**3. Effectiveness of intranasally or intravenously administered OT in ASD subjects**

Four randomized, double-blind, placebo-controlled trials of short-term OT administration in subjects with high-functioning ASD have been published since 2003 (Table 2) [32-35].


**Table 2.** Randomized, double-blind, placebo-controlled trials of short-term oxytocin administration in subjects with high-functioning autism spectrum disorder

The designs were naturally different between these studies in terms of age and gender of participants, medication methods, doses of OT and outcomes, so no conclusions could be drawn regarding the treatment of ASD patients based on a single-dose design. However, OT may play a role in alleviating repetitive symptoms [32] and modifying social impairments [33-35].

Is Intranasal Administration of Oxytocin Effective for Social Impairments in Autism Spectrum Disorder? 101

Age (years)

NCT01417026 11 August 2011 68 12-17 Male Profound mental retardation

Gender Intellectual

Primary and secondary outcome measures

Test,social attention, reward/motivation, perception, and cognition tasks

Improvement. Yale Brown Obsessive Compulsive Scale, Repetitive Behavior Scale-Revised, Diagnostic Analysis of Nonverbal Accuracy-2

Responsiveness Scale, Clinical Global Impressions Scale- Improvement, Repetitive Behavior Scale-Revised, Child Yale-Brown Obsessive-Compulsive Scale

Child Behavior Checklist, Autism Diagnostic Observation Schedule, Childhood Autism Rating Scale

Scale, Zung Self-Rating Depression Scale, State-Trait Anxiety Inventory

Autism Rating Scale 2, Psychological paradigms to test social cognition and behavior

Aberrant Behavior Checklist, Global Assessment of Functioning, Interaction Rating Scale Advanced

Clinical Global Impressions, Preferential attention to social stimuli, Developmental Behavior Checklist, Social behavior scale

Test, Repetitive Behavior Scale, Clinician Global Assessment

5 weeks Positive social interaction, Severity of repetitive behavior,

8 weeks Social Responsiveness Scale, Reading the Mind in the Eyes

12 weeks Diagnostic Analysis of Nonverbal Accuracy, Social

disability

excluded

intellectual disability

Nine pioneering clinical trials are in progress (Table 3). Although there is considerable diversity in age and gender of participants, oxytocin doses and trial duration, primary and secondary outcome measures would be the most noticeable items and are discussed here.

> Estimated enrollment

NCT01337687 10 December 2010 34 18-55 Both Excluded NCT01256060 22 November 2010 84 12-18 Both Excluded UMIN000003812 7 January 2010 20 10-14 Male Not excluded UMIN000005211 8 March 2011 60 >15 Both Excluded UMIN000007122 1 February 2012 20 18-54 Male Excluded UMIN000007250 9 February 2012 30 15-44 Male Restricted to subjects with

ACTRN12611000061932 17 January 2011 40 3-8 Both Not excluded ACTRN12609000513213 29 June 2009 40 12-18 Male Excluded

NCT01417026 24 IU 5 days Part/Whole Identity Test, Reading the Mind in the Eyes

NCT01337687 48 IU 8 weeks Clinical Global Impressions Scale- Severity and

UMIN000005211 Unknown Unknown Aberrant Behavior Checklist, Childhood Autism Rating

UMIN000007122 48 IU 6 weeks Autism Diagnostic Observation Schedule, Childhood

UMIN000007250 16 IU 8 weeks Childhood Autism Rating Scale, Clinical Global Impressions,

**Table 3.** Randomized, double-blind, placebo-controlled trials of intranasally short-term oxytocin administration in subjects with high-functioning autism spectrum disorder based on the public databases

Oxytocin duration

12 months

Registered identifier Registered

Registered number Oxytocin

NCT01256060 0.8 IU /

UMIN000003812 Maximum

ACTRN12611000061932 Maximum

ACTRN12609000513213 12-18

date

doses per day

kg

24 IU

12 IU

IU

With regard to social impairments, Hollander et al. investigated the effectiveness of intravenously administered OT on comprehension of affective speech in 15 subjects with ASD in a randomized, double-blind, placebo-controlled, cross-over design [33]. The task was fairly easy for the participants resulting in the same improvements of scores of those who were administered placebo in the first condition as those who were administered OT in the first condition. However, after an interval between the first and second conditions (days: mean = 16.07; SD = 14.26), the scores at baseline in the second condition were retained in the participants administered OT and dropped in those administered placebo. These results suggested that OT may play a role in social memory acquisition in social cognition in ASD subjects.

Andari et al. investigated the effectiveness of intranasally administered OT on trust and preference toward opponent players using a social ball tossing game in 13 subjects with ASD by randomized, double-blind, placebo-controlled, within-subject design [34] (No results of face perception tasks shown in the study are noted here). ASD subjects administered OT trusted more and showed stronger preference for good than bad opponent players regardless of the perception of monetary rewards. No significant differences were found under placebo conditions. These results suggest that OT may play a role in prosocial behavior in subjects with ASD. Moreover, it was noted that plasma OT concentration at 10 min after nasal administration of OT show a significant increase compared to baseline concentration.

Guastella et al. investigated the effectiveness of intranasally administered OT on emotion recognition using the Reading the Mind in the Eyes Test-Revised [36] in 16 subjects with ASD by randomized, double-blind, placebo-controlled, cross-over design [35]. The improved performance by OT compared to placebo was restricted to the younger participants aged 12 to 15 and easy items in the test. These results suggest that OT may play a role in emotion recognition in social cognition for ASD subjects, although age and task difficulty may act as modulators.

Taken together, short-term (continuous intravenous infusion over 4 h or nasal spray of certain doses at a time) administration of OT may show effectiveness on social cognition and prosocial behavior in ASD subjects with situational differences or individual factors as confounders taken into account. The next step should be to investigate whether long-term administration of OT modulates social impairments in ASD.
