TABLE 1.

Randomized control trials (RCT) with excitatory/inhibitory (E/I) modulators in ASD.

	RCT	Age of participants and number (N)	Medication dosage mg/day	Effect size (d)	Outcome measures	Main findings
Arbaclofen
Veenstra-VanderWeele et al., 2017	12 week randomized placebo-controlled	5–21 years N = 150	5–10 mg	NS	ABC, CGI	No differences between placebo and treatment. CGI scores improvement
Bumetanide
Lemonnier et al., 2012 Lemonnier et al., 2017	12 week randomized double-blind 12 week randomized, double-blind, placebo-controlled (phase 2B trial)	3–11 years N = 60 2–17 years N = 88	0.5 mg 0.5, 1.0- 2.0 mg twice daily	NS	CARS, CGI, ADOS CARS, CGI, SRS	No differences between placebo and treatment CGI scores improvement CARS, CGI, SRS scores significantly improved
Memantine
Ghaleiha et al., 2013 Aman et al., 2017	10 week, double-blind (1) 12 week parallel-group, flexible-dose (2) 48 week open-label extension	4–12 years N = 40 6–12 years N = 121 N = 102	5 mg daily Weight 60 kg, max 15 mg/day; 40–59 kg, max 9 mg/day; 20–39 kg, max 6 mg/day; <20 kg, max 3 mg/day.	NS NS	ABC-C SRS	Significant improvement in irritability, stereotyped behaviors and hyperactivity in memantine treated group No differences between placebo and treatment at the end of week 12 Trend of improvement at the end of week 48 extension
N-acetyl cysteine (NAC)
Hardan et al., 2012 Ghanizadeh and Moghimi-Sarani, 2013 Nikoo et al., 2015 Dean et al., 2017 Wink et al., 2016	12 week, double-blind, placebo-controlled 8 week double-blind placebo-controlled 10 week randomized, double-blind, placebo-controlled 6 months double-blind, placebo-controlled 12-week randomized, double-blind, placebo-controlled	3.2–10.7 years N = 33 3.5–16 years N = 40 4–12 years N = 40 3.1–9.9 years N = 98 4–12 years N = 31	900 mg daily for 4 weeks, then 900 mg twice-daily for 4 weeks and 900 mg three-times-daily for 4 weeks 1,200 mg daily Risperidone 1- 2 mg/d; NAC 600–900 mg/day 500 mg/day Target dose of NAC: 60 mg/kg/day	0.96 NS 0.99 NS 0.7 NS 0.75 NS NS NS	ABC-I ABC-Stereotypy subscale SRS social SRS ABC-I ABC-SW ABC–I ABC-SW ABC-C irritability subscale SRS, CCC2, RBS-R CGI-I	Significant improvements on ABC-Irritability subscale Significant improvements in the group treated with NAC + risperidone vs. placebo + risperidone treated group Significant reduction in irritability and hyperactivity scales in the group treated with NAC + risperidone vs. placebo + risperidone treated group No significant differences between placebo and NAC treated group on any of the outcome measure No significant improvement on social impairment between NAC and placebo groups

ADOS, Autism Diagnostic Observation Scale; ABC, Aberrant Behavior Checklist; ABC-I, ABC-Irritability subscale; ABC-SW, ABC-Social Withdrawal subscale; ABC-C, ABC–Communication Scale; CARS, Childhood Autism Rating Scale; CGI-I, CGI-Improvement; CGI-S, CGI-Severity Scale; CGI-TI, CGI Therapeutic Index; CCC-2, Children’s Communication Checklist; RBS-R, Repetitive Behaviors Scale-Revised; SRS, Social Responsiveness Scale; NS, not significant.