Intranasal Vasopressin Treatment Improves Social Abilities in Children with Autism

Background: There are currently no medications that target autism spectrum disorder (ASD)’s core social deficits. However, neurobiological systems that are critical for social functioning are arguably one of the most promising for ASD therapeutic target discovery. Arginine vasopressin (AVP) is one such candidate; it plays a critical role in promoting social behavior and experimental dysregulation of the AVP signaling pathway produces social deficits in animal models.

Objectives: We tested the safety and efficacy of 4-week intranasal AVP administration to improve social abilities in children with ASD using a double-blind randomized placebo-controlled trial design.

Methods: Participants were medically healthy outpatients (N=18 males, N=4 females), aged 6 to 12 years. Participants underwent comprehensive diagnostic and behavioral testing, and blood samples for safety monitoring and biomarker quantification were obtained. Participants were then randomized 1:1 to receive either AVP treatment (a maximum of 12 IU BID or 16 IU BID based on age) or placebo treatment. The primary outcome measure was change in social ability as assessed by parent ratings on the Social Responsiveness Scale 2 (SRS-2) between baseline and after treatment. Throughout the trial, drug safety was assessed. Upon completion of treatment, SRS-2 ratings and participants’ blood samples were again obtained. Blood AVP levels and oxytocin receptor (OXTR) and AVP receptor v1a (AVPRv1a) gene expression levels were quantified via enzyme immunoassay and qPCR, respectively.

Results: Using a general linear model, including treatment (drug vs. placebo) and the biomarker measures, we found that treatment efficacy depended on pre-treatment AVP levels (F1,9=7.3544; P=0.0239). Further analysis revealed that pre-treatment AVP levels predicted treatment response in participants receiving drug (P=0.0099), but not in those receiving placebo, suggesting that pre-treatment AVP levels may be useful in discerning children most likely to respond to AVP treatment. The treatment x AVP levels interaction therefore informed our comparison of drug-treated and placebo-treated participants. AVP-treated participants improved by an average of 12.8 ± 3.5 points on the SRS-2 Total Score (P=0.0102), but placebo-treated participants’ SRS-2 Total Scores did not significantly differ from a 0 point improvement. We also observed a pre-treatment “biomarker signature” that predicted treatment efficacy. Thus, in addition to the effect of pre-treatment AVP levels, participants with lower OXTR gene expression, and higher AVPRv1a gene expression, showed greater improvement in SRS-2 Total Scores, particularly when relative expression was contrasted in each participant (F1,9=8.060; P=0.0194). Finally, no differences in the rates of adverse events were observed between the placebo-treated and AVP-treated groups, and there were no changes from baseline in patients' electrocardiogram, vital signs, or clinical laboratory measurements during AVP treatment.

Conclusions: This is the first study to show that intranasal AVP treatment is well tolerated and improves social abilities in individuals with ASD. Findings from this pilot study also suggest that pre-treatment neuropeptide measures may help identify patients most likely to benefit from AVP treatment. This research has high potential to lead to development of the first effective and personalized medication to treat ASD’s currently intractable social deficits.