Oxytocin and Autism Spectrum Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Yoon Phaik Ooi; Shih-Jen Weng; Joe Kossowsky; Heike Gerger; Min Sung

doi:10.1055/s-0042-109400

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2017; 50(01): 5-13
DOI: 10.1055/s-0042-109400

Review

Oxytocin and Autism Spectrum Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Authors

Yoon Phaik Ooi

¹Clinical Psychology and Psychotherapy, Department of Psychology University of Basel, Switzerland

²Department of Child and Adolescent Psychiatry, Institute of Mental Health, Singapore
Shih-Jen Weng

²Department of Child and Adolescent Psychiatry, Institute of Mental Health, Singapore

³Clinical Sciences, DUKE-NUS Medical School
Joe Kossowsky

¹Clinical Psychology and Psychotherapy, Department of Psychology University of Basel, Switzerland

⁴Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, USA

⁵Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, USA
Heike Gerger

¹Clinical Psychology and Psychotherapy, Department of Psychology University of Basel, Switzerland
Min Sung

²Department of Child and Adolescent Psychiatry, Institute of Mental Health, Singapore

Abstract

Aim: Oxytocin presents an exciting potential to target the core symptoms of autism spectrum disorder (ASD) pharmacologically in an easily administered, cost-effective form with possibly minimal adverse effects. But, there are still major gaps in this area of research. This paper reviewed randomized controlled trials (RCTs) examining the effects of oxytocin administration on social cognition and restricted, repetitive behaviors in individuals with an ASD.

Method: Electronic literature searches were conducted from PsycINFO, PubMed, Web of Knowledge, and EMBASE for RCTs published through June 2015.

Results: 12 RCTs were included in this review. 7 out of the 11 studies that examined social cognition reported improvements. Additionally, one out of the 4 studies on restricted, repetitive behaviors, reported improvements following oxytocin administration. However, results from our meta-analyses suggest that oxytocin has no significant effect on these 2 domains.

Conclusion: Previous evidence revealed mixed findings about the effects of oxytocin on ASD. Given the limited number of RCTs, our summary of findings on the effectiveness of oxytocin on ASD should still be considered tentative.

Key words

autism spectrum disorders - oxytocin - social cognition - emotion recognition - restricted - repetitive behaviors

Full Text

References

References
1 American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders (DSM-5). American Psychiatric Pub; Washington DC: 2013
2 Barneveld PS, Swaab H, Fagel S et al. Quality of life: a case-controlled long-term follow-up study, comparing young high-functioning adults with autism spectrum disorders with adults with other psychiatric disorders diagnosed in childhood. Comp Psychiatry 2014; 55: 302-310
3 Elsabbagh M, Divan G, Koh YJ et al. Global prevalence of autism and other pervasive developmental disorders. Autism Research 2012; 5: 160-179
4 Baxter AJ, Brugha TS, Erskine HE et al. The epidemiology and global burden of autism spectrum disorders. Psychol Med 2015; 45: 601-613
5 Paynter J, Riley E, Beamish W et al. The double ABCX model of family adaptation in families of a child with an autism spectrum disorder attending an Australian early intervention service. Res Autism Spectr Disord 2013; 7: 1183-1195
6 Rivard M, Terroux A, Parent-Boursier C et al. Determinants of stress in parents of children with autism spectrum disorders. J Autism Dev Disord 2014; 44: 1609-1620
7 Lavelle TA, Weinstein MC, Newhouse JP et al. Economic burden of childhood autism spectrum disorders. Pediatrics 2014; 133: E520-E529
8 Reichow B. Overview of meta-analyses on early intensive behavioral intervention for young children with autism spectrum disorders. J Autism Dev Disord 2012; 42: 512-520
9 Virues-Ortega J, Julio FM, Pastor-Barriuso R. The TEACCH program for children and adults with autism: a meta-analysis of intervention studies. Clin Psychol Rev 2013; 33: 940-953
10 Posey DJ, Erickson CA, McDougle CJ. Developing drugs for core social and communication impairment in autism. Child Adolesc Psychiatry Clin N Am 2008; 17: 787-801 viii–ix
11 McDougle CJ, Barr LC, Goodman WK et al. Possible role of neuropeptides in obsessive compulsive disorder. Psychoneuroendocrinology 1999; 24: 1-24
12 Green JJ, Hollander E. Autism and oxytocin: new developments in translational approaches to therapeutics. Neurotherapeutics 2010; 7: 250-257
13 Drago F, Pedersen CA, Caldwell JD et al. Oxytocin potently enhances novelty-induced grooming behavior in the rat. Brain Res 1986; 368: 287-295
14 Olazabal DE, Young LJ. Oxytocin receptors in the nucleus accumbens facilitate “spontaneous” maternal behavior in adult female prairie voles. Neuroscience 2006; 141: 559-568
15 Harony H, Wagner S. The contribution of oxytocin and vasopressin to mammalian social behavior: potential role in autism spectrum disorder. Neurosignals 2010; 18: 82-97
16 Van IJzendoorn MH, Bakermans-Kranenburg MJ. A sniff of trust: meta-analysis of the effects of intranasal oxytocin administration on face recognition, trust to in-group, and trust to out-group. Psychoneuroendocrinology 2012; 37: 438-443
17 Bakermans-Kranenburg MJ, van IJzendoorn MH. Sniffing around oxytocin: review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Transl Psychiatry 2013; 3: e258
18 Shahrestani S, Kemp AH, Guastella AJ. The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: a meta-analysis. Neuropsychopharmacology 2013; 38: 1929-1936
19 Carson DS, Berquist SW, Trujillo TH et al. Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children. Mol Psychiatry 2015; 20: 1085-1090
20 Aoki Y, Watanabe T, Abe O et al. Oxytocin’s neurochemical effects in the medial prefrontal cortex underlie recovery of task-specific brain activity in autism: a randomized controlled trial. Mol Psychiatry 2015; 20: 447-453
21 Kosaka H, Munesue T, Ishitobi M et al. Long-term oxytocin administration improves social behaviors in a girl with autistic disorder. BMC Psychiatry 2012; 12: 110
22 Tachibana M, Kagitani-Shimono K, Mohri I et al Long-term administration of intranasal oxytocin is a safe and promising therapy for early adolescent boys with autism spectrum disorders. J Child Adolesc Psychopharmacol 2013; 23: 123-127
23 Baribeau DA, Anagnostou E. Social communication is an emerging target for pharmacotherapy in autism spectrum disorder: a review of the literature on potential agents. J Can Acad Child Adolesc Psychiatry 2014; 23: 20-30
24 Guastella AJ, Hickie IB. Oxytocin treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry 2016; 79: 234-242
25 Dawson G, Jones E, Merkle K et al. Early behavioral intervention is associated with normalized brain activity in young children with autism. J Am Acad Child Adolesc Psychiatry 2012; 51: 1150-1159
26 Yatawara CJ, Einfeld SL, Hickie IB et al. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Mol Psychiatry 2015; [Epub ahead of print]
27 Feng C, Hackett PD, DeMarco AC et al. Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans. Brain Imaging Behav 2015; 9: 754-764
28 Rilling JK, Demarco AC, Hackett PD et al. Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 2014; 39: 237-248
29 Scheele D, Kendrick KM, Khouri C et al. An oxytocin-induced facilitation of neural and emotional responses to social touch correlates inversely with autism traits. Neuropsychopharmacology 2014; 39: 2078-2085
30 Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2^nd ed Erlbaum; Hillsdale NJ: 1988
31 Brockwell SE, Gordon IR. A comparison of statistical methods for meta-analysis. Stat Med 2001; 20: 825-840
32 Cochran WG. The combination of estimates from different experiments. Biometrics 1954; 10: 101-129
33 Higgins JP, Thompson SG, Deeks JJ et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557-560
34 Egger M, Smith GD, Schneider M et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634
35 Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088-1101
36 Duval S, Tweedie R. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. J Am Stat Assoc 2000; 95: 89-98
37 Anagnostou E, Soorya L, Chaplin W et al. Intranasal oxytocin versus placebo in the treatment of adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 2012; 3: 16
38 Andari E, Duhamel JR, Zalla T et al. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 2010; 107: 4389-4394
39 Auyeung B, Lombardo MV, Heinrichs M et al. Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism. Transl Psychiatry 2015; 5: e507
40 Dadds MR, MacDonald E, Cauchi A et al. Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. J Autism Dev Disord 2014; 44: 521-531
41 Domes G, Heinrichs M, Kumbier E et al. Effects of intranasal oxytocin on the neural basis of face processing in autism spectrum disorder. Biol Psychiatry 2013; 74: 164-171
42 Domes G, Kumbier E, Heinrichs M et al. Oxytocin promotes facial emotion recognition and amygdala reactivity in adults with Asperger syndrome. Neuropsychopharmacology 2014; 39: 698-706
43 Gordon I, Vander Wyk BC, Bennett RH et al. Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci USA 2013; 110: 20953-20958
44 Guastella AJ, Einfeld SL, Gray KM et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010; 67: 692-694
45 Guastella AJ, Gray KM, Rinehart NJ 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: 444-452
46 Hollander E, Bartz J, Chaplin W et al. Oxytocin increases retention of social cognition in autism. Biol Psychiatry 2007; 61: 498-503
47 Hollander E, Novotny S, Hanratty M et al. Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 2003; 28: 193-198
48 Watanabe T, Abe O, Kuwabara H et al. Mitigation of sociocommunicational deficits of autism through oxytocin-induced recovery of medial prefrontal activity: a randomized trial. JAMA Psychiatry 2014; 71: 166-175
49 LoParo D, Waldman ID. The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry 2015; 20: 640-646
50 Parker KJ, Garner JP, Libove RA et al. Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder. Proc Natl Acad Sci USA 2014; 111: 12258-12263
51 Macdonald K, Feifel D. Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders. Front Neurosci 2013; 7: 35