The atypical antipsychotics risperidone,clozapine and olanzapine differ regarding their sedative potency in rats

The atypical antipsychotics risperidone, clozapine and olanzapine were studied for their ability to antagonise apomorphine-induced stereotypy and to affect electroencephalographic (EEG) activity in rats. The compounds antagonised apomorphine-induced stereotypy with ED(50)s of 0.15 mg/kg s.c. for risperidone, 0.42 mg/kg s.c. for olanzapine and 1.3 mg/kg s.c. for clozapine. At a dose close to that required for apomorphine antagonism (0.16 mg/kg s.c.), risperidone induced only minor changes in EEG power spectral activity. At a higher dosage (0.63 mg/kg s.c.) it increased the power density in the high frequency range (9.8-18.6 Hz), characteristic of a sedative-like effect. Olanzapine and clozapine caused a dose-dependent increase in power density in all frequency bands. These effects were already present at doses (0.04 and 0.16 mg/kg s.c., respectively) 10 times below those required for apomorphine antagonism. The effects increased dose-dependently and were pronounced at the doses required for apomorphine antagonism. These results in rats are in agreement with the clinical observation that risperidone has less propensity for inducing sedation at therapeutic dose levels than olanzapine and clozapine.     

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.     

Rehospitalization rates of chronically ill schizophrenic patients discharged on a regimen of risperidone, olanzapine, or conventional antipsychotics

OBJECTIVE: The purpose of this study was to compare the rehospitalization rates of patients discharged from the hospital while being treated with risperidone, olanzapine, or conventional antipsychotics. METHOD: By using Israel's National Psychiatric Hospitalization Case Registry, rehospitalization status was monitored for all patients with schizophrenia who were discharged from any inpatient psychiatric facility in Israel while taking risperidone (N=268) or olanzapine (N=313) between Jan. 1, 1998, and Dec. 31, 1998, and a group of patients discharged during that time who were treated with conventional antipsychotics (N=458). Time to readmission over the course of 2 years was measured by the product-limit (Kaplan-Meier) formula. RESULTS: The readmission rate for patients discharged while taking conventional antipsychotics was higher than the rates for patients treated with either risperidone or olanzapine. At 24 months, 67% of the risperidone-treated patients and 69% of the olanzapine-treated patients remained in the community, as compared to 52% of the patients treated with conventional antipsychotics. CONCLUSIONS: This study suggests that the rehospitalization rates of patients taking the novel antipsychotics risperidone and olanzapine are not different from each other and are considerably lower than the rate for patients treated with conventional antipsychotics. The results confirm findings of previous studies suggesting that the levels of overall effectiveness of risperidone and olanzapine are not very different and offers evidence that these drugs are more effective in preventing rehospitalization than conventional antipsychotic drugs.     

Improvement in cognitive function following a switch to ziprasidone from conventional antipsychotics, olanzapine, or risperidone in outpatients with schizophrenia

OBJECTIVE: To assess changes in cognitive function in stable outpatients with schizophrenia switched to ziprasidone from conventional antipsychotics (n = 108), olanzapine (n = 104), or risperidone (n = 58) because of suboptimal efficacy or poor tolerability. METHODS: In three separate 6-week trials, patients received ziprasidone 40 mg b.i.d. for 2 days, followed by 20-80 mg b.i.d. for the next 40 days. Before switching, and at endpoint, patients were evaluated with tests of working and secondary verbal memory, vigilance, visuomotor speed, verbal fluency, and executive functioning. Principal components factor analysis was performed to test for clustering of cognitive variables. RESULTS: Significant improvements were seen at endpoint in secondary verbal memory (in all three groups), vigilance (in patients switched from conventional antipsychotics or risperidone), executive function (in patients switched from conventional antipsychotics or risperidone), and verbal fluency. Factor analysis on baseline scores suggested reduction of the cognitive variables to three factors: verbal skills, attention and short-term memory, and executive functioning. Analysis of z-transformed mean change in factor scores showed significant improvement in verbal skills and global score following the switch from conventional antipsychotics, olanzapine, or risperidone. CONCLUSIONS: Patients requiring a change in antipsychotic therapy may exhibit cognitive improvement following a switch to ziprasidone.     

Newer antipsychotics and glucose metabolism: a comparison between olanzapine and risperidone

In order to estimate the degree of glucose tolerance impairment, oral glucose tolerance test was conducted in the group of 15 schizophrenic patients taking olanzapine, the group of 15 schizophrenic patients taking risperidone and in the group of 14 healthy volunteers. In the olanzapine group the tolerance was impaired in 33% of the patients, contrary to the risperidone group in which impairment amounted to 20% of the patients. The authors discuss possible mechanisms responsible for impaired glucose tolerance in patients taking newer antipsychotic drugs.     

Improvement in hyperprolactinemia and reproductive comorbidities in patients with schizophrenia switched from conventional antipsychotics or risperidone to olanzapine

This open-label, prospective, 4-month study in hyperprolactinemic patients with schizophrenia explored whether prolactin levels decrease after switching antipsychotic therapy to olanzapine. A secondary objective was to determine if reproductive morbidities and sexual dysfunction occurring with hyperprolactinemia improved with prolactin normalization. Clinically stable patients with schizophrenia, who had hyperprolactinemia defined as >18.8 ng/ml for males and >24.2 ng/ml for females, were randomized to: remain on current therapy (n=27) or switch to olanzapine, 5-20 mg/day, (n=27). Baseline prolactin levels in female patients randomized to receive olanzapine (n=14) were 66.3+/-38.7 ng/ml and were 82.0+/-37.6 (p=.32) in those remaining on their pre-study antipsychotic medication (n=14). In male patients, baseline prolactin levels were 33.7+/-12.1 and 33.5+/-13.8 ng/ml (p=.97), respectively, for those randomized to olanzapine (n=13) or remaining on pre-study treatment (n=13). At study end, patients switched to olanzapine experienced significant reductions in mean serum prolactin levels of 19.8+/-18.1 ng/ml in males (p=.02), and 32.3+/-47.5 ng/ml in females (p=.01), but prolactin continued to be elevated in patients who remained on pre-study antipsychotic treatment. After switching to olanzapine treatment, male patients experienced significantly (p=.03) increased free testosterone levels but there were no significant improvements in total testosterone levels; some female patients experienced improved menstrual cycling, as well as resolution of galactorrhea and gynecomastia, and sexual functioning was significantly improved in both genders. Patients switched to olanzapine, as well as those remaining on their pre-study medication, maintained clinical stability, their symptoms continued to improve, although there were no significant between-treatment differences in improvement. Treatment-emergent adverse events did occur in both treatment groups; however, they were not significantly different between groups. Olanzapine-treated patients experienced significantly lower eosinophil counts and higher elevations in low-density lipoproteins and standing blood pressure than non-switched patients. Olanzapine treatment may offer sustained reduction in serum prolactin and improvement in sexual and reproductive comorbid symptoms in patients with schizophrenia who have treatment-emergent hyperprolactinemia.     

Cost-effectiveness of risperidone,olanzapine, and conventional antipsychotic medications

To assess the cost and effectiveness of risperidone, olanzapine, and conventional antipsychotic medications under "usual practice" conditions in a large, public mental health system, 108 persons diagnosed with schizophrenia or schizoaffective disorder were randomly assigned to one of these three medication groups and followed prospectively over a 12-month period using standard instruments and procedures. Psychiatric medication costs increased more over time in both the olanzapine and risperidone groups than in the conventional medication group. Compliance with the prescribed medication was higher in the olanzapine group than in the conventional group. No differential effects by medication group were evident in this sample on the symptoms of schizophrenia, side effects, psychosocial functioning, time to discharge for index hospitalization, survival to initial rehospitalization, or client satisfaction with services. These results extend findings from previous efficacy and naturalistic studies in several ways but are limited chiefly by the small number of subjects who completed 6 to 12 months of the clinical trial, and the resulting power to detect differences in the statistical analyses.     

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.     

Differential effects of haloperidol, clozapine and olanzapine on learning and memory functions in mice

Many schizophrenic patients exhibit impairments in neurocognitive functions. Typical antipsychotic drugs such as haloperidol, have limited or even detrimental influence on cognitive functions. In contrast, atypical antipsychotic drugs, such as clozapine and olanzapine, may improve memory function in schizophrenics. However, only a few studies have been conducted to directly compare the effects of olanzapine, clozapine and haloperidol on memory functions in animal models. Thus, their effects on this issue were investigated in the present studies by using one-way step-through passive avoidance task and Morris water maze as models of learning and memory. The results showed that olanzapine did not affect acquisition, consolidation or retrieval process in step-through test. Moreover, it improved spatial learning function in mice in Morris water maze task. Clozapine and haloperidol appeared to impair acquisition process and consolidation process, respectively, in step-through test. Both drugs impaired spatial learning function in mice in Morris water maze task. The results suggested a positive implication for the clinical medication of olanzapine in schizophrenic treatment.     

Atypical antipsychotics and weight gain in Chinese patients: a comparison of olanzapine and risperidone

OBJECTIVE: To compare the effect of olanzapine with that of risperidone on weight change among Chinese patients in Hong Kong. METHOD: The body weight of subjects maintained on olanzapine or risperidone treatment was recorded at the outpatient clinic of a teaching hospital. Pretreatment weight of the subjects was retrieved from case records. Subjects on olanzapine treatment were matched in sex, age, and diagnosis with those on risperidone treatment, and demographic and clinical data were analyzed. The study was conducted in May and June 2002. RESULTS: Twenty-eight olanzapine-risperidone matched pairs were studied. All were diagnosed with DSM-IV schizophrenia. In patients treated with olanzapine and risperidone, respectively, mean +/- SD duration of treatment with atypical neuroleptics was 103.5 +/- 47.4 weeks and 93.2 +/- 50.6 weeks (range, 21-255 weeks), and mean doses were 12.4 +/- 6.7 mg/day and 4.5 +/- 2.8 mg/day. The mean +/- SD weight gain of subjects on treatment with olanzapine and risperidone, respectively, was 8.34 +/- 5.97 kg (18.53 +/- 13.27 lb) and 2.74 +/- 8.09 kg (6.09 +/- 17.98 lb) with a statistically significant difference at p < .005. Lower baseline body weight and body mass index were associated with greater weight gain in both olanzapine- and risperidone-treated subjects. Gender, age, mean daily dose, and duration of treatment had no effect on weight change. CONCLUSION: Treatment with olanzapine was associated with significantly greater weight gain than treatment with risperidone in Chinese schizophrenia patients in Hong Kong. The effect of adjunctive anticonvulsant treatment on weight gain requires further study.     

Neurocognitive effects of clozapine,olanzapine, risperidone,and haloperidol in patients with chronic schizophrenia or schizoaffective disorder

OBJECTIVE: Newer antipsychotic drugs have shown promise in ameliorating neurocognitive deficits in patients with schizophrenia, but few studies have compared newer antipsychotic drugs with both clozapine and conventional agents, particularly in patients who have had suboptimal response to prior treatments. METHOD: The authors examined the effects of clozapine, olanzapine, risperidone, and haloperidol on 16 measures of neurocognitive functioning in a double-blind, 14-week trial involving 101 patients. A global score was computed along with scores in four neurocognitive domains: memory, attention, motor function, and general executive and perceptual organization. RESULTS: Global neurocognitive function improved with olanzapine and risperidone treatment, and these improvements were superior to those seen with haloperidol. Patients treated with olanzapine exhibited improvement in the general and attention domains but not more than that observed with other treatments. Patients treated with risperidone exhibited improvement in memory that was superior to that of both clozapine and haloperidol. Clozapine yielded improvement in motor function but not more than in other groups. Average effect sizes for change were in the small to medium range. More than half of the patients treated with olanzapine and risperidone experienced "clinically significant" improvement (changes in score of at least one-half standard deviation relative to baseline). These findings did not appear to be mediated by changes in symptoms, side effects, or blood levels of medications. CONCLUSIONS: Patients with a history of suboptimal response to conventional treatments may show cognitive benefits from newer antipsychotic drugs, and there may be differences between atypical antipsychotic drugs in their patterns of cognitive effects.     

Differential effects of olanzapine, haloperidol and risperidone on calcitonin gene-related peptide in the rat brain

Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide which acts on central nervous system (CNS) neurons and is involved in activities related to dopamine. These effects of CGRP suggest that the peptide may have a role in pathophysiology and treatment of schizophrenia where dopaminergic system hypoactivity in the frontal cortex and hyperactivity in the subcortical structures have been demonstrated. In this study we measured by radioimmunoassay (RIA) the brain levels of CGRP-like immunoreactivity (CGRP-LI) in rats treated with either classical (haloperidol) or atypical (risperidone and olanzapine) antipsychotic drugs. Both haloperidol and risperidone decreased CGRP-LI in the striatum. Risperidone also decreased CGRP-LI in the occipital cortex. On the other hand, olanzapine increased CGRP-LI in the striatum, the frontal cortex and hypothalamus. The differential effects on CGRP could reflect a different profile of side effects and further suggest that CGRP is involved in CNS functions related to psychiatric disorders.     

The impact upon extra-pyramidal side effects,clinical symptoms and quality of life of a switch from conventional to atypical antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia

BACKGROUND: Atypical antipsychotics are commonly used in the management of schizophrenia in late life with evidence suggesting they induce lower rates of motor disturbance, but have similar efficacy to conventional antipsychotics. Trials in the elderly have been either retrospective, small, of short duration or of a single-arm design. AIMS: To demonstrate the effects upon motor side-effects, efficacy, safety and quality of life (QOL) of switching elderly patients with schizophrenia from conventional antipsychotics to olanzapine or risperidone. METHODS: Elderly patients with schizophrenia were randomly allocated to olanzapine or risperidone and followed through an open-label crossover period. Between and within group intention to treat analyses were conducted. RESULTS: 66 patients were randomised (mean age 69.6 [SD +/- 6.2]). Four (11.8%) patients on olanzapine and 8 (26.7%) patients on risperidone failed to complete the crossover because of treatment failure [Odds Ratio (OR) = 2.73[0.73-10.2] p = 0.14]. The mean doses upon completion of switching in each arm were 9.9 mg (SD = 4.2) and 1.7 mg (SD = 1.2) for olanzapine and risperidone respectively. In both arms there was improvement in Parkinsonism, though only olanzapine was associated with a reduction in dyskinetic symptoms. The Brief Psychiatric Rating Scale, Scale for the assessment of Negative Symptoms and Montgomery and Asberg Depression Rating Scale scores all improved through the crossover period in both arms with no between group differences. Treatment with olanzapine was associated with a better response over risperidone on the psychological domain of the World Health Organisation-Quality Of Life [Brief] (WHO-QOL-BREF) scale ( p = 0.02). Patients in the olanzapine arm also demonstrated improvement from baseline in the WHO-QOL-BREF physical, psychological and health satisfaction domains, but risperidone had no effect on any Quality of Life (QOL) measure. CONCLUSIONS: After switching from a conventional antipsychotic, olanzapine and risperidone were associated with improvement in core symptoms of schizophrenia and motor side effects. Subjects switched to olanzapine were more likely to complete the switching process and show an improvement in psychological QOL.     

Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia.

OBJECTIVE: This study compared the specific antiaggressive effects of clozapine with those of olanzapine, risperidone, and haloperidol. METHODS: A total of 157 inpatients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a double-blind 14-week trial. The trial was divided into two periods: eight weeks during which the dosage was escalated and then fixed, and six weeks during which variable dosages were used. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the items that reflect positive symptoms of schizophrenia (delusions, suspiciousness or feelings of persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinations) and the sedation item of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). RESULTS: Patients differed in their treatment response as measured by the hostility item of the PANSS. The scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone. The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on other PANSS items that reflect delusional thinking, a formal thought disorder, or hallucinations and independent of sedation as measured by the NOSIE. Neither risperidone nor olanzapine showed superiority to haloperidol. CONCLUSION: Clozapine has a relative advantage over other antipsychotics as a specific antihostility agent.     

奥氮平替换利培酮对催乳素及糖脂代谢的影响

目的探讨用奥氮平替换利培酮治疗精神分裂症后,催乳素水平及糖脂代谢的变化。方法对52例服用利培酮治疗的精神分裂症患者换为奥氮平治疗8周。于基线及换药后第8周测空腹催乳素、胰岛素、血糖、甘油三酯、胆固醇、脂蛋白及体重。结果换用奥氮平8周后,催乳素水平显著下降,胰岛素、甘油三酯、栽脂蛋白A1、载脂蛋白B水平均显著升高,体重显著增加（均P〈0．05）。总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇水平略有升高,空腹血糖略有下降,但差异均无统计学意义（均P〉0．05）。结论奥氮平替换治疗能够明显的改善利培酮所致的高催乳素血症,但也可能会引起脂代谢异常。     

A naturalistic comparison of clozapine, risperidone, and olanzapine in the treatment of bipolar disorder

BACKGROUND: Our purpose was to evaluate the overall efficacy and tolerability of novel antipsychotic medications for patients with bipolar disorder type I. METHOD: A retrospective study of the Massachusetts General Hospital Bipolar Clinic database was carried out to identify 50 consecutive treatment trials in patients with DSM-IV bipolar disorder type I who had received adjunctive treatment with risperidone, olanzapine, or clozapine, along with standard mood stabilizers. The treatment charts of those patients (N = 42) were reviewed for details of adverse effects, tolerability, and efficacy of medication. RESULTS: Overall results indicated equivalent efficacy in novel antipsychotic treatments according to change in Clinical Global Impressions scale score. Levels of extrapyramidal symptoms were similar in all groups and occurred in 12/42 patients (28.6%). Prolactin-related side effects were not observed in any patients. There were no cases of affective switch or worsening of mania. Substantial weight gain of more than 10 lb (4.5 kg) was significantly greater in patients treated with olanzapine. CONCLUSION: These results suggest that the efficacy and tolerability of risperidone, olanzapine, and clozapine are similar in patients with bipolar disorder. One major differentiation factor of these drugs appears to be weight gain, particularly between olanzapine and risperidone. This may, in part, also be related to the need to use mood-stabilizing agents, like lithium or divalproex sodium, which may potentiate the weight-gain effect of novel antipsychotics.     

Prevalence and outcomes of pharmaceutical industry-sponsored clinical trials involving clozapine, risperidone, or olanzapine.

OBJECTIVE: The literature continues to highlight the debate on the ethics and merits of trials sponsored by the pharmaceutical industry. This study attempts to determine the prevalence and outcomes of industry-sponsored trials involving clozapine, risperidone, or olanzapine. METHODS: We searched the literature from January 1, 1990, to December 31, 2001, to capture all eligible clinical trials involving clozapine, risperidone, or olanzapine. The primary outcome measured was the clinical outcome of industry-sponsored studies. Secondary outcome measures included the following parameters: disclosure of any sponsorship and financial support, author(s) employed by the industry, use of comparator drug(s) within the trial, sample size, blinding, and use of placebo. RESULTS: The database comprised 372 articles. Of these trials, 124 (33.3%) were sponsored by the pharmaceutical industry. In general, trials sponsored by Eli Lilly or Janssen had better research design than trials not funded by the pharmaceutical industry. With regard to authorship, more trials funded by Eli Lilly (74.6%) were coauthored by an employee of the company, compared with trials funded by either Janssen (23.3%) or Novartis/Sandoz (5.6%). Further, more trials sponsored by Eli Lilly reported positive outcomes (92.1%), compared with Janssen-sponsored trials (88.4%) and Sandoz/Novartis-sponsored trials (72.2%). No negative results were reported in any of the industry-funded trials. CONCLUSIONS: One-third of the published clinical trials involving clozapine, risperidone, or olanzapine were funded by their respective manufacturer. The reported outcomes of the sponsored trials highly favour the manufacturer's product.