A pharmaco-EEG study on antipsychotic drugs in healthy volunteers

RATIONALE: Both psychotropic drugs and mental disorders have typical signatures in quantitative electroencephalography (EEG). Previous studies found that some psychotropic drugs had EEG effects opposite to the EEG effects of the mental disorders treated with these drugs (key-lock principle). OBJECTIVES: We performed a placebo-controlled pharmaco-EEG study on two conventional antipsychotics (chlorpromazine and haloperidol) and four atypical antipsychotics (olanzapine, perospirone, quetiapine, and risperidone) in healthy volunteers. We investigated differences between conventional and atypical drug effects and whether the drug effects were compatible with the key-lock principle. METHODS: Fourteen subjects underwent seven EEG recording sessions, one for each drug (dosage equivalent of 1 mg haloperidol). In a time-domain analysis, we quantified the EEG by identifying clusters of transiently stable EEG topographies (microstates). Frequency-domain analysis used absolute power across electrodes and the location of the center of gravity (centroid) of the spatial distribution of power in different frequency bands. RESULTS: Perospirone increased duration of a microstate class typically shortened in schizophrenics. Haloperidol increased mean microstate duration of all classes, increased alpha 1 and beta 1 power, and tended to shift the beta 1 centroid posterior. Quetiapine decreased alpha 1 power and shifted the centroid anterior in both alpha bands. Olanzapine shifted the centroid anterior in alpha 2 and beta 1. CONCLUSIONS: The increased microstate duration under perospirone and haloperidol was opposite to effects previously reported in schizophrenic patients, suggesting a key-lock mechanism. The opposite centroid changes induced by olanzapine and quetiapine compared to haloperidol might characterize the difference between conventional and atypical antipsychotics.     

Differential rates of treatment discontinuation in clinical trials as a measure of treatment effectiveness for olanzapine and comparator atypical antipsychotics for schizophrenia

Antipsychotic treatment discontinuation can be used to measure overall treatment effectiveness. Our goal was to investigate differential treatment discontinuation comparing olanzapine with other atypical antipsychotics. A post hoc pooled analysis of 4 randomized, double-blind, 24- to 28-week schizophrenia clinical trials included 822 olanzapine-treated and 805 risperidone-, quetiapine-, or ziprasidone-treated patients. A checklist was used to record the reason for discontinuation. Treatment differences were assessed between olanzapine and the other 3 antipsychotics combined. Poor response/symptom worsening was the primary reason for discontinuation, regardless of medication. The rate of discontinuation due to poor response/symptom worsening significantly varied by treatment (olanzapine, 14.23%, vs. other atypical antipsychotics, 24.60%; P < 0.0001). The rate of discontinuation due to intolerability of medication did not significantly vary by treatment (olanzapine, 5.60%, vs. other atypical antipsychotics, 7.45%; P = 0.13). Consequent to the differential rates of discontinuation due to poor response/symptom worsening, the olanzapine-treated patients experienced a significantly greater likelihood of overall treatment completion (53.9% vs. 39.3%; P < 0.001) and a significantly longer duration of treatment (19.1 vs. 16.1 weeks; P < 0.0001) than other atypical-treated patients. The predominant reason for the significantly lower discontinuation rate of treatment for patients taking olanzapine compared with that of patients taking other atypical antipsychotics was the significantly higher dropout rates in other atypical antipsychotics because of poor response/symptom worsening.     

Subjective response to antipsychotics of schizophrenia patients treated in routine clinical practice: a naturalistic comparative study

In routine practice, subjective response to antipsychotics is becoming a critical outcome measure among schizophrenia patients. This study sought to compare subjective response to atypical (risperidone and olanzapine) and typical antipsychotic drugs. Using a naturalistic cross-sectional design, we examined subjective response to antipsychotics (satisfaction with medication and subjective tolerability), psychopathology, side effects, emotional distress, and awareness in schizophrenia patients stabilized on atypical (n = 78) and typical (n = 55) drugs. Analysis of variance and multiple regression analysis were applied. We found that atypical drugs were superior to typical antipsychotics in both measures of subjective response, which were positively correlated (r = 0.52, P < 0.001). Poor subjective response was associated with severity of emotional distress, negative, and activation symptoms in the atypical group and with extrapyramidal side effects and positive symptoms in the typical group. Awareness of treatment is a positive factor that accounted for 20% and 34% of variation in the subjective responses to atypical and typical antipsychotic drugs, respectively. Demographic variables, age of onset, illness duration, and adjunctive drugs did not relate significantly to subjective response to antipsychotic drugs. Thus, atypical drugs are characterized by better subjective response compared with typical antipsychotics; their determinants differed considerably. Satisfaction with medication together with subjective tolerability needs to be considered in clinical trials.     

非典型抗精神病药治疗700例精神分裂症住院患者的应用分析

目的：了解我院精神分裂症住院患者非典型抗精神病药的应用现状,探讨临床使用非典型抗精神病药的特点。方法：随机抽查本院2008年住院的700例诊断为精神分裂症患者应用非典型抗精神病药,采用WHO药物统计合作中心设定的限定日剂量（DDD）计算我院非典型抗精神病药的用药频度（DDDs）、药物利用指数（DUI）及联合用药情况。结果：非典型抗精神病药的DDDs排序为：喹硫平、利培酮、氯氮平、阿立哌唑、齐拉西酮、奥氮平。单一药物治疗496例,占70.86%;二联或三联用药204例,占29.14%。DUI≤1。结论：我院非典型抗精神病药用药结构倾向合理。对于精神分裂症的临床治疗应以单一药物治疗为主。     

我院2010-2012年住院患者抗精神病药物使用分析

目的：了解本院住院患者抗精神病药品的使用情况及发展趋势,为临床合理用药提供参考.方法：采用回顾性方法,对本院2010-2012年度住院患者抗精神病药物的销售金额、用药频度（DDDs）和日均费用（DDDc）等情况进行统计分析.结果：本院住院患者抗精神病药物销售金额和用药频度整体呈逐年上升趋势,典型抗精神病药物用药频度逐年下降,非典型抗精神病药物销售金额和用药频度逐年上升,其中利培酮和喹硫平始终占据用药频度前两位,奥氮平销售金额增幅最大.结论：非典型抗精神病药由于其疗效好、不良反应较少,已成为本院住院患者抗精神病药的用药主体,其中利培酮和喹硫平由于疗效好,价格适中,使用频度最高.奥氮平因其不良反应较小,使用不断增加,销售金额增幅最高.     

How effective is it to sequentially switch among Olanzapine, Quetiapine and Risperidone?—A randomized, open-label study of algorithm-based antipsychotic treatment to patients with symptomatic schizophrenia in the real-world clinical setting

Rationale Evidence on sequential trial with atypical antipsychotics has been scarce. Objectives We conducted an algorithm-based antipsychotic pharmacotherapy. Materials and methods In this open-label study, patients with schizophrenia (DSM-IV) were treated with antipsychotic monotherapy, step-by-step, with each trial lasting up to 8 weeks. At baseline, they were highly symptomatic to score more than 54 in the total Brief Psychiatric Rating Scale (BPRS_1–7) score. When the posttreatment BPRS score was above 70% of the baseline, they were subsequently treated with another and up to three atypicals. Basically, anticholinergics were prohibited, and only adjunctive allowed was lorazepam. The secondary endpoint was a clinical status good enough to be discharged for 66 inpatients and a successful continuation therapy with the same antipsychotic agent for more than 6 months for 12 outpatients. Results Three groups of 26 patients each were randomized to Olanzapine, Quetiapine, or Risperidone. Thirty-nine (50%) responded to the first agent (Olanzapine16, Quetiapine9, Risperidone14), and 14 responded to the second. Only two showed response to the third, and 16 failed to respond to all three antipsychotics, with only 7 dropouts. Overall, there were 22 Olanzapine, 14 Quetiapine, and 19 Risperidone responders. Based on the secondary outcome, 20 Olanzapine-treated (average maximum dose, 15.4 mg), 10 Quetiapine-treated (418 mg), and 20 Risperidone-treated (4.10 mg) patients responded. The difference in response as the first choice was significant (p < 0.05). Relative doses of those failing to respond were comparable (Olanzapine 18.3 mg, Quetiapine 564 mg, Risperidone5.47 mg). Extrapyramidal symptoms did not change significantly. Conclusions When the first atypical antipsychotic is inadequate, switching to the second is worth trying, although some remain treatment-refractory. Quetiapine may be inferior to Olanzapine and Risperidone in symptomatic patients.     

Neuroleptic treatment effect on mitochondrial electron transport chain: peripheral blood mononuclear cells analysis in psychotic patients

A limitation in the use of classic neuroleptic drugs is the eventual appearance of extrapyramidal symptoms. Some studies, mainly based on experimental situations, have related these symptoms with a defect in the mitochondrial electron transport chain (ETC), especially with complex I (CI). One of the advantages of the "atypical" neuroleptics is a lower incidence of movement disorders. We studied peripheral blood mononuclear cells from naive schizophrenic patients (n = 25) and patients under chronic treatment with 1 "typical" neuroleptic (haloperidol, n = 15) or 1 "atypical" neuroleptic (risperidone, n = 23; or clozapine, n = 21). Patients were on standard clinical situation, on treatment for at least 28 months, and did not present signs or symptoms of extrapyramidal dysfunction. Absolute enzyme activities of ETC complexes I to IV were spectrophotometrically quantified, and oxygen consumption with substrates of different complexes was measured polarographically. As an indirect measure of oxidative damage, we quantified membrane lipid peroxidation through the loss of cis-parinaric acid fluorescence. We found differences among groups when comparing the activity of CI, which was decreased in patients receiving neuroleptics, either assessed enzymatically or through oxygen consumption. This effect was lower for atypical neuroleptics than for haloperidol. Haloperidol was also associated with a significant increase of peripheral blood mononuclear cell membrane peroxidation. We conclude that antipsychotics given at clinical standard doses, either typical or atypical, inhibit CI of the ETC. It remains to be established if this finding in a nontarget tissue for antipsychotics may account for the lower incidence of movement disorders observed in patients on atypical agents.     

某院2011～2013年抗精神病药使用调查分析

目的：了解本院抗精神病药的使用情况及临床用药的发展趋势,为制订基本用药目录,促进临床合理用药提供参考。方法：采用回顾性方法,对本院2011～2013年度抗精神病药的销售金额、用药频度（DDDs）和日均费用（DDDc）等情况进行统计分析。结果：本院抗精神病药销售金额和用药频率整体呈逐年上升趋势,典型抗精神病药用药频度整体逐年下降。非典型抗精神病药用药频度整体逐年上升。其中利培酮和奥氮平占抗精神病药销售金额的65%以上,典型抗精神病药奋乃静、舒必利仍受到患者的欢迎。结论：我院药品费用增长平稳,临床抗精神病药使用合理。     

Atypical Antipsychotic Augmentation for Treatment-Resistant Depression: A Systematic Review and Network Meta-Analysis

Background:

Previous meta-analyses of atypical antipsychotics for depression were limited by few trials with direct comparisons between two treatments. We performed a network meta-analysis, which integrates direct and indirect evidence from randomized controlled trials (RCTs), to investigate the comparative efficacy and tolerability of adjunctive atypical antipsychotics for treatment-resistant depression (TRD).

Methods:

Systematic searches resulted in 18 RCTs (total n = 4422) of seven different types and different dosages of atypical antipsychotics and a placebo that were included in the review.

Results:

All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo. In terms of tolerability, all standard-dose atypical antipsychotics, apart from risperidone, had significantly more side-effect discontinuations than placebo (odds ratios [ORs] ranged from 2.72 to 6.40). In terms of acceptability, only quetiapine (mean 250–350mg daily) had significantly more all-cause discontinuation than placebo (OR = 1.89). In terms of quality of life/functioning, standard-dose risperidone and standard-dose aripiprazole were more beneficial than placebo (SMD = -0.38; SMD = -0.26, respectively), and standard-dose risperidone was superior to quetiapine (mean 250–350mg daily).

Conclusions:

All standard-dose atypical antipsychotics for the adjunctive treatment of TRD are efficacious in reducing depressive symptoms. Risperidone and aripiprazole also showed benefits in improving the quality of life of patients. Atypical antipsychotics should be prescribed with caution due to abundant evidence of side effects.     

Cocaine and amphetamine use in patients with psychiatric illness: a randomized trial of typical antipsychotic continuation or discontinuation

Animal studies indicate that typical antipsychotics (neuroleptics) increase cocaine and amphetamine self-administration. Patients with psychiatric illnesses have high rates of substance abuse and frequently receive chronic typical antipsychotic therapy. This open, pilot study examined the effect of typical antipsychotic discontinuation on cocaine and amphetamine use in patients with psychiatric illnesses. Twenty-four evaluable outpatients were randomized to continue (n = 12) or discontinue (n = 12) chronic typical antipsychotic therapy. The atypical antipsychotic quetiapine was instituted, when necessary, for psychosis in the discontinuation group (n = 8). Participants were assessed weekly over 12 weeks with measures of psychiatric symptoms, drug use, and drug craving. Those discontinuing typical antipsychotics (n = 12) had significant reductions in drug craving compared with those continuing typical antipsychotics. No significant between-group differences in drug use were found. Typical antipsychotic discontinuation combined with a quetiapine switch for those with psychotic symptoms was associated with reduced drug craving. Definitive trials of typical antipsychotic discontinuation in dual-diagnosis patients are warranted.     

Quality of life outcomes of risperidone, olanzapine, and typical antipsychotics among schizophrenia patients treated in routine clinical practice: a naturalistic comparative study

Findings in previous studies investigating the beneficial effect of risperidone and olanzapine versus typical antipsychotics on quality of life (QOL) are controversial since they did not adjust for various factors contributing to QOL. To test this assumption in a naturalistic cross-sectional design, we evaluated general and domain-specific QOL scores for baseline data of schizophrenia outpatients stabilized on atypical (N = 78, risperidone or olanzapine) and typical (N = 55) agents. Self-report and observer-rated QOL outcomes of both risperidone and olanzapine with typical antipsychotic therapy were compared across demographic, illness-related, and treatment-related factors using analysis of variance, multivariate analysis of variance, and correlation analysis. No significant differences were found in QOL outcomes of risperidone-treated and olanzapine-treated patients. Both self-report and rater-observed QOL measures indicated superiority of atypical over typical antipsychotic agents after adjusting for daily doses, duration of treatment, subjective tolerability, and adjuvant antidepressants. Lower daily doses and longer antipsychotic treatment were associated with better QOL. Self-report and observer-rated QOL scores correlated positively (r = 0.64, P < 0.001). Gender, marital status, age, education, living arrangement and employment status, age of onset, illness duration, symptom severity, emotional distress, subtypes of schizophrenia, and side effects did not affect QOL outcomes in either group. Risperidone and olanzapine revealed an advantage over typical agents in terms of QOL. Findings suggest that when calculating the beneficial effects of atypical antipsychotic therapy on QOL outcomes, daily doses, duration of treatment, and subjective tolerability may be intervening variables and should be adjusted accordingly to clearly appreciate benefits of atypical antipsychotics.     

Comparison of treatment discontinuation and hospitalization among nonadherent patients initiating depot or oral typical antipsychotic medications

This analysis compared the effectiveness (treatment discontinuation and hospitalization) of depot and oral typical antipsychotics in nonadherent outpatients with schizophrenia. Data from the 3-year, prospective, observational Schizophrenia Outpatient Health Outcome study were used. Time to treatment discontinuation, percentage of patients hospitalized and the mean numbers of hospitalizations were compared for previously nonadherent patients initiating depot typical or oral typical monotherapy. Cox proportional hazards, linear and logistic regression models were used to adjust for differences between the treatment groups at the index visit. Of 1642 nonadherent patients, 431 (26%) started an oral typical (n=169) or depot typical (n=262) antipsychotic and were included in the analysis. After adjusting for index variables, treatment discontinuation was significantly lower in the depot typical cohort (hazard ratio: 0.72, 95% confidence interval: 0.54-0.97, P<0.05). Younger age and more severe positive symptoms were also associated with higher discontinuation. The frequency of hospitalization and the mean number of hospitalizations were both significantly lower for the depot typical cohort at 6 months (P<0.05) compared with oral typicals. In the usual care of outpatients with schizophrenia, treatment continuation among nonadherent patients is longer for depot typicals compared with oral typicals and is accompanied by less hospitalization in the short term.     

The use of atypical antipsychotics in the treatment of schizophrenia in North Staffordshire

AIMS: To examine the long-term effectiveness of atypical antipsychotics in a naturalistic setting for patients with schizophrenia. METHOD: A retrospective analysis of atypical antipsychotic prescribing in one Health District between 1994 and 2001. Time to discontinuation of the first atypical antipsychotic prescribed was calculated using survival analysis. RESULTS: 253 patients were identified. Clozapine had a significantly lower discontinuation rate compared with olanzapine and risperidone (p = 0.018). Patients taking risperidone were 1.3 times more likely to discontinue than those taking olanzapine (p = 0.23). Older age (p = 0.0001), male sex (p = 0.016) and exposure to antidepressants (p = 0.014) significantly predicted compliance. CONCLUSIONS: Clozapine is an effective long-term schizophrenia treatment. The trend to superior effectiveness of olanzapine over risperidone in the long-term has not been reported before and warrants further investigation.     

Benefit-risk assessment of atypical antipsychotics in the treatment of schizophrenia and comorbid disorders in children and adolescents.

Evidence on the efficacy and safety of atypical antipsychotics in children and adolescents with schizophrenia is limited. The purpose of this review is to assess the published data on the use of atypical antipsychotics in children and adolescents with schizophrenia alone and with comorbid disorders, and to establish benefit-risk guidelines for clinicians.Risperidone, olanzapine and clozapine were found to be effective in the treatment of aggression and mania. Risperidone, and possibly also olanzapine, may be the drugs of choice in children with comorbid tic disorders. Ziprasidone has some monoamine reuptake inhibition properties and may be administered as an augmenting agent in children and adolescents with schizophrenia and comorbid anxiety and mood disorders.Compared with the typical antipsychotics, the atypical drugs seem to be more effective, better tolerated and lead to better patient adherence. Importantly, the atypical antipsychotics have a lower propensity to induce extrapyramidal symptoms and a potential (shown so far only in adults) to improve cognitive function and inhibit suicidal behaviour (especially clozapine). Yet, the adverse effects associated with these agents, especially weight gain, which may also have long-term effects, can lead to non-compliance in the young population. In children and adolescents receiving clozapine, olanzapine and quetiapine (but not ziprasidone, which does not have a pro-appetite effect), particularly those with obesity or a family history of diabetes mellitus, fasting blood glucose and lipid levels must be monitored frequently. Weight gain might be better controlled when the children and their parents are properly informed about this adverse effect and diet is regulated. Another major disadvantage of the atypical antipsychotics, especially risperidone, is their association with hyperprolactinaemia, which can lead to hypogonadism-induced osteoporosis, galactorrhoea, gynaecomastia, irregular menstruation and sexual dysfunction, all seen also with typical antipsychotics. Other atypical antipsychotics, namely olanzapine and ziprasidone, have been reported to be prolactin sparing in adults, but may not be completely devoid of hyperprolactinaemic effects in children and adolescents. Thus, prolactin levels should be assessed routinely in young patients treated with atypical antipsychotics. Further, children and adolescents with hyperprolactinaemia-related effects should be switched to a prolactin-sparing agent, such as quetiapine. All atypical antipsychotics may induce sedation and they are not devoid of extrapyramidal symptoms (especially risperidone). The use of typical antipsychotics has been limited to patients who are resistant to atypical antipsychotics, intolerant to their adverse effects, or require injections or depot preparations.Further double-blind, placebo-controlled trials and long-term safety assessments are needed before definitive conclusions can be reached about the place of atypical antipsychotics in the therapeutic armamentarium of childhood-onset schizophrenia.     

Typical neuroleptics vs. atypical antipsychotics in the treatment of acute mania in a natural setting

The present retrospective chart review documents the treatment practice of in-patients suffering from acute manic or hypomanic episodes, at the Department of General Psychiatry, Medical University of Vienna between 1997 and 2001. The aim of the study was to compare the efficacy of typical neuroleptics and atypical antipsychotics as add-on therapy to mood stabilizers. A total of 119 episodes of consecutively admitted patients with ICD-10-defined acute mania (n=106) or hypomania (n=13) were included in a retrospective analysis. Two subgroups were separated out of the whole patient sample according to the medication used: (a) mood stabilizer+typical neuroleptic (n=27) and (b) mood stabilizer+atypical antipsychotic (n=39). The treatment patterns of both subgroups during the first 14 d of in-patient treatment were evaluated. The therapeutic effect was measured by the Clinical Global Impression Scale (CGI). Both patient groups showed no differences on CGI at admission. Patients treated with atypical antipsychotics showed a significantly greater clinical improvement after 14 d (p<0.005) and on discharge (p<0.05) than patients treated with typical neuroleptics. Furthermore, patients treated with atypical antipsychotics developed significantly less extrapyramidal side-effects (p<0.01) and were significantly treated less often with benzodiazepines (p<0.05) during the first 14 d compared to the group receiving typical neuroleptics. Based on our evaluation and the data available in the literature atypical antipsychotics can be considered as first choice for the treatment of acute mania as add-on therapy to mood stabilizers because of their better efficacy and side-effect profile compared to typical neuroleptics.     

A markov model of the cost effectiveness of olanzapine treatment for agitation and psychosis in Alzheimer's disease

BACKGROUND AND OBJECTIVE: Antipsychotics have long been used to treat agitation and psychosis related to Alzheimer's disease, but in a limited fashion because of troubling adverse effects. The new atypical antipsychotics are thought to be at least as effective as first-generation drugs and to cause fewer adverse effects. These drugs, however, are currently not US FDA-approved for use among elderly demented subjects due to a slight increase in the risk of death and serious cardiovascular events within this population. However, their favourable adverse effect profile has led many physicians to prescribe these drugs as first-line therapy for behaviourally disturbed patients with Alzheimer's disease. Clinical trials to evaluate the use of atypical antipsychotics have produced varying results, and clarity has not yet been achieved. Thus, a quantitative summary of the risks and benefits may help inform complex decisions that must be made in this area. In this study we set out to compare the expected costs and outcomes for a community-dwelling cohort of patients with Alzheimer's disease with agitation and/or psychosis who are (a) untreated, or (b) treated with olanzapine. METHODS: We constructed a Markov state-transition model using the best published data from several sources for Alzheimer's disease patient progression and treatment. This model allowed us to compare the expected costs and outcomes associated with olanzapine treatment compared with no treatment for a synthetic cohort of US adults aged > or =65 years. The model cycles every 6 months and continues until all patients die from Alzheimer's disease progression or from co-morbid conditions. Outcome estimates included the incremental cost-effectiveness ratio (ICER) and cost per quality-adjusted life-year (QALY) gained. The robustness of the estimates was examined by sensitivity analyses of key parameters, including cost of care, olanzapine effectiveness and Alzheimer's disease progression rates. RESULTS: Results indicated that olanzapine was a cost-effective treatment for agitation and psychosis related to Alzheimer's disease when compared with no treatment (ICER <$US50,000). In addition, sensitivity analyses demonstrated that olanzapine remained cost effective despite multiple variations of several parameters, both alone and concurrently. CONCLUSION: Olanzapine treatment for agitation and psychosis related to Alzheimer's disease is cost effective when compared with no treatment. Further analysis should be performed as atypical antipsychotics become generic, as more information on health utilities in the Alzheimer's disease population becomes available, and to compare atypical antipsychotics with first-generation antipsychotics.