Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1

References

  1. 1.

    Lai M-C, Lai M-C, Lombardo MV, Baron-Cohen S. Autism. Lancet. 2014;383:896–910.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    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  Google Scholar 

  3. 3.

    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.

    CAS  PubMed  Google Scholar 

  4. 4.

    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  Google Scholar 

  5. 5.

    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.

    Google Scholar 

  6. 6.

    Harris JC, Carter CS. Therapeutic interventions with oxytocin: current status and concerns. J Am Acad Child Adolesc Psychiatry. 2013;52:998–1000.

    PubMed  Google Scholar 

  7. 7.

    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  Google Scholar 

  8. 8.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    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  Google Scholar 

  10. 10.

    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  Google Scholar 

  11. 11.

    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  PubMed Central  Google Scholar 

  12. 12.

    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  PubMed Central  Google Scholar 

  13. 13.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Walum H, Waldman ID, Young LJ. Statistical and methodological considerations for the interpretation of intranasal oxytocin studies. Biol Psychiatr. 2016;79:251–7.

    CAS  Google Scholar 

  15. 15.

    Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatr. 2016;79:243–50.

    CAS  Google Scholar 

  16. 16.

    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  PubMed Central  Google Scholar 

  17. 17.

    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  PubMed Central  Google Scholar 

  18. 18.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Guy W. ECDEU assessment manual for psychopharmacology. Rockville, MD:U.S. 1976. https://archive.org/details/ecdeuassessmentm1933guyw

  20. 20.

    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.

  21. 21.

    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.

    CAS  PubMed  Google Scholar 

  22. 22.

    Wechsler D. The psychometric tradition—developing the Wechsler Adult Intelligence Scale. Contemp Educ Psychol. 1981;6:82–85.

    Google Scholar 

  23. 23.

    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.

    CAS  PubMed  Google Scholar 

  24. 24.

    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  Google Scholar 

  25. 25.

    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.

    CAS  PubMed  Google Scholar 

  26. 26.

    Spielberger C, Gorsuch R, Lushene R. Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press; 1983.

    Google Scholar 

  27. 27.

    Radloff L. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1:385–401.

    Google Scholar 

  28. 28.

    Aas I. Guidelines for rating Global Assessment of Functioning (GAF). Ann Gen Psychiatry. 2011;10:2.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    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.

  30. 30.

    Pocock SJ, Stone GW. The primary outcome fails—what next? N Engl J Med. 2016;375:861–70.

    PubMed  Google Scholar 

  31. 31.

    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  PubMed Central  Google Scholar 

  32. 32.

    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.

    CAS  PubMed  Google Scholar 

  33. 33.

    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.

    Google Scholar 

  34. 34.

    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.

    CAS  PubMed  Google Scholar 

  35. 35.

    Brown WA. Expectation, the placebo effect and the response to treatment. R I Med J. 2015;98:19–21.

    Google Scholar 

  36. 36.

    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.

    CAS  PubMed  Google Scholar 

  37. 37.

    Guastella AJ, Mitchell PB, Dadds MR. Oxytocin increases gaze to the eye region of human faces. Biol Psychiatr. 2008;63:3–5.

    CAS  Google Scholar 

  38. 38.

    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.

    CAS  Google Scholar 

  39. 39.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    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.

    CAS  PubMed  Google Scholar 

  42. 42.

    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.

    CAS  PubMed  Google Scholar 

  43. 43.

    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.

    CAS  PubMed  Google Scholar 

  44. 44.

    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  PubMed Central  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hidenori Yamasue.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading