Loy Jik H, Merry Sally N, Hetrick Sarah E, Stasiak Karolina
Child and Adolescent Mental Health, Waikato DHB, 206 Colllingwood Street, Hamilton, New Zealand.
Cochrane Database Syst Rev. 2017 Aug 9;8(8):CD008559. doi: 10.1002/14651858.CD008559.pub3.
This is an update of the original Cochrane Review, last published in 2012 (Loy 2012). Children and youths with disruptive behaviour disorders may present to health services, where they may be treated with atypical antipsychotics. There is increasing usage of atypical antipsychotics in the treatment of disruptive behaviour disorders.
To evaluate the effect and safety of atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths. The aim was to evaluate each drug separately rather than the class effect, on the grounds that each atypical antipsychotic has different pharmacologic binding profile (Stahl 2013) and that this is clinically more useful.
In January 2017, we searched CENTRAL, MEDLINE, Embase, five other databases and two trials registers.
Randomised controlled trials of atypical antipsychotics versus placebo in children and youths aged up to and including 18 years, with a diagnosis of disruptive behaviour disorders, including comorbid ADHD. The primary outcomes were aggression, conduct problems and adverse events (i.e. weight gain/changes and metabolic parameters). The secondary outcomes were general functioning, noncompliance, other adverse events, social functioning, family functioning, parent satisfaction and school functioning.
We used standard methodological procedures expected by Cochrane. Two review authors (JL and KS) independently collected, evaluated and extracted data. We used the GRADE approach to assess the quality of the evidence. We performed meta-analyses for each of our primary outcomes, except for metabolic parameters, due to inadequate outcome data.
We included 10 trials (spanning 2000 to 2014), involving a total of 896 children and youths aged five to 18 years. Bar two trials, all came from an outpatient setting. Eight trials assessed risperidone, one assessed quetiapine and one assessed ziprasidone. Nine trials assessed acute efficacy (over four to 10 weeks); one of which combined treatment with stimulant medication and parent training. One trial was a six-month maintenance trial assessing symptom recurrence.The quality of the evidence ranged from low to moderate. Nine studies had some degree of pharmaceutical support/funding. Primary outcomesUsing the mean difference (MD), we combined data from three studies (238 participants) in a meta-analysis of aggression, as assessed using the Aberrant Behaviour Checklist (ABC) ‒ Irritability subscale. We found that youths treated with risperidone show reduced aggression compared to youths treated with placebo (MD -6.49, 95% confidence interval (CI) -8.79 to -4.19; low-quality evidence). Using the standardised mean difference (SMD), we pooled data from two risperidone trials (190 participants), which used different scales: the Overt Aggression Scale ‒ Modified (OAS-M) Scale and the Antisocial Behaviour Scale (ABS); as the ABS had two subscales that could not be combined (reactive and proactive aggression), we performed two separate analyses. When we combined the ABS Reactive subscale and the OAS-M, the SMD was -1.30 in favour of risperidone (95% CI -2.21 to -0.40, moderate-quality evidence). When we combined the ABS Proactive subscale and OAS-M, the SMD was -1.12 (95% CI -2.30 to 0.06, moderate-quality evidence), suggesting uncertainty about the estimate of effect, as the confidence intervals overlapped the null value. In summary, there was some evidence that aggression could be reduced by risperidone. Data were lacking on other atypical antipsychotics, like quetiapine and ziprasidone, with regard to their effects on aggression.We pooled data from two risperidone trials (225 participants) in a meta-analysis of conduct problems, as assessed using the Nisonger Child Behaviour Rating Form ‒ Conduct Problem subscale (NCBRF-CP). This yielded a final mean score that was 8.61 points lower in the risperidone group compared to the placebo group (95% CI -11.49 to -5.74; moderate-quality evidence).We investigated the effect on weight by performing two meta-analyses. We wanted to distinguish between the effects of antipsychotic medication only and the combined effect with stimulants, since the latter can have a counteracting effect on weight gain due to appetite suppression. Pooling two trials with risperidone only (138 participants), we found that participants on risperidone gained 2.37 kilograms (kg) more (95% CI 0.26 to 4.49; moderate-quality evidence) than those on placebo. When we added a trial where all participants received a combination of risperidone and stimulants, we found that those on the combined treatment gained 2.14 kg more (95% CI 1.04 to 3.23; 3 studies; 305 participants; low-quality evidence) than those on placebo. Secondary outcomesOut of the 10 included trials, three examined general functioning, social functioning and parent satisfaction. No trials examined family or school functioning. Data on non-compliance/attrition rate and other adverse events were available from all 10 trials.
AUTHORS' CONCLUSIONS: There is some evidence that in the short term risperidone may reduce aggression and conduct problems in children and youths with disruptive behaviour disorders There is also evidence that this intervention is associated with significant weight gain.For aggression, the difference in scores of 6.49 points on the ABC ‒ Irritability subscale (range 0 to 45) may be clinically significant. It is challenging to interpret the clinical significance of the differential findings on two different ABS subscales as it may be difficult to distinguish between reactive and proactive aggression in clinical practice. For conduct problems, the difference in scores of 8.61 points on the NCBRF-CP (range 0 to 48) is likely to be clinically significant. Weight gain remains a concern.Caution is required in interpreting the results due to the limitations of current evidence and the small number of high-quality trials. There is a lack of evidence to support the use of quetiapine, ziprasidone or any other atypical antipsychotic for disruptive behaviour disorders in children and youths and no evidence for children under five years of age. It is uncertain to what degree the efficacy found in clinical trials will translate into real-life clinical practice. Given the effectiveness of parent-training interventions in the management of these disorders, and the somewhat equivocal evidence on the efficacy of medication, it is important not to use medication alone. This is consistent with current clinical guidelines.
这是对原始Cochrane系统评价的更新，该评价上次发表于2012年（洛伊，2012年）。患有破坏性行为障碍的儿童和青少年可能会寻求医疗服务，在那里他们可能会接受非典型抗精神病药物治疗。非典型抗精神病药物在治疗破坏性行为障碍中的使用正在增加。
评估与安慰剂相比，非典型抗精神病药物治疗儿童和青少年破坏性行为障碍的疗效和安全性。目的是分别评估每种药物，而不是评估药物类别效应，因为每种非典型抗精神病药物具有不同的药理结合特性（斯塔尔，2013年），且这样做在临床上更有用。
2017年1月，我们检索了Cochrane中心对照试验注册库（CENTRAL）、医学期刊数据库（MEDLINE）、荷兰医学文摘数据库（Embase）、其他五个数据库以及两个试验注册库。
针对年龄在18岁及以下、诊断为破坏性行为障碍（包括共病注意力缺陷多动障碍（ADHD））的儿童和青少年，比较非典型抗精神病药物与安慰剂的随机对照试验。主要结局指标为攻击行为、品行问题和不良事件（即体重增加/变化和代谢参数）。次要结局指标为总体功能、不依从性、其他不良事件、社交功能、家庭功能、家长满意度和学校功能。
我们采用Cochrane系统评价预期的标准方法程序。两名综述作者（JL和KS）独立收集、评估和提取数据。我们采用GRADE方法评估证据质量。除代谢参数外，我们对每个主要结局指标进行了Meta分析，因为结局数据不足。
我们纳入了10项试验（涵盖2000年至2014年），共涉及896名5至18岁的儿童和青少年。除两项试验外，所有试验均来自门诊环境。八项试验评估了利培酮，一项试验评估了喹硫平，一项试验评估了齐拉西酮。九项试验评估了急性疗效（为期4至10周）；其中一项试验将治疗与刺激性药物和家长培训相结合。一项试验是为期六个月的维持试验，评估症状复发情况。证据质量从中等到低不等。九项研究获得了一定程度的制药公司支持/资助。
主要结局指标
使用平均差（MD），我们对三项研究（238名参与者）的数据进行了Meta分析，以评估攻击行为，攻击行为采用异常行为检查表（ABC）-易激惹分量表进行评估。我们发现，与接受安慰剂治疗的青少年相比，接受利培酮治疗的青少年攻击行为减少（MD -6.49，95%置信区间（CI）-8.79至-4.19；低质量证据）。使用标准化平均差（SMD），我们汇总了两项利培酮试验（190名参与者）的数据，这两项试验使用了不同的量表：修订版外显攻击量表（OAS-M）和反社会行为量表（ABS）；由于ABS有两个无法合并的子量表（反应性攻击和主动性攻击），我们进行了两项单独的分析。当我们将ABS反应性子量表和OAS-M合并时，支持利培酮的SMD为-1.30（95%CI -2.21至-0.40，中等质量证据）。当我们将ABS主动性子量表和OAS-M合并时，SMD为-1.12（95%CI -2.30至0.06，中等质量证据），这表明效应估计存在不确定性，因为置信区间与无效值重叠。总之，有一些证据表明利培酮可以减少攻击行为。关于喹硫平和齐拉西酮等其他非典型抗精神病药物对攻击行为的影响，缺乏相关数据。
我们汇总了两项利培酮试验（225名参与者）的数据，以评估品行问题，品行问题采用尼桑格儿童行为评定量表-品行问题子量表（NCBRF-CP）进行评估。结果显示，利培酮组的最终平均得分比安慰剂组低8.61分（95%CI -11.49至-5.74；中等质量证据）。
我们通过进行两项Meta分析来研究对体重的影响。我们希望区分仅使用抗精神病药物的效果和与刺激性药物联合使用的效果，因为后者可能因抑制食欲而对体重增加有抵消作用。汇总两项仅使用利培酮的试验（138名参与者）的数据，我们发现服用利培酮的参与者比服用安慰剂的参与者体重多增加2.37千克（kg）（95%CI 0.26至4.49；中等质量证据）。当我们纳入一项所有参与者均接受利培酮和刺激性药物联合治疗的试验时，我们发现接受联合治疗的参与者比服用安慰剂的参与者体重多增加2.14 kg（95%CI 1.04至3.23；3项研究；305名参与者；低质量证据）。
次要结局指标
在纳入的10项试验中，三项试验考察了总体功能、社交功能和家长满意度。没有试验考察家庭功能或学校功能。所有10项试验均提供了关于不依从/脱落率和其他不良事件的数据。
有一些证据表明，短期内利培酮可能会减少患有破坏性行为障碍的儿童和青少年的攻击行为和品行问题。也有证据表明，这种干预与显著的体重增加有关。
对于攻击行为，ABC-易激惹分量表上6.49分的得分差异（范围为0至45）可能具有临床意义。解释两个不同的ABS子量表上差异结果的临床意义具有挑战性，因为在临床实践中可能难以区分反应性攻击和主动性攻击。对于品行问题，NCBRF-CP上8.61分的得分差异（范围为0至48）可能具有临床意义。体重增加仍然是一个问题。
由于现有证据的局限性和高质量试验数量较少，在解释结果时需要谨慎。缺乏证据支持使用喹硫平、齐拉西酮或任何其他非典型抗精神病药物治疗儿童和青少年的破坏性行为障碍。对于五岁以下儿童，没有证据支持使用这些药物。临床试验中发现的疗效在多大程度上能转化为实际临床实践尚不确定。鉴于家长培训干预措施在管理这些疾病方面的有效性，以及药物疗效方面有些模糊的证据，重要的是不要单独使用药物。这与当前的临床指南一致。
