Abstract
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.
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References
Lai M-C, Lai M-C, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383:896–910.
Yamasue H. Promising evidence and remaining issues regarding the clinical application of oxytocin in autism spectrum disorders. Psychiatry Clin Neurosci. 2016;70:89–99.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Acknowledgements
We thank Dr. Haruhiko Shimoyama for coordinating the study, as well as Yukiko Saotome for assisting with psychological assessments. We also give special thanks to Kyoko Minamoto and Munenori Takata from the Clinical Research Support Center of the University of Tokyo Hospital for their data management. The study design was reviewed and approved by the institutional review board of the University of Tokyo Hospital.
Author contributions
H.Y., T.O., T.M., H.H., No.O., and Hi.Ko. designed the study. H.Y., T.O., T.M., Mi.Ku., T.F., Y.U., K.M., Hi.Ku., D.M., Y.O., Y.Y., Yu.Ka., Y.A., Ma.Ko., T.Y., K.O., W.Y., I.K., S.B., Na.O., Y.E., N.K., Y.U., M.Y., Yu.Ka., K.K., H.H., No.O., and Hi.Ko. participated in data collection and/or clinical assessments and/or recruitment of participants. H.Y., T.O., T.M., Mi.Ku., T.F., Hi.Ku., Y.U., and Hi.Ko. analyzed the data, discussed the results, and wrote the manuscript.
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Yamasue, H., Okada, T., Munesue, T. et al. Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial. Mol Psychiatry 25, 1849–1858 (2020). https://doi.org/10.1038/s41380-018-0097-2
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DOI: https://doi.org/10.1038/s41380-018-0097-2
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