title: A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder.
abstract: The core symptoms of autism spectrum disorder (ASD) include impaired social communication, repetitive behaviors, and restricted interests. No effective pharmacotherapy for these core deficits exists. Within the domain of social communication, the vasopressin system is implicated in social cognition and social signaling deficits of ASD, and represents a potential therapeutic target. We assessed the effects of a single 20 mg intravenous dose of the arginine vasopressin receptor 1A (V1a) antagonist, RG7713, on exploratory biomarkers (eye tracking), behavioral and clinical measures of social cognition and communication (affective speech recognition (ASR), reading the mind in the eyes, olfactory identification, scripted interaction), and safety and tolerability in a multicenter, randomized, double-blind, placebo-controlled, cross-over study of 19 high-functioning adult male subjects with DSM-IV Autistic Disorder (age 18-45 years; full scale IQ >70; ABC-Irritability subscale ⩽13). Eye-tracking showed an increase in biological motion orienting preference with RG7713 (ES=0.8, p=0.047) and a non-significant improvement in the composite score (ES=0.2, p=0.29). RG7713 reduced ability to detect lust (ES=-0.8, p=0.03) and fear (ES=-0.7, p=0.07) in ASR. However, when all eight individual emotion subscales were combined into an overall ASR performance score, the reduction was non-significant (ES=-0.1, p=0.59). Thirteen adverse events were reported in 10 subjects; all were of mild (11/13) or moderate (2/13) severity. Although interpretation should be cautious due to multiple comparisons and small sample size, these results provide preliminary evidence from experimental and behavioral biomarkers, that blockade of the V1a receptor may improve social communication in adults with high-functioning ASD. ClinicalTrials.gov identifier: NCT01474278 A Study of RO5028442 in Adult Male High-Functioning Autistic Patients. Available at: https://clinicaltrials.gov/ct2/show/NCT01474278.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, F. Hoffmann - La Roche, Ltd., Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Umbricht
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, F. Hoffmann - La Roche, Ltd., Basel, Switzerland.
authors.forename: Marta
authors.initials: M
authors.lastname: Del Valle Rubido
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Montefiore Medical Center Bronx, New York, NY, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hollander
authors.affiliation: Psychiatry and Biobehavioral Sciences, CART, UCLA Semel Institute, Los Angeles, CA, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: McCracken
authors.affiliation: Child Study Center, Yale University, New Haven, CT, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Shic
authors.affiliation: Department of Pediatrics, Emory University, Marcus Autism Center, Atlanta, GA, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Scahill
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, F. Hoffmann - La Roche, Ltd., Basel, Switzerland.
authors.forename: Jana
authors.initials: J
authors.lastname: Noeldeke
authors.affiliation: Roche Product Development Neuroscience, Basel, Switzerland.
authors.forename: Lauren
authors.initials: L
authors.lastname: Boak
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, F. Hoffmann - La Roche, Ltd., Basel, Switzerland.
authors.forename: Omar
authors.initials: O
authors.lastname: Khwaja
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, F. Hoffmann - La Roche, Ltd., Basel, Switzerland.
authors.forename: Lisa
authors.initials: L
authors.lastname: Squassante
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, F. Hoffmann - La Roche, Ltd., Basel, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Grundschober
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center, F. Hoffmann - La Roche, Ltd., Basel, Switzerland.
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Kletzl
authors.affiliation: Roche Product Development Neuroscience, Basel, Switzerland.
authors.forename: Paulo
authors.initials: P
authors.lastname: Fontoura
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D003071:Cognition / Q000187:drug effects; D003142:Communication; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D000074286:Preliminary Data; D011619:Psychotropic Drugs / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D017483:Receptors, Vasopressin / Q000378:metabolism; D012938:Social Perception; D013141:Spiro Compounds / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000599871:AVPR1A protein, human; D007211:Indoles; D011619:Psychotropic Drugs; D017483:Receptors, Vasopressin; D013141:Spiro Compounds; C000598571:(6-chloro-1-(2-(dimethylamino)ethyl)indol-3-yl)-spiro(1H-isobenzofuran-3,4'-piperidine)-1'-yl-methanone