新型非典型抗精神病药临床应用评价

目前非典型抗精神病药应用越来越广泛,有逐渐取代典型抗精神病药的趋势,不但用于精神分裂症的治疗,而且作为心境稳定剂治疗情感障碍。本文对非典型抗精神病药的概念、治疗阴性症状和较少锥体外系不良反应的机制、在精神分裂症和情感障碍治疗中的临床应用评价等文献进行综述,重点讨论奥氮平、利司哌酮、喹硫平、阿立哌唑、齐哌西酮、氨磺必利和哌罗匹隆。     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

The use of antipsychotics in children and adolescents with bipolar disorders

The use of antipsychotics, particularly the atypical antipsychotics, has increased dramatically in child and adolescent populations over the last decade. This class of psychotropics has been used to treat a variety of psychiatric disorders in pediatric populations, including bipolar disorder (BPD). The present clinical guidelines for treating BPD in younger populations closely follow those for managing adult BPD, as reasoning for using the atypicals is many times initially based on the outcomes of adult studies and indications. As in adult populations, metabolic parameters such as body mass index, blood glucose levels and fasting lipid profiles should be routinely monitored throughout the course of treatment. Of the several studies undertaken thus far, it appears that atypical antipsychotics are efficacious in the treatment of pediatric BPD. However, the number of controlled studies demonstrating their efficacy in younger subjects is limited and further investigation is required to evaluate if effectiveness and potential for side effects differ significantly than that for adult populations.     

Neuroleptic malignant syndrome induced by atypical antipsychotics

A review of the English literature confirms that neuroleptic malignant syndrome (NMS) occurs with both traditional and atypical antipsychotic medications. Published reports of NMS induced by the traditional antipsychotics have given the practitioner valuable information on the prevention and treatment of this adverse effect. Case reports have also been published concerning NMS and clozapine, risperidone, olanzapine and quetiapine. By evaluating the case reports of atypical antipsychotic-induced NMS, valuable information may be obtained concerning similarities or differences from that induced by the traditional antipsychotics. The case reports of NMS with atypical antipsychotics were evaluated for diagnosis, age/sex of patient, risk factors, antipsychotic doses and duration of use, symptoms of NMS, and clinical course.     

非典型抗精神病药物血液系统不良事件信号挖掘和数据分析

目的 基于美国食品药品监督管理局（FDA）不良事件报告系统（FAERS）挖掘6种非典型抗精神病药物氯氮平、奥氮平、阿立哌唑、喹硫平、利培酮、齐拉西酮血液系统不良事件（ADE）信号,为临床安全使用非典型抗精神病药物提供参考。方法 下载2017年第1季度—2021年第3季度共19个季度的FAERS数据,采用比值失衡法中的报告比值比（ROR）法和综合标准法（MHRA）检测数据库中非典型抗精神病药物的ADE信号,统计并分析血液系统ADE信号的相关信息。结果 从FAERS数据库得到以氯氮平、奥氮平、阿立哌唑、利培酮、喹硫平、齐拉西酮6种非典型抗精神病药物为首要怀疑药物的ADE共389431例次,涉及报告病例116706例。血液系统ADE报告共计47144例次,涉及报告病例9658例。氯氮平产生血液系统信号22个,涉及报告病例6808例;奥氮平产生血液系统信号19个,涉及报告病例736例;喹硫平产生血液系统信号18个,涉及报告病例560例;阿立哌唑产生血液系统信号8个,涉及报告病例60例;利培酮产生血液系统信号3个,涉及报告病例16例;齐拉西酮产生血液系统信号1个,涉及报告病例5例。结论 基于真实世界的非典型抗精神病药物血液系统ADE信号挖掘有助于开展安全性评价,为临床安全应用提供参考。     

Weight gain and antipsychotics: a drug safety review

Introduction: Second-generation antipsychotics (SGAs) are widely used in several psychiatric disease entities and exert to a different extent a risk for antipsychotic-induced weight gain (AIWG). As AIWG is associated with an increase in metabolic syndrome or cardiovascular events, knowledge of these risks is crucial for further monitoring and the initiation of counteractive measures.

Areas covered: We searched PubMed and Web of Sciences for randomized-controlled trials and naturalistic observational studies published between 2010 and 2014 with sample sizes exceeding 100, including all marketed SGAs apart from zotepine, and providing data on weight increase. We also summarized relevant systematic reviews and meta-analyses of head-to-head comparisons.

Expert opinion: Recently published data still support the hierarchical ranking of SGAs already proposed in previous reviews ranking clozapine and olanzapine as having the highest risk, followed by amisulpride, asenapine, iloperidone, paliperidone, quetiapine, risperidone and sertindole in the middle, and aripiprazole, lurasidone and ziprasidone with the lowest risk. Number needed to harm varied considerably in our meta-analysis. Younger patients and patients with a lower baseline body mass index are most vulnerable. The greatest amount of weight gain occurs within the first weeks of treatment. AIWG occurs in all diagnostic groups and is also common in treatment with first-generation antipsychotics; therefore, awareness of this adverse event is essential for anyone prescribing antipsychotics.     

Atypical antipsychotics in the treatment of bipolar disorder

Atypical antipsychotic medications are widely used for the treatment of bipolar disorder. Most empirical support suggests that these medications are efficacious in the treatment of acute mania, but there is considerably less support for the utility of these drugs in other phases of bipolar disorder. However, it is likely that several of these drugs will demonstrate efficacy in relapse prevention, and perhaps antidepressant efficacy in bipolar disorder as more studies are conducted. Atypical antipsychotics offer different side effect profiles than older antipsychotics, which may be of benefit for some patients. Consequently, atypical antipsychotics provide an important treatment option for bipolar patients.     

非典型抗精神病的药物代谢及药物相互作用

对非典型抗精神病药物氯氮平（clozapine)，利培酮（risperidone), 奥氮平（olanzapine)，奎硫平（quetiapine)，齐派思酮（ziprasidone)，舍吲哚（sertindole)的相互作用进行综述。非典型抗精神病药的代谢主要由细胞色素P450催化，影响药物代谢酶活性的各种因素均可能导致非典型抗精神病药物代谢的改变，从而升高或者降低血药浓度，导致药理作用和毒性的增加或减少，预报药物相互作用时不仅要考虑联用药对酶的抑制作用，同时要考虑药物代谢的途径，对于多途径多酶催化代谢药物如：奎硫平、奥氮平等，尽管发生药物相互作用，但是多数相互作用无临床意义。对氯氮平、利培酮、齐派思酮，舍吲哚等由于代谢途径较少或者催化酶较为单一，则可能发生明显的具有临床意义的药物相互作用。     

Review of antipsychotics in children and adolescents

The use of antipsychotics in children and adolescents in the clinical setting is increasing. This article reviews 77 clinical trials published in the last 10 years, investigating their efficacy, effectiveness, safety and pharmacokinetic data in paediatric populations. The diagnostic categories in which the antipsychotics are commonly used (schizophrenia, pervasive developmental disorders, Tourette’s disorder, mental retardation/subaverage intelligence, mood disorders and disruptive behaviour disorders) were used in order to review the evidence and effectiveness. All randomised, double-blind, placebo-controlled trials from the past decade are also summarised. This review refers to recent relevant practice parameters, guidelines and reviews throughout the text. Consistent with previous reviews, it is concluded that the recent trend of increased use of antipsychotics in children and adolescents is not adequately supported by evidence. Specific suggestions have been provided on how to incorporate the existing evidence base into clinical decision making. The review ends with the authors’ opinion on the clinical and research implications for the field and future directions.     

Generalization testing with atypical and typical antipsychotic drugs in rats trained to discriminate 5.0 mg/kg clozapine from vehicle in a two‐choice drug discrimination task

Clozapine (CLZ) drug discrimination is used as a preclinical model to evaluate compounds for putative atypical antipsychotic properties. In rats, a 1.25 mg/kg CLZ training dose appears to have greater pharmacological specificity for atypical antipsychotic drugs than the traditional 5.0 mg/kg CLZ training dose; however, methodological differences among studies have precluded a direct comparison between these training doses. In the present study, rats were trained to discriminate a 5.0 mg/kg CLZ dose from vehicle in a two‐choice drug discrimination task using methods similar to those in a previous study from our laboratory that used a 1.25 mg/kg CLZ training dose. Clozapine produced full substitution (≥80% CLZ‐lever responding) for itself at the training dose (5.0 mg/kg). The atypical antipsychotics olanzapine, quetiapine, and ziprasidone also produced full substitution for 5.0 mg/kg CLZ, whereas the atypical antipsychotics risperidone and sertindole produced partial substitution (≥60% CLZ‐lever responding). The typical antipsychotic, thioridazine, produced full substitution for the 5.0 mg/kg CLZ training dose, but the typical antipsychotics chlorpromazine, fluphenazine, and haloperidol failed to substitute for clozapine. In a subgroup of 1.25 mg/kg CLZ‐trained rats, ziprasidone produced strong partial substitution (73.0 % CLZ‐lever responding) for the 1.25 mg/kg CLZ training dose. Based on these findings, some atypical antipsychotic drugs (i.e., quetiapine and ziprasidone) produce full substitution only for the 5.0 mg/kg CLZ training dose, whereas other atypical antipsychotic drugs (i.e., sertindole and risperidone) produce full substitution only for the 1.25 mg/kg CLZ training dose. Thus, both of these training doses are important for the screening of putative atypical antipsychotic drugs with the clozapine drug discrimination assay. Drug Dev. Res. 64:55–65, 2005. © 2005 Wiley‐Liss, Inc.     

Higher than Physician’s Desk Reference (US) doses on atypical antipsychotics

The Physician’s Desk Reference (PDR) was established to provide for the practicing of a complete listing of all medications with the FDA-approved labelling, including dosage recommendations. Perhaps in order to maximise individual usage of medications, pharmaceutical companies have frequently targeted lowest possible doses for FDA approval. However, many patients with a variety of illnesses due to resistance and/or multiple illnesses, may need higher than these dose ranges to maximise therapeutic response. In terms of regularly prescribed atypical antipsychotics released over the past 10 years, only risperidone initially obtained approval for a dose for psychosis (16 mg) higher than that suggested currently (maximum of 8 mg). The dose that was approved for mania was lower: a maximum of 6 mg. The others: respectfully, olanzapine (schizophrenia:15 mg, mania:20 mg), quetiapine (schizophrenia: 750 mg; mania: 800 mg), ziprasidone (schizophrenia and mania: 160 mg) and aripiprazole (schizophrenia and mania: 30 mg) obtained approvals for psychosis that may limit adverse events but, at the same time, limit benefits. Other data from various sources (double-blind trials, open-label trials, reviews and case reports) have found safety and/or efficacy for the following maximum doses: olanzapine (40 mg), quetiapine (1600 mg), ziprasidone (320 mg) and aripiprazole (75 mg). Reports above those doses are included, but either are insufficient in numbers or bring up questions on safety. In many situations, feared increase in adverse events were not magnified by use of higher doses.     

Pharmacotherapy of bipolar disorder: the role of atypical antipsychotics and experimental strategies

Bipolar disorder, despite being a common and debilitating illness, has remarkably few pharmacological therapeutic options, the majority of which, with the exception of lithium, have been borrowed from other medical indications. Furthermore the quantity and quality of controlled clinical data are considerably smaller than in conditions of comparable severity and frequency. Not surprisingly, the clinical outcome of bipolar disorder is frequently suboptimal. Fortunately there are a growing number of novel therapeutic options for its treatment such as atypical antipsychotics, calcium channel blockers and omega-3 fatty acids. This paper summarizes some of the data regarding these "experimental" therapeutic options, focusing principally on atypical antipsychotics as these are now widely prescribed in the management of bipolar disorder.     

Paediatric uses of atypical antipsychotics

Antipsychotics are commonly prescribed to children and adolescents. With the relatively recent availability of the atypical antipsychotics, physicians have begun prescribing these agents to young people in the hope of finding safe, effective alternatives to the typical antipsychotics. This report reviews what is currently known about the use of the atypical antipsychotics in young people. Most of the currently available data are based on case reports and case series. The results of only a handful of prospective trials pertaining to the use of the atypical antipsychotics in youths have been reported. Based on the available information, it appears that clozapine has a role in juvenile treatment resistant schizophrenia. When considered as a group, the 'first-line' atypical antipsychotics risperidone, olanzapine and quetiapine appear to have promise as treatments for several neuropsychiatric disorders in young people. These conditions include psychotic, mood, disruptive, movement and pervasive developmental disorders. Unfortunately, as has historically been the case, the demand to address the clinical needs of young patients with neuropsychiatric disorders has outpaced empirically based information. This is particularly important because significant side effects can occur when children or adolescents are treated with atypical antipsychotics. Since there is a paucity of short-term and almost no long-term safety data pertaining to these agents in young people, careful consideration must be made prior to initiating atypical antipsychotic treatment for a child or teenager. Based upon what is known about these agents, a rational approach to the use of these drugs in juveniles is offered.     

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.     

4种药物治疗精神分裂症的药物经济学分析

目的:比较4种抗精神病药物治疗精神分裂症的疗效和费用,运用药物经济学原理,探讨最适合患者治疗的药物。方法:对服用氯丙嗪、利培酮、奥氮平、氯氮平的精神分裂症患者,进行疗效、不良反应、生活质量和治疗费用进行调查。结果:氯丙嗪、利培酮、奥氮平、氯氮平这4种抗精神病药物有效率相当,没有显著性差异;生活质量有差异,但没达到显著性差异;在1年内服用利培酮、奥氮平、氯氮平、氯丙嗪的费用分别是8 260.50±2 438.56元,19 328.60±6 573.29元,1 709.60±925.87元,1 512.00±823.65元,有显著性差异,P<0.05或P<0.01。结论:新型抗精神病药物奥氮平费用太昂贵,利培酮较较适合我国精神病患者使用,氯氮平费用低但不良反应较多,一般用于重精神病患者;服用传统抗精神病药氯丙嗪费用低,但不良反应多且严重,随着人们对生活质量的要求提高,会逐渐减少使用。     

Antipsychotics: impact on prolactin levels

Hyperprolactinaemia has been associated with a variety of side effects including amenorrhoea, galactorrhoea, sexual dysfunction, breast engorgement and osteoporosis. Since the mid-1970s, the impact of antipsychotics on human prolactin (hPrl) levels has been investigated. Baseline levels of hPrl were found to be similar in healthy controls and patients who were diagnosed as having schizophrenia. Short-term acute studies done after single parenteral or oral doses of phenothiazines found rapid two- to tenfold increases in hPrl. Similar increases were found in longer term studies that reported increases of three times in both men and women after 3 days that doubled again after several weeks of treatment. A study of longer term injectable fluphenazine enanthate found that elevation induced by a single injection lasted up to 28 days. The same results with significant increases have been reported with the butyrophenone, haloperidol. Substantial increases are found after single injections (up to nine times) and after weeks of treatment (up to three times sustained). Thus, early literature believed that there might be an association between these induced changes and response to therapy. However, prolactin is secreted by the anterior pituitary and is under inhibitory control of dopamine released from the tuberoinfundibular neurons. Thus, increases in prolactin are due to antipsychotic impact on tuberoinfundibular tract, one of four dopamine-related tracts. With the application of clozapine and other atypical antipsychotics, it was found that medications can successfully treat psychosis without increasing hPrl. In fact, early single-dose trails found clozapine to reduce hPrl by 16%. Later studies replicated this result and also found that up to 6 weeks of administration led to reductions in hPrl of up to 80%. Risperidone, however, has been found to persistently elevate hPrl in studies, despite its impact on other receptor sites. Olanzapine, quetiapine and ziprasidone have all been found to have little effect or produce decreases in hPrl. Most recently, aripiprazole, in early studies, appears to produce significant reductions in hPrl while maintaining therapeutic efficacy for psychosis.     

非典型抗精神病药物在儿童多发性抽动障碍治疗中的研究进展

多发性抽动障碍（TS）是儿童期常见的神经精神疾病,临床特征表现为运动性抽动和发声性抽动,抽动症状在青春期后有所改善,但部分患者可能出现抽动相关的共患病。在传统治疗措施失败,且某些精神合并症使临床表现复杂化时,非典型抗精神病药物成为治疗TS的新选择。然而,非典型精神病药物治疗TS的研究证据比较有限。研究证据显示,非典型性抗精神病药物广泛应用于TS的治疗,其中利培酮是研究证据相对充足的有效药物,阿立哌唑是治疗TS具有较好前景的药物,齐拉西酮、奥氮平与喹硫平能改善抽动症状,但随机对照试验缺乏,有待进一步研究证实。甲氧氯普胺和氯氮平研究证据缺乏,且副作用明显,不推荐用于治疗TS。