5-3-14 evidence based practice project

Jane Potter Baumer Evidence Based Practice Project Spring 2014, GSR 615

PIO Question: What effect does peripherally administered oxytocin have on the social and communicative behaviors of children and adolescents with autism spectrum disorder?

Target population and description of disorder:The target population for this evidence-based practice paper is children and

adolescents between from the ages of 7-18 who have been diagnosed with autism spectrum disorder (ASD), using criteria established in the DSM-IV or the more recent DSM-V (2013).

While children with ASD vary in terms of the severity of their disorder and the types of symptoms they present, each struggles to some extent with social and communicative behaviors. One of the most serious social and communicative deficits experienced by children with ASD is their inability to understand and participate in the give-and-take of daily social interactions. Children with ASD have difficulty making and maintaining eye contact with others. Additionally, they may not be aware that other people have thoughts and feelings, which makes interpreting facial expressions and gestures very challenging for them.

Children with ASD may also have difficulties with spoken language, or may not speak at all. Those who can speak may fail to respond to questions, or fail to take turns in conversation. They may have difficulty maintaining a conversational topic, or may not understand how to establish and maintain an appropriate vocal volume and rate of speech in conversation. Children with ASD may also have great difficulty expressing their own emotions effectively, because they lack the language to talk about their feelings. Lastly, parents complain that their children with ASD do not seem to form appropriate emotional attachments to others, making relationships with parents and family members difficult.

The “clinical dilemma:”The brain chemical oxytocin, sometimes called the “love” or “trust” hormone,

functions as a neurotransmitter, and is made by the pituitary gland in the brain. Responsible for initiating labor in women, oxytocin also plays an important role in breastfeeding, and interacts with other hormones in social interactions. Oxytocin is the hormone that is released, for example, when we interact with our pets, or cuddle up with someone else. It also has a dark side, however; the presence of too much of it in the brain is thought to be related to gambling, addiction, and negative bonding, such as that which occurs between an abuser and his or her victim. While oxytocin’s many roles are not yet completely understood, one thing is certain: it plays a critical role in human interactions.

Much has been written in the media in the last few years about the role that oxytocin plays in autism. Articles within the last six months in the New York Times (Oxytocin Found to Stimulate Social Brain Regions in Children With Autism, Dec. 2, 2013), in the magazines Psychology Today and Forbes, and on the webpage for Autism Speaks (http://www.autismspeaks.org/blog/2013/12/02/oxytocin-treating-autism-not-so-fast-%E2%80%A6), point to growing public interest, spurred by scientific inquiry, into the potential of oxytocin as a drug therapy option for the treatment of the social deficits of autism.

As the numbers of people diagnosed with autism increase to 1 in 68 (1 in 42 for boys), and autism becomes the fastest-growing serious developmental disability in the United States (http://www.cdc.gov/Features/GrandRounds/), parents of children with

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http://www.autismspeaks.org/blog/2013/12/02/oxytocin-treating-autism-not-so-fast-%E2%80%A6

http://www.autismspeaks.org/blog/2013/12/02/oxytocin-treating-autism-not-so-fast-%E2%80%A6


autism are increasingly interested in discovering both the causes of autism and the best (or better) treatment options. Clearly, even in the world of autism, there is a flurry of interest around this issue. A recent search of www.autismspeaks.org, using the word “oxytocin” led to 71 articles on recent research and opinion about oxytocin and its possible effects on the symptoms of autism.

Speech language pathologists are often engaged in the treatment of the social dysfunction of children and adults with autism. A number of non-drug options for therapy have been developed by SLPs and professionals in related fields, including the Picture Exchange System (PECS), ABA (Applied Behavior Analysis), DIY/Floortime, AAC (Alternative and Adaptive Communication), PRT (Pivotal Response Training), and SCERTS, to name just a few.

While these therapies have all been successful with certain clients at certain points in their development, none of them have the potential for producing the immediate (and potentially long-lasting) changes in social communication and behavior that a drug therapy could offer. If the recent media coverage of oxytocin research is any indication, intranasal or intravenous oxytocin may be a solution to the deficits in social functioning of children with ASD.

Evidence on the roles and functions of oxytocin on the brains of normal subjects and individuals with ASD is mounting in the medical research community, and SLP’s need to be ready to support and advise parents of children with ASD and adults with the disorder as to the current efficacy and future directions of this potentially life-altering substance.

Search process: I conducted a search on EBSCO Host using the search terms “autism” or “autism

spectrum disorders” and “oxytocin – therapeutic use.” This yielded a large number of articles, so I added limiters suggested by the search engine, including “communicative competence,” “social skills,” “communication,” “intranasal medication,” and “randomized controlled trials” (since articles on this subject are researched by medical professionals and not speech language pathologists).

This yielded over two hundred articles, but I was easily able to determine from the list which studies would pertain to my question of interest. After deciding to use one article from this search, Dadds et al., (2014), “Nasal oxytocin for social deficits in childhood autism: A randomized controlled trial,” I was directed to similar articles available on Science Direct. Following these leads, I selected the Guastella et al. (2010) article, “Intranasal Oxytocin Improves Emotion Recognition for Youth with Autism Spectrum Disorders.” I was then led to an article in the Proceedings of the National Academy of Sciences, entitled “Oxytocin Enhances Brain Function in Children with Autism,” by Gordon et al. (2013), also on Science Direct. These articles all describe randomized, double-blind, placebo-controlled experiments using single dose administrations of intranasal oxytocin in small groups of children and youth, ranging in age from 7 to 19 years old. The details of these articles can be found in my Critically Appraised Topic Summaries (CATS).

In reviewing the literature on this topic, I read several other articles listed in the bibliography, including an article by McCullough et al. (2013) entitled, “Problems with measuring peripheral oxytocin: Can the data on oxytocin and human behavior be trusted?” This article was useful in critiquing the methodology of the three main studies cited in this paper.

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References:

Dadds, M. R., McDonald, E., Cauchi, A., Williams, K., Levy, F., & Brennan, J. (2014). Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. Journal of Autism and Developmental Disorders, 44, 521-531. Retrieved from DOI 10.1007/s10803-013-1899-3

Gordon, I., Vander Wyck, B. C., Bennett, R. H., Cordeaux, C., Lucas, M. V., Eilbott, J. A., et al. (2013). Oxytocin enhances brain function in children with autism. Proceedings of the National Academy of Sciences, 110, 20953-20958.

Guastella, A. J., Einfeld, S. L., Gray, K. M., Rinehart, N. J., Tonge, B. J., Lambert, T. J., & Hickie, I. B. (2010). Intranasal Oxytocin Improves Emotion Recognition for Youth with Autism Spectrum Disorders. Biological Psychiatry. Retrieved from DOI:10.1016/j.biopsych.2009.09.020

McCullough, M. E., Churchland, P. S., & Mendez, A. J. (2013). Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted? Neuroscience and Biobehavioral Reviews, 37, 1485-1492. Retrieved from hhtp://www.elsevier.com/locate/neubiorev

EvidenceOxytocin (OT) is one of several hormones known to play a significant role in social

communication and behavior in mammals. The role of OT in human social communication skills has been of interest to researchers since the 1970s. More recent research has focused on the importance of OT in the social deficits of various brain disorders, including schizophrenia and autism. In one seminal study on autism, “Plasma oxytocin levels in autistic children,” published in Society of Biological Psychiatry, Modahl et al., (1998) found that children with autism had abnormally low levels of OT in their blood plasma. More recently, researchers have been trying to determine how OT levels can be increased, how best to increase them, and whether an increase will cause a positive change in the social deficits of autism.

Studies on animals (who are said not to be capable of having autism) have focused on whether centrally administered OT (directly into the brain) affects their social behaviors. The results have been positive for knockout mice, and for prairie voles, whose social habits (mating for life, maternal instincts, etc.) are similar to those of humans.

Central delivery of OT would be too invasive for humans, however, so studies on both adults and children with autism have focused on methods for delivering OT peripherally to subjects, either intravenously, or intranasally. This paper seeks to answer the question of whether peripherally administered intranasal OT has a positive effect on the social communication and behaviors of children with autism, and if so, whether the administration of intranasal OT is a viable treatment option for children with autism, either alone or in combination with face-to-face therapy. Given the increasing interest in this topic in American media, it is reasonable to assume that SLP’s treating children with autism will soon face questions about the efficacy of OT as a remedy for social deficits.

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In this paper, I examined three recent studies on the effects of intranasal OT on children, ages 7-19, with autism. The table below shows the similarities and differences between the studies:

Dadds et al. (2014) Gordon et al. (2013) Guastella et al. (2010)

Study Design

Randomized, placebo-controlled, blinded study, the highest level of constraint

Randomized, placebo-controlled, double-blind, cross-over functional MRI (fMRI) study, the highest level of constraint

Randomized, placebo-controlled, double-blind, cross-over trial, the highest level of constraint

Sample Size 38 males with autism between the ages of 7-16

17 children and adolescents (ages 8-16.5 years) with autism spectrum disorder (ASD)

3 girls + 14 boys

16 males aged 12-19 years who were diagnosed with Autism or Asperger’s (DSM-IV)

Questions: In young males with ASD, does intranasal OT

improve social communication skills such as eye contact, warmth, and verbal content?

reduce repetitive behaviors?

improve emotion recognition?

bring about generalized improvements beyond immediate effects?

Does a single dose of intranasal oxytocin (OT) have an effect on the social and communicative behaviors of children and adolescents with ASD?

Do subjects show greater emotion recognition on the Reading the Mind in the Eyes Test –Revised (RMET) given intranasal OT vs. placebo?

Can intranasal OT be considered an effective treatment for emotion recognition deficits in children and adolescents with ASD?

Treatment; Methods

Tx: OT or placebo (12-24 IU) nasal spray

Dose: 1x/day, for 4 consecutive days


Dose: 1x/session for 2 sessions, 3-78 days apart


Dose: 1x/session for 2 sessions, one week apart

Procedures Subjects completed: Parent Child

Interaction tasks using Mindreading

Subjects completed the Reading the Mind in the Eyes task (RMET), labeling

Subjects completed the RMET 45 minutes after drug administration

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Program – emotional recognition & social interaction skills

3-part Family Interaction Task: free play (10 m.), emotion talk (10 m.), I-love-you task (2 m.)

mental states indicated in photos of:

the eyes (social) and the category of

automobile in photos of vehicles (non-social), while fMRI was taken

5 images in a block x 10 blocks = 50 images/session for 2 sessions

Assessments Data taken at initial, pre-test, Time 1, Time 2, Time 3, post-test and 3 months post-experiment.

Parent interviews Parent checklists Questionnaire:

Social Skills Rating Scale

Video recordings coded at 7 points during Tx, using Family Observation Schedule; data on:

social interaction (talk, warmth, responsiveness & eye contact), positive body language, verbal content & asking questions

RMET given during fMRI

measurement of concentration of OT in saliva from baseline to 30 min. post-administration

RMET alone

Types of Statistics

ICC (intraclass correlation): describes how strongly units in the same group resemble each other

CI (confidence interval): indicates the reliability of an estimate

p-value: how much

Statistics for image acquisition, motion control, & fMRI

Rel. between fMRI and salivary OT: level of activity during judgments of Eyes relative to judgments of Vehicles was positively associated with reactivity in

p-value: how much evidence there is to reject the most common explanation for the data set

t-value

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evidence there is to reject the most common explanation for the data set

Chi-squared: an estimate on the agreement between a set of observed data and a random set of data that you expected the measurements to fit.

salivary OT levels (P < 0.05, corrected; K ≥1,620 mm3).

Determination of Salivary OT was performed using a commercial OT ELISA kit (Assay Design) consistent with previous research

Measurements of saliva were performed 2x; concentrationsof samples were calculated using MATLAB 7 according to relevant standard curves. The intraassay and interassay coefficient are 12.4% and 14.5%, respectively.

Results NO effects of intranasal OT on social behaviors of children with autism (no effects extended beyond post-treatment to the 3-month assessment)

A single dose of intranasal OT enhanced brain activity in areas that are specialized for reward, social attention, perception, cognition, and detecting, decoding, and reasoning about others’ mental states

Responsiveness varied by severity of ASD as measured by the Social Responsiveness Scale (SRS)

Performance on the RMET improved with oxytocin for 60% of the participants (p = 0.03, two-sided)

With placebo, subjects answered 45% of the total items correctly; with oxytocin, they answered 49% of the total items correctly.

Subjects under the age of 16 answered the easy items on the RMET with 54% accuracy under placebo, while answering the easy items correctly 62% of the time under oxytocin.

no effect of oxytocin

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on the harder test items on the RMET for any age

Quality of Study(poor, fair, good)

Good Good Good

Dates of studies, level of constraint: All three studies were completed within the last five years, and all were randomized, placebo-controlled, double-blind studies, which are the highest level of constraint. The high level of constraint indicates a high likelihood that the findings of each study are strong.

Research questions: Overall, each study sought to determine what effect OT or placebo had on aspects of social communication in children with autism. In both Dadds et al. (2014), and in Guastella et al. (2010), researchers asked what effect intranasal OT or placebo had on emotion recognition. There were differences between the two studies, however. In Guastella et al. (2010), researchers asked specifically about whether OT or placebo had an effect on emotion recognition, as assessed in the Reading the Mind in the Eyes Test (RMET), and on concentrations of OT in saliva at 30 minutes post-administration. In contrast, the Dadds et al. (2014) study asked whether intranasal OT or placebo affected social behaviors of children as they interacted with their parents in various tasks.

Gordon et al. (2010) had the broadest research question: “Does a single dose of intranasal oxytocin (OT) have an effect on the social and communicative behaviors of children and adolescents with ASD?” Researchers in this study, however, also asked whether OT had a future as a possible pharmacological therapy for children with autism. Outcomes were measured with the Reading the Mind in the Eyes Test (RMET) alone.

Populations/sample sizes: The studies’ subjects were all between 7-19 years of age, and were mostly male. While in some areas of research, an emphasis on male subjects would be a threat to internal validity, in studies on autism, a preponderance of male subjects seems to be an asset: the Centers for Disease Control reports that 1 out of every 42 boys is diagnosed with autism, compared with 1 out of 189 girls (http://www.autismspeaks.org/what-autism). In two of the studies reviewed in this paper, the subjects were all male (n=38, n=16), and in the remaining study, 14 of the 17 subjects were males.

Subjects in all three studies had received diagnoses of autism or Asperger’s syndrome (if diagnosed under DSM-IV, prior to 2013), or autism spectrum disorder (ASD) (if diagnosed under DSM-V, 2013 or later) using standard diagnostic tests for autism administered by qualified professionals.

The most significant concern in the populations of these studies is the wide range in age. While the researchers attempted to compensate for this by dosing the OT or placebo according to age/weight, the studies’ subjects still vary widely in terms of mental and physical development. This poses a threat to external validity, especially since only one of the studies (the earliest one, Guastella et al., 2010) breaks subjects out by age groups in its

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analysis. It is significant that Guastella at al. (2010) found that younger subjects performed better on the ‘easy’ portion of the RMET than older ones did. It is unfortunate that the later studies did not replicate this type of analysis. It would be interesting to know, for example, if the younger subjects in the Dadds et al. (2014) study improved in emotion recognition at a different rate or intensity than their older peers. Knowing how age interacts with OT administration might help researchers determine what age range, if any, OT would be most useful for if it were to become a therapeutic option for autism in the future.

Doses of OT or placebo: All of the studies administered up to 24 International Units (IU) of intranasal OT or placebo in single doses, with subjects receiving the dose appropriate for their age/weight only once per day on the each of the trial days. Two of the studies used doses ranging from 12-24 IU, while Guastella et al. (2010) administered doses at 18-24 IU. In all cases, the doses were prepared not by the authors, but by labs, lowering the threat of instrumentation. While each trial used a different lab to prepare the intranasal sprays, we are not given reasons to doubt the preparation of the medication in any of the trials. Both researchers and subjects were blinded to the contents of the nasal sprays (whether OT or placebo).

Procedures: In terms of procedural tasks required of the subjects, the Dadds et al. (2014) study was the most demanding. Following the administration of either OT or placebo, subjects were asked to perform two different interactive tasks, each having multiple parts, with their parents. The Parent Child Interaction task consisted of emotional recognition and social interaction activities. The three-part Family Interaction Task consisted of 10 minutes each of free play and emotion talk, and a two-minute “I love you” task, in which the subject’s reactions were observed while the parent told the child how and why s/he loved the subject. Each interaction was video-recorded. Trained observers made tallies of various social behaviors (eye gazes, etc.) at seven specified times before, during, and after the tasks. These observers coded the subjects’ performance from the videotapes. Parents were asked to assess the subjects’ social behaviors using a standardized measure (Social Skills Rating Scale), and parental questionnaires. These procedures were repeated daily for four days, and the subjects were randomized as to task and drug (OT or placebo). Subjects were assessed again at three months post-treatment, using all previous measures.

The procedural demands of the Gordon et al. (2013) study were just as challenging for the subjects that those of the Dadds study, but for a different reason. Following administration of the single dose of OT or placebo, participants were asked to label the mental states of social (eyes) photographs, or identify the categories of non-social (vehicles) photographs, as presented in the Reading the Mind in the Eyes Test (RMET). In each of two treatment periods, subjects were shown 5 blocks of 10 images each, separated by precise intervals, including rest periods. Images were randomly ordered. While the participants viewed the images, they received a functional magnetic resonance imaging test (fMRI) to assess differences in and locations of brain activity under OT vs. placebo. Participants repeated this entire procedure one week later, receiving placebo in one treatment, and OT in the other.

The purpose of these studies was similar, but there were significant procedural differences between them. The time elapsed between trials, for example, differed greatly

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between these three studies. Dadds et al. (2014) took place in four consecutive days, while Gordon et al. (2013) took place in two trials one week apart. Guastella et al. (2010) completed its trial period in one day, administering only a single dose of OT or placebo. The studies also differed in the overall amount of the drug administered. Because of the differing lengths of the trials, Dadds et al. (2014) administered twice the amount of OT or placebo overall than Gordon et al (2013), and four times the amount of Guastella et al (2010).

The studies also required different tasks of the participants, and measured outcomes in different ways. The tasks in Dadds et al. (2014) were similar to real communication tasks that might occur between any parent and child. This study used traditional measures, such as parent questionnaires and video-coding of behaviors to assess outcomes. By contrast, in Gordon et al. (2013), participants were asked to look at images in the RMET while lying completely still in a fMRI machine, a task that surely must have been challenging (at the very least) for children with autism. Gordon et al. (2013) also measured the concentration of OT in the saliva of participants 45 minutes post-administration, and was the only study to do so. Guastella et al. (2010) required children only to take the RMET test, administered by the authors in a face-to-face setting, following the administration of OT or placebo.

Dadds et al. (2014), which contained tasks very similar to real communication tasks of children with autism, is the strongest and most valid of the three studies I examined. The other studies have their strong points too, however. While Guastella et al. (2014) measured only one aspect of social behavior (emotion recognition), it did so in a face-to-face manner, using the RMET test. This makes the study highly valid for this particular social task. In the Gordon et al. (2013) study, it seems possible that the experience of the fMRI machine could be an extraneous variable. The experience of being in the machine and lying still in a loud environment for a relatively long period of time could certainly have been a factor in the images obtained. Nonetheless, Gordon et al. (2013), provides strong objective data on the brain’s reactions to emotion depicted in eyes following the administration of OT. Gordon et al. (2013) is simply a more robust measure of the tasks required in Guastella et al. (2010).

Each of the studies has strengths and weaknesses in regard to validity. The Dadds et al. (2014) study controlled for history and maturation threats by treating the subjects for four consecutive days, housing them together, and requiring that they had no other obligations during the study. The psychiatrist who trained the subjects in the tasks removed herself when the tasks were performed, to eliminate the possibility of influencing the outcomes. These factors make the study strong in terms of internal validity. In Gordon et al. (2013), the lengths between sessions varied from between 3 to 78 days. The variance in lengths of time between administrations of the drug created serious history and maturation threats to this study. The researchers did not mention limiting subjects’ exposure to other treatments for autism during the time between administrations. These factors weaken this study’s internal validity. Guastella et al (2013) controlled more effectively for the length of time between administrations of OT. Researchers in this study administered OT or placebo 1x/day on two different days, but controlled for maturation by prescribing an interval of one week between sessions. Apart from these threats, there were no other significant threats to validity.

Types of data recorded: Two of the studies (Gordon et al., 2013, and Guastella et al., 2010) recorded specific data on emotion recognition using the Reading the Mind in the

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Eyes Test-Revised (RMET). The Gordon et al. (2013) study took data in two additional ways, however: 1) the authors recorded functional MRI data (mentioned previously) while the subjects took the RMET, to determine what areas of the brain were activated for social vs. non-social stimuli, and 2) they recorded concentrations of OT in saliva as an indicator of the presence and level of the drug in the subjects’ systems.

While the assessment procedures for Gordon et al. (2013) were strengthened by their diversity (fMRI, saliva testing, and RMET scores), the Dadds et al. (2014) study demonstrated its strength through a diversity of observational data recording methods. It collected data via the Social Skills Rating Scale (a parent questionnaire), parent interviews, and video recordings of the sessions, which were coded at seven specific points in time by trained coders, using the Family Observation Schedule. Coders were blind to the purpose of the study, and re-coded 20% of the video samples to obtain an inter-rater reliability score of greater than or equal to 80%.

While the Gordon study obtained data on 1) the subjects’ ability to recognize emotions in photographs, (RMET), 2) the areas of the brain activated for social stimuli (fMRI), and 3) the subjects’ salivary concentrations of OT, the Dadds study obtained much more functional data, including data on precisely how children with autism interacted with their parents in relatively natural communication settings and tasks. Subjects in the Dadds study were examined for numbers of eye gazes exchanged with parents, aspects of social interaction (talk, warmth, and verbal content), asking questions, and positive body language. Furthermore, the Dadds study examined subjects for these behaviors pre-treatment, following the administration of drug or placebo at multiple points, post-treatment, and 3 months following the administration. The tasks in the Gordon study, while appropriate tasks for children with autism, measured by a reliable test (RMET), were not performed in natural settings. Instead, the RMET uses photographs to test emotion recognition, and only photographs of human eyes. In natural setting, however, emotions are conveyed by more than just eyes; real conversations provide a number of other social cues that could be used to infer meaning. In this sense, the Dadds study provided a much more realistic, and reliable, test of the social communication skills of children with autism. The Guastella et al. (2013) study, which only recorded data on subjects’ performance on the RMET, is the weakest of the three in terms of its assessment.

Statistical strengths and weaknesses: The Dadds article reported statistics using CI (Confidence Interval), ICC (Intraclass

Correlation), p-values, and chi-squared numbers. The CI, which reveals the reliability of an estimate, was used in the discussion of inter-rater reliability between the two video coders. The coders received at 95% CI, which indicates that there is a 95% chance that the 20% sample of videos that they recoded predicts the inter-rater reliability for all videos coded. This means we can feel confident about the results obtained by the video coders.

The ICC, used on the same sample, indicated how strongly units in the same group resemble each other. ICC= 0.801, p <0.001, which means that each coders’ work was 80% internally consistent. We can accept the ICC statistic with confidence because of the p-value, which should be less than or equal to 0.05.

Chi-squared was used in the authors’ explanation of 1) demographics and clinical sample, and 2) subjective awareness in the “Results” section. Chi-squared compared observed data to the data that might occur by chance alone. In the case of demographics

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and the clinical sample, the authors state that there were no significant baseline differences between groups in demographics or clinical variables, and that even though there was a high level of co-morbid diagnosis (ADD, ODD, anxiety, use of psychotropic medications), the co-morbidity was equally distributed between treatment groups. For the use of psychotropic medications between groups, χ2(33) = 0.79, p = 0.37. This indicates that the use of psychotropic medication was spread across both groups. For the section on subjective awareness (whether the subjects could guess whether they had received OT or placebo), χ2(1) = 4.0, p = 0.046. This suggests that a significant number of subjects were actually able to guess which medication they had received (placebo or OT), which means that the study was not as “blinded” to subjects as researchers may have hoped. We should take this into consideration as we look at the effects of OT on the subjects’ behaviors with their parents on the tasks assigned.

The Gordon study reported statistics for fMRI, which were beyond my ability to read and interpret. For the relationship between fMRI and salivary OT, however, the authors reported that the level of brain activity during judgments of social stimuli (eyes) relative to judgments of non-social stimuli (vehicles) was positively associated with reactivity in salivary OT levels (p < 0.05, corrected; K ≥1,620 mm3). This means that when activity in the brain was detected (in the presence of social stimuli), there was a corresponding rise in salivary OT.

The Gordon study also reported that the determination of salivary OT was performed using a commercial OT ELISA kit (Assay Design), consistent with previous research. The intraassay and interassay coefficients were 12.4% and 14.5%, meaning that there was a 12.4% variation between the results obtained in the first measurement and the results obtained in the second measurement, and a 14.5% variation in the results obtained within the entire data set. This seems like a significant amount of variation for the measurements of salivary OT, so I turned to McCullough et al. (2013) for an explanation.

Researchers McCullough et al. (2013), in their article “Problems with measuring peripheral oxytocin: Can the data on oxytocin and human behavior be trusted?,” argue that the way in which OT moves throughout the body is not yet understood. Therefore, the various delivery methods for OT used in recent studies (intranasal or intravenous administration for humans) should be called into question, since no one knows with certainty that these methods actually deliver OT where it was needed. Furthermore, it is unknown how (or if) externally administered OT actually reaches the brain (McCullough, 2013, p. 1485), because measuring levels of OT directly in the brain would be too invasive for humans.

McCullough et al. (2013) also questions the practice of measuring brain levels of hormones through saliva. The authors note that researcher Horvat-Gordon (2002) claims that measurements of bioavailable OT in saliva do not necessarily indicate meaningful change in OT in the brain. Furthermore, Horvat-Gordon’s “initial reasons for skepticism about the presence of bioactive OT in saliva remain unaddressed ten years on” (McCullough et al, 2013, p. 1488). Finally, the authors note, “clearly, the field knows less about the measurement of OT in human fluids than many published reports might imply” (McCullough, 2013, p. 1489).

The problems identified above with the measurement of OT in saliva seriously weaken the correlation Gordon et al. (2013) find between increased OT levels in saliva and increased activity in the brain while looking at pictures of eyes. The overall study is still

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strong, however. While the lack of convincing data from saliva is a flaw in the study, the fMRI images and the improved results on the RMET in the study still stand as measures of increased brain activity for a social communication task for children under the influence of OT. The lack of salivary evidence of OT in the brain does not change the fact that the drug changed subjects’ brains when they were presented with social stimuli. Therefore, the results from Gordon et al., (2013) remain convincing.

In the final study examined in this project, by Guastella et al. (2010), results indicated that OT improved performance on the RMET for 60% of participants, t(14) = 2.43, p = .03. The researchers then split the RMET analysis into “easy” and “hard” items. The effect for OT was highly significant for the easier items on the test, t(14) = 4.39, p = .001. Next, the authors looked at participants under the age of 16, since this was the first study on the effects of intranasal OT on this age group. OT was shown to be beneficial for emotion recognition performance for subjects aged 12-15, t(10) = 2.76, p = .02. There was no difference in subject awareness of drug vs. placebo, t(14) = 1.29, p = .21.

Results: Dadds et al. (2014) found no effect of intranasal OT on the social communication deficits of children and adolescents with autism over time. OT did have an immediate effect on the social abilities of the subjects, but it was not retained post-treatment.

The authors Gordon et al. (2013) found that a single dose of intranasal OT enhanced brain activity for approximately 30 minutes following drug administration in areas that are specialized for reward, social attention, perception, cognition, and reasoning about others’ mental states. This study also found that responsiveness varied by severity of ASD as measured by the Social Responsiveness Scale (SRS).

Guastella et al. (2010) found that performance on the RMET, given 45 minutes post-treatment, improved under oxytocin for 60% of the participants. The study also concluded that under placebo, subjects answered 45% of the total items correctly, while under OT, subjects answered 49% of the total items correctly. This study analyzed young subjects separately, finding that under placebo, subjects under the age of 16 answered the “easy” items on the RMET with 54% accuracy. When under OT, however, subjects under the age of 16 answered the “easy” items correctly 62% of the time. Guastella et al. (201) found no effect of oxytocin on the harder test items on the RMET for any age. There was no assessment of the effects of OT at intervals beyond 45 minutes after the drug administration.

While it would seem that the results of these three studies are quite different, taken together, they paint a picture of the effects of OT on children with autism over time. Subjects in these studies experienced an increase in social skills while under the influence of OT, but the Dadds study showed conclusively that the effects of OT are limited to a short time (perhaps 45 to 60 minutes) following administration. The Dadds study also showed that social skills learned while under the brief influence of a single dose of oxytocin are not retained post-treatment.

Conclusion and Take-Home Message: If I were advising a parent of a child with autism about the efficacy of intranasal OT as a treatment for the social deficits of autism, I would tell the parent two things, based on the articles I have read.

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First, I would say that, based on the results of the Dadds et al. (2014) study, there is no evidence that single doses of OT will change the social and communicative behaviors of children with autism in the long term. We can believe in the results of the Dadds et al. (2014) study, because it is strong in design, procedures, and assessment, and examined the effects of OT on children using realistic communicative tasks. It also measured a number of communication modes before treatment, at multiple points during treatment, and following treatment. While the study found that social and communicative behaviors improved in the subjects during the administration of OT, these improvements were not lasting, as verified by both researchers’ data and parental reports. Since the medical profession has cannot yet administer OT over the long-term to humans, however, and the effects of long-term OT treatment are unknown, there is no benefit or justification to giving the drug to children with autism.

Secondly, however, I would tell parents that there is hope for the future of OT as a pharmacological treatment for the social deficits of children with autism. Gordon et al. (2013) found, through fMRI imaging and the RMET, that OT produces temporary positive changes in emotion recognition and brain activity of children with autism. The Gordon et al. (2013) study, like the Dadds et al. (2014) is strong in design, procedures, and assessment. The results of Gordon et al. (2013) are limited, however, because it focused on a single behavior in children with autism: the ability to correctly interpret emotions from photographs of human eyes that reflected various emotional states. If the study had examined the effects of OT on realistic social communication behaviors, its results would be more generalizable to all social deficits in autism. Nonetheless, the fact that the study found improved performance on the Reading the Mind in the Eyes Test (RMET) in conjunction with increased brain activity suggests that it is highly likely that the changes in emotion recognition are due to the administration of intranasal OT. The weaknesses in measuring OT in saliva in this study do not invalidate those results. The increases in emotion recognition abilities seen in this study were only temporary, though, and there is no evidence in this study that a single dose of intranasal OT would lead to broader changes in social and communication behaviors of children with autism.

In conclusion, I would tell parents that until researchers are able to 1) find more effective ways to better measure brain levels of OT, 2) determine the best mode of delivery of OT to the brain, 3) develop a permanent way to infuse OT or induce the body to create more of it, and 4) verify that the administration of the drug over time can produce lasting changes in social and communicative behaviors of children with autism, intranasal OT therapy should not be given to children with autism, either alone or in conjunction with face-to-face therapy.

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Critically Appraised Topic Summary


Dadds, M. R., McDonald, E., Cauchi, A., Williams, K., Levy, F., & Brennan, J. (2014). Nasal oxytocin for social deficits in childhood autism: a randomized controlled trial. Journal of Autism and Developmental Disorders, 44, 521-531. Retrieved from DOI 10.1007/s10803-013-1899-3

Study MethodsThe purpose of this study was to test the role of oxytocin (OT) in potentiating the

performance, development, and generalization of interpersonal social skills in young children with Autism Spectrum Disorder (ASD). In this randomized, controlled trial, 38 males between the ages of 7-16 were given a dose of intranasal OT or placebo once a day for four days and observed in various parent-child interactions.

The questions asked in the study were 1) does OT improve social communication skills such as eye contact, warmth, and verbal content?; 2) does OT reduce repetitive behaviors?; 3) does OT improve emotion recognition?; 4) does OT bring about generalized improvements beyond immediate effects?

OT or placebo was administered through intranasal spray in doses of 12-24 International Units (IU) according to subjects’ weight. Subjects then completed Parent-Child Interaction tasks using the Mindreading (MR) Program (Baron-Cohen, 2007). These tasks focus on teaching both emotion recognition and social interaction skills. Subjects also completed a three-part Family Interaction Task, consisting of 1) free play (10 min.); 2) emotion talk (10 min.); 3) I-love-you task (2 min).

Assessments, consisting of parent interviews, checklists, and questionnaires, and coded video recordings of sessions, were conducted to assess side effects, social interaction skills, repetitive behaviors, emotion recognition, and generalized effects. Results

This study showed that, compared to placebo, intranasal oxytocin did not significantly improve emotion recognition, social interaction skills, or general behavior adjustment in male youths with ASD (528). Strengths

Randomized, controlled, blinded study , which is the highest level of constraint Subject selection : subjects given five norm-referenced diagnostic tools for autism,

pre- and post-treatment; only males were selected since more boys have autism, and there is evidence that females process OT differently (De Vries, 2008, cited in Dadds, 2014, 522)

History : subjects and families were housed near test location for 5 days of study; no other appointments

Drug or placebo administration : Sprays were primed; subjects practiced administering the sprays prior to the study. Researchers were blind to the contents of the spray (OT or placebo).

Inter-rater reliability : Coders for video were trained; they re-coded 20% of each others’ work with a high degree of reliability (80% or better)

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Tester bias : testers did not interact with children during the experiment; coders blinded to purpose of study; Parent-Interaction trainer was licensed child psychologist who underwent formal training

Weaknesses Subject selection : High level of comorbid disorders (20=ADD, 13=Oppositional

defiant disorder, 6=anxiety disorder, 17=psychotropic medications) Intranasal OT administration : subjects reported strange smell and feeling of liquid

going down their throats Conclusions

This study demonstrated that intranasal OT, administered once daily to males between the ages of 7-16 over a 4-day period, had no effect on the subjects’ social communication behaviors over time. Why? First, autism is a variable disorder that manifests itself somewhat differently in everyone who has it. Second, it may be that people with ASD have dysfunctional OT receptor systems that do not respond to peripherally administered OT (Gordon, 20955). In order to verify the results of this study, the authors suggest that new research should focus on finding the best ways to deliver OT, determine which group or groups are the most likely to benefit from it, and what its limitations are in therapy for ASD.

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Gordon, I., Vander Wyck, B. C., Bennett, R. H., Cordeaux, C., Lucas, M. V., Eilbott, J. A., et al. (2013). Oxytocin enhances brain function in children with autism. Proceedings of the National Academy of Sciences, 110, 20953-20958.

Study Methods: The primary research question was whether a single dose of intranasal oxytocin (OT) would have an effect on the social and communicative behaviors of 17 children and adolescents (ages 8-16.5 years) with autism spectrum disorder (ASD).

In this randomized, placebo-controlled, cross-over functional MRI (fMRI) study, subjects were administered a single dose of intranasal OT or placebo in two separate sessions. Subjects were dosed according to age; 16-19 year-olds received 24 International Units (IU), 12-15 year-olds received 18 IU, and 7-11 year-olds received 12 IU. Participants were then asked to label the mental state indicated in photographs of pairs of human eyes (social entities), and the category of automobile shown in photographs of vehicles (nonsocial objects) using the “Reading the Mind in the Eyes Test” (RMET). During these tasks, brain functions of the subjects were analyzed using an fMRI. Finally, participants’ reactivity to OT was measured by testing the concentration of OT in saliva, from baseline, to 30 minutes post-administration (20954).

Results: The administration of a single dose of intranasal OT enhanced brain activity in areas that are specialized for reward, social attention, perception, cognition, and detecting, decoding, and reasoning about others’ mental states (20955). In addition, OT increased participants’ brain activity for eyes > vehicles in certain regions of the brain over placebo, and this responsiveness varied by severity of ASD as measured by the Social Responsiveness Scale (SRS).

How OT works in the brain remains unclear, but OT receptors are spread throughout the brain, not just in areas primed for social cognition (20955). OT may enhance the perception of social stimuli, while suppressing perceptions or reactions to non-social stimuli (20955). Administering OT intra-nasally did not change the behaviors of the individual children studied; it merely improved their perception of social communication (20956).

Is OT useful as a pharmacological treatment for children with ASD, either alone, or in combination with therapy? The authors believed that it might be most useful when given immediately prior to an evidence-based treatment (20956). Strengths:

Experimental research design : the highest level of constraint Subject selection : ASD diagnoses made via ADOS and Autism Diagnostic interview-

revised; racially varied; age range is wide which increases external validity Drug administration : researchers and participants blinded to content of spray (OT

or placebo); drug dosage adjusted to age and weight of individual fMRI administration and saliva samples : described in detail, seemingly well-

controlled Assessment: the findings of the RMET were complemented by the fMRI.

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Weaknesses: Subject selection : not reliably predictive for girls with autism, since there were only

3 girls in the sample Sample : the researchers tested three different age groups (7-11, 12-15, and 16-19

years old) with three different doses of OT, which is a threat to internal validity Threats to validity of saliva sample as a measurement of OT :

o one participant had a sharp increase in salivary OT; this could be because OT administered intranasally can drip back into the mouth

o measurement of OT peripherally in saliva is disputed as being reliably correlated with central OT (McCullough, Churchland & Mendez, 2013, 1489)

History threat : drug and placebo administrations were separated by 3-78 days Conclusions: Testing for concentrations of oxytocin in saliva is problematic. This

study compensates for this weakness, however, by measuring changes in brain activity with the fMRI. Images show that following OT, the brains of the subjects are clearly more active in areas responsible for social communication.

The results would be more convincing if they were accompanied by equal improvements in social behavior. A better study of this type would follow OT administration with an evidence-based practice treatment in pragmatics or social communication, so that the efficacy of combining intranasal OT with behavioral therapy could be assessed.

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Guastella, A. J., Einfeld, S. L., Gray, K. M., Rinehart, N. J., Tonge, B. J., Lambert, T. J., & Hickie, I. B. (2010). Intranasal Oxytocin Improves Emotion Recognition for Youth with Autism Spectrum Disorders. Biological Psychiatry. Retrieved from DOI:10.1016/j.biopsych.2009.09.020

Study Methods: In a double-blind, randomized, crossover trial, 16 males aged 12-19 years who were diagnosed with Autism or Asperger’s (DSM-IV) were given a single dose of oxytocin (OT) nasal spray (18-24 IU) or placebo in two separate sessions one week apart. Participants aged 12-15 received a dose of 18 IU, while older subjects received 24 IU. Participants then completed the Reading the Mind in the Eyes task (RMET) 45 minutes after drug administration. The researchers’ primary questions were 1) do subjects would show greater emotion recognition on the RMET given OT vs. placebo?, and 2) can intranasal OT could be considered an effective treatment for emotion recognition deficits?

Results indicated that compared with placebo, performance on the RMET improved with oxytocin for 60% of the participants. With placebo, subjects answered 45% of the total items correctly; with oxytocin, they answered 49% of the total items correctly. Subjects under the age of 16 answered the easy items on the RMET with 54% accuracy under placebo, but improved to 62% accuracy under OT. There was no effect of OT on the harder test items on the RMET.

The authors indicated that this study was the first trial of nasal oxytocin spray on children between 12-16 years old, and that they were not aware of any other brief intervention that improved the ability to perceive or understand emotion in autism spectrum disorders. The authors felt that this study suggested that there was potential for nasal OT treatment to enhance social communication at a young age, which might increase the possibility of improved functional outcomes.

Strengths Experimental research design : the highest level of constraint Subject selection : subjects scored >17 (high functioning autism) using parent

version of Developmental Behavior Checklist The sample size of 16, based on previous oxytocin/autism studies, makes the results

easier to compare to those of previous studies. Drug administration : researchers and participants blind to content of spray (OT or

placebo); drug dosage adjusted to age/weight of individual Test practice threat controlled; subjects were randomized for treatment

Weaknesses Subject selection :

o Subjects varied widely in age, from 12-19; hard to apply results to any one age group

o Comorbid disorders: subjects taking medications or having comorbid disorders such as ADD were not identified.

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The sample size of 16 is a small, so the effect size will be small, and the results difficult to apply to any specific population.

Assessment: only one assessment for emotion recognition was given; the RMET test is a combination of higher and lower-order processes which may not be ideally suited to the wide range of ages in this study.

History : The researchers do not tell readers what other treatments may have occurred in between the treatments, or what treatments the subjects may have already received prior to the experiment.ConclusionsAs an early study on OT in children with autism, this was a landmark study. While it

included subjects between the ages of 12-19, it was the first experiment to assess nasal oxytocin spray on emotion recognition in subjects between the ages of 12-16. Results indicated that under OT, emotion recognition on the RMET improved by 4-8% for 60% of the subjects. While this is statistically significant, I wondered if an improvement of 4-8% in emotion recognition would be noticeable in a conversation with a child with autism. The point is moot, however, in light of the findings in Dadds et al. (2014), which demonstrated that gains cannot be maintained once OT is taken away from subjects.

One avenue for a follow-up study to Guastella et al. (2010) would be to determine why the gains were more significant for the “easy” items on the RMET than for the “total” items, and why the scores for the emotion recognition of “hard” items did not improve at all with oxytocin. Furthermore, it would be interesting to add a face-to-face emotion recognition treatment to this study, following the administration of the drug. Would the subjects have made more permanent gains in the traditional therapy with the drug than without? Hopefully future studies will be able to answer this question, and provide a drug therapy that reduces social deficits in children with autism.

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