A 16-year-old girl with her mother visited our department presenting with incomprehensibility of others’ mind and aggressive behaviors including self-injury. She showed a marked impairment in social interactions (i.e., having few friends, lack of empathy, poor understanding of others’ mind). She also showed echolalia in her childhood, and she was obsessed with playing video games and showed a strong interest in wearing flashy clothes. She had mood fluctuations and often upset other people with her temper tantrums. She had no history of neurological or psychiatric diseases, except for autistic symptoms, or maltreatment, and her brain magnetic resonance imaging (MRI) showed no apparent abnormal findings.
The author H.K. diagnosed her as having autistic disorder on the basis of the classifications in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR; American Psychiatric Association, 2000) and standardized criteria using the Diagnostic Interview for Social and Communication Disorders (DISCO) [10
]. Her full-scale intelligence quotient was 92, as determined using the Wechsler adult intelligence scale-third edition. Her aberrant behavior checklist (ABC) [11
] completed by her mother at the initial visit showed a very high score of 69 for items such as hyperirritability, strong aggression, poor empathy, and bizarre behaviors. For several months, she received behavioral psychoeducational treatment as well as adequate trials of medications including risperidone and antianxiety agents; but these were ineffective and the medications caused extrapyramidal symptoms and drowsiness.
Then, her mother learned from the internet about the efficacy of nasal oxytocin spray for autism, and she decided to try it on her at an intranasal dose of 8
IU of oxytocin per day (Syntocinon spray, Novartis; one puff each in the morning and evening) for personal use. Her mother decided to use a smaller amount of intranasal oxytocin than that indicated in previous reports [3
]. Using some checklists and by physical examinations, we monitored the patient’s behavioral symptoms and verified the mother's impressions and observations at every visit. One month after starting nasal oxytocin spray administration, the girl’s social behaviors began to improve. The duration in which she closeted herself in her room became short. She greeted other people and made small talk with them, and she also showed empathy for others’ sickness and worries. She became able to express gratitude to her family for their support. She became able to carefully listen to her family’s conversation, and showed attenuated expressions of rebellion to the family’s words of caution. Even when she lost her temper, she calmed down immediately. A teacher who taught her about culture and who did not know about her treatment noted decreases in the numbers of episodes of irritability and self-injury, and was surprised at the increases in the frequencies of daily conversations and happy facial expressions in the presence of other people. Her score in ABC completed by her mother markedly decreased from 69 to 15, two months after starting oxytocin treatment. Marked decreases were found in her subscale scores for the (I) Irritability and Agitation item (from 28 to 12) and (IV) Hyperactivity and Noncompliance item (from 20 to 2). Her score of the Clinical Global Impression (CGI) - Severity scale also decreased from 6 (“severely ill”) to 3 (“mildly ill”); her CGI-Improvement score was 1, which indicates "Very much improved". Even after six months of administration, her improved social behaviors continued with 7 of ABC scores completed by her mother. There were no obvious adverse effects of oxytocin, including anaphylactic reaction, nausea, or vomiting, as described in the package insert. Her menstrual cycle remained regular and milk ejection was not observed. No marked changes were observed in her sex hormone levels. A complete blood count test, renal and liver function tests, and brain MRI confirmed the absence of abnormal findings.
This is the first case report of a female patient with autistic disorder whose aberrant social behaviors and related autistic symptoms were improved by long-term nasal oxytocin administration. Although there was a study including two females with ASDs receiving a single dose of 24
IU oxytocin during a social game [7
], there are no reports of long-term nasal oxytocin administration to female subjects with ASDs. The observed effects in the present case are in accordance with our previous report of an autistic boy receiving long-term oxytocin administration [9
]. There is a possibility that her symptoms were improved by other confounding factors. However, she has not received any other medication since the administration of oxytocin nasal spray, and her symptoms had not been improved by psychoeducational treatment, which she received for several months before the administration of oxytocin. Although ABC and CGI used to assess this patient are subjective evaluation scales that may be influenced by the rater's expectations, for this patient, all the family members observed that her symptoms began to improve gradually and the improvements continued for more than six months. Moreover, other people associated with her such as her teacher also made similar observations.
Regarding safety issues, no adverse effects related to long-term oxytocin treatment were observed in the present case. This is partly because the expression level of oxytocin receptors in nonpregnant myometrium is markedly lower than that during the period of delivery [12
], and the oxytocin dose of the present case is 8
IU per day, which is much lower than that (single dose of 24
IU oxytocin) in previous reports [3
The amygdala is part of the "social brain" and is proposed to be one of the several neural regions that are abnormal in autism [1
]. The amygdala theory of autism, which involves deficits in “social intelligence”, is supported by many researchers [1
]. Regarding the association between the amygdala and the oxytocin receptor, the amygdala has abundant oxytocin receptors. A functional MRI study showed that a single dose of oxytocin attenuated amygdala responses to emotional faces [13
]. It is also suggested that the rs2254298A allele of the oxytocin receptor, which is associated with ASDs, was significantly associated with larger bilateral amygdala volume [14
]. Rosenfeld et al.
] proposed a model comprising abnormalities in oxytocinergic and dopaminergic signalings in the amygdala that result in impaired emotional salience processing with consequent social cognitive deficits. Considering these findings, exogenous oxytocin administration may modulate these signalings in patients with social impairments, via the amygdala. Research on whether long-term administration of oxytocin leads to a decrease in expression levels of oxytocin receptors is also needed [8