Intranasal oxytocin in the treatment of autism spectrum disorders: A review of literature and early safety and efficacy data in youth

Abstract

Background

There is a paucity of treatments targeting core symptom domains in Autism Spectrum Disorder (ASD). Several animal models and research in typically developing volunteers suggests that manipulation of the oxytocin system may have therapeutic potential for the treatment of social deficits. We review the literature for oxytocin and ASD and report on early dosing, safety and efficacy data of multi-dose oxytocin on aspects of social cognition/function, as well as repetitive behaviors and co-occurring anxiety within ASD. Methods: Fifteen children and adolescents with verbal IQs≥70 were diagnosed with ASD using the ADOS and the ADI-R. They participated in a modified maximum tolerated dose study of intranasal oxytocin (Syntocinon). Data were modeled using repeated measures regression analysis controlling for week, dose, age, and sex. Results: Among 4 doses tested, the highest dose evaluated, 0.4 IU/kg/dose, was found to be well tolerated. No serious or severe adverse events were reported and adverse events reported/observed were mild to moderate. Over 12 weeks of treatment, several measures of social cognition/function, repetitive behaviors and anxiety showed sensitivity to change with some measures suggesting maintenance of effect 3 months past discontinuation of intranasal oxytocin. Conclusions: This pilot study suggests that daily administration of intranasal oxytocin at 0.4 IU/kg/dose in children and adolescents with ASD is safe and has therapeutic potential. Larger studies are warranted.

This article is part of a Special Issue entitled Oxytocin and Social Behav.

Introduction

Autism Spectrum Disorder (ASD) refers to a group of neurodevelopmental disorders characterized by impairments in social communication, and repetitive behaviors and restricted interests (www.DSM5.org). The rates of ASD are on the rise with recent CDC numbers estimating the prevalence of the disorder at 1 in 88 children (CDC, 2008).

The social communication construct as it pertains to the ASD diagnosis has been debated extensively, even within versions of the DSM classification criteria, but there is agreement that it includes difficulties in social-emotional reciprocity, including difficulties in forming or maintaining peer relationships, deficits in nonverbal behaviors and in play skills. Restricted interests and repetitive behaviors are conceptualized to include repetitive motor behaviors such as arm flapping, rocking, bouncing, and spinning behaviors, as well as higher-level compulsive-like behaviors including rigid routines, ritualistic behaviors, and restrictive interests.

Despite the high burden of this disorder, there is no medication to date approved anywhere in the world for the treatment of social deficits or repetitive behaviors associated with ASD. A paucity of molecular targets available for the development of novel therapeutics related to the pathophysiology of ASD has been postulated to contribute to this gap. Specifically, drugs that were developed for other disorders with potentially overlapping phenotypes were tested in ASD, assuming that phenotypic spectra would be associated with neurobiologic spectra. The approach has been useful for the treatment of associated symptoms of ASD (e.g. atypical antipsychotics and irritability associated with ASD, McCracken et al., 2002), but has not produced a single agent shown to be effective for core symptoms. With the explosion of findings related to the biology of ASD and the biology of underlying core symptom domains associated with ASD, there is an opportunity for translational research to facilitate the development of novel therapeutics.

Oxytocin is a nine-amino-acid peptide (nonapeptide), which is synthesized primarily in the paraventricular and supraoptic nucleus of the hypothalamus, and released into the bloodstream by axon terminals in the posterior pituitary. Peripheral release of oxytocin facilitates uterine contractions during labor and milk letdown. Other peripheral targets of oxytocin include the kidneys and the pancreas. In addition to its peripheral role as a hormone, oxytocin is also widely distributed throughout the Central Nervous System (CNS) and functions as a neuromodulator. For example, oxytocin is released within the bed nucleus of the stria terminalis, the spinal cord, the anterior commissural nucleus, and the medial amygdala. Oxytocin fibers are evident in a variety of brain regions thought to be involved in social perception and cognition, as well as emotion regulation, including the amygdala and hippocampus and the ventral tegmental area of the midbrain (Gordon et al., 2011). Oxytocin receptors are also widely distributed in the CNS, although their distribution is highly species specific (e.g. Donaldson and Young, 2008). Oxytocin tract studies, at least in voles, would suggest that oxytocin release is not limited to the synaptic cleft, that dendritic release occurs and that it is independent of neuronal firing (Ludwig and Leng, 2006). The mechanisms by which central and peripheral release of oxytocin is coordinated remain poorly explained.

Central release of oxytocin and its closely related peptide, Arginine Vasopressin (AVP), are involved in aspects of social cognition and function including social recognition, social memory, affiliative behaviors, mother–infant and male–female pair-bond formation, separation distress, and other aspects of social attachment, as well as the regulation of stress response (Meyer-Lindenberg et al., 2011). Of note, oxytocin and AVP differ only by two amino acids, share evolutionary history, have overlapping functions, influence each other׳s pathways or receptors throughout development (Hirasawa et al., 2003, Landgraf and Neumann, 2004, Ragnauth et al., 2004) and as such they should be considered together in biobehavioral contexts.

In animal models, oxytocin has been shown to play critical roles in social processing, recognition, and bonding, and also to influence stereotyped behaviors such as exaggerated grooming (Carter, 1998, Insel et al., 1999, Winslow et al., 2003). In mammals, the Oxytocin Receptor (OXTR) is expressed at higher levels in early development (Shapiro Shapiro and Insel, 1989, Tribollet et al., 1989). Oxytocin knockout-mice have been shown to maintain olfaction and cognitive performance, but suffer deficits in social recognition that were recovered by intraventricular oxytocin (OXT), although not by AVP administration (Ferguson et al., 2000). OXTR knockout mice emit fewer ultrasonic vocalizations compared to the wild type, in response to social isolation, experience deficits in social discrimination, and demonstrate more aggressive behavior (Takayanagi et al., 2005). Similarly, AVPR1A knock-out mice have been reported to exhibit social memory deficits (Bielsky and Young, 2004), and the expression of the receptor gene in the lateral septum enhances social recognition (Bielsky et al., 2005). The pattern of AVPR1A receptor expression in the brain appears to be determined by variation in the length of a microsatellite in the promoter region of the gene (Hammock and Young, 2005).

An explosion of studies has examined the effect of administering a single dose on OXT and social cognition in humans. This work has been reviewed elsewhere extensively (e.g. Macdonald and Feifel, 2013, Guastella and MacLeod, 2012, McCall and Singer, 2012, Kumsta and Heinrichs, 2013). Single dose studies in healthy volunteers have reported on increased trust (Kosfeld et al., 2005), empathic accuracy (Domes et al., 2006, Guastella et al., 2009), time spent looking at eyes (Guastella et al., 2008), and face identity recognition memory (Savaskan et al., 2008, Rimelle et al., 2009). Attenuation of amydgala activity has been documented with single dose of OXT vs. placebo (Kirsch et al., 2005, Zink and Meyer-Lindenberg, 2012, Domes et al., 2007). Such imaging studies suggest that manipulation of the oxytocin system may produce circuitry modification that is relevant to social deficits.

A number of researchers have hypothesized that OXT may be connected to autism given that repetitive behaviors and deficits in social interaction are core features of the disorder, and that this neuropeptide is involved in the regulation of social cognition and some repetitive behaviors. Abnormalities in the neural pathway for OXT could account for many features of autism including the early onset, predominance in males, genetic loading, and neuroanatomical abnormalities (Insel et al., 1999, Domes et al., 2007).

Individuals with ASD have been reported to have lower than average levels of blood OXT level in comparison to typically developing controls matched for age (Modahl et al., 1998, Andari et al., 2010), although not universally, depending on gender differences and assay methodology utilized (Miller et al., 2013). Higher levels of oxytocin precursor peptides have also been reported to be expressed in early ASD development with subsequent decrease with age (Green et al., 2001).

Accumulating studies are reporting that single nucleotide polymorphisms of the OXTR gene are associated with ASD and related disorders (Wu et al., 2005, Jacob et al., 2007, Lerer et al., 2008, Yrigollen et al., 2008, Ebstein et al., 2012, Liu et al., 2010, Wermter et al., 2010). However, most SNPs reported are outside the protein coding regions and their functional significance remains unknown. There has been a recent report of a rare genetic variation of the OXTR gene within the protein coding region associated with ASD (Ma et al., 2013). A heterozygous deletion of the OXTR gene has also been reported in a patient with ASD and family history of OCD (Gregory et al., 2009). In addition to variations in coding sequence, there is some early data to suggest potential epigenetic modification related to the OXTR gene in ASD. Gregory et al. (2009) reported increased methylation of the OXTR gene promoter as compared to controls in two independent samples, including postmortem temporal cortex tissue from 8 ASD/control pairs.

There have been a growing number of OXT single dose studies in the last decade. Initially, an intravenous administration of oxytocin vs. placebo over a 4 h period (Hollander et al., 2003, Hollander et al., 2007) facilitated the retention of social cognition in participants with ASD and produced significant reduction in repetitive behaviors – i.e., needing to know, repeating, ordering, needing to tell/ask, self-injury, and touching. Subsequent single dose studies have employed the intranasal formulation. Guastella et al. (2010) randomized 16 adolescents to a cross-over placebo-controlled study of a single dose of intranasal oxytocin and reported significant improvements in empathic accuracy as measured by the Reading-the-Mind-in-the-Eyes task (RMET) with minimal adverse effects. Andari et al. (2010) randomized 13 adults with ASD to a single dose of intranasal oxytocin and reported stronger interactions with a cooperative partner during a computerized ball game, increased trust, and time spent looking at eyes. However, single dose studies have limited ability to predict the therapeutic potential of administering intranasal oxytocin over a period of time and as such multi-dose studies are critical in evaluating the compound׳s long-term therapeutic potential (Macdonald and Feifel, 2013).

A small number of studies designed to evaluate the effect of multi-dose intranasal oxytocin on core symptom domains in ASD is available. In a single case report, Kosaka et al. (2012), reported on a 16 year old girl with ASD who received 8IU every day for 2 months. The authors reported that it was well tolerated and that improvements were noted both in social communication as well as irritability, based on clinician judgment and parent report on a standardized scale. Tachibana et al. (2013) reported on a case series of 8 male youth (ages 10–14 years) who received a total of 6 months exposure of oxytocin in the following manner: for the first 2 months they received 8 IU per dose twice a day followed by 2 months of 16 IU per dose twice a day, and finally 2 months of 24 IU per dose. Before each step, a 1–2 week period of placebo was administered. Improvements were noted in social and communication scores based on direct observation on a structured assessment, but not on parental reports of maladaptive behaviors. In addition, Dadds et al. (2013) evaluated a 5-day intervention with 38 male youths with ASD (ages 7–16 years). Boys were administered oxytocin (12 or 24 IU units depending on weight) or placebo during parent-child interaction training. No improvements were noted in emotion recognition, social skills and other behavioral domains compared to placebo, based on parent, clinician, or direct observation measures. Although the model of combining oxytocin with a social learning activity is of great interest, this study is limited by several factors including the use of an experimental psychosocial intervention with unknown effects as a ‘monotherapy’, as well as limited exposure (e.g. 5 days) to treatments targeting core skills deficits. Our group also recently published a pilot randomized trial of intranasal oxytocin vs. placebo in 19 adults with ASD (Anagnostou et al., 2012). Adults with ASD demonstrated improvements in empathic accuracy, lower order repetitive behaviors and quality of life on both self-report and experimental testing.

Oxytocin is metabolized in the gut by chymotrypsin and as such it cannot be administered orally. Despite its short half-life in the blood, the intravenous formulation has been found to produce behavioral effects (Hollander et al., 2003, Hollander et al., 2007, Ring et al., 2006), but it is too invasive to administer. One alternative is intranasal oxytocin; it is thought to be absorbed through the highly permeable nasal mucosa and, in the case of the related peptide vasopressin, it has been shown to cross the blood brain barrier (Born et al., 2002), and produce rising CNS levels for at least 4 h after intranasal administration, mitigating concerns about the peripheral half-life of this compound. It is also easy to self-administer.

Given that oxytocin is involved in the regulation of social communication and some repetitive behaviors, and based on emerging pilot data, the authors received funding by the Department of Defense to conduct a series of studies of intranasal oxytocin in children and adolescents with ASD. First, a modified Maximum-Tolerated-Dose (MTD) study was agreed upon in collaboration with Health Canada to identify a maximum dose for multi-dose studies in children up to a maximum of 24 IU/per dose adjusted for weight. The study also aimed at evaluating safety of multi-dose dosing in this age group and identifying measures sensitive to change to be used in a follow-up randomized controlled trial in this population. We report here the results of the MTD study.