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.

Guanfacine for Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder, and/or Oppositional Defiance Disorder

“…All 4 systematic reviews had broader search inclusion criteria than relevant to this report. Two included systematic reviews, 1 with 203 eligible RCTs, 21 and the other with 8 eligible RCTs, 22 had 1 relevant RCT each reporting about guanfacine. Both these systematic reviews included only double-blinded RCTs.…”

“…24 It was not specified whether the included RCTs were blinded. 24 The systematic reviews included articles from 1980 to November 2021, 21 database inception to April 2021, 23 from database inception to September 2017, 22 and to up to March 29, 2017. 24 The systematic reviews had some overlap.…”

“…One systematic review included children and adults (analyzed separately) diagnosed with ASD using at least Diagnostic and Statistical Manual (DSM)-III or other validated diagnostic tools. 21 Two systematic reviews included individuals diagnosed with ADHD. 23,24 One systematic review, included children and adults diagnosed with primary ADHD according to DSM-III, DSM-III-R, DSM-IV(TR), DSM-5, International Classification of Disease (ICD)-9, or ICD-10.…”

“…22 In the systematic reviews without age restriction, the studies pertaining to guanfacine were done in children only. 21,23 One of the RCTs was conducted in children aged 6 to 12 years with a primary diagnosis of predominantly inattentive, hyperactive or impulsive, or combined subtype based on DSM-IV diagnosis of ADHD. The children had to be taking a stable methylphenidate or amphetamine (stimulant) regimen for at least 30 days with ongoing executive function difficulties.…”

“…One systematic review included dietary-supplements in addition to medications, except for those given in combination with behavioural interventions or risperidone. 21 Findings comparing guanfacine to dietary-supplements were not included in this review. Another systematic review specified amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate and modafinil given as oral therapy, alone or in combination with other drugs.…”