中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 单纯烁, 郑国庆
, SHAN Chunshuo, ZHENG Guoqing,
精神分裂症发病率高,社会和家庭负担重。随着近半个世纪抗精神病药物在临床上的广泛应用,其治疗遵循早期、有效和维持的原则,临床预后日趋改善。该文从精神分裂症不同时期的临床特征,结合近年抗精神病药物的研究进展,阐述精神分裂症治疗药物的临床选择。
The high incidence of schizophrenia causes a greater burden on society and family.In the past of half century, with the widespread use of schizophrenic drugs,the prognosis of clinical schizophrenia has been substantially improved after following the principles of early, effective and maintenance therapy.In this overview,the clinical characteristics at different stages of disease progression with the recent advances in drug therapy of schizophrenia was combined,to introduce clinical selection of schizophrenic drugs.
[编者按] 随着社会竞争的加剧,人们生活节奏的加快,精神障碍已成为严重而又耗资巨大的全球性卫生问题,影响着不同年龄、不同文化、不同工种的人群。世界精神病学协会从1992年起,把每年的10月10日定为世界精神卫生日。为了全面系统地报道精神疾病最新治疗进展和抗精神病药物的合理应用与安全性评价,本刊从1999年起,每年组编一期抗精神病药物专栏,经过17年的努力,该专栏已经成为本刊特色性栏目,受到广大作者和读者极大的关注。本期专栏特向温州医科大学附属第二医院精神神经学科郑国庆教授研究团队组织精神疾病治疗进展系列文章,包括精神分裂症、抑郁症、失眠、阿尔茨海默病治疗进展等4篇综述,从疾病的治疗目标、治疗原则、治疗策略、药物治疗及出现不良反应后应对措施等方面进行系统介绍,以飨读者。
全球精神分裂症的终生患病率高,为3.8‰~8.4‰[3]。大多数患者呈现慢性病程,一旦罹患,病情易迁移或反复发作,导致明显的精神功能减退。同时,精神分裂症患者的生活质量明显受损,失业率高,为80%~90%[4],平均预期寿命减少10~20岁[5],超过半数患者最终出现精神残疾,给患者、家属和社会带来巨大的负担。在我国,由于经济发展不均衡,社会对疾病的认识不足,未接受正规治疗的比例高达30%,自然预后较差,社会功能损害更明显[6]。因此,正确认识精神分裂症,早期有效的抗精神病治疗十分关键。患者的病情控制通常需要医院和社区的协作管理,其中经济有效的方式是抗精神病药物的治疗。自1952年第一个抗精神病药氯丙嗪上市以来,精神分裂症的治疗治疗进入一个新的时代。半个多世纪以来,随着各种抗精神病药物在临床上的广泛应用,患者的临床缓解率明显提高。荟萃分析显示,精神分裂症的良好预后可能与抗精神病药物的普遍使用,显著提高缓解程度和改善社会功能有关[7]。现就精神分裂症的药物治疗进展阐述如下。
精神分裂症多为慢性复发性病程,表现为间断性发作或持续性病程。首次发作患者中,经过有效的治疗,75%患者可达到临床治愈,但后续出现反复发作或恶化概率较高。目前认为,影响本病预后的关键点在于发病后5年内是否进行规范的抗精神病药物治疗,因为即使病情波动,也较少进一步损伤精神功能。因此,在精神分裂症发病早期,就应尽快制定长期疾病管理规划[8]。积极的抗精神分裂症药物治疗:一者在急性发作期选择快速起效的药物控制病情,二者为防止病情的复发进行长期的药物维持治疗[9]。不同时期治疗的具体目标不同,急性期重点在预防伤害,控制异常行为,降低精神病性阳性症状如激越、攻击等,阴性症状如低落、退缩等及情感症状的严重性,寻找导致急性发作发生的可能因素;维持期的关键在于维持症状持续缓解,降低复发率,促进患者功能水平的持续改善;两期共同的目标是避免出现严重药物不良反应,提高患者依从性,最终改善预后。
精神分裂症药物治疗原则包括如下几点。①尽早治疗:一旦患者被确诊为精神分裂症,应尽早选择合适的抗精神分裂药物进行治疗。②单药治疗:一般不联合使用两种抗精神病药物进行治疗。治疗一般从小剂量开始,逐渐增加至有效剂量。药物调整速度取决于患者症状改善程度及不良反应的发生情况。维持治疗期间,剂量可适当进行调整,但疗程必须足够。③原药治疗:急性加重患者,包括复发和病情恶化的患者,依照以前的药物治疗继续使用原药。如果无效,可酌情加量或换药。疗效差者再考虑使用氯氮平,但应严格检查血液中白细胞和嗜中性粒细胞。④个体化治疗:定期评估药物疗效及时调整用药方案。⑤关注药物不良事件:药物不良反应是导致患者自行停药的主要原因,药物不良反应会诱发或加重患者的精神病症状,严重影响患者的预后[3]。
精神分裂症病因目前尚不明确。目前认为,遗传与环境因素是主要诱因,中枢神经系统内神经递质及受体功能失调是可能的发病机制。抗精神分裂症药物根据作用机制不同可分为:①第1代抗精神病药物,又称为经典抗精神病药物[10],主要作用于中枢神经系统内的多巴胺能(D2)受体;②第2代抗精神病药物,也称为非经典抗精神病药物,其作用机制不局限于对D2受体的阻断,也可对5-羟色胺(5-hydroxytryptamine,5-HT)及谷氨酸能系统进行调节。经典的第一代抗精神病药物为氯丙嗪(chlorpromazine)、舒必利 (sulpiride)、奋乃静(perphenazine)和氟哌啶醇 (haloperidol)。该类药物可改善大部分患者的幻觉、妄想、兴奋、激越等急性的阳性症状,也可控制部分慢性患者的症状,但对退缩、低落等阴性症状及伴发抑郁症状疗效不佳。另外,由于药物在阻断中脑-大脑皮质和中脑-边缘系统的多巴胺D2受体发挥治疗效果的同时,也影响到黑质-纹状体和结节-漏斗系统的DA功能[11],会引起锥体外系反应(extrapyramidal reactions,EPS)。当药物作用于其他神经传导系统时,可影响心血管系统、自主神经系统,导致体质量增加、肥胖、嗜睡等不良反应。在接受长期维持治疗者中不良反应尤其明显,显著降低患者生活质量,以致影响服药依从性,结果导致复发率上升。因此,该类药物在临床上已被新一代抗精神病药物所取代[10]。但在我国,由于这些药物价格低廉,对经济状况不佳、耐受不良反应的患者仍是一种合适的选择。
第2代抗精神病药物的作用机制不局限于对D2受体的阻断,还具有较高5-HT2受体阻断作用,合称D2-5-HT2受体拮抗剂,又称为非典型抗精神病药物[12]。1990年以来,非典型抗精神病药逐渐开始应用于临床。目前已在国内上市并应用广泛的包括氯氮平(clozapine)、奥氮平(olanzapine)、利培酮(risperidone)、喹硫平(quetiapine)、齐拉西酮(ziprazidone)、 帕利哌酮(paliperidone)和阿立哌唑(aripiprazole) 等。这类药物对精神分裂症的阳性和阴性症状均有治疗作用,可在一定程度上改善认知功能。同时,由于临床适应证广泛、较少引发锥体外系反应,已逐渐取代经典抗精神病药成为治疗初发急性精神分裂症的一线选择。它们的作用机制各异,适应不同症状,在不良反应方面也各不相同,因此可为不同患者提供个体化选择[13]。
精神分裂症应重视早发现、早诊断和早治疗,但是由于精神分裂症患者对自己的疾病缺乏自省力,而其周围的人包括家属及同事,通常不能在早期发现异常,甚至讳疾忌医,因此精神分裂症的诊疗常会延误。目前针对初发精神分裂症药物治疗的一致观点是:首次症状发生时治疗十分关键,此时患者对抗精神病药物的治疗反应最好,所需剂量也较低,如能获得有效治疗,康复概率最大,长期预后也最好[9]。研究认为,精神分裂症发病后2~3年为治疗的关键时期,在此期间如得不到有效药物治疗,预后不良将难以避免[14]。据指南推荐,精神分裂症急性期的治疗策略据患者的主要症状不同,相应的可选择药物也各不相同。
急性期以幻觉、妄想等阳性症状为主要表现的患者,指南推荐口服第2代抗精神病药物如奥氮平、喹硫平、利培酮、帕利哌酮、齐拉西酮、阿立哌唑或氨磺必利。起始治疗应从小剂量开始逐渐加量,根据药动学特点在2周内加至目标剂量。对于不能配合服药的患者可选择口服液或口崩片等剂型。除了抗精神病药物,为了快速控制病情,达到更好治疗效果,临床上常联用苯二氮类镇静药物如劳拉西泮、氯硝西泮或地西泮注射液等[15]。对于自知力丧失完全不配合治疗的患者,通常不用口服剂型,而选择起效快速注射制剂。过去几十年临床上使用较多的是第1代抗精神病药物的针剂,如氟哌啶醇短效针剂、氯丙嗪短效针剂,疗程一般为3~7 d。近年来,第2代抗精神病药的使用比例大幅上升,如肌内注射齐拉西酮短效针剂20~40 mg·d-1,有明确的疗效和安全性,正逐渐取代第1代药物。
以兴奋、激越和暴力行为等阳性症状为主要表现的患者,在迅速完成患者躯体情况评估和精神科初步诊断后,应选用肌内注射这种起效较快的给药方式以尽快控制症状,防止发生伤害事件。首选第2代抗精神病药齐拉西酮进行肌内注射,或根据患者病情以及医院具体情况选择一代抗精神病药物如氟哌啶醇或氯丙嗪进行肌内注射。另外,还应根据患者兴奋激越的严重程度考虑同时合用苯二氮类,如劳拉西泮或氯硝西泮注射液。患者急性症状得到控制后,应尽快改为口服药物。口服药物的选择应充分考虑到长期治疗的要求而选择非典型抗精神病药(氯氮平除外)。如果上述治疗效果不佳,可以尝试以氯氮平为主的治疗,但要注意监测血液学指标。
以阴性症状为主患者首选第2代非典型抗精神病药治疗[16],目前指南推荐的药物是阿立哌唑(10~20 mg·d-1)、奥氮平(5~10 mg·d-1)、喹硫平(100~300 mg·d-1)、帕利哌酮(3~6 mg·d-1)和齐拉西酮(40~80 mg·d-1),与阳性症状为主患者相比选择小剂量,更有利于阴性症状的改善。如果首选药物治疗无效,可更换另一种化学结构不同的第2代抗精神病药包括氯氮平(50~100 mg·d-1)。一般精神分裂症治疗原则是单药治疗,但由于阴性症状为主型精神分裂症的特殊性,药物治疗效果较差,预后不佳,可在单药治疗基础上加用另一种抗精神病药,具体可根据患者病情选择,以氯氮平为主联合其他非典型抗精神病药,或以一种非典型抗精神病药为主联合小剂量氯氮平治疗。
由于精神分裂症的病因不明,目前药物治疗仅能对症治疗,而不能从病因角度根治疾病。因此当患者急性期症状缓解后仍需要继续服用药物,预防症状反复或复发。复发导致的结果是大脑神经元的丢失增多[18],使急性期的治疗难度加大,症状缓解十分缓慢,并且更难恢复到之前的功能水平[19]。因此,为改善患者长期预后,关键在于预防复发,降低停药风险及提高患者依从性。另外,认知功能减退作为精神分裂症的核心症状之一,在长期治疗过程中有加重进展的风险,认知减退对患者日常生活影响巨大,因此延缓认知功能下降十分关键,目前用于认知症状改善的药物有多奈哌齐,但效果并不十分显著,尚有大量新药正在研发当中[20]。
药物维持治疗的目的在于保持急性期治疗获得的临床疗效,减少不良反应的发生,提高患者的生活质量。一般维持治疗的所需的持续时间为:首发患者至少需要2年;一次复发的患者需要3~5年;多次复发者需维持治疗>5年[3]。由于治疗持续时间较长,服药期间不良反应发生率高,部分患者存在病耻感等原因,导致患者难以坚持服药,使病情反复。因此,维持期治疗首选仍是第2代抗精神病药物,原因在于不良反应相对较小,使患者能坚持服药,依从性较高。对于治疗依从性差的患者可以考虑第2代抗精神病的长效制剂。国内已经上市有利培酮长效注射剂(每次25 mg)和帕利哌酮长效注射剂 (每次75~150 mg)。长效利培酮注射剂有很好的临床疗效,每2周肌内注射1次,使用方便,不良反应比其口服制剂更少。棕榈酸帕利哌酮2011年在国内上市,该药每个月仅需注射1次,且兼具急性期起效快速,维持期持续症状改善的优点,安全性高,使用便捷,目前在临床上广泛使用[21]。长效抗精神病药物相比口服制剂更能提高患者的依从性,减少用药中断率,有效降低疾病复发率。另外,在维持治疗期间还需要关注患者认知功能的减退情况。当患者有强迫或抑郁障碍等共患病时,可加用相应治疗药物,但值得注意的是避免长期使用抗焦虑和治疗失眠的苯二氮类药物,以免产生耐受性与依赖性。
TRS是指足剂量、足疗程地使用两种化学结构不同的抗精神病药物后,仍不起效的病例[22]。近年来研究结果显示TRS发病具有神经系统发育异常的基础,10%~15%患者在早期起病时即为TRS[22]。对TRS的治疗主要分为两步:第一审视既往治疗方案,了解患者既往用药史,评估患者既往的治疗依从性,个体化使用药物。第二重新制定治疗方案,更换另一种抗精神病药,有效剂量、有效疗程治疗。尤其应考虑氯氮平[23],近年来由于其存在血液系统的不良反应风险,用药期间需监测血液学指标,氯氮平一般不作为精神分裂症的首选药物。但研究表明,氯氮平治疗TRS患者效果显著,可有效减轻患者的攻击性行为,降低自杀风险。如果经过上述治疗后症状仍未改善者,需考虑联合使用电抽搐治疗,以尽快控制症状,改善预后。
第1代和第2代抗精神病药物由于在药物作用机制上的差异,它们的不良反应也有所不同。第1代抗精神病药物经常引起EPS,而第2代抗精神病药物由于作用机制不同,较少引起EPS,但引起体质量增加及糖脂代谢异常等代谢综合征的不良反应可能性大。治疗精神分裂症药物的主要不良反应包括如下几种。 ①EPS:首先应选择合适药物,最容易引起EPS的是第1代抗精神病药物,在第2代抗精神病药物中顺序是利培酮和帕利哌酮较高,阿立哌唑与齐拉西酮次之,奥氮平和喹硫平较少,而氯氮平几乎没有。当出现EPS时首先换用发生率较小药物,必要时合用其他药物,如丁苯那嗪片;如仍无效可尝试合用维生素E和维生素B6、多奈哌齐。但指南不推荐使用抗胆碱能药物,可能会使症状恶化,临床上存在争议[12]。②代谢异常:体质量增加及糖脂代谢异常目前已成为药物治疗中需要重视的问题,严重影响患者服药的依从性,增加心血管疾病和糖尿病的风险。因此在用药期间因监测血糖血脂等代谢指标,及早预防。最新研究提示二甲双胍对抗精神病药物所致体质量增加控制有效,对血糖、血脂代谢异常也具有临床疗效[24]。③其他:抗精神分裂症药可能出现不良反应较多,具体存在内分泌紊乱、心血管不良反应、镇静作用、流涎、体温调节紊乱、抗胆碱能不良反应、肝功能损伤、癫痫发作、血液系统改变等,临床上应警惕这些不良反应发生,并及时处理。
The authors have declared that no competing interests exist.
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A meta-review, or review of systematic reviews, was conducted to explore the risks of all-cause and suicide mortality in major mental disorders. A systematic search generated 407 relevant reviews, of which 20 reported mortality risks in 20 different mental disorders and included over 1.7 million patients and over a quarter of a million deaths. All disorders had an increased risk of all-cause mortality compared with the general population, and many had mortality risks larger than or comparable to heavy smoking. Those with the highest all-cause mortality ratios were substance use disorders and anorexia nervosa. These higher mortality risks translate into substantial (10-20 years) reductions in life expectancy. Borderline personality disorder, anorexia nervosa, depression and bipolar disorder had the highest suicide risks. Notable gaps were identified in the review literature, and the quality of the included reviews was typically low. The excess risks of mortality and suicide in all mental disorders justify a higher priority for the research, prevention, and treatment of the determinants of premature death in psychiatric patients.
DOI:10.1002/wps.20128
URL
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精神分裂症是一类常见而严重的疾病。近半个多世纪以来，随着抗精神病药物的广泛应用，临床精神分裂症的预后日趋改善。已有大量研究证明，精神分裂症患者需要接受抗精神病药物治疗，而积极的药物治疗有两层概念：即急性期的药物控制治疗及康复期的药物维持治疗。本文综述相关药物治疗策略的进展。
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Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.
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Abstract Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the world's population. This disease is associated with considerable morbidity placing a major financial burden on society. Antipsychotics have been the mainstay of the pharmacological treatment of schizophrenia for decades. The traditional typical and atypical antipsychotics demonstrate clinical efficacy in treating positive symptoms, such as hallucinations and delusions, while are largely ineffective and may worsen negative symptoms, such as blunted affect and social withdrawal, as well as cognitive function. The inability to treat these latter symptoms may contribute to social function impairment associated with schizophrenia. The dysfunction of multiple neurotransmitter systems in schizophrenia suggests that drugs selectively targeting one neurotransmission pathway are unlikely to meet all the therapeutic needs of this heterogeneous disorder. Often, however, the unintentional engagement of multiple pharmacological targets or even the excessive engagement of intended pharmacological targets can lead to undesired consequences and poor tolerability. In this article, we will review marketed typical and atypical antipsychotics and new therapeutic agents targeting dopamine receptors and other neurotransmitters for the treatment of schizophrenia. Representative typical and atypical antipsychotic drugs and new investigational drug candidates will be systematically reviewed and compared by reviewing structure-activity relationships, pharmacokinetic properties, drug metabolism and safety, pharmacological properties, preclinical data in animal models, clinical outcomes and associated side effects.
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Abstract The dopamine system is unique among the brain's modulatory systems in that it has discrete projections to specific brain regions involved in motor behaviour, cognition and emotion. Dopamine neurons exhibit several activity patterns - including tonic and phasic firing - that are determined by a combination of endogenous pacemaker conductances and regulation by multiple afferent systems. Emerging evidence suggests that disruptions in these regulatory systems may underlie the pathophysiology of several psychiatric disorders, including schizophrenia and depression.
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Objectives: A growing number of atypical antipsychotics are available for clinicians to choose from in the treatment of psychotic disorders. However, a number of important questions concerning medication selection, dosing and dose equivalence, and the management of inadequate response, compliance problems, and relapse have not been adequately addressed by clinical trials. To aid clinical decision-making, a consensus survey of expert opinion on the pharmacologic treatment of psychotic disorders was undertaken to address questions not definitively answered in the research literature.Method: Based on a literature review, a written survey was developed with 60 questions and 994 options. Approximately half of the options were scored using a modified version of the RAND 9-point scale for rating the appropriateness of medical decisions. For the other options, the experts were asked to write in answers (e.g., average doses) or check a box to indicate their preferred answer. The survey was sent to 50 national experts on the pharmacologic treatment of psychotic disorders, 47 (94%) of whom completed it. In analyzing the responses to items rated on the 9-point scale, consensus on each option was defined as a non random distribution of scores by chi-square "goodness-of-fit"test. We assigned a categorical rank (first line/preferred choice,second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. Results: The expert panel reached consensus on 88% of the options rated on the 9-point scale. The experts overwhelmingly endorsed the atypical antipsychotics for the treatment of psychotic disorders. Risperidone was the top choice for first-episode and multi-episode patients, with the other newer atypicals rated first line or high second line depending on the clinical situation.Clozapine and a long-act
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精神分裂症急性期患者临床症状鲜明，宜采取积极的强化性药物治疗，争取病状缓解，预防病情的不稳定性。本文对精神分裂症急性期患者的药物治疗疗效及治疗策略研究进展作一综述，以供临床工作者参考。
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Abstract Overwhelming research evidence suggests that the negative symptoms of schizophrenia (NSS) contribute more to impaired quality of life and poor functioning than positive symptoms, and that NSS, including affective flattening, alogia and avolition are present in at least one-fifth of patients diagnosed with schizophrenia. Despite this, management of NSS continues to be a major clinical unmet need as treatment with current antipsychotic medication seems to reach at best modest efficacy. A critical review of the current pharmacological, non-pharmacological and psychosocial treatments available for NSS is presented here, using data retrieved from the MEDLINE/PUBMED, the Cochrane Database of Systematic Reviews and the ClinicalTrials.gov databases. An early and accurate diagnosis using selective scales is essential for documentation and monitoring of change in NSS according to treatment response. Typical and atypical antipsychotic drugs, showed modest efficacy in managing NSS. Conflicting results were obtained with the use of glycinergic neuromodulators, anticholinergics, antidepressants, anticonvulsants, psychostimulants, modafinil and 5-HT3 receptor antagonists. Moreover, non-pharmacological therapies including psychological therapies have failed to address NSS effectively. At present, it appears that the best effective approach for clinical management of NSS is achieved by complementing drug therapy with psychosocial therapies. Continuing basic and clinical research for the understanding of the genetic, behavioral and neural basis of NSS should yield novel pharmacotherapies with superior efficacy, tolerability and long-term maintenance for improved treatment of NSS. Copyright 脗漏 2015 Elsevier Inc. All rights reserved.
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目的了解伴抑郁症状的精神分裂症的临床特症。方法对８１例伴抑郁症状的精神分裂症、１００例不伴抑郁症状的精神分裂症及６０例抑郁症患者进行临床对照研究。结果伴抑郁症状的精神分裂症具有每次发病时间长、易复发的特点，临床表现以罪恶妄想、疑病妄想、虚无妄想、贫穷妄想多见，抑郁症状以无助、无望感及精神运动性迟滞突出；加用与不加用抗抑郁剂比较，在治疗起效时间、症状改善时间方面的差异均有非常显著性（Ｐ＜０．０１）。结论对伴抑郁症状的精神分裂症患者给予适当的社会支持、治疗上加用抗抑郁剂是缩短疗程的有效途径之一
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Although treatment resistance may be an enduring feature of a patient, present at illness onset and throughout, more commonly it develops over the course of patients鈥 illnesses. Evidence from both retrospective and prospective studies suggests that a longer duration of untreated psychosis in the early stage of schizophrenia is associated with a longer time to remission and a lower level of recovery, a greater likelihood of relapse and a worse overall outcome. The pattern of deterioration observed is analogous to a well replicated neurobiologic phenomenon, termed behavioral sensitization. In sensitized animals a pathologic behavioral process emerges whereby the response to a pharmacologic or stress challenge is progressively increased in proportion to the number of pretreatments. Thus, endogenous neurochemical sensitization resulting from the inability to regulate presynaptic dopamine release in the limbic striatum may be a useful way to conceptualize the continuum of response-refractoriness that is clearly evident in schizophrenia patients. Most importantly, early detection, intervention and optimal maintenance treatment may improve the long term course of schizophrenia.
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Abstract Clozapine represented the first significant advance in the pharmacotherapy of schizophrenia since the introduction of conventional antipsychotic drugs in the 1950's. Despite its superior efficacy and potential to reduce substantially the morbidity of schizophrenia and improve the outcomes, of patients, clozapine has not been used on a widespread basis or as a first-line treatment due to its potential for agranulocytosis. With the introduction of risperidone and the imminent prospect of other atypical antipsychotic drugs (olanzapine, sertindole, quetiapine, ziprasidone), clinicians may be able to improve dramatically the methods and manner in which they treat schizophrenia and related psychotic disorders. If we accept the premise that atypical antipsychotic drug provide superior efficacy, reduced side effects, and the prospect of better compliance, their greatest impact may be when used in patients at the beginning of their illness. The following article provides a rationale and hypothesis for the use of atypical antipsychotic drugs as a first-line treatment of schizophrenia.
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Abstract Cognitive impairment in schizophrenia is a core feature of the illness (i.e., not a result of clinical symptoms or drug treatments) that is related to the daily functioning of patients. Because schizophrenia is associated with poor community functioning, there is considerable interest in finding treatments to improve cognition in schizophrenia in the hopes that such improvement will yield functional benefits. Before the U.S. Food and Drug Administration could consider granting approval to any new drug for improving cognition in schizophrenia, it was first necessary to achieve consensus on the measurements and methods that would be used in clinical trials, as well as neuropharmacological targets. The U.S. National Institute of Mental Health launched an initiative to help address these obstacles to drug approval (MATRICS). This initiative has generated several additional follow-up initiatives including a clinical trial network and consensus projects for other clinical targets, such as negative symptoms. This review describes how an area that was primarily of academic interest (cognition in schizophrenia) became a focus of public health concerns and drug-development policy.
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棕榈酸帕利哌酮是非典型抗精神病长效针剂,兼具急性期快速起效,维持期持续改善症状的作用。它疗效确实,使用便捷,有利于患者持续有效的药物治疗,预防复发,为精神分裂症的治疗提供了新的选择。作为目前中国唯一的每月注射1次长效针剂,棕榈酸帕利哌酮于2011年12月被我国批准用于精神分裂症的急性期和维持期治疗。经中华医学会精神医学分会精神分裂症协作组讨论,组织专家,通过复习国内外的相关文献,并结合临床实践,就棕榈酸帕利哌酮的药理学特性、适用人群、临床用法用量及不良反应和处理撰写了本文,为临床合理使用该药提供参考,以期使更多的患者获益。
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Abstract OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHOD: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.
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Although clozapine (CLZ) is considered the best evidence-based therapeutic option for treatment of resistant schizophrenia patients, a significant proportion of CLZ-treated patients show a partial or inadequate response to treatment, leading to increased healthcare cost and poor quality of life for affected individuals.This paper comprises a review of main research in CLZ augmentation strategies for treatment-refractory schizophrenia, with a focus on research conducted between 1990 and 2014. Databases that were searched include: PubMed, CINAHL, EMBASE PsychINFO, AgeLine and Cochrane Database of Systematic Reviews. Primary search terms were 'clozapine augmentation', 'clozapine and add-on' and 'treatment-resistant schizophrenia', with cross reference to specific agents covered in this article. We reviewed the available evidence on CLZ augmentation with antipsychotics, antidepressants, mood stabilizers and other agents.Many drugs have been evaluated as CLZ add-on therapies without demonstrating convincing efficacy in treating refractory schizophrenia symptoms. More research is needed to better define outcomes in schizophrenia, the topic of treatment-resistance and more well-designed trials are required to establish true efficacy and safety of CLZ augmentation strategies.
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Abstract BACKGROUND: Antipsychotic-induced metabolic adversities are often difficult to manage. Using concomitant medications to counteract these adversities may be a rational option. OBJECTIVE: To systematically determine the effectiveness of medications to counteract antipsychotic-induced metabolic adversities in patients with schizophrenia. DATA SOURCES: Published articles until November 2013 were searched using 5 electronic databases. Clinical trial registries were searched for unpublished trials. STUDY SELECTION: Double-blind randomized placebo-controlled trials focusing on patients with schizophrenia were included if they evaluated the effects of concomitant medications on antipsychotic-induced metabolic adversities as a primary outcome. DATA EXTRACTION: Variables relating to participants, interventions, comparisons, outcomes, and study design were extracted. The primary outcome was change in body weight. Secondary outcomes included clinically relevant weight change, fasting glucose, hemoglobin A1c, fasting insulin, insulin resistance, cholesterol, and triglycerides. DATA SYNTHESIS: Forty trials representing 19 unique interventions were included in this meta-analysis. Metformin was the most extensively studied drug in regard to body weight, the mean difference amounting to -3.17 kg (95% CI: -4.44 to -1.90 kg) compared to placebo. Pooled effects for topiramate, sibutramine, aripiprazole, and reboxetine were also different from placebo. Furthermore, metformin and rosiglitazone improved insulin resistance, while aripiprazole, metformin, and sibutramine decreased blood lipids. CONCLUSION: When nonpharmacological strategies alone are insufficient, and switching antipsychotics to relatively weight-neutral agents is not feasible, the literature supports the use of concomitant metformin as first choice among pharmacological interventions to counteract antipsychotic-induced weight gain and other metabolic adversities in schizophrenia. 脗漏 The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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