Wang Yijun, Xia Jun, Helfer Bartosz, Li Chunbo, Leucht Stefan
Neuro-Cognitive Psychology Master Program, Ludwig-Maximilians-Universität München, Thalkirchner Str. 9, Munich, Bavaria, Germany, D-80337.
Cochrane Database Syst Rev. 2016 Nov 24;11(11):CD004028. doi: 10.1002/14651858.CD004028.pub4.
BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with ordinary antipsychotic drug treatment. In these cases, various add-on medications are used, and valproate is one of these. OBJECTIVES: To examine whether:1. valproate alone is an effective treatment for schizophrenia and schizoaffective psychoses; and2. valproate augmentation of antipsychotic medication is an effective treatment for the same illnesses. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (July 2002; February 2007; July 2012; March 04, 2016). We also contacted pharmaceutical companies and authors of relevant studies in order to identify further trials. SELECTION CRITERIA: We included all randomised controlled trials comparing valproate to antipsychotics or to placebo (or no intervention), whether as the sole agent or as an adjunct to antipsychotic medication for the treatment of people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We independently inspected citations and, where possible, abstracts, ordered papers, and re-inspected and quality-assessed these. At least two review authors independently extracted data. We analysed dichotomous data using risk ratio (RR) and its 95% confidence intervals (CI). We analysed continuous data using mean differences (MD) and their 95% CI. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table. MAIN RESULTS: The 2012 update search identified 19 further relevant studies, most of which were from China. Thus the review currently includes 26 studies with a total of 2184 participants. All trials examined the effectiveness of valproate as an adjunct to antipsychotics. With the exception of two studies, the studies were small, the participants and personnel were not blinded (neither was outcome assessment), and most were short-term and incompletely reported.For this update we prespecified seven main outcomes of interest: clinical response (clinically significant response, aggression/agitation), leaving the study early (acceptability of treatment, overall tolerability), adverse events (sedation, weight gain) and quality of life.Adding valproate to antipsychotic treatment resulted in more clinically significant response than adding placebo to antipsychotic drugs (14 RCTs, n = 1049, RR 1.31, 95% CI 1.16 to 1.47, I = 12%, low-quality evidence). However, this effect was removed after excluding open RCTs in a sensitivity analysis. In terms of acceptability of treatment (measured by the number of participants leaving the study early due to any reason) valproate was just as acceptable as placebo (11 RCTs, n = 951, RR 0.76, 95% CI 0.47 to 1.24, I = 55%). Also overall tolerability (measured by the number of participants leaving the study early for adverse events) between valproate and placebo was similar (6 RCTs, n = 974, RR 1.33, 95% CI 0.90 to 1.97, I = 0).Participants in the valproate group were found to be less aggressive than the control group based on the Modified Overt Aggression Scale (3 RCTs, n = 186, MD -2.55, 95% CI -3.92 to -1.19, I = 82%, very low-quality evidence). Participants receiving valproate more frequently experienced sedation (8 RCTs, n = 770, RR 1.38, 95% CI 1.07 to 1.79, I = 0, low-quality evidence) but were no more likely to gain weight than those receiving placebo (4 RCTs, n = 427, RR 1.17, 95% CI 0.76 to 1.82, I = 0, low-quality evidence). No study reported on the important outcome of quality of life. AUTHORS' CONCLUSIONS: There is limited evidence, based on a number of trials, that the augmentation of antipsychotics with valproate may be effective for overall clinical response, and also for specific symptoms, especially in terms of excitement and aggression. However, this evidence was entirely based on open RCTs. Moreover, valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups. Further randomised studies which are blinded are necessary before any clear recommendation can be made. Ideally these would focus on people with schizophrenia and aggression, on those with treatment-resistant forms of the illness and on those with schizoaffective disorders.
背景:许多精神分裂症患者采用普通抗精神病药物治疗未能取得满意的治疗效果。在这些情况下,会使用各种辅助药物,丙戊酸盐就是其中之一。 目的:探讨:1. 单独使用丙戊酸盐对精神分裂症和分裂情感性精神病是否有效;2. 丙戊酸盐联合抗精神病药物对上述疾病是否有效。 检索方法:我们检索了Cochrane精神分裂症研究组的试验注册库(2002年7月;2007年2月;2012年7月;2016年4月3日)。我们还联系了制药公司和相关研究的作者以识别更多试验。 入选标准:我们纳入了所有比较丙戊酸盐与抗精神病药物或安慰剂(或无干预)的随机对照试验,无论是作为单一药物还是作为抗精神病药物的辅助药物用于治疗精神分裂症或类精神分裂症患者。 数据收集与分析:我们独立检查了文献引用,并在可能的情况下检查了摘要、订购论文,并对这些进行了重新检查和质量评估。至少两名综述作者独立提取数据。我们使用风险比(RR)及其95%置信区间(CI)分析二分数据。我们使用平均差(MD)及其95%CI分析连续数据。我们评估了纳入研究的偏倚风险,并使用GRADE(推荐分级评估、制定与评价)创建了一个“结果总结”表。 主要结果:2012年更新检索识别出另外19项相关研究,其中大多数来自中国。因此,本综述目前包括26项研究,共2184名参与者。所有试验均考察了丙戊酸盐作为抗精神病药物辅助药物的有效性。除两项研究外,这些研究规模较小,参与者和研究人员未设盲(结果评估也未设盲),且大多数为短期研究且报告不完整。 对于本次更新,我们预先设定了七个主要关注结果:临床反应(具有临床意义的反应、攻击/激越)、提前退出研究(治疗的可接受性、总体耐受性)、不良事件(镇静、体重增加)和生活质量。 在抗精神病药物治疗中添加丙戊酸盐比添加安慰剂产生了更多具有临床意义的反应(14项随机对照试验,n = 1049,RR 1.31,95%CI 1.16至1.47,I² = 12%,低质量证据)。然而,在敏感性分析中排除开放随机对照试验后,这种效果消失。就治疗的可接受性(通过因任何原因提前退出研究的参与者数量衡量)而言,丙戊酸盐与安慰剂一样可接受(11项随机对照试验,n = 951,RR 0.76,95%CI 0.47至1.24,I² = 55%)。丙戊酸盐与安慰剂之间的总体耐受性(通过因不良事件提前退出研究的参与者数量衡量)也相似(6项随机对照试验,n = 974,RR 1.33,95%CI 0.90至1.97,I² = 0)。 根据改良外显攻击量表,丙戊酸盐组的参与者比对照组攻击性更低(3项随机对照试验,n = 186,MD -2.55,95%CI -3.92至-1.19,I² = 82%,极低质量证据)。接受丙戊酸盐治疗的参与者更频繁地出现镇静(8项随机对照试验,n = 770,RR 1.38,95%CI 1.07至1.79,I² = 0,低质量证据),但体重增加的可能性并不比接受安慰剂的参与者更高(4项随机对照试验,n = 427,RR 1.17,95%CI 0.76至1.82,I² = 0,低质量证据)。没有研究报告生活质量这一重要结果。 作者结论:基于多项试验,有有限的证据表明丙戊酸盐联合抗精神病药物可能对总体临床反应有效,对特定症状也有效,尤其是在兴奋和攻击方面。然而,这一证据完全基于开放随机对照试验。此外,丙戊酸盐与一些不良事件相关,其中镇静和头晕出现的频率明显高于对照组。在做出明确推荐之前,有必要进行更多的随机双盲研究。理想情况下,这些研究应聚焦于患有精神分裂症且有攻击行为的患者、难治性精神分裂症患者以及分裂情感性障碍患者。
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