Table 1.

Examples of preclinical and clinical evaluations of drug treatments for autism

Mechanistic class	Preclinical model	Compound	Preclinical phenotype rescues	Reference
mGluR5 modulation	BTBR C58/J	MPEP MTEP GRN529	Improved sociability Reduced repetitive behavior Improved cognition	Silverman et al. (2010a), Silverman et al. (2012) and Seese et al. (2014)
	Fmr1	AFQ056 CTEP MTEP MPEP Fenobam JNJ16259685	Rescued abnormal dendritic spine morphology Corrected excessive protein synthesis Normalized altered long-term depression Reduced seizure susceptibility Decreased hyperactivity Rescued cognitive deficits Rescued sensorimotor gating Reduced repetitive behavior	Yan et al. (2005b), De Vrij et al. (2008), Busquets-Garcia et al. (2013), Michalon et al. (2012), Gantois et al. (2013), Thomas et al. (2012), Gandhi et al. (2014) and Pop et al. (2014)
	Shank2	CDPPB	Restored abnormal long-term potentiation and long-term depression Improved sociability	Won et al. (2012)
	Valproic acid	MPEP	Reduced repetitive behavior	Mehta et al. (2011)
	Clinical population	Treatment	Phase	Reference*
	ASD—5 to 17 years old	Acamprosate	Phases 2 and 3; single-blind placebo lead-in trial	NCT01813318; Erickson et al. (2014b)
	ASD—6 to 13	Acamprosate	Open label	Erickson et al. (2011a)
	Fragile X males with ASD—18 to 23 years old	Acamprosate	Open label	Erickson et al. (2010)
	Fragile X—5 to 17 years old	Acamprosate	Phase 3; open label	NCT01300923; Erickson et al. (2013)
	Fragile X—3 to 11 years old	AFQ056	Phase 1	NCT01482143
	Fragile X—12 to 17 years old	AFQ056	Phases 2 and 3	NCT01357239, NCT01433354
	Fragile X—18 to 45 years old	AFQ056	Phase 2	NCT01253629, NCT01348087, NCT00718341
	Fragile X—5 to 13 years old	RO4917523	Phase 2	NCT01750957
	Fragile X—14 to 50 years old	RO4917523	Phase 2	NCT01517698, NCT01015430
GABAB modulation	BTBR C58/J	R-Baclofen	Improved sociability Reduced repetitive behavior	Silverman et al. (2015)
	Fmr1	STX209 (Arbaclofen)	Normalized normal dendritic spine morphology Corrected excessive protein synthesis Reduced seizure susceptibility	Henderson et al. (2012)
	NMDA NR1 subunit knockout mice	Racemic baclofen	Improved excitation/inhibition balance Rescued gamma EEG band deficits Reduced hyperactivity Rescued sensorimotor gating deficits	Gandal et al. (2012)
	Clinical population	Treatment	Phase	Reference*
	ASD—5 to 21 years old	STX209 (Arbaclofen)	Phases 2 and 3	NCT01706523, NCT01288716; Frye (2014)
	ASD—6 to 17 years old	STX209 (Arbaclofen)	Phase 2; open label	NCT00846547; Erickson et al. (2014a) and Frye (2014)
	Fragile X—6 to 40 years old	STX209 (Arbaclofen)	Phase 2	NCT00788073; Berry-Kravis et al. (2012)
	Fragile X—12 to 50 years old	STX209 (Arbaclofen)	Phase 3	NCT01282268
GABAA modulation	BTBR	Diazepam Low dose of benzodiazepines L-838,417	Increased GABAergic inhibitory neurotransmission Improved social interactions Ameliorated cognitive deficits	Pobbe et al. (2011) and Han et al. (2014)
	Clinical population	Treatment	Phase	Reference*
	ASD—18 to 45 years old	Pregnanolone	Phase 2	NCT01881737
	High functioning ASD—18 to 35 years old	AZ7325	Phase 2	NCT01966679
mTOR inhibitors	BTBR	Rapamycin	Improved sociability	Burket et al. (2014)
	Pten	Rapamycin RAD001 (Everolimus)	Improved macrocephaly Inhibits neuronal hypertrophy Improved abnormal sociability Reduced seizures	Zhou et al. (2009)
	Tsc1		Improved survival rates and weight gain Prevented seizures Ameliorated abnormal EEG Improved neuronal morphology Prevented cell loss Restored myelination abnormalities Improved motor phenotypes Improved sociability Ameliorated cognitive deficits	Meikle et al. (2008), Zeng et al. (2008), Sato et al. (2012) and Tsai et al. (2012)
	Tsc2		Improved cognition Improved sociability	Ehninger et al. (2008) and Sato et al. (2012)
	Fmr1	Temsirolimus	Rescued cognitive impairment Reduced seizure susceptibility	Busquets-Garcia et al. (2013)
	Clinical population	Treatment	Phase	Reference*
	Tuberous sclerosis complex—4 to 15 years old	Rapamycin (Sirolimus) RAD001 (Everolimus)	Phases 2 and 3	NCT01730209
	Tuberous sclerosis complex—2 to 61 years old		Phases 1, 2, and 3	NCT01929642, NCT00789828, NCT00790400, NCT00411619; Krueger et al. (2010), Tillema et al. (2012), Bissler et al. (2013) and Franz et al. (2013), Krueger et al. (2013)
Neuropeptides	BTBR	Oxytocin	No behavioral effects	Bales et al. (2014)
	C57BL6/J		Reduced several social behaviors	Huang et al. (2014)
	C58/J		Improved sociability	Teng et al. (2013)
	Oxytocin knockout mice		Improved sociability	Ferguson et al. (2001)
	Oxytocin receptor mice		Improved sociability Restored cognitive inflexibility	Sala et al. (2011)
	Clinical population	Treatment	Phase	Reference*
	ASD—3 to 17 years old	Oxytocin	Phases 2 and 3	NCT01944046, NCT01308749, NCT01624194; Tachibana et al. (2013)
	ASD—12 to 17 years old			NCT01417026, NCT02090829, NCT01931033, NCT02007447, ACTRN12609000513213; Guastella et al. (2014)
	ASD—18 to 60 years old			NCT00490802, NCT01337687, NCT01788072; Hollander et al. (2003) and Lin et al. (2014)
	ASD—21 to 38 years old		Randomized cross-over double-blind study	UMIN000002241, UMIN000004393; Aoki et al. (2014a, b) and Watanabe et al. (2014)
	ASD—19 to 56 years old		Randomized, placebo-controlled, double-blind study	Hollander et al. (2007)
	ASD—6 to 12 years old	Vasopressin	Phase 2	NCT01962870
	ASD—18 to 55 years old	RG-7314	Phase 2	NCT01793441
Growth factors	Fmr1	BDNF	Rescued long-term potentiation abnormalities	Lauterborn et al. (2007)
	Shank3	IGF1	Improved long-term potentiation	Bozdagi et al. (2013)
	Mecp2−/−		Reversed respiration deficits	Tropea et al. (2009)
	Clinical population	Treatment	Phase	Reference*
	ASD—5 to 12 years old	IGF1	Phase 2	NCT01970345
	22q13 deletion (Phelan-McDermid syndrome)			NCT01525901
	Rett syndrome—4 to 11 years old	IGF1	Pilot study; case study	Pini et al. (2012, 2014)
NMDA glutamate receptor modulation	Fmr1	Memantine	Corrected spine morphology	Wei et al. (2012)
	Shank2	D-cycloserine	Improved sociability	Won et al. (2012)
	Clinical population	Treatment	Phase	Reference
	ASD—3 to 12 years old	D-cycloserine	Phase 3; Prospective, open label study	NCT00198120; Owley et al. (2006)
	ASD—14 to 25 years old		Pilot study; double-blind randomized trial	Posey et al. (2004) and Urbano et al. (2014)
	ASD—2 to 26 years old	Memantine	Open label; retrospective study	Chez et al. (2007) and Erickson et al. (2007)
	ASD—6 to 12 years old		Phase 2	NCT01592786, NCT01592773
	ASD—13 to 17 years old		Phase 3	NCT01972074
	ASD—18 to 85 years old		Phase 4	NCT01078844, NCT01333865
AMPA glutamate receptor modulation	BTBR	AMPAkines CX546 CX1837 CX1739	Improved facets of sociability	Silverman et al. (2013)
	Mecp2		Reversed respiration deficits	Ogier et al. (2007)
	Clinical population	Treatment	Phase	Reference*
	Fragile X or ASD—18 to 50 years old	CX516	Phase 2	NCT00054730; Berry-Kravis et al. (2006)
Atypical antipsychotics	BTBR	Risperidone M100907	Improved reversal learning	Amodeo et al. (2014a)
		Risperidone	Failed to improve sociability	Chadman (2011) and Gould et al. (2011)
	Cntnap2	Risperidone	Reduced hyperactivity Decreased repetitive behavior	Penagarikano et al. (2011)
	Clinical population	Treatment	Phase	Reference*
	ASD—30 months to 17 years old	Aripiprazole	Phase 2, 3 and 4	NCT00619190, NCT01617447, NCT00337571, NCT02069977, NCT00198107
	ASD—12 to 18 years old	Aripiprazole	Phase 2	NCT00208533
		Ziprasidone	Phase 2	NCT00208559
	ASD—5 to 18 years old	Aripiprazole	Phases 3 and 4; Pilot study; Open label, Chart review	NCT00332241, NCT00337571, NCT01227668, NCT00365859;, Marcus et al. (2009), Owen et al. (2009), Blankenship et al. (2010), Marcus et al. (2011a, b), Robb et al. (2011), Varni et al. (2012), Ishitobi et al. (2013), Mankoski et al. (2013), Findling et al. (2014), Maloney et al. (2014) and Adler et al. (2015)
		Risperidone	Phases 2, 3, and 4; Open label; Randomized, double-blind trial	NCT01171937, NCT00576732, NCT01624675, NCT00005014; McDougle et al. (2000), McCracken et al. (2002), McDougle et al. (2005), Rausch et al. (2005), Desousa (2010), Handen et al. (2013), Kent et al. (2013a, b), Scahill et al. (2013), Ghaeli et al. (2014) and Ghanizadeh and Ayoobzadehshirazi (2015)
		Lurasidone	Phase 3	NCT01911442
	Fragile X—6 to 25 years old	Aripiprazole	Open label	Erickson et al. (2011b)
Serotonin reuptake inhibitors	BTBR	Busprione	Enhanced social interactions	Gould et al. (2011)
		Fluoxetine	Increased sociability	Chadman (2011) and Gould et al. (2011)
	Fmr1		Reduced anxiety Reduced locomotor activity	Uutela et al. (2014)
	Clinical population	Treatment	Phase	Reference*
	ASD—2 to 6 years old	Buspirone	Phase 2	NCT00873509
	ASD—6 to 17 years old		Open label	NCT01850355, IRCT201307303930N28; Ghanizadeh and Ayoobzadehshirazi (2015)
	ASD—5 to 17 years old	Citalopram	Phase 2; Randomized controlled trial	NCT00086645, NCT00211770; King et al. (2009)
		Fluoxetine	Phase 3; Open label; Placebo-controlled crossover trial	NCT00515320, ACTRN12608000173392; Buchsbaum et al. (2001), Hollander et al. (2005), Desousa (2010), Chantiluke et al. (2014a, b) and Mouti et al. (2014)
	ASD—3 to 10 years old	Fluvoxamine Sertraline	Phase 3	NCT00655174
	ASD—3 to 12 years old	Olanzapine	Phase 2	NCT00057408
	ASD—6 to 16 years old		Open pilot study; double-blind, placebo-controlled trial	Potenza et al. (1999), Malone et al. (2001), Kemner et al. (2002) and Hollander et al. (2006)
	ASD—18 to 39 years old	Sertraline	Open label	McDougle et al. (1998)
	ASD—18 to 53 years old	Fluvoxamine	Double-blind, placebo-controlled trial	McDougle et al. (1996)
	ASD—18 to 65 years old	Fluoxetine	Double-blind, placebo-controlled trial; open trial	NCT00027404; Fatemi et al. (1998) and Hollander et al. (2012)
	Fragile X—12 to 50 months old	Sertraline	Retrospective chart review	Indah Winarni et al. (2012)
Acetylcholine modulation	BTBR	Donepezil	Improved cognitive flexibility Enhanced sociability	Karvat and Kimchi (2014)
	Valproic acid		Improved sociability Reduced repetitive behavior Reduced hyperactivity	Kim et al. (2014a)
	Clinical population	Treatment	Phase	Reference*
	ASD—22 to 44 months	Donepezil	Phase 2	NCT01887132
	ASD—2 to 7 years old		Open label	Buckley et al. (2011)
	ASD—7 to 19 years old		Double-blind, placebo-controlled trial	Hardan and Handen (2002) and Handen et al. (2011)
	ASD—10 to 18 years old		Phase 4	NCT01098383
	ASD—4 to 12 years old	Mecamylamine	Phase 2	NCT00773812; Arnold et al. (2012)
	Fragile X males—6 to 15 years old	Donepezil	Randomized, double-blind, placebo-controlled pilot study	CTRI-2008-000229; Sahu et al. (2013)

^aIdentifier numbers for clinical trials were indexed from clinicaltrials.gov (NCT), anzctr.org.au (ACTRN), umin.ac.jp/ctr (UMIN), irct.ir (IRCT), and ctri.nic.in/Clinicaltrials (CTRI) Web sites