JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 23, Number 2, 2013 ª Mary Ann Liebert, Inc. Pp. 123–127 DOI: 10.1089/cap.2012.0048
Brief Report
Long-Term Administration of Intranasal Oxytocin Is a Safe and Promising Therapy for Early Adolescent Boys with Autism Spectrum Disorders Masaya Tachibana, MD,1,2 Kuriko Kagitani-Shimono, MD, PhD, 1,2,3 Ikuko Mohri, MD, PhD,1,2,3 Tomoka Yamamoto, PhD, 1,3 Wakako Sanefuji, PhD,1,3 Ayumi Nakamura, BPharm,4 Masako Oishi, PhD,4 Tadashi Kimura, MD, PhD,5 Tatsushi Onaka, MD, PhD,6 Keiichi Ozono, MD, PhD,2 and Masako Taniike, MD, PhD1,2,3
Abstract
Objective: Oxytocin (OT) has been a candidate for the treatment of autism spectrum disorders (ASD), and the impact of intranasally delivered OT on ASD has been investigated. However, most previous studies were conducted by single-dose administration to adults; and, therefore, the long-term effect of nasal OT on ASD patients and its effect on children remain to be clarified. Methods: We conducted a singled-armed, open-label study in which OT was administered intranasally over the long term to eight male youth with ASD (10–14 years of age; intelligence quotient [IQ] 20–101). The OT administration was performed in a stepwise increased dosage manner every 2 months (8, 16, 24 IU/dose). A placebo period (1–2 weeks) was inserted before each step. The outcome measures were Autism Diagnostic Observation Schedule – Generic (ADOS-G), Child Behavior Checklist (CBCL), and the Aberrant Behavior Checklist (ABC). In addition, side effects were monitored by measuring blood pressure and examining urine and blood samples. Results: Six of the eight participants showed improved scores on the communication and social interaction domains of the ADOS-G. However, regarding the T-scores of the CBCL and the scores of the ABC, we could not find any statistically significant improvement, although several subcategories showed a mild tendency for improvement. Caregivers of five of the eight participants reported certain positive effects of the OT therapy, especially on the quality of reciprocal communication. All participants showed excellent compliance and no side effects. Conclusions: Although our results on the efficacy of long-term nasal OT therapy still remain controversial, to the best of our knowledge, this is the first report documenting the safety of long-term nasal OT therapy for children with ASD. Even though our data are too preliminary to draw any definite conclusions about efficacy, they do suggest this therapy to be safe, promising, and worthy of a large-scale, double-blind placebo-controlled study.
Introduction
A
utism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impaired social reciprocal interaction and communication, and by restricted interests and repetitive behaviors. As the prevalence of ASD is estimated to be as high as 1% (Rice 2009), curative treatments for the core symptoms of ASD have been intensively sought. Oxytocin (OT) is a neuropeptide, and it has been shown to play an important role in the regulation of the social behaviors of animals such as prairie voles (reviewed in Modi and Young 2012).
Animal models with alterations in the OT system suggest that this system may be a possible treatment target for psychiatric disorders characterized by social deficits in humans, such as ASD (Guastella et al. 2009; Pedersen et al. 2011; Modi and Young 2012; Young and Flanagan-Cato 2012). During recent decades, the impact of OT on adults with ASD has been investigated (Hollander et al. 2003; Guastella et al. 2010). The vast majority of these previous studies almost exclusively involved single-dose administration, with the outcome measured in terms of improvements in social cognitive tasks (Green and Hollander 2010; MacDonald et al. 2011). Until now, there have been only a few
1 Molecular Research Center for Children’s Mental Development and 3Divison of Developmental Science, Department of Child Development, United Graduate School of Child Development, and Departments of 2Pediatrics and 5Obstetrics and Gynecology, Graduate School of Medicine, Osaka University, Suita, Japan. 4 Department of Pharmacy, Osaka University Hospital, Suita, Japan. 6 Department of Physiology, Jichi Medical University, Shimotsuke, Japan.
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FIG. 1. Protocol used for the open-label, single-arm study on long-term intranasal administration of oxytocin (OT). The dosage of OT was increased in a stepwise manner every 2 months, from 8 IU/dose to 24 IU/dose, and a placebo period of 1–2 weeks (P) took place before the start of treatment and was inserted between the steps. ADOS, Autism Diagnostic Observation Schedule – Generic; CBCL, Child Behavior Checklist; ABC, Aberrant Behavior Checklist; Osm, osmolarity; BAP, bone-specific alkaline phosphatase. The graphs at the bottom of the figure show improvement in ADOS-G scores during OT administration. Because two modules were used, the ADOS-G score before oxytocin was set at zero, and the changes in the scores at the end of the third stage are shown as ‘‘post’’ scores. The dysfunctional domains that each ADOS-G subscale covered are the following: ADOS A, communication; ADOS B, reciprocal social interaction; ADOS C, play, imagination; ADOS D, repetitive behaviors and restricted interests. Asterisks indicate a significant change ( p < 0.05). reports about the effects and side effects of the long-term, daily use of OT on adult patients with schizophrenia (Feifel et al. 2010) or social anxiety disorder (Guastella et al. 2009), but none with respect to ASD. In addition, the effects of OT on young people with ASD have never been documented except in the study by Guastella et al. (2010), who reported improvement in an emotion recognition task after singledose intranasal OT administration. Although long-term and daily use of OT is plausibly required for improvement of daily functioning of children with ASD, the effects and side effects of long-term administration of OT even in adult ASD remain to be investigated, as does the permissible and appropriate dose of OT for children. According to the product information from the Netherlands, the possible side effects of OT are headaches, nausea, allergic dermatitis (< 1/1000), and abnormal uterine contractions (< 1/100).
Previous studies investigating the effect of OT on maternal lactation have shown no severe side effects, but it has been reported that prolonged, excessive use of intranasal OT together with a large volume of fluid causes water intoxication along with hyponatremia (Seifer et al. 1985). MacDonalds et al. (2011) reviewed 38 randomized controlled trials (RCTs) of intranasal OT used in human research and concluded that intranasal OT had no remarkable side effects; however, these RCTs included only four studies involving daily and long-term OT treatment. In order to investigate the efficacy and side effects of long-term, daily administration of OT on children with ASD, we conducted a pilot study, administering intranasal OT to nine preadolescent boys, 10–14 years of age (mean = 11.9; SD = 1.3). Because the appropriate dosage for children had not been established yet, we selected the single-armed, open-label, dose titration method.
LONG-TERM OXYTOCIN ADMINISTRATION TO BOYS WITH AUTISTIC DISORDERS Methods Subjects All participants were recruited through the Osaka University Hospital if they met the clinical diagnosis for ASD as assessed by use of American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). We performed the Autism Diagnosis Observation Schedule – Generic (ADOS-G) (Lord et al. 2000) on all participants before inclusion, and confirmed the diagnosis. The exclusion criteria included cardiovascular disease and any changes in the use of other psychoactive medications during the study. During the protocol, we did not allow any change in medication or psychoeducational treatment. All procedures were performed with the adequate understanding and written consent of the participants’ caregivers, and were approved by the local Institutional Review Board of the Faculty of Medicine, Osaka University. This trial has been registered in Japan Primary Registries Network (trial ID: UMIN000003812), which participates in the World Health Organization (WHO)’s International Clinical Trial Registry Platform. Dosing plan Each subject was scheduled to receive OT via an intranasal spray twice a day for about 7 months (Fig. 1). The dosage of OT (Syntocinon; Novartis, Basel, Switzerland) was raised in a stepwise manner every 2 months by 8 IU/dose, increasing from 8 IU/dose to 24 IU/dose. One to two weeks’ administration of a placebo was performed before the OT, and inserted between the dosing steps as a washout period. The concentration of OT in the nasal spray was changed according to the protocol so that a total of six puffs/dose twice a day was maintained throughout the protocol. This protocol was chosen in order to improve the compliance of ASD children, who are sensitive to and dislike changes in routine. The placebo solution and OT at different concentrations were dispensed by the Department of Pharmacy of Osaka University Hospital. Outcome measures The outcome measures were ADOS-G scores determined before and at the end of the administration period, and the Aberrant Behavior Checklist (ABC) (Aman et al. 1985) and Child Behavior Checklist (CBCL) (Achenbach 1991), completed by the caregivers before the administration and at the end of each dose period. Although previous studies usually used cognitive or learning tasks to estimate the short-term efficacy of OT (Hollander et al. 2003; Guastella et al. 2010), we chose ADOS-G, ABC, and CBCL because we intended to elucidate the efficacy of OT on the three core symptoms of ASD and behaviors in daily life rather than on a specific cognitive function measured by a specific task. Among the four modules of the ADOS-G, the module most appropriate for the language expression level of each participant was selected; the same module was used at the beginning and at the end of the protocol. Three raters were assigned to administer the ADOS-G to the participants, which evaluation was made before and at the end of the OT period. The administrators of pre- and post-OT were different for each participant, and they had no knowledge of the treatment. One rater (W.S.) was trained to be research reliable and the other two (M.T. and T.Y.) had participated in the authentic ADOS-G training course. All trials were video recorded, and six sessions were randomly chosen after all the administrations had been completed. Additional codings were performed separately on
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the sessions by the two other raters, who were also unaware of the pre- or post-OT treatment. These triple-coded sessions were used to estimate inter-rater reliability. The concordance rate of the coding among the three raters was 0.90. In addition, pediatric neurologists (M.T., K.K.S.) interviewed the caregivers about the changes in the participants at home and at school every time the participants visited the hospital. Safety data In order to detect possible water intoxication caused by OT treatment, each subject was measured for blood pressure (BP), urine osmolarity, and urine sodium concentration in addition to the OT concentration of his second urine in the morning whenever he came to the hospital during the trial. Blood examinations including serum osmolarity, serum sodium concentration, and plasma OT concentration were conducted before administration and at the end of each dosing step. OT concentrations were measured by using the method previously reported (Nagasawa et al. 2009). Plasma samples without extraction were used. Coefficients of inter- and intraassay variations were 10% and 4%, respectively. The minimum detection limit was 2 pg/mL. As OT reportedly has an anabolic effect on bone (Tamma et al. 2009), we also checked serum bone-specific alkaline phosphatase (BAP), a marker for bone formation, in addition to the plasma OT concentration. Also, because there is a report documenting a patient with obsessive compulsive disorder (OCD) who received 4 weeks of OT administration and developed significant memory impairment (Ansseau et al. 1987), we checked the short-term memory by use of picture cards that fitted each participant’s interests. For the four participants who were unable to understand the tasks because of their lower intelligence quotient (IQ), their memory impairment was judged based on the information obtained from their caregivers. Statistical analysis One-way repeated measures ANOVA, or two-tailed paired t test was used for the statistical analysis. Differences were considered significant at p < 0.05. Results Of the nine participants, one dropped out of the study during the second step (16 U/dose) because of family reasons; although the parents reported obvious positive changes in social interaction with no side effects. Therefore, eight participants completed the protocol. At the beginning of the protocol, three patients (Nos. 2, 3, and 7) had been medicated with drugs at the same dose for > 6 months (Table 1); and three patients (Nos. 3, 6, and 8) had been receiving psychoeducational therapies for > 6 months. However, during the protocol, we did not allow any change in medication or psychoeducational treatment. The profiles of the eight participants are shown in Table 1. ADOS-G Among the four modules of the ADOS, module 1 was applied to five participants; and module 3 was applied to the others. In order to combine the results obtained with these two modules, we analyzed the changes between the scores pre-OT and those at the final stage. The ADOS scores of ‘‘A. communication,’’ ‘‘B. social interaction,’’ and the sum of A + B were significantly improved after OT
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TACHIBANA ET AL. Table 1. Clinical Features of the Participants
Participant 1 2 3 4 5 6 7 8
Age(yrs)
IQ-DQ
Diagnosis
Comorbidity
Medication
12.7 14.4 10.8 12.4 10.0 12.8 11.1 11.2
20 20 26 26 40 56 88 101
Autism Autism Autism Autism Autism Autism HFA HFA
Epilepsy Epilepsy Cortical dysplasia, epilepsy Post West syndrome
CBZ, ATX, RSD CBZ, TPM, ATX, RSD
Epilepsy MPH,ATX
Language expression level No words No words Three-word utterances Three-word utterances Three-word utterances Sentences Fluent speech Fluent speech
IQ, intelligence quotient; DQ, developmental quotient; HFA, high-functioning autism; CBZ, carbamazepine; ATX, atomoxetine; RSD, risperidone; TPM, topiramate; MPH, methylphenidate.
treatment (t[7] = - 3.21, p = 0.015 for A; t[7] = - 3.32, p = 0.013 for B; t[7] = - 3.53, p = 0.010 for A + B); whereas the ADOS scores of C and D, reflecting the quality of play/ imagination and severity of repetitive behaviors and restricted interests, respectively, were not changed by the administration (Fig. 1). Changes in the questionnaires as regards problematic behaviors We could find no statistically significant improvement in the Tscores of the CBCL by ANOVA; but two of the subcategories, ‘‘V. Thought problems’’ and ‘‘VII. Delinquent behavior,’’ showed a mild tendency for improvement when evaluated by the paired t test (t[7] = - 2.12, p = 0.07 [two-tailed] for V[pre-24 IU]; t(7) = - 1.98, p = 0.09 (two-tailed) for VII[pre-24 IU]) (data not shown). Moreover, when we set the criterion for improvement as a > 25% decrease in the scores (‘‘T-score minus 50’’), because the T-score of each subscale would be 50 when the raw score in that region was 0, five of the eight participants showed improved internalizing and externalizing T-scores of more than one point during the therapy (data not shown). ANOVA was also unable to detect any significant difference in the total ABC score. However, the subscale ‘‘II. Lethargy, social withdrawal’’ showed a tendency for improvement between pre-OT and 24 IU/dose, as assessed by the paired t test (pre-24 IU: t[7] = - 1.92, p = 0.096 [two-tailed]) (Suppl. Fig. 1) (See supplemental Figure 1 at www.liebertpub.com/cap). Safety data BP showed no significant change during the protocol, nor did serum osmolarity, mean serum sodium concentration, urine osmolarity, or urine sodium (corrected by creatinine) (Suppl. Fig. 2a, 2c–f ) (See supplemental Figure 2 at www.liebertpub.com/cap). With regard to the bone metabolism, there was no change detected in the plasma BAP level during OT treatment periods (Suppl. Fig.2b). Although the plasma OT level at 2 hours after administration showed no significant rise during the protocol (Suppl. Fig. 2g), urinary OT (corrected by creatinine) increased during OT administration compared with its content before the administration (Suppl. Fig.2h), indicating that the OT administered to the participants was absorbed into the bloodstream and quickly cleared into the urine. Impairment of short-term memory was neither detected nor reported during the protocol. Discussion Our results on the efficacy of OT were complicated. First, the decrement of the score in the ADOS-G may suggest that OT can
improve the quality of social interaction and communication among the core defects of ASD in preadolescent boys with ASD, whereas there remains the possibility that these improvements were the result of the natural course of their mental development. However, the improvements were remarkably rapid in emergence for the boys at early adolescence, suggesting the possibility that the improvements may have been related to the nasal OT therapy. To clarify this, double-blind, placebo-controlled study is imperative in the future. In spite of the improvement in the ADOS scores after OT treatment, we could not detect any significant improvement in either CBCL or ABC scores. One of the reasons for this discrepancy might be the small sample size. In addition, as behaviors of ASD individuals are easily influenced and affected by multiple factors including social stress and environmental changes in their daily lives such as a new classroom or school events, one can easily assume that the efficacy of long-term administration would be much harder to be evaluated compared with that of single-dose administration. This possibility might explain the failure to detect any significant improvement in CBCL and ABC scores. Another possibility is that the outcome measures that we adopted failed to detect the area in which OT might have the largest impact on ASD patients. Considering that the improvements in the ADOS were related to communication and social interaction, other questionnaires tailored to measure social aspects might have been able to detect the impact of long-term use of OT. If we had included some measures to detect such cognitive function, for example, the eye tracker, we might have been able to detect some changes during OT use. The reports from the caregivers were interesting and suggestive, although they were less objective and may have been biased by the open-label design of this study. Although caregivers of three participants reported no changes in the daily lives of their children, five caregivers reported that their children had certain positive changes during OT administration. The reported changes were related to improvement, especially in the quality of social communication, such that the participant came to express his intentions verbally and to communicate more reciprocally and more interactively after the initiation of the treatment. These changes were prominent in the mildly or moderately mentally retarded, but verbal, children who were able to express words and phrases (Case Nos. 3, 4, and 6). In addition, whereas Case No. 4 had been able to draw only lines and circles, he was suddenly able to draw a picture of his mother’s face with the word ‘‘mama’’ written in Japanese Hiragana characters on it (Suppl. Fig. 3) (See supplemental Figure 3 at www .liebertpub.com/cap). The fact that he suddenly acquired the ability to draw a portrait of his mother may suggest his increased
LONG-TERM OXYTOCIN ADMINISTRATION TO BOYS WITH AUTISTIC DISORDERS awareness of and interest in his mother’s face. These effects had no correlation with the plasma OT level, and no dose dependency was recognized. On the other hand, nonverbal children with very low IQs (Case Nos. 1 and 2) and ASD with high IQs (Case Nos. 7 and 8) showed less obvious improvement in caregiver’s reports following OT treatment. No remarkable changes in restricted interests were observed in any of the children. These reports from caregivers may suggest which patients would be possible responders to OT therapy and which symptoms would be possibly improved by OT. With regard to the safety of long-term OT administration, no remarkable side effects were detected in any of the participants. Our results are the first to indicate that the long-term use of intranasal OT would be a safe and tolerable therapy for children with ASD. In our protocol, we increased the dosage of OT in a stepwise manner, but no clear dose dependency on the efficacy of OT was detected. However, the ADOS scores at the 24 IU/dose period improved from the baseline; and the CBCL and ABC scores tended to show improvement between the baseline and the 24 IU/dose period. Therefore, a 24 IU/dose twice a day would seem to be a safe and optimal dose of OT for preadolescent boys with ASD. Conclusions As our sample size was too small and there remains room for controversy over the efficacy of OT, a randomized, placebocontrolled study needs to be performed to clarify the efficacy issue. However, our data suggest OT to be a safe and promising therapy, and they support future large-scale, double-blind, crossinstitutional RCTs. In particular, the tendency for the greatest efficacy in mentally retarded verbal children should be confirmed in order to select the best candidates for OT therapy. Clinical Significance This is the first study to reveal the safety of the long-term OT on young people with ASD, as well as the possible efficacy of this therapy. The results of this study should encourage researchers planning to conduct a long-term RCT of OT, as well as patients and their families hoping for the therapeutic use of OT. Acknowledgments We thank Dr. Taiichi Katayama, Dr. Yuri Kitamura, Dr. Saeko Sakai, and Dr. Noriyuki Namba for being the safety committee for judging the safety and side effect of OT. We also thank all the participants and their families for having participated in this trial. Disclosures Drs. Tachibana, Kagitani-Shimono, Mohri, Yamamoto, Sanefuji, Nakamura, Oishi, Kimura, Onaka, Ozono, and Taniike have no conflicts of interest or financial ties to disclose. References Achenbach TM: Integrative Guide for the 1991 CBCL/4-18, YSR, and TRF Profiles. Burlington, VT: Department of Psychiatry, University of Vermont; 1991. Aman MG, Singh NN, Stewart AW, Field CJ: The Aberrant Behavior Checklist: A behavior rating scale for the assessment of treatment effects. Am J Ment Defic 89:485–491, 1985. Ansseau M, Legros JJ, Mormont C, Cerfontaine JL, Papart P, Geenen V, Adam F, Franck G: Intranasal oxytocin in obsessive-compulsive disorder. Psychoneuroendocrinology 12:231–236, 1987.
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Feifel D, MacDonald K, Nguyen A, Cobb P, Warlan H, Galangue B, Minassian A, Becker O, Cooper J, Perry W, Lefebvre M, Gonzales J, Hadley A: Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients. Biol Psychiatry 68:678–680, 2010. Green JJ, Hollander E: Autism and oxytocin: new developments in translational approaches to therapeutics. Neurotherapeutics 7:250– 257, 2010. Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ, Hickie IB: Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 67:692–694, 2010. Guastella AJ, Howard AL, Dadds MR, Mitchell P, Carson DS: A randomized controlled trial of intranasal oxytocin as an adjunct to exposure therapy for social anxiety disorder. Psychoneuroendocrinology 34:917–923, 2009. Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, Mosovich S: Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 28:193–198, 2003. Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC, Pickles A, Rutter M: The Autism Diagnostic Observation Schedule–Generic: A standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 30:205–223, 2000. MacDonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ: A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology 36:1114–1126, 2011. Modi ME, Young LJ: The oxytocin system in drug discovery for autism: Animal models and novel therapeutic strategies. Horm Behav 61:340–350, 2012. Nagasawa M, Kikusui T, Onaka T, Ohta M: Dog’s gaze at its owner increases owner’s urinary oxytocin during social interaction. Horm Behav 55: 434–441, 2009. Pedersen CA, Gibson CM, Rau SW, Salimi K, Smedley KL, Casey RL, Leserman J, Jarskog LF, Penn DL: Intranasal oxytocin reduces psychotic symptoms and improves Theory of Mind and social perception in schizophrenia. Schizophr Res 132:50–53, 2011. Rice C: Prevalence of autism spectrum disorders – Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR Surveill Summ 58:1–20, 2009. Seifer DB, Sandberg EC, Ueland K, Sladen RN: Water intoxication and hyponatremic encephalopathy from the use of an oxytocin nasal spray. A case report. J Reprod Med 30:225–228, 1985. Tamma R, Colaianni G, Zhu LL, DiBenedetto A, Greco G, Montemurro G, Patano N, Strippoli M, Vergari R, Mancini L, Colucci S, Grano M, Faccio R, Liu X, Li J, Usmani S, Bachar M, Bab I, Nishimori K, Young LJ, Buettner C, Iqbal J, Sun L, Zaidi M, Zallone A: Oxytocin is an anabolic bone hormone. Proc Natl Acad Sci USA 106:7149–7154, 2009. Young LJ, Flanagan–Cato LM: Editorial comment: Oxytocin, vasopressin and social behavior. Horm Behav 61:227–229, 2012.
Address correspondence to: Masako Taniike, MD, PhD Molecular Research Center for Children’s Mental Development and Department of Child Development United Graduate School of Child Development Osaka University 2-2 Yamadaoka Suita, Osaka, 565-0871 Japan E-mail:
[email protected]
