A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome.
ASD
Autism spectrum disorder
Oxytocin
PMS
Phelan-McDermid syndrome
Shank3
Journal
Molecular autism
ISSN: 2040-2392
Titre abrégé: Mol Autism
Pays: England
ID NLM: 101534222
Informations de publication
Date de publication:
30 09 2021
30 09 2021
Historique:
received:
22
02
2021
accepted:
19
07
2021
entrez:
1
10
2021
pubmed:
2
10
2021
medline:
7
4
2022
Statut:
epublish
Résumé
Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U = 50, p = 0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084.
Sections du résumé
BACKGROUND
Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS.
METHODS
Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period.
RESULTS
There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U = 50, p = 0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events.
LIMITATIONS
The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results.
CONCLUSION
Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084.
Identifiants
pubmed: 34593045
doi: 10.1186/s13229-021-00459-1
pii: 10.1186/s13229-021-00459-1
pmc: PMC8482590
doi:
Substances chimiques
Oxytocin
50-56-6
Banques de données
ClinicalTrials.gov
['NCT02710084']
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
62Informations de copyright
© 2021. The Author(s).
Références
J Neurosci. 2008 Jun 25;28(26):6607-15
pubmed: 18579733
Psychoneuroendocrinology. 2010 Jan;35(1):83-93
pubmed: 19632787
Elife. 2017 Jan 31;6:
pubmed: 28139198
Science. 2010 Jun 11;328(5984):1408-11
pubmed: 20538951
Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):8119-8124
pubmed: 28696286
Res Dev Disabil. 2002 Jan-Feb;23(1):45-60
pubmed: 12071395
Cell Mol Life Sci. 2021 Mar;78(6):2517-2563
pubmed: 33263776
Physiol Rev. 1991 Apr;71(2):331-70
pubmed: 1672455
Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4389-94
pubmed: 20160081
PLoS Genet. 2014 Sep 04;10(9):e1004580
pubmed: 25188300
J Psychopharmacol. 2009 May;23(3):241-8
pubmed: 18801829
J Neurosci. 2009 Jan 7;29(1):38-42
pubmed: 19129382
Behav Neurosci. 2012 Feb;126(1):97-109
pubmed: 22141469
Mol Psychiatry. 2016 Sep;21(9):1225-31
pubmed: 26503762
Mol Autism. 2012 Dec 05;3(1):16
pubmed: 23216716
Am J Ment Defic. 1985 Mar;89(5):485-91
pubmed: 3993694
J Child Psychol Psychiatry. 2015 Apr;56(4):444-52
pubmed: 25087908
Psychol Sci. 2008 Nov;19(11):1092-4
pubmed: 19076479
Proc Natl Acad Sci U S A. 2013 Dec 24;110(52):20953-8
pubmed: 24297883
Nat Rev Neurosci. 2017 Mar;18(3):147-157
pubmed: 28179641
Mol Autism. 2020 Nov 17;11(1):89
pubmed: 33203459
Psychopharmacology (Berl). 2012 Mar;220(2):319-30
pubmed: 21956239
Physiol Rev. 2001 Apr;81(2):629-83
pubmed: 11274341
Autism Res. 2017 Jan;10(1):25-41
pubmed: 27651096
Neurosci Biobehav Rev. 2013 Sep;37(8):1445-65
pubmed: 23648680
PLoS Genet. 2011 Jul;7(7):e1002173
pubmed: 21779178
CNS Neurosci Ther. 2010 Jun;16(3):e92-123
pubmed: 20557568
Front Cell Neurosci. 2019 Mar 26;13:111
pubmed: 30971895
J Neurosci. 2016 Feb 24;36(8):2517-35
pubmed: 26911697
Nature. 2005 Jun 2;435(7042):673-6
pubmed: 15931222
Cell Tissue Res. 2006 Nov;326(2):409-22
pubmed: 16865346
Nat Neurosci. 2019 Aug;22(8):1223-1234
pubmed: 31332372
Horm Behav. 2005 Dec;48(5):522-7
pubmed: 16109416
Neurosci Biobehav Rev. 2015 Feb;49:182-92
pubmed: 25526824
Brain. 2014 Nov;137(Pt 11):3073-86
pubmed: 25149412
Biol Psychiatry. 2008 Jan 1;63(1):3-5
pubmed: 17888410
Acta Neuropathol. 2017 Oct;134(4):537-566
pubmed: 28584888
Biol Psychiatry. 2016 Feb 1;79(3):243-50
pubmed: 26049207
Mol Cell Endocrinol. 1996 Nov 29;124(1-2):25-32
pubmed: 9027321
Clin Neuropsychol. 2018 Aug - Oct;32(7):1226-1255
pubmed: 29265961
Mol Cell Endocrinol. 2020 Dec 1;518:110924
pubmed: 32619581
Mol Psychiatry. 2015 Apr;20(4):447-53
pubmed: 25070538
Neuron. 2008 May 22;58(4):639-50
pubmed: 18498743
Neuroscience. 2020 Oct 1;445:83-94
pubmed: 31917352
Nature. 1992 Apr 9;356(6369):526-9
pubmed: 1313946
Cell Mol Neurobiol. 2018 Jan;38(1):371-378
pubmed: 28493233
Horm Behav. 2009 Jun;56(1):128-32
pubmed: 19344725
Mol Psychiatry. 2021 Feb;26(2):710-720
pubmed: 30262887
Biol Psychiatry. 2008 Aug 1;64(3):256-8
pubmed: 18343353
Biol Psychiatry Cogn Neurosci Neuroimaging. 2019 Dec;4(12):1042-1048
pubmed: 30954442
Biol Psychiatry. 2009 May 1;65(9):728-31
pubmed: 19027101
Cogn Affect Behav Neurosci. 2009 Sep;9(3):237-41
pubmed: 19679759
Neurosci Biobehav Rev. 2020 Nov;118:538-567
pubmed: 32858083
Psychoneuroendocrinology. 2008 Apr;33(3):368-74
pubmed: 18221838
Child Neuropsychol. 2016;22(5):556-69
pubmed: 25833070
Mol Autism. 2010 Dec 17;1(1):15
pubmed: 21167025
J Autism Dev Disord. 1994 Oct;24(5):659-85
pubmed: 7814313
J Autism Dev Disord. 2000 Jun;30(3):237-43
pubmed: 11055459
Neuropsychopharmacology. 2014 Feb;39(3):698-706
pubmed: 24067301
J Neurosci. 2012 May 9;32(19):6525-41
pubmed: 22573675
J Child Neurol. 2015 Dec;30(14):1861-70
pubmed: 26350728
Brain Res. 2014 Sep 11;1580:57-68
pubmed: 24231551
J Med Genet. 2006 Oct;43(10):822-8
pubmed: 16284256
Front Neurosci. 2013 Jul 18;7:127
pubmed: 23882178
Biol Psychiatry. 2010 Apr 1;67(7):692-4
pubmed: 19897177
JAMA Psychiatry. 2014 Feb;71(2):166-75
pubmed: 24352377
Nat Genet. 2007 Jan;39(1):25-7
pubmed: 17173049
J Child Adolesc Psychopharmacol. 2013 Mar;23(2):123-7
pubmed: 23480321
Front Neuroendocrinol. 2016 Jan;40:1-23
pubmed: 25951955
Biol Psychiatry. 2013 Aug 1;74(3):164-71
pubmed: 23510581
Mol Autism. 2013 Jun 11;4(1):18
pubmed: 23758760
Psychiatry Clin Neurosci. 2018 Mar;72(3):140-151
pubmed: 29232031