Overt aggression and psychotic symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol

The subjects were 157 treatment-resistant inpatients diagnosed with chronic schizophrenia or schizoaffective disorder. They were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol in a 14-week, double-blind trial. Incidents of overt aggression were recorded and their severity was scored. The Positive and Negative Syndrome Scale was administered. Atypical antipsychotics showed an overall superiority over haloperidol, particularly after the first 24 days of the study when the dose escalation of clozapine was completed. Once an adequate therapeutic dose of clozapine was reached, it was superior to haloperidol in reducing the number and severity of aggressive incidents. Patients exhibiting persistent aggressive behavior showed less improvement of psychotic symptoms than the other patients. There was an interaction between aggressiveness, medication type, and antipsychotic response: risperidone and olanzapine showed better antipsychotic efficacy in patients exhibiting less aggressive behavior; the opposite was true for clozapine. Clozapine appears to have superior antiaggresive effects in treatment-resistant patients; this superiority develops after the patient has been exposed to an adequate dose regimen.     

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms. Additional fluvoxamine, at the dose of 100 mg/day, was administered for 4 weeks to patients stabilized on risperidone (3-6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidone and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administration with fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initial fluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of five subjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developed extrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone.     

利培酮与氯氮平治疗精神分裂症对照研究

目的比较利培酮和氯氮平治疗精神分裂症的疗效和不良反应。方法将40例精神分裂症患者随机分成两组,利培酮组和氯氮平组各20例,于治疗前和治疗第2、4、6周末采用症状量表（PANSS）及副反应量表（TESS）评定疗效及不良反应。结果两组PANSS减分率比较差异无统计学意义（P〉0．05）,利培酮组不良反应少。结论利培酮与氯氮平治疗精神分裂症疗效相当,但利培酮不良反应少。     

利培酮与氯氮平治疗精神分裂症对照研究

目的 比较利培酮和氯氮平治疗精神分裂症的疗效和不良反应.方法 将40例精神分裂症患者随机分成两组,利培酮组和氯氮平组各20例,于治疗前和治疗第2、4、6周末采用症状量表(PANSS)及副反应量表(TESS)评定疗效及不良反应.结果 两组PANSS减分率比较差异无统计学意义(P>0.05),利培酮组不良反应少.结论 利培酮与氯氮平治疗精神分裂症疗效相当,但利培酮不良反应少.     

Comparison of neuropsychological effects of adjunctive risperidone or quetiapine in euthymic patients with bipolar I disorder

Although associations between antipsychotic use and neuropsychological impairment in bipolar I disorder have been observed, there is a lack of studies comparing the effects of specific agents used in this population. We compared performance between patients receiving maintenance treatment with mood stabilizer monotherapy (n=15), adjunctive risperidone (n=15) or quetiapine (n=17), and a group of demographically matched healthy controls (n=28) on tests of executive function (working memory, set shifting, and inhibition) and verbal learning. Despite having a similar clinical profile, patients being treated with risperidone showed significantly impaired working memory, set-shifting, and verbal learning (P<0.05) compared with those either on mood stabilizer monotherapy or adjunctive quetiapine. Although randomized controlled trials are required to confirm the cognitive side effects of medications prescribed for maintenance treatment of bipolar I disorder, preliminary results indicate that addition of risperidone to a mood stabilizer has a negative impact on executive function and verbal learning, an effect not shared with quetiapine.     

Cardiovascular variability during treatment with haloperidol, olanzapine or risperidone in recent-onset schizophrenia

This study aimed to investigate the effects of treatment with haloperidol, olanzapine and risperidone on cardiovascular variability in patients with recent-onset schizophrenia by means of spectral analysis. Unmedicated patients (n = 18) had a higher mean heart rate and a tendency for a lower high-frequency power of heart rate variability than healthy control subjects (n = 57), indicating a decreased cardiac vagal control in unmedicated patients with schizophrenia. Patients treated with haloperidol (n = 10) showed significantly lower low-frequency power of heart rate and systolic blood pressure variability compared with olanzapine-treated patients, suggesting that haloperidol attenuated sympathetic functioning. On the contrary, olanzapine-treated patients (n = 10) showed the highest power in the low-frequency range of heart rate and systolic blood pressure variability, suggesting an increased sympathetic cardiac functioning. No significant effects of risperidone (n = 13) were found. None of the antipsychotic agents differed in their parasympathetic cardiovascular effects. We conclude that young, unmedicated patients with schizophrenia differed from controls in their parasympathetic functioning, but the antipsychotic agents haloperidol, risperidone and olanzapine induced only minor cardiovascular side effects.     

喹硫平或奥氮平联合丙戊酸钠缓释片治疗维族双相障碍精神病的疗效研究

目的 探讨喹硫平、奥氮平联合丙戊酸钠缓释片对维族双相障碍精神病临床疗效的影响。方法 选择2015年6月—2016年6月在乌鲁木齐市第四人民医院治疗双相障碍精神病的患者100例,随机分为2组,每组50例,对照组患者服用奥氮平联合丙戊酸钠缓释片,观察组患者服用喹硫平联合丙戊酸钠缓释片,服药1、4、8周时患者于医院进行复查,填写17项HMDM评分表、BRMD评分表以及GSI-IS评分表评估两组患者在不同时间的抑郁、躁狂情况和临床疗效。结果 两组患者在治疗期间,临床症状减轻,治疗1、4、8周时HMDM评分、BRMD评分以及GSI-IS评分均显著低于治疗前（P＜0.05）,且随疗程的延长,症状趋于减轻甚至消失;观察组各量表评分比对照组低,但是统计学分析无显著差异。记录两组患者治疗过程中发生不良反应的情况,结果显示观察组患者不良反应的总发生率和头晕嗜睡的发生率较对照组明显降低（P＜0.05）。结论 奥氮平或喹硫平联合丙戊酸钠缓释片可以有效控制维族双相障碍患者抑郁、躁狂症状,且奥氮平联合丙戊酸钠缓释片可以显著降低不良反应发生率,值得临床推广应用。     

Serum ghrelin concentrations in patients receiving olanzapine or risperidone

Rationale Although enhanced appetite and weight gain are potential side effects of treatment with antipsychotic agents, particularly olanzapine and clozapine, the mechanism is poorly understood.Objectives To test the hypothesis that ghrelin, a gastrointestinal hormone that enhances appetite, is involved in increased food intake and weight gain during treatment with antipsychotics.Methods Serum ghrelin concentrations were investigated in schizophrenic patients receiving olanzapine or risperidone, and in healthy volunteers.Results Serum ghrelin concentrations did not increase, but rather decreased, in patients treated with olanzapine or risperidone in comparison with healthy volunteers. No significant difference was found in serum ghrelin concentration between patients treated with olanzapine and risperidone.Conclusions Our results indicate that ghrelin is not a direct cause of increased food intake and weight gain during treatment with olanzapine or risperidone, whereas ghrelin is associated with metabolic change in patients receiving these agents.     

Effect of open-label lamotrigine as monotherapy and adjunctive therapy on the self-assessed cognitive function scores of patients with bipolar I disorder

Cognitive deficits in patients with bipolar disorder are likely to impair occupational and social functioning. In a post hoc analysis of data from a prospective, open-label study of lamotrigine in 1175 patients 13 years or older with bipolar I disorder, changes in the self-rated cognitive function scores of patients receiving lamotrigine as monotherapy or as adjunctive therapy were evaluated. Lamotrigine was given for 12 weeks, with a target dosage of 200 mg/d. Cognitive function was assessed at baseline and week 12 with the self-rated Medical Outcomes Study Cognitive (MOS-Cog) Scale. Mean MOS-Cog scores improved significantly from baseline in the overall group (+8.4 +/- 22.55 points, P < 0.0001) and in subgroups of patients receiving and not receiving concomitant valproate, antidepressants, or antipsychotics. Patients receiving lamotrigine and not receiving concomitant antipsychotics, however, exhibited a small but significantly greater degree of improvement than patients who were receiving concomitant antipsychotics (adjusted mean difference = 4.05; 95% confidence interval, 1.30-6.81; P = 0.0039). Statistically significant improvement was seen in patient subgroups with a depressive (mean change from baseline, 8.8 +/- 21.97; P < 0.0001) or a manic (mean change from baseline, 7.5 +/- 22.62; P = 0.0007) index episode. Improvements in MOS-Cog scores significantly correlated with improvement in both depressive (correlation coefficient, -0.339; P < 0.0001) and manic (correlation coefficient, -0.151; P < 0.0001) symptoms. Overall, self-rated cognitive function scores improved during open-label lamotrigine therapy in patients with bipolar I disorder whether or not they were receiving concomitant valproate, antidepressants, or antipsychotics. Additional research is needed to explore the clinical relevance of these findings.     

Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.

This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n = 249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p = 0.020) and PANSS positive scale scores (p = 0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.     

Simultaneous high-performance liquid chromatographic determination of olanzapine and lamotrigine in plasma of bipolar patients

An original method based on the use of high-performance liquid chromatography with both coulometric and diode array detection has been developed for the therapeutic drug monitoring of patients with bipolar disorders being treated with olanzapine and lamotrigine. Chromatographic separation was achieved on a reversed-phase C8 column (150 x 4.6 mm internal diameter, 5 microm) using a mobile phase composed of methanol (27%) and a 50.0 mmol/L, pH 3.5 phosphate buffer (73%). For the analysis of olanzapine and its main metabolite, N-desmethylolanzapine, a coulometric detector was used, with electrode 1 set at -200 mV and electrode 2 at +500 mV. Lamotrigine was determined using a diode array detection at 220 nm. The two detectors were connected in series. For the analysis of biological samples, a clean-up procedure was implemented by means of solid-phase extraction using phenyl cartridges and eluting the analytes with methanol; only a small volume of plasma (150 microL) was needed to analyze both olanzapine and lamotrigine. Linear responses were obtained between 0.1 and 50.0 ng mL(-1) for olanzapine, 0.1 and 25.0 ng mL(-1) for N-desmethylolanzapine, and between 0.25 and 10.0 microg mL(-1) for lamotrigine. The extraction yield values were always higher than 90% for all the analytes, with precision (expressed as relative standard deviation values) lower than 3.4%. The method was applied successfully to some human plasma samples drawn from bipolar patients undergoing combined therapy with the two drugs. Satisfactory values for accuracy were obtained, with mean recovery higher than 91%. Thus, the method appears suitable for the investigation of the chemical-clinical correlations in patients receiving therapy with olanzapine and lamotrigine.     

A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia

Cognitive impairment is a core feature of schizophrenia and a major impediment to social and vocational rehabilitation. A number of studies have claimed cognitive benefits from treatment with various atypical antipsychotic drugs (APDs). The currently available evidence supporting cognitive improvement with atypical APDs was evaluated in two meta-analyses. Studies that (1) prospectively examined cognitive change to the atypical APDs clozapine, olanzapine, quetiapine, and risperidone, (2) included a commonly used neuropsychological test, and (3) provided data from which relevant effect sizes could be calculated, were included. Forty-one studies met these criteria. Neuropsychological test data from each study were combined into a Global Cognitive Index and nine cognitive domain scores. Two meta-analyses were carried out. The first included 14 controlled, random assignment trials that assigned subjects to an atypical APD and a typical APD control arm. The second analysis included all prospective investigations of atypical treatment and the within-group change score divided by its standard deviation served as an estimate of effect size (ES). The first analysis revealed that atypicals are superior to typicals at improving overall cognitive function (ES=0.24). Specific improvements were observed in the learning and processing speed domains. The second analysis extended the improvements to a broader range of cognitive domains (ES range=0.17-0.46) and identified significant differences between treatments in attention and verbal fluency. Moderator variables such as study blind and random assignment influence results of cognitive change to atypical APDs. Atypical antipsychotics produce a mild remediation of cognitive deficits in schizophrenia, and specific atypicals have differential effects within certain cognitive domains.     

Probabilistic classification and gambling in patients with schizophrenia receiving medication: comparison of risperidone, olanzapine, clozapine and typical antipsychotics

Rationale

We have previously shown that patients with schizophrenia treated with typical antipsychotics were impaired on the weather prediction probabilistic classification learning (PCL) task that relies on striatal function, and that similar patients treated with atypical antipsychotics were impaired on the Iowa gambling task (IGT) that depends on medial prefrontocortical function.

Objectives

We tested the hypothesis that test performance of patients treated with risperidone will be more similar to those treated with typical rather than atypical antipsychotics.

Results

Groups of schizophrenia patients treated with risperidone, olanzapine, clozapine or typical antipsychotics did not differ on the Positive and Negative Syndrome Scale or the Mini Mental State Exam (MMSE) but scored lower than controls on the MMSE. For the PCL task, patients treated with clozapine improved over trials while those treated with typical antipsychotics, olanzapine, or risperidone did not. For the IGT, patients treated with typical antipsychotics or risperidone improved over trials while those treated with clozapine or olanzapine did not.

Conclusions

Results generally supported the hypothesis that patients treated with risperidone perform more like those treated with typical antipsychotics than those treated with other atypical antipsychotics.     

Cross-sectional comparison of fasting lipids in normoglycemic patients with schizophrenia during chronic treatment with olanzapine, risperidone, or typical antipsychotics

We compared fasting lipids and other metabolic parameters in 211 normoglycemic patients meeting the DSM-IV diagnosis of schizophrenia or schizoaffective disorder undergoing continuous treatment with olanzapine, risperidone, or typical antipsychotics for at least 1 year. Blood samples were obtained after an 11-hour (+/-1 h) observed fast. Olanzapine-treated patients had significantly higher mean fasting triglyceride levels (2.3 +/- 1.8 mmol/L) than risperidone- (1.7 +/- 0.9 mmol/L, P = 0.022), but not typical antipsychotic-treated patients (1.8 +/- 1 mmol/L). There were no significant differences in total low-density (LDL-C) or high-density lipoprotein cholesterol levels. Apolipoprotein-B and very low density lipoprotein cholesterol levels were significantly higher in the olanzapine- versus risperidone-treated patients, but there were no significant differences between olanzapine- and typical antipsychotic-treated patients. Treatment groups did not differ significantly in LDL particle size, the prevalence of an "atherogenic" lipid profile, or estimated insulin sensitivity. Although interpretation of this study is limited by the cross-sectional study design, it provides additional insight concerning the relationship between antipsychotic use and plasma lipid parameters in this population.     

奥氮平、利培酮及阿立哌唑治疗慢性精神分裂症患者认知功能损害的疗效观察

目的：探讨奥氮平、利培酮及阿立哌唑治疗慢性精神分裂症患者认知功能损害的疗效观察。方法对93例慢性精神分裂症患者随机分为奥氮平组、利培酮组及阿立哌唑组各31例,分别给予奥氮平、利培酮及阿立哌唑进行治疗,比较3组患者认识功能。结果阿立哌唑组患者分类完成、言语流畅、记忆力及显性判断方面的表现明显优于其它2组（P ＜0．05）,3组患者持续错误的比较差异无显著性（P ＞0．05）;奥氮平组患者与利培酮组患者认知功能比较差异无显著性（P ＞0．05）。结论奥氮平、利培酮及阿立哌唑对精神分裂症患者分类完成、持续错误、言语流畅、记忆力及线性判断方面的作用不同,阿立哌唑对患者认知功能的改善更为显著。     

Lack of a pharmacokinetic interaction between mirtazapine and the newer antipsychotics clozapine, risperidone and olanzapine in patients with chronic schizophrenia.

The effect of mirtazapine on steady-state plasma concentrations of the newer atypical antipsychotics clozapine, risperidone and olanzapine was investigated in 24 patients with chronic schizophrenia. In order to treat residual negative symptoms, additional mirtazapine (30 mg per day) was administered for six consecutive weeks to nine patients stabilized on clozapine therapy (200-650 mg per day), eight on risperidone (3-8 mg per day) and seven on olanzapine (10-20mg per day). There were only minimal and statistically insignificant changes in mean plasma concentrations of clozapine and its metabolite norclozapine, risperidone and its metabolite 9-hydroxyrisperidone, and olanzapine during the study period. Mirtazapine co-administration with either clozapine, risperidone or olanzapine was well tolerated. In the overall sample, a slight improvement in negative symptomatology, as assessed by the Scale for Assessment of Negative Symptoms, was observed at final evaluation (P<0.01) and six patients (two in each treatment group) were classified as responders. While double-blind, controlled studies are needed to evaluate the potential clinical benefits of mirtazapine in chronic schizophrenia, our findings indicate that mirtazapine has a negligible effect on the metabolism of clozapine, risperidone and olanzapine and can be added safely to an existing treatment with these antipsychotics.     

Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone

A post hoc analysis of the SPECTRUM trial was carried out to evaluate whether the improvements in efficacy and tolerability gained on switching to quetiapine occurred consistently for patients previously treated with either: haloperidol (n = 43); olanzapine (n = 66); or risperidone (n = 55) monotherapy. Patients were initiated with quetiapine to 400 mg/day over 7 days, and then flexibly dosed (300-750 mg/day) for 11 weeks. The mean (SD) modal dose of quetiapine was 501 (138) mg/day in the haloperidol subgroup, 472 (147) mg/day in the olanzapine subgroup and 485 (141) mg/day in the risperidone subgroup at the study endpoint. Switching to quetiapine induced significant improvements from baseline in PANSS scores, with least square mean changes in total scores of -32.5, -15.4, and -18.5 for patients previously treated with haloperidol, olanzapine and risperidone, respectively, (all p < 0.001 vs baseline). Significant improvements were also noted in CDSS scores, particularly for patients clinically depressed at baseline (all p < 0.001 vs baseline). There were significant reductions in EPS on the SAS and BAS for all subgroups (all p < 0.001 vs baseline). Switching to quetiapine produced efficacy and tolerability benefits regardless of whether their previous antipsychotic was haloperidol, olanzapine or risperidone.