**4. Long-term randomized, double-blind, placebo-controlled trials of OT in subjects with ASD registered in the public databases**

We searched the public databases, i.e., Clinicaltrials.gov (http://clinicaltrials.gov), UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index-j.htm), and Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/), for long-term clinical trials of OT in ASD. In other databases of EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) and ISRCTN Register (http://www.isrctn.org/), we could not obtain the detailed information about long-term clinical trials of OT in ASD.

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.

100 Neuroendocrinology and Behavior

difficulty may act as modulators.

administration of OT modulates social impairments in ASD.

about long-term clinical trials of OT in ASD.

**in subjects with ASD registered in the public databases** 

[33-35].

may play a role in alleviating repetitive symptoms [32] and modifying social impairments

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

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

may play a role in social memory acquisition in social cognition in ASD subjects.

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

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

**4. Long-term randomized, double-blind, placebo-controlled trials of OT** 

We searched the public databases, i.e., Clinicaltrials.gov (http://clinicaltrials.gov), UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index-j.htm), and Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/), for long-term clinical trials of OT in ASD. In other databases of EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) and ISRCTN Register (http://www.isrctn.org/), we could not obtain the detailed information


**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 The Social Responsiveness Scale provides quantitative measurements of social impairments in ASD by assessing domain of sociality such as social awareness and social information processing [37], and has been used as an outcome measure for interventions [38, 39]. The Reading the Mind in the Eyes Test [36] measures an aspect of social cognition by having the subjects assess emotion through the look of an actor's eye in photographs and has been adopted in many experimental trials [35, 40]. The Diagnostic Analysis of Nonverbal Accuracy Scale measures receptive and expressive abilities for receiving and sending emotions in faces, gestures, postures, and prosody [41], and has been used in the researches of not only ASD [42] but also of other mental disorders [43]. The Childhood Autism Rating Scale helps to identify subjects with ASD and determine symptom severity and has been commonly used in research and clinical settings. The scale assesses various domains of symptoms in ASD, including social impairments. The Autism Diagnostic Observation Schedule is a tool for assessment of symptoms of ASD through structured and semistructured activities with subjects and provides scores in communication, social, and restricted and repetitive domains [44]. This tool has been regarded as the gold standard for assessing and diagnosing ASD. The Interaction Rating Scale Advanced assesses a practical index of social skills using five-minute video recorded interaction session [45]. It is interesting to note that this new tool may provide a validated measure of social impairments of ASD. The evaluations mentioned above provide quantitative values of social impairments of ASD based on caregivers' self-reports or behavioral observations.

Is Intranasal Administration of Oxytocin Effective for Social Impairments in Autism Spectrum Disorder? 103

When one points at something, others are invariably around. When one points at something, one invariably attempts to convey any information to others around. A toddler pulls his/her mother's sleeve, points to a miniature car on a shelf, and then looks at his/her mother's face (requesting pointing). When a preschool child sees a rainbow in the sky after rain, he/she runs up to his/her mother, takes her to the garden, and points to the rainbow while looking at her (declarative pointing). Liszkowski et al. found that twelve-month-old infants show different attitudes according to experimenter's reactions when infants point declaratively [47]. When experimenters responded to infants' declarative pointing but attended an incorrect referent with positive attitude, infants repeated pointing to redirect the experimenters' attention. When experimenters identified the correct referent with negative attitude, infants did not repeat pointing. When experimenters identified the correct referent and shared interest in it, infants appeared satisfied. Pointing is a prototypical behavior of interpersonal exchange, i.e., sociality. Toddlers with ASD display a reduced incidence of declarative pointing compared to typically developing toddlers [48]. Declarative pointing constitutes a significantly diagnostic sign as well as social interest and joint attention for early detection of ASD [49]. Individuals

We consider that it would be essential to refer to one's own self and others if social impairments in ASD are discussed, because our own selves are embedded in a society full of others [20]. Individuals with ASD may be unable to mentalize the inner states of typically developing individuals, and this raises the question of whether typically developing individuals can mentalize the inner states of individuals with ASD. "Theory of mind" tasks would be regarded as tasks in ASD with "altered" self-consciousness proposed by

According to the standpoint of traditional German psychopathology, self-consciousness (Ichbesstsein in German) is formally comprised of four prototypical representations. First, one's own self is identical at all times. Second, one's own self is always consistent. Third, all of one's own acts belong to one's own self. Finally, one's own self differs from others' own self. These representations deeply embedded in social interactions are intrinsically selfevident and underlie interpersonal exchange of sociality. While one exists almost without reflection on these representations in daily life, severe disruption of self-consciousness would have fairly serious consequences, such as dissociative identity crisis, doppelganger, xenopathic experiences and delusions of possession. Interestingly, children with ASD performed significantly less well on the self-test question than the other-person test question using tasks in which participants have to reflect an awareness of one's own prior belief [50]. These results suggest that individuals with ASD represent altered self-consciousness as

Although self-consciousness have been investigated using functional magnetic resonance imaging in ASD and healthy individuals [22, 23], the effects of OT on self-consciousness in

It is essential but difficult to answer questions regarding improvements of social impairments associated with treatment of patients with ASD. However, it may be useful to

with ASD have an innate disability in the social domain.

mentioned above: "all of one's own acts belong to one's own self."

individuals with "intact" self-consciousness.

humans have not been examined.

At present, there is no commonly used assessment of symptoms in ASD, especially social and communication domains, for any interventions in contrast to the Positive and Negative Symptom Scale in schizophrenia and Hamilton Rating Scale for Depression in major depressive disorder, which are widely used as almost definitive measures. In the wellknown research in which risperidone, a second-generation antipsychotic, was shown to be effective for reduction of irritability in subjects with ASD, the authors stated that they were unable to identify a validated measure for the core symptoms of ASD, i.e., social impairments [46].

A key question is whether these outcome measures could be used to sensitively assess improvements in sociality, which may only be subtle changes. This question remains unanswered before publication of the results of these trials.
