Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
08
11
2017
accepted:
06
03
2018
revised:
20
02
2018
pubmed:
30
6
2018
medline:
23
3
2021
entrez:
30
6
2018
Statut:
ppublish
Résumé
Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.
Identifiants
pubmed: 29955161
doi: 10.1038/s41380-018-0097-2
pii: 10.1038/s41380-018-0097-2
doi:
Substances chimiques
Oxytocin
50-56-6
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
1849-1858Références
Lai M-C, Lai M-C, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383:896–910.
pubmed: 24074734
pmcid: 24074734
Yamasue H. Promising evidence and remaining issues regarding the clinical application of oxytocin in autism spectrum disorders. Psychiatry Clin Neurosci. 2016;70:89–99.
pubmed: 26394796
Gordon I, Vander WBC, Bennett RH, Cordeauxa C, Lucasa MV, Eilbotta JA, et al. Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci USA. 2013;110:20953–8.
pubmed: 24297883
Ma Y, Shamay-Tsoory S, Han S, Zink CF. Oxytocin and social adaptation: insights from neuroimaging studies of healthy and clinical populations. Trends Cogn Sci. 2016;20:133–45.
pubmed: 26616296
Andaria E, Duhamela J, Zalla T, Herbrechtb E, Leboyerb M, Sirigu A. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA. 2010;107:4389–94.
Harris JC, Carter CS. Therapeutic interventions with oxytocin: current status and concerns. J Am Acad Child Adolesc Psychiatry. 2013;52:998–1000.
pubmed: 24074464
Watanabe T, Kuroda M, Kuwabara H, Aoki Y, Iwashiro N, Tatsunobu N, et al. Clinical and neural effects of six-week administration of oxytocin on core symptoms of autism. Brain. 2015;138:3400–12.
pubmed: 26336909
Anagnostou E, Anagnostou E, Soorya L, Bartz J, Halpern D, Wasserman S, et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism. 2012;3:16.
pubmed: 23216716
pmcid: 3539865
Dadds MR, Macdonald E, Cauchi A, Williams, Levy F, Brennan J. Nasal Oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord. 2014;44:521–31.
pubmed: 23888359
Guastella AJ, Gray KM, Rinehart NJ, Alvares GA, Tonge BJ, Hickie IB, et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J Child Psychol Psychiatry. 2015;56:444–52.
pubmed: 25087908
Yatawara CJ, Einfeld SL, Hickie IB, Davenport TA, Guastella AJ. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry. 2015;21:1225–31.
pubmed: 26503762
pmcid: 4995545
Munesue T, Nakamura H, Kikuchi M, Miura Y, Takeuchi N, Anme T, et al. Oxytocin for male subjects with autism spectrum disorder and comorbid intellectual disabilities: a randomized pilot study. Front Psychiatry. 2016;7:2.
pubmed: 26834651
pmcid: 4720778
Kosaka H, Okamoto Y, Munesue T, Yamasue H, Inohara K, Fujioka T, et al. Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial. Transl Psychiatry. 2016;6:e872.
pubmed: 27552585
pmcid: 5022092
Walum H, Waldman ID, Young LJ. Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol Psychiatr. 2016;79:251–7.
Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatr. 2016;79:243–50.
Fujisawa TX, Tanaka S, Saito DN, Kosaka H, Tomoda A. Visual attention for social information and salivary oxytocin levels in preschool children with autism spectrum disorders: an eye-tracking study. Front Neurosci. 2014;8:295.
pubmed: 25278829
pmcid: 4166357
Fujioka T, Inohara K, Okamoto Y, Masuya Y, Ishitobi M, Saito DN, et al. Gazefinder as a clinical supplementary tool for discriminating between autism spectrum disorder and typical development in male adolescents and adults. Mol Autism. 2016;7:19.
pubmed: 27011784
pmcid: 4804639
Constantino JN, Kennon-McGill S, Weichselbaum C, Marrus N, Haider A, Glowinski AL, et al. Infant viewing of social scenes is under genetic control and is atypical in autism. Nature. 2017;547:340–4.
pubmed: 28700580
pmcid: 5842695
Guy W. ECDEU assessment manual for psychopharmacology. Rockville, MD:U.S. 1976. https://archive.org/details/ecdeuassessmentm1933guyw
American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders: DSM-IV. 4th ed. Washington, DC: American Psychiatric Association; 1994.
Lord C, Rutter M, Le Couteur A. Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994;24:659–85.
pubmed: 7814313
Wechsler D. The psychometric tradition—developing the Wechsler Adult Intelligence Scale. Contemp Educ Psychol. 1981;6:82–85.
Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord. 2001;31:5–17.
pubmed: 11439754
Constantino JN, Davis SA, Todd RD, et al. Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J Autism Dev Disord. 2003;33:427–33.
pubmed: 12959421
Lord C, Rutter M, Goode S, Heemsbergen J, Jordan H, Mawhood L, et al. Autism diagnostic observation schedule: a standardized observation of communicative and social behavior. J Autism Dev Disord. 1989;19:185–212.
pubmed: 2745388
Spielberger C, Gorsuch R, Lushene R. Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press; 1983.
Radloff L. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385–401.
Aas I. Guidelines for rating Global Assessment of Functioning (GAF). Ann Gen Psychiatry. 2011;10:2.
pubmed: 21251305
pmcid: 3036670
European Medicines Agency. The European Agency for the Evaluation of Medicinal Products. Evaluation of medicines for human use. http://www.ema.europa.eu/ . Accessed 19 September 2002.
Pocock SJ, Stone GW. The primary outcome fails—what next? N Engl J Med. 2016;375:861–70.
pubmed: 27579636
Hus V, Lord C. The autism diagnostic observation schedule, module 4: revised algorithm and standardized severity scores. J Autism Dev Disord. 2014;44:1996–2012.
pubmed: 24590409
pmcid: 4104252
Parker KJ, Oztan O, Libove RA, Sumiyoshia RD, Jacksona LP, Karhson DS, et al. Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proc Natl Acad Sci USA. 2017;114:8119–24.
pubmed: 28696286
Keck PE, Welge JA, McElroy SL, Arnold LM, Strakowski SM. Placebo effect in randomized, controlled studies of acute bipolar mania and depression. Biol Psychiatr. 2000;47:748–55.
Gossen A, Gossen A, Hahn A, Prinz S, Schultz RT, Gründer G, et al. Oxytocin plasma concentrations after single intranasal oxytocin administration - a study in healthy men. Neuropeptides. 2012;46:211–5.
pubmed: 22884888
Brown WA. Expectation, the placebo effect and the response to treatment. R I Med J. 2015;98:19–21.
Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology. 2003;28:193–8.
pubmed: 12496956
Guastella AJ, Mitchell PB, Dadds MR. Oxytocin increases gaze to the eye region of human faces. Biol Psychiatr. 2008;63:3–5.
Freeman SM, Inoue K, Smith AL, Goodman MM, Young LJ. The neuroanatomical distribution of oxytocin receptor binding and mRNA in the male rhesus macaque (Macaca mulatta). Psychoneuroendcrin. 2014;45:128–41.
Quintana DS, Westlye LT, Rustan ØG, Tesli N, Poppy CL, Smevik H, et al. Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment. Transl Psychiatry. 2015;5:e602.
pubmed: 26171983
pmcid: 5068727
Quintana DS, Westlye LT, Hope S, Nærland T, Elvsåshagen T, Dørum E, et al. Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial. Transl Psychiatry. 2017;7:e1136.
pubmed: 28534875
pmcid: 5584522
Quintana DS, Alvares GA, Hickie IB, Guastella AJ. Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. Neurosci Biobehav Rev. 2015;49:182–92.
pubmed: 25526824
Valstad M, Alvares GA, Egknud M, Matziorinisa AM, Andreassena OA, Westlye LT, et al. The correlation between central and peripheral oxytocin concentrations: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2017;78:117–24.
pubmed: 28442403
Choleris E, Choleris E, Gustafsson J-A, Muglia LJ, Pfaff DW, Ogawa S. An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice. Proc Natl Acad Sci USA. 2003;100:6192–7.
pubmed: 12730370
Kramer KM, Yoshida S, Papademetriou E, Cushing BS. The organizational effects of oxytocin on the central expression of estrogen receptor alpha and oxytocin in adulthood. BMC Neurosci. 2007;8:71.
pubmed: 17825097
pmcid: 2048512