were found in both groups. In the comorbid cannabis-using group (n = 41, 32%), a similar decrease in craving for cannabis was found in both treatment conditions. CONCLUSIONS: Both olanzapine and risperidone were associated with improved subjective well-being. No evidence was found for a differential effect of olanzapine or risperidone on subjective experience or on craving for cannabis in dosages leading to comparable dopamine D(2) occupancy. Clinical Trial Registration Number: ISRCTN46365995.