Oxytocin for the treatment of autism spectrum disorder in children

Oxytocin

Oxytocin, a neuropeptide produced in the hypothalamus and released by the posterior pituitary gland, is involved in stimulating uterine contractions, increasing local prostaglandin production, contracting myoepithelial cells in the breast,³ and regulating the social behaviour of all vertebrates.⁴ It has a plasma half-life of 5 to 12 minutes.³ In Canada, synthetic oxytocin is approved for intravenous use in the induction of labour, as adjunctive therapy in the management of incomplete or inevitable abortion, and to control postpartum bleeding or hemorrhage.³ Intranasal oxytocin is also used off-label for the treatment of several neuropsychiatric disorders characterized by deficits in the social domain, including ASD.⁴ With no curative therapy available, interventions for ASD are limited to the treatment of symptoms. Several animal studies have shown that oxytocin decreases the stress response while increasing social approach, social recognition, and social memory.⁵ Studies involving neurotypical (nonautistic) participants have shown that intranasal oxytocin creates an attentional bias toward happy over angry faces⁶ and increases their ratings of the trustworthiness and attractiveness of human faces.⁷ Another small US study involving neurotypical participants found that those in the oxytocin group were 80% more generous toward others compared with those in the placebo group, as measured by a blinded, one-shot decision on how to split a sum of money with a stranger (P = .005, N = 68).⁸

Oxytocin in adults with ASD

The first study on the efficacy of oxytocin in improving behaviour associated with ASD, published in 2003, reported that 87% of participants who received intravenous oxytocin experienced significant reductions in repetitive behaviour from baseline to 240 minutes after infusion compared with 40% of participants who received placebo (P = .027).⁹

A randomized controlled trial (RCT) from Japan reported that participants improved their performance on measures of social cognition (measured using a task requiring participants to make judgments regarding the intentions of others based on sociocommunicational content in which the verbal and nonverbal information conflicts) after the administration of a single dose of intranasal oxytocin compared with placebo in 32 men with ASD (t₃₂ = 2.2, P = .03, Cohen d = 0.55).¹⁰ Functional magnetic resonance imaging data also showed increased activity in the dorsal medial prefrontal cortex (t₃₂ = 5.8, P < .001) and anterior cingulate cortex (t₃₂ = 3.6, P < .001) during nonverbal tasks following the administration of intranasal oxytocin to individuals with ASD.¹⁰

A study using twice-daily dosing of intranasal oxytocin for a duration of 6 weeks also showed significant improvement in social cognition (measured using the Reading the Mind in the Eyes Test [RMET], P = .002, Cohen d = 1.2) in 19 adults (84% male) with ASD.¹¹ However, this study showed no significant improvement in social responsiveness (measured using the Social Responsiveness Scale [SRS]) or repetitive behaviour (measured using the Repetitive Behavior Scale) with oxytocin when compared with placebo.¹¹

Oxytocin in children with ASD

In the late 1990s a study of 29 boys with ASD between 6 and 11 years old and 30 matched controls showed that the ASD group had lower levels of plasma oxytocin than the non-ASD group (t₅₈ = 3.00, P < .004).¹² However, a meta-analysis published in 2016 of 7 cross-sectional studies that included 269 children with ASD and 287 matched controls without ASD showed no evidence that peripheral oxytocin levels are impaired in children with ASD.¹³ An Australian crossover RCT with 16 boys between 12 and 19 years old with ASD reported improved performance in emotion recognition (measured as improvement in the RMET score) for 60% of the participants (t₁₄ = 2.43, P = .03) following a single dose of intranasal oxytocin compared with their performance after being given placebo.¹⁴ A similar study of 17 children (82% male) between 8 and 16 years old with ASD using a modified RMET reported no improvement after they received a similar, single dose of intranasal oxytocin versus placebo.¹⁵ Functional magnetic resonance imaging data showed that oxytocin enhanced activity in areas of the brain associated with reward (the dorsal and ventral striatum, including the nucleus accumbens; t₁₆ = 4.817, P = .0001) and the area associated with detecting, decoding, and reasoning about mental states (medial prefrontal cortex; t₁₆ = 4.208, P = .0006).¹⁵

Multiple-dose intranasal oxytocin studies have also shown mixed results.^16-19 An RCT with 38 boys between 7 and 16 years old with ASD indicated no significant improvement between pre- and posttreatment scores on measures of emotion recognition (measured using the University of New South Wales facial emotion recognition task) and social interaction skills (measured using the Social Skills Rating Scale) when given a 4-day course of intranasal oxytocin compared with placebo.¹⁶ However, a crossover RCT with 31 young children (87% male) between 3 and 8 years old with ASD reported significant improvements in caregiver-rated SRS scores (t₃₀ = 2.32, P < .05) and experimenter-rated Clinical Global Impression–Improvement scores( = 5.15, P < .05), versus placebo, when the children were given intranasal oxytocin twice daily for 4 weeks.¹⁷ No significant differences were noted in repetitive behaviour scores using the Repetitive Behavior Scale.¹⁷ Similarly, a 4-week RCT from 2017 involving 32 children (84% male) between 6 and 12 years old with ASD showed improvements in SRS scores (F_1,21 = 5.6083, P = .0275) when they were given intranasal oxytocin twice daily for 4 weeks, but the study did not show a reduction in repetitive behaviour or anxiety symptoms.¹⁸ Additionally, individuals with the lowest pretreatment plasma oxytocin concentrations showed the greatest improvements in SRS scores (F_1,18 = 6.0333; P = .0244).¹⁸

In the largest study to date on social interaction assessments and ASD, which involved 290 children (87% male) between 3 and 17 years old with ASD, the 146 individuals in the treatment group showed no significant improvements on pre- and posttreatment scores on the Aberrant Behavior Checklist modified Social Withdrawal subscale (least-squares mean difference = -0.2, 95% CI -1.5 to 1.0, P = .61) following a 24-week course of daily intranasal oxytocin when compared with the 144 children assigned to the placebo group.¹⁹ There were also no significant differences in social motivation (measured using the SRS-2 Social Motivation subscale; 95% CI -1.0 to 2.9, Cohen d = 0.9) or intelligence (using the Stanford-Binet Intelligence Scales 5th Edition abbreviated IQ measure; 95% CI -2.9 to 3.0, Cohen d = 0.1).¹⁹ There was no significant difference in the rate of adverse events for those receiving oxytocin (82%) compared with that of the placebo group (83%).¹⁹ The trial group had higher incidences of increased appetite compared with those in the placebo group (16% vs 10%, respectively), increased energy (10% vs 3%), restlessness (8% vs 2%), subjective weight loss (7% vs 3%), increased thirst (6% vs 3%), and inattention (6% vs 3%).¹⁹

In summary, results have been equivocal across various studies in social functioning in children with ASD; however, the largest and most recent study to date did not show treatment benefits. Small sample sizes and differences in participant age, oxytocin formulation and dose, treatment duration, outcome measures, and analytic methods may help explain some of these disparities. Heterogeneous effects may also be explained by a growing body of research pointing to individual variations in the oxytocin receptor gene.²⁰ Finally, the fact that ASD has a range of clinical presentations may contribute to mixed results since the target populations in different studies may also vary.