Pharmacological and dietary-supplement treatments for autism spectrum disorder: a systematic review and network meta-analysis

Abstract

Background: 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.

Methods: 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.

Results: 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.

Limitations: 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.

Conclusions: 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.

Keywords: ADHD; Anxiety; Autism; Caregiver stress; Irritability; Meta-analysis; Response; Restricted and repetitive behaviors; Social communication; Treatment.

Fig. 1

Forest plots of network meta-analysis for the primary outcomes, i.e., social-communication difficulties (SCD), repetitive behaviors (RB), and overall core symptoms (OCS), in children/adolescents and adults. Placebo was used as reference. The squares and bars represent the effect-sizes (standardized mean differences-SMD) along with their 95% confidence intervals. The size of the square is proportional to the inverse standard error of the effect size. The color represents confidence in the estimates as evaluated with the CINeMA framework, i.e., blue = moderate, yellow = low, and red = very low. SMDs > 0 indicate more improvement with the medication in comparison with placebo, SMDs = 0 indicate no difference between medication and placebo, and SMDs < 0 indicate less improvement with the medication in comparison with placebo. SMDs could be interpreted as small (SMD =|0.2|), medium (SMD =|0.5|) and large (SMD =|0.8|), and these thresholds are presented with dashed lines. k = total number of studies for the intervention; n = total number of participants on the intervention

Fig. 2

Summary forest plots for commonly used medications, i.e., antipsychotics, ADHD medications, antiepileptic/mood-stabilizers, sleep medications. Effect-sizes (standardized mean differences—SMDs and their 95% confidence intervals) of comparisons with placebo are presented for each medication, outcome and age group. SMDs are presented with squares in children/adolescents and circles in adults, and their size is proportional to the inverse standard error of the effect size. For dichotomous outcomes (response, dropouts due to any cause or adverse event, any adverse event, sedation, weight gain, extrapyramidal symptoms), odds ratios were converted to SMDs. The results are based on network meta-analysis, except for irritability, response, sedation, weight gain and extrapyramidal symptoms (EPS) in children/adolescents, since pairwise meta-analyses were conducted due to incoherence or disconnected networks. SMDs > 0 indicate more improvement or fewer dropouts/adverse events with the medication in comparison with placebo, SMDs = 0 indicate no difference between medication and placebo, and SMDs < 0 indicate less improvement or more dropouts/adverse events with the medication in comparison with placebo. SMDs could be interpreted as small (SMD =|0.2|), medium (SMD =|0.5|) and large (SMD =|0.8|), and these thresholds are presented with dashed lines. There were no usable data for methylphenidate, and effect-sizes for this drug are not presented. k = total number of studies for the intervention with data for at least an outcome and age group, n = total number of participants on the intervention with data for at least an outcome and age group. EPS extrapyramidal symptoms, RB repetitive behaviors, SCD social-communication difficulties

Fig. 3

Summary forest plots for experimental medications. Effect-sizes (standardized mean differences—SMDs and their 95% confidence intervals) of comparisons with placebo are presented for each medication, outcome and age group. SMDs are presented with squares in children/adolescents and circles in adults, and their size is proportional to the inverse standard error of the effect size. For dichotomous outcomes (response, dropouts due to any cause or adverse event, any adverse event, sedation, weight gain, extrapyramidal symptoms), odds ratios were converted to SMDs. The results are based on network meta-analysis, except for irritability, response, sedation, weight gain and extrapyramidal symptoms (EPS) in children/adolescents, since pairwise meta-analyses were conducted due to incoherence or disconnected networks. SMDs > 0 indicate more improvement or fewer dropouts/adverse events with the medication in comparison with placebo, SMDs = 0 indicate no difference between medication and placebo, and SMDs < 0 indicate less improvement or more dropouts/adverse events with the medication in comparison with placebo. SMDs could be interpreted as small (SMD =|0.2|), medium (SMD =|0.5|) and large (SMD =|0.8|), and these thresholds are presented with dashed lines. There were no usable data for dextromethorphan/quinidine and effect-sizes for this drug are not presented. k = total number of studies for the intervention with data for at least an outcome and age group; n = total number of participants on the intervention with data for at least an outcome and age group; EPS: extrapyramidal symptoms, IGOH: oral human immunoglobulin; RB: repetitive behaviors; SCD: social-communication difficulties

Fig. 4

Summary plots for dietary-supplements. Effect-sizes (standardized mean differences—SMDs and their 95% confidence intervals) of comparisons with placebo are presented for each medication, outcome and age group. SMDs are presented with squares in children/adolescents and circles in adults, and their size is proportional to the inverse standard error of the effect size. For dichotomous outcomes (response, dropouts due to any cause or adverse event, any adverse event, sedation, weight gain, extrapyramidal symptoms), odds ratios were converted to SMDs. The results are based on network meta-analysis, except for irritability, response, sedation, weight gain and extrapyramidal symptoms (EPS) in children/adolescents, since pairwise meta-analyses were conducted due to incoherence or disconnected networks. SMDs > 0 indicate more improvement or fewer dropouts/adverse events with the medication in comparison with placebo, SMDs = 0 indicate no difference between medication and placebo, and SMDs < 0 indicate less improvement or more dropouts/adverse events with the medication in comparison with placebo. SMDs could be interpreted as small (SMD =|0.2|), medium (SMD =|0.5|) and large (SMD =|0.8|), and these thresholds are presented with dashed lines. There were no usable data for pyridoxine, and effect-sizes for this dietary-supplement are not presented. k = total number of studies for the intervention with data for at least an outcome and age group; n = total number of participants on the intervention with data for at least an outcome and age group. EPS extrapyramidal symptoms, IGOH oral human immunoglobulin, RB repetitive behaviors, SCD social-communication difficulties