Behavioural Neurology / 2016 / Article / Tab 2

Review Article

Pediatric Traumatic Brain Injury and Autism: Elucidating Shared Mechanisms

Table 2

Selected compounds under consideration for the treatment of ASD.

TargetCompoundPutative mechanism of actionStudy designMajor findingsRefs

GlutamateAFQ056mGluR5 antagonistRandomized, double-blind, placebo-controlled crossover study in patients with Fragile X Syndrome (FXS), the most common inherited cause of intellectual disability and autism; (i) No significant effects overall on Aberrant Behavior Checklist–Community Edition (ABC-C) score or repetitive behaviors
(ii) Patients with full FMR1 promoter methylation had improved ABC-C score, while those with partial promoter methylation had no response
(iii) Most common adverse events were fatigue and headache
Memantine NMDA antagonistOpen-label, add-on therapy offered to 151 patients with ASD(i) Improvements on language function, social behavior, and self-stimulatory behaviors, although self-stimulatory behaviors comparatively improved to a lesser degree[23]
Open-label retrospective study in youths with ASD; (i) Eleven responders [rating of “much improved” or “very much improved” on the Clinical Global Impressions-Improvement scale (CGI-I)]
(ii) Improvement was primarily seen clinically in social withdrawal and inattention
(iii) Adverse effects occurred in seven subjects patients and led to drug discontinuation in 4 of 18 (22%) patients.
Randomized, double-blind, placebo-controlled, 10-week study in children with autism; (i) Adjunct therapy to risperidone produced greater reduction in ABC-C subscale scores for irritability, stereotypic behavior, and hyperactivity
(ii) Most common adverse events were sedation and dizziness
Open-label, 8-week trial in children with ASD; (i) Significant improvement on memory test (Children’s Memory Scale Dot Learning Subtest)
(ii) No significant effects on expressive or receptive language or nonverbal IQ
(iii) Significant improvements on a number of ABC subscales, including hyperactivity, lethargy, and irritability.
Open-label trial with patients with FXS and ASD; (i) Four showed global clinical benefit on ratings with the CGI-I
(ii) No significant effects on symptom specific rating scales (ABC subscales)

agonistRandomized, double-blind, placebo-controlled crossover study in patients with FXS; (i) No significant effects on ABC-Irritability (ABC-I) subscale or on irritability
(ii) Favorable effects on social function, with improvements on the ABC-Social Avoidance scale and Vineland II–Socialization raw score
(iii) Most common adverse events were sedation and headache
Open-label, 8-week trial in children and adolescents with ASD and a score ≥ 17 on the ABC-I subscale; (i) Improvements on ABC-I and the Lethargy/Social Withdrawal subscales, the Social Responsiveness Scale, the CY-BOCS-PDD, and clinical global impression scales
(ii) Most common adverse events were transient agitation and irritability, which were often felt to represent spontaneous variation in underlying symptoms
Acamprosate agonist and mGluR5 antagonistOpen-label trial in youths with autism; (i) Five subjects (mean age, 9.5 years) had improvements in social functioning
(ii) Well-tolerated, with mild gastrointestinal adverse effects noted in three subjects
Open-label trial in adults with FXS and autism; (i) All three subjects had improved linguistic communication over an average of 21.3 weeks of treatment
(ii) Also showed global clinical benefit as rated with the CGI-I scale
Open-label, 10-week trial in youths with FXS; (i) Associated with improvement in social behavior and a reduction in inattention/hyperactivity
(ii) Pre- and posttreatment blood biomarker analyses looking at brain-derived neurotrophic factor (BDNF) levels found a significant increase in BDNF with treatment
Single-blind, placebo lead-in, 12-week study in youths with autism; (i) Six responders (rating of “very much improved” or “much improved” on the CGI-I scale and ≥25% improvement on the ABC-Social Withdrawal subscale)[33]

Neuropeptide Oxytocin Oxytocin receptorRandomized, double-blind, placebo-controlled trial in male youths with ADS; (i) No significant effects on emotion recognition, social interaction skills, or general behavioral adjustment[34]
Randomized, double-blind, placebo-controlled crossover trial in adults with ASD; (i) Significant improvements in affective speech comprehension from pre- to postinfusion[35]
Randomized, double-blind, placebo-controlled crossover trial in male youths with ASD; (i) Improved performance on the Reading the Mind in the Eyes Task (RMET), a test of emotion recognition[36]
Randomized, double-blind, placebo-controlled crossover trial in adults with ASD; (i) Significant reduction in repetitive behaviors[37]
Randomized, double-blind, placebo-controlled cross over trial in adults with ADS; (i) Improved social interactions in a simulated ball game where participants interacted with fictitious partners
(ii) Increased subjects’ gazing time on the socially informative region of the face, namely the eyes, during free viewing of pictures of faces
Randomized, double-blind, placebo-controlled, parallel trial in adults with ASD; (i) No significant effects on measures of social function/cognition (the Diagnostic Analysis of Nonverbal Accuracy) and repetitive measures (Repetitive Behavior Scale Revised)
(ii) Improvements in measures of social cognition (RMET), and quality of life (World Health Organization Quality of Life Questionnaire-Emotion)

Ach DonepezilAcetylcholinesterase inhibitor (AChEI)Open-label retrospective study in youths with autism; (i) Four had significant improvements in irritability and hyperactivity
(ii) No changes in the inappropriate speech, lethargy, or stereotypes
Randomized, double-blind, placebo-controlled, 10-week trial in youths with ADS; (i) Despite improvement on a number of executive functioning measures, no statistically significant difference found compared to placebo[41]
GalantamineAChEIOpen-label trial in adults with autism; (i) Decreased aggressive behavior in one and modest improvement on verbal fluency in the other two[42]
RivastigmineAChEIOpen-label, 12-week trial in children with autism; (i) Significant improvements in expressive speech and overall autistic behavior over baseline[43]

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