title: Oxytocin for Male Subjects with Autism Spectrum Disorder and Comorbid Intellectual Disabilities: A Randomized Pilot Study.
abstract: Approximately half of autism spectrum disorder (ASD) individuals suffer from comorbid intellectual disabilities (IDs). Oxytocin (OXT) receptors are highly expressed in temporal lobe structures and are likely to play a modulatory role in excitatory/inhibitory balance, at least based on animal model findings. Thus, it is feasible that in the highly representative group of Kanner-type ASD subjects, OXT could have a beneficial effect on social communication and social interaction. The aim of this pilot study is to investigate the feasibility and adverse events, such as epilepsy, of the long-term administration of intranasal OXT for adolescent and adult ASD subjects with ID because such patients frequently have seizures. We also addressed the question on how to scale the OXT effects to the core symptoms of social deficits because of the relative difficulty in obtaining objective measurements. Twenty-nine males (aged 15-40 years old) participated in a randomized, double-blind, and placebo-controlled crossover study (each for 8 weeks) with OXT (16 IU/day). Except for seizures experienced by one participant, other serious adverse events did not occur. The primary and secondary outcomes measured using the Childhood Autism Rating Scale and several standard scales, respectively, revealed no difference between the OXT and placebo groups. Instead, in an exploratory analysis, the social interactions observed in the play sessions or in daily life were significantly more frequent in the initial half period in the OXT-first arm of the crossover trial. There were also significant correlations between the plasma OXT concentration and subscale scores for irritability on the Aberrant Behavior Checklist. In conclusion, this pilot study demonstrates that long-term administration of intranasal OXT is tolerable in a representative cohort of ASD individuals with ID and suggests that future multicenter trials of OXT are warranted and should include measurements of reciprocal social interactions based on daily life under closer surveillance for epilepsy.
  
  
  BACKGROUND
  UMIN000007250.
authors.affiliation: Research Center for Child Mental Development, Kanazawa University , Kanazawa , Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Munesue
authors.affiliation: Department of Environmental and Preventive Medicine, Graduate School of Medical Sciences, Kanazawa University , Kanazawa , Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Research Center for Child Mental Development, Kanazawa University , Kanazawa , Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Kikuchi
authors.affiliation: Research Center for Child Mental Development, Kanazawa University , Kanazawa , Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Research Center for Child Mental Development, Kanazawa University , Kanazawa , Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Takeuchi
authors.affiliation: International Community Care and Lifespan Development, Empowerment Sciences, Faculty of Medicine, University of Tsukuba , Tsukuba , Japan.
authors.forename: Tokie
authors.initials: T
authors.lastname: Anme
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , Yonago , Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , Yonago , Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Department of Pharmacy, Kanazawa University Hospital , Kanazawa , Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Tsubouchi
authors.affiliation: Department of Pharmacy, Kanazawa University Hospital , Kanazawa , Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.affiliation: Department of Pharmacy, Kanazawa University Hospital , Kanazawa , Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
authors.affiliation: Advanced Science Research Center, Kanazawa University , Kanazawa , Japan.
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Horike
authors.affiliation: Research Center for Child Mental Development, Kanazawa University , Kanazawa , Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yokoyama
authors.affiliation: Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan; Department of Psychiatry and Neurobiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Nakatani
authors.affiliation: Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan; Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan.
authors.forename: Yo
authors.initials: Y
authors.lastname: Niida
authors.affiliation: Research Center for Child Mental Development, University of Fukui , Fukui , Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kosaka
authors.affiliation: Research Center for Child Mental Development, Kanazawa University, Kanazawa, Japan; Department of Psychiatry and Neurobiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Minabe
authors.affiliation: Research Center for Child Mental Development, Kanazawa University , Kanazawa , Japan.
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Higashida
keywords: Kanner type; autism spectrum disorder; intranasal administration; oxytocin; social behavior
references.citation: Can J Psychiatry. 2012 May;57(5):275-83
references.pmid: 22546059
references.citation: Psychoneuroendocrinology. 2013 Dec;38(12):2996-3002
references.pmid: 24064220
references.citation: J Am Acad Child Adolesc Psychiatry. 2009 Nov;48(11):1110-9
references.pmid: 19797985
references.citation: Biol Psychiatry. 2010 Apr 1;67(7):692-4
references.pmid: 19897177
references.citation: Autism Res. 2012 Jun;5(3):160-79
references.pmid: 22495912
references.citation: J Am Acad Child Adolesc Psychiatry. 1989 Jul;28(4):538-41
references.pmid: 2768149
references.citation: Br J Psychiatry. 2005 Jun;186:525-8
references.pmid: 15928364
references.citation: Science. 2008 May 30;320(5880):1177-80
references.pmid: 18511681
references.citation: Neuropsychopharmacology. 2003 Jan;28(1):193-8
references.pmid: 12496956
references.citation: Neurosci Res. 2010 Jun;67(2):181-91
references.pmid: 20435366
references.citation: Arch Gen Psychiatry. 1998 Jul;55(7):633-41
references.pmid: 9672054
references.citation: Neuropsychopharmacology. 2014 Feb;39(3):698-706
references.pmid: 24067301
references.citation: Mol Autism. 2012 Dec 05;3(1):16
references.pmid: 23216716
references.citation: JAMA. 2015 Apr 21;313(15):1524-33
references.pmid: 25898050
references.citation: Conscious Cogn. 2011 Mar;20(1):130-40
references.pmid: 20932779
references.citation: Psychosomatics. 1995 May-Jun;36(3):267-75
references.pmid: 7638314
references.citation: Ann N Y Acad Sci. 2003 Oct;1001:134-44
references.pmid: 14625359
references.citation: Obstet Gynecol Surv. 2007 Nov;62(11):731-8
references.pmid: 17925046
references.citation: Neuropeptides. 2012 Oct;46(5):211-5
references.pmid: 22884888
references.citation: Nature. 2007 Mar 1;446(7131):41-5
references.pmid: 17287729
references.citation: Brain. 2014 Nov;137(Pt 11):3073-86
references.pmid: 25149412
references.citation: Lancet. 1996 Mar 2;347(9001):623
references.pmid: 8596357
references.citation: Sci Rep. 2013 Dec 06;3:3440
references.pmid: 24310737
references.citation: J Child Adolesc Psychopharmacol. 2013 Mar;23(2):123-7
references.pmid: 23480321
references.citation: J Child Adolesc Psychopharmacol. 2014 Mar;24(2):54-68
references.pmid: 24679173
references.citation: MMWR Surveill Summ. 2012 Mar 30;61(3):1-19
references.pmid: 22456193
references.citation: Psychosom Med. 2011 Jun;73(5):393-400
references.pmid: 21636661
references.citation: Nature. 2015 Apr 23;520(7548):499-504
references.pmid: 25874674
references.citation: Brain Dev. 1999 Mar;21(2):103-6
references.pmid: 10206527
references.citation: Psychoneuroendocrinology. 2013 Oct;38(10):1985-93
references.pmid: 23579082
references.citation: Lancet. 2014 Mar 8;383(9920):896-910
references.pmid: 24074734
references.citation: J Child Psychol Psychiatry. 2015 Apr;56(4):444-52
references.pmid: 25087908
references.citation: Nat Rev Drug Discov. 2013 Mar;12(3):191-204
references.pmid: 23449306
references.citation: BMC Psychiatry. 2013 Dec 23;13:344
references.pmid: 24359174
references.citation: Ment Retard Dev Disabil Res Rev. 2005;11(2):164-70
references.pmid: 15977316
references.citation: Mol Neurobiol. 2014 Oct;50(2):626-46
references.pmid: 24705860
references.citation: J Autism Dev Disord. 2014 Mar;44(3):521-31
references.pmid: 23888359
references.citation: Brain Res. 2014 Sep 11;1580:199-218
references.pmid: 24462936
references.citation: Brain Res. 2014 Sep 11;1580:188-98
references.pmid: 24508578
references.citation: Autism Res. 2013 Dec;6(6):468-78
references.pmid: 24124067
references.citation: Biol Psychiatry. 1998 Feb 15;43(4):270-7
references.pmid: 9513736
references.citation: Biol Psychiatry. 2008 Oct 1;64(7):577-82
references.pmid: 18565495
references.citation: Autism. 2010 Sep;14(5):391-407
references.pmid: 20926456
references.citation: ISRN Pediatr. 2011;2011:272913
references.pmid: 22389772
references.citation: Am J Ment Defic. 1985 Mar;89(5):485-91
references.pmid: 3993694
references.citation: Transl Psychiatry. 2013 May 21;3:e258
references.pmid: 23695233
references.citation: Lancet. 2006 Jul 15;368(9531):210-5
references.pmid: 16844490
references.citation: JAMA Psychiatry. 2014 Feb;71(2):166-75
references.pmid: 24352377
references.citation: Biol Psychiatry. 2007 Feb 15;61(4):498-503
references.pmid: 16904652
references.citation: J Autism Dev Disord. 2013 Mar;43(3):739-46
references.pmid: 23104617
references.citation: Neurosci Biobehav Rev. 2013 Sep;37(8):1485-92
references.pmid: 23665533
references.citation: Am J Psychiatry. 2005 Jun;162(6):1142-8
references.pmid: 15930063
references.citation: J Neurosci. 2012 Oct 10;32(41):14109-17
references.pmid: 23055480
references.citation: N Engl J Med. 2002 Aug 1;347(5):314-21
references.pmid: 12151468
references.citation: Neuron. 2015 Aug 19;87(4):684-98
references.pmid: 26291155
references.citation: Autism. 2016 Jul;20(5):528-37
references.pmid: 26187059
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4389-94
references.pmid: 20160081