title: Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.
abstract: Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kosaka
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Munesue
authors.affiliation: Department of Neuropsychiatry, School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamasue
authors.affiliation: Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.|Department of Informatics, Graduate School of Informatics and Engineering, The University of Electro-Communications, Chofu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Inohara
authors.affiliation: Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujioka
authors.affiliation: International Community Care and Lifespan Development, Empowerment Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Anme
authors.affiliation: Department of Obstetrics and Gynecology, University of Fukui, Eiheiji, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Orisaka
authors.affiliation: Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.|Department of Child and Adolescent Mental Health, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ishitobi
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Jung
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.
authors.forename: T X
authors.initials: TX
authors.lastname: Fujisawa
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Arai
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.|Biomedical Imaging Research Center, University of Fukui, Eiheiji, Japan.
authors.forename: D N
authors.initials: DN
authors.lastname: Saito
authors.affiliation: Department of Cerebral Research, National Institute for Physiological Sciences, Okazaki, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Sadato
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Tomoda
authors.affiliation: Faculty of Nursing and Social Welfare Sciences, Fukui Prefectural University, Eiheiji, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Omori
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.|Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Japan.|Division of Developmental Neuroscience, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.|Biomedical Imaging Research Center, University of Fukui, Eiheiji, Japan.
authors.forename: H
authors.identifier: 0000-0001-7046-3383
authors.initials: H
authors.lastname: Okazawa
authors.affiliation: Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Higashida
authors.affiliation: Research Center for Child Mental Development, University of Fukui, Eiheiji, Japan.|Department of Neuropsychiatry, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.|Division of Developmental Higher Brain Functions, Department of Child Development United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Eiheiji, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Wada
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000188:drug therapy; D001321:Autistic Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010120:Oxytocics / Q000008:administration & dosage* / Q000627:therapeutic use; D010121:Oxytocin / Q000008:administration & dosage* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D018045:Receptors, Oxytocin / Q000235:genetics; D012737:Sex Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C569600:OXTR protein, human; D010120:Oxytocics; D018045:Receptors, Oxytocin; D010121:Oxytocin