Abstract：
There is still no approved medication for the core symptoms of autism spectrum disorder (ASD). This network meta-analysis investigated pharmacological and dietary-supplement treatments for ASD.
We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses.
We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles.
Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms.
Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.
We searched for randomized-controlled-trials (RCTs) with a minimum duration of seven days in ClinicalTrials.gov, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (from inception up to July 8, 2018), CENTRAL and PubMed (up to November 3, 2021). The co-primary outcomes were core symptoms (social-communication difficulties-SCD, repetitive behaviors-RB, overall core symptoms-OCS) measured by validated scales and standardized-mean-differences (SMDs). Associated symptoms, e.g., irritability/aggression and attention-deficit/hyperactivity disorder (ADHD) symptoms, dropouts and important side-effects, were investigated as secondary outcomes. Studies in children/adolescents and adults were analyzed separately in random-effects pairwise and network meta-analyses.
We analyzed data for 41 drugs and 17 dietary-supplements, from 125 RCTs (n = 7450 participants) in children/adolescents and 18 RCTs (n = 1104) in adults. The following medications could improve at least one core symptom domain in comparison with placebo: aripiprazole (k = 6 studies in analysis, SCD: SMD = 0.27 95% CI [0.09, 0.44], RB: 0.48 [0.26, 0.70]), atomoxetine (k = 3, RB:0.49 [0.18, 0.80]), bumetanide (k = 4, RB: 0.35 [0.09, 0.62], OCS: 0.61 [0.31, 0.91]), and risperidone (k = 4, SCM: 0.31 [0.06, 0.55], RB: 0.60 [0.29, 0.90]; k = 3, OCS: 1.18 [0.75, 1.61]) in children/adolescents; fluoxetine (k = 1, RB: 1.20 [0.45, 1.96]), fluvoxamine (k = 1, RB: 1.04 [0.27, 1.81]), oxytocin (k = 6, RB:0.41 [0.16, 0.66]) and risperidone (k = 1, RB: 0.97 [0.21,1.74]) in adults. There were some indications of improvement by carnosine, haloperidol, folinic acid, guanfacine, omega-3-fatty-acids, probiotics, sulforaphane, tideglusib and valproate, yet imprecise and not robust. Confidence in these estimates was very low or low, except moderate for oxytocin. Medications differed substantially in improving associated symptoms, and in their side-effect profiles.
Most of the studies were inadequately powered (sample sizes of 20-80 participants), with short duration (8-13 weeks), and about a third focused on associated symptoms. Networks were mainly star-shaped, and there were indications of reporting bias. There was no optimal rating scale measuring change in core symptoms.
Some medications could improve core symptoms, although this could be likely secondary to the improvement of associated symptoms. Evidence on their efficacy and safety is preliminary; therefore, routine prescription of medications for the core symptoms cannot be recommended. Trial registration PROSPERO-ID CRD42019125317.
摘要：
目前还没有批准的药物治疗自闭症谱系障碍（ASD）的核心症状。该网络荟萃分析调查了ASD的药理和饮食补充治疗。
我们在ClinicalTrials.gov中搜索了最短持续时间为7天的随机对照试验（RCT），EMBASE,MEDLINE,PsycINFO,世卫组织-ICTRP（自成立至2018年7月8日），CENTRAL和PubMed（截至2021年11月3日）。共同主要结果是核心症状(社交沟通困难-SCD，重复行为-RB，总体核心症状-OCS）通过经过验证的量表和标准化平均差异（SMD）进行测量。相关症状，例如，易怒/攻击性和注意力缺陷/多动障碍（ADHD）症状，辍学和重要的副作用，作为次要结局进行调查。在随机效应配对和网络荟萃分析中，分别对儿童/青少年和成人的研究进行了分析。
我们分析了41种药物和17种膳食补充剂的数据，来自儿童/青少年的125项RCT（n=7450名参与者）和成人的18项RCT（n=1104）。与安慰剂相比，以下药物可以改善至少一个核心症状领域：阿立哌唑（k=6项分析研究，SCD：SMD=0.2795%CI[0.09，0.44]，RB:0.48[0.26,0.70]),托莫西汀（k=3，RB：0.49[0.18，0.80]），布美他尼（k=4，RB：0.35[0.09，0.62]，OCS:0.61[0.31,0.91]),和利培酮(k=4，SCM：0.31[0.06，0.55]，RB：0.60[0.29，0.90]；k=3，OCS：1.18[0.75，1.61]）儿童/青少年；氟西汀（k=1，RB：1.20[0.45，1.96]），氟伏沙明（k=1，RB：1.04[0.27，1.81]），成人催产素(k=6,RB:0.41[0.16,0.66])和利培酮(k=1,RB:0.97[0.21,1.74])。有一些肌肽改善的迹象，氟哌啶醇,亚叶酸,胍法辛,omega-3-脂肪酸，益生菌，萝卜硫素,tidegusib和丙戊酸盐，但不精确也不健壮。对这些估计的信心非常低或很低，除了适度的催产素。药物在改善相关症状方面有很大不同，以及他们的副作用。
大多数研究动力不足(20-80名参与者的样本量)，持续时间短（8-13周），大约三分之一的人集中在相关症状上。网络主要是星形的，并且有报告偏倚的迹象。没有测量核心症状变化的最佳评定量表。
一些药物可以改善核心症状,尽管这可能是次要的相关症状的改善。关于其有效性和安全性的证据是初步的；因此，不推荐针对核心症状的常规药物处方。试用注册PROSPERO-IDCRD42019125317。
我们在ClinicalTrials.gov中搜索了最短持续时间为7天的随机对照试验（RCT），EMBASE,MEDLINE,PsycINFO,世卫组织-ICTRP（自成立至2018年7月8日），CENTRAL和PubMed（截至2021年11月3日）。共同主要结果是核心症状(社交沟通困难-SCD，重复行为-RB，总体核心症状-OCS）通过经过验证的量表和标准化平均差异（SMD）进行测量。相关症状，例如，易怒/攻击性和注意力缺陷/多动障碍（ADHD）症状，辍学和重要的副作用，作为次要结局进行调查。在随机效应配对和网络荟萃分析中，分别对儿童/青少年和成人的研究进行了分析。
我们分析了41种药物和17种膳食补充剂的数据，来自儿童/青少年的125项RCT（n=7450名参与者）和成人的18项RCT（n=1104）。与安慰剂相比，以下药物可以改善至少一个核心症状领域：阿立哌唑（k=6项分析研究，SCD：SMD=0.2795%CI[0.09，0.44]，RB:0.48[0.26,0.70]),托莫西汀（k=3，RB：0.49[0.18，0.80]），布美他尼（k=4，RB：0.35[0.09，0.62]，OCS:0.61[0.31,0.91]),和利培酮(k=4，SCM：0.31[0.06，0.55]，RB：0.60[0.29，0.90]；k=3，OCS：1.18[0.75，1.61]）儿童/青少年；氟西汀（k=1，RB：1.20[0.45，1.96]），氟伏沙明（k=1，RB：1.04[0.27，1.81]），成人催产素(k=6,RB:0.41[0.16,0.66])和利培酮(k=1,RB:0.97[0.21,1.74])。有一些肌肽改善的迹象，氟哌啶醇,亚叶酸,胍法辛,omega-3-脂肪酸，益生菌，萝卜硫素,tidegusib和丙戊酸盐，但不精确也不健壮。对这些估计的信心非常低或很低，除了适度的催产素。药物在改善相关症状方面有很大不同，以及他们的副作用。
大多数研究动力不足(20-80名参与者的样本量)，持续时间短（8-13周），大约三分之一的人集中在相关症状上。网络主要是星形的，并且有报告偏倚的迹象。没有测量核心症状变化的最佳评定量表。
一些药物可以改善核心症状,尽管这可能是次要的相关症状的改善。关于其有效性和安全性的证据是初步的；因此，不推荐针对核心症状的常规药物处方。试用注册PROSPERO-IDCRD42019125317。
