Researchers are making progress in evaluating the potential therapeutic benefit of oxytocin for PWS. Here, we review some of the most prominent research studies in this area and their implications for PWS.
Oxytocin is a hormone involved in numerous human behaviors including mother-infant bonding, trust, social interactions, and appetite. Oxytocin signaling plays a role in neurodevelopment in early infancy, contributing to long-term social and cognitive abilities. Studies have shown a deficiency of oxytocin-producing neurons in the brains of individuals with PWS (Bochukova, 2018), and there is also strong evidence in animal models to support the possible therapeutic benefit of oxytocin for PWS (Meziane, 2015). Clinical trials in people with PWS have yielded mixed results so far (Rice, 2018), but research continues to evaluate the therapeutic potential of oxytocin.
Oxytocin Biology and Questions in PWS
Researchers are trying to determine the exact nature and impact of oxytocin deficiency in people with PWS, whether there are benefits to treating with oxytocin, and how to best measure those benefits. For example, Dr. Einfeld's group at the University of Sydney has initiated an FPWR–funded study to better understand changes in oxytocin biology in individuals with PWS compared to typical individuals, as well as the impact of these changes on emotional and physiological function. With respect to oxytocin treatment for PWS, many questions remain including appropriate dosing, timing of treatment, possible side effects, as well as the potential variables that contribute to the complex and mixed clinical trial results to date. Thus far, a number of small clinical trials have examined the effects of oxytocin and a related drug, carbetocin, in PWS at different ages (infants, children, adolescents and adults), at different doses, and with respect to some genetic variables. Additional, larger studies are planned or ongoing, which will continue to build our knowledge of how best to use oxytocin in PWS.
Oxytocin Trials in Children and Adults with PWS
Among the clinical trials in PWS to date, four studies of oxytocin and one study of carbetocin have been reported so far in children and adults with PWS. An initial, placebo-controlled study administered a single dose of oxytocin in 24 adults with PWS, and showed short term improvements in trust and decreased disruptive behaviors (Tauber et al, 2011), setting the stage for further evaluation. A second study enrolled 30 adolescents and adults (age 12-29), but showed less encouraging results (Einfeld et al, 2014). This study used a “randomized, double blind, placebo controlled, crossover” design, where participants received either oxytocin or a placebo for 8 weeks, then were switched to the other for 8 weeks. Overall, no significant improvements in hyperphagia, behaviors and social interactions were detected when the study participants were receiving oxytocin compared to when they received placebo. In fact, at higher doses of oxytocin, there was an increase in the frequency of temper outbursts, which some researchers have speculated may due to oxytocin activation a related receptor (vasopressin) when higher doses of oxytocin are given.
A third study, published by Dr. Hokken-Koelega and colleagues at the Dutch Growth Research Foundation in 2016, examined the effects of oxytocin treatment on social behavior, food-related behavior, food intake, satiety, weight and body composition in 25 children with PWS, age 6-14 years old (Promising effects of oxytocin on social and food-related behaviour in young children with Prader-Willi syndrome: a randomized, double-blind, controlled crossover trial). Like the previous oxytocin clinical trials, no adverse events (safety problems) were found during the study period, which is encouraging. However in looking at the results for the entire group of 25 children, oxytocin did not produce significant improvement in social or food-related behavior, food intake, satiety, weight or body composition in oxytocin versus placebo groups. However, when researchers looked at the results broken down by age groups, some differences were seen (see Hirji, 2009 for limitations of subgroup analysis). In the younger children only (those under 11 years old, 17 individuals in the study). Features such as anger, sadness and conflict improved significantly with oxytocin treatment in the younger group compared to a placebo. Most other measures (happiness, social interaction, disruptive behavior, eating behavior, weight and BMI) were not significantly changed in children receiving oxytocin compared to placebo and only one measure of food-related behavior showed more reports of improvement in the younger age group. Overall these authors concluded that intranasal oxytocin administration is a promising treatment for young children with PWS. But, the results were not as promising in the older children.
The reason for lack of benefit in older children is unclear, and it’s important to note that the sample of 'older children' was small (n=8), so additional work is needed before form conclusions can be made. The authors do speculate, however, that there may be an age-related effect resulting in a decline in the oxytocin system as children reach puberty — a possibility that should be further investigated. Alternatively, changing the treatment period or dosing regimen might improve effectiveness. Additional studies are needed to better understand these issues.
A fourth study in 24 younger children with PWS (ages 5-11) was reported by Dr. Jennifer Miller and colleagues. They examined five days of oxytocin therapy compared to 5 days of placebo in the same children: Oxytocin treatment in children with Prader-Willi syndrome: A double-blind, placebo-controlled, crossover study. This study looked at changes in social responsiveness, repetitive behavior, other challenging behaviors, and appetite (hyperphagia). Although none of the individual measures showed significant change during the treatment period, there were trends in improvement for all of the measures. Parents reported that the most important improvement they noticed was a decrease in anxiety in their child. The researchers concluded that oxytocin may be a safe and effective treatment in PWS, but longer studies with more participants are needed to confirm these trends.
Aside from oxytocin, a study reported in 2018 examined the use of an "analog" of oxytocin, carbetocin, in PWS [Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome]. Carbetocin is interesting because it acts on the oxytocin receptor, but doesn't engage the vasopressin receptor, so might be able bypass some of the problematic issues that could occur at higher doses of oxytocin. In this study, children with PWS, age 10-18, were given carbetocin or placebo, 3 times a day for 14 days. Those receiving carbetocin had significantly reduced hyperphagia as well as a reduction in obsessive compulsive behaviors compared to those who received placebo, as rated by both the parents and the clinicians in the study. The generally positive outcomes of this study have led to the development of a larger, longer (Phase 3) study sponsored by Levo Therapeutics, to determine the safety and efficacy of carbetocin in children with PWS (more information below).
Altogether, these studies add to the growing knowledge of oxytocin for PWS, they are also a reminder that there remain significant limitations in understanding how best to use oxytocin or carbetocin in PWS. For example, are the beneficial effects really confined to younger children, or is the lack of improvement seen in older children reflective of small sample size, or dosing and duration that isn’t appropriate for this age group? In addition, although there appears to be some benefits in the younger children, the response is still quite variable. Parents whose children responded positively to oxytocin therapy were enthusiastic about the improvement, but not all families report improvements.
It is still unclear what might separate those seeing benefit from those who don’t. Some possible explanations related to this:
- Genetic reasons: Baseline oxytocin levels, oxytocin receptor variants (which are known to influence responsiveness in the normal population) and expression differences, or differences in overall hormone processing unique to PWS (see study below).
- Metabolic or environmental factors: Are there certain medications that improve or interfere with beneficial effects of oxytocin? Do behavioral methods or certain environmental factors strengthen or diminish the biological effects of oxytocin?
- Dosing: Dosing is challenging with oxytocin, and it's possible that administering too much oxytocin will negate a positive effect or cause a negative response in PWS.
- Outcome measures: Are the assessments of changes in social interaction, anxiety and food behavior used in previous studies adequately capturing the changes so that they “show up” in rigorous statistical analyses? Looking ahead, it’s clear that additional, validated measures to capture anxiety, social and food behavior changes across age groups is a priority, as is the ability to accurately quantify the level of oxytocin (active form) in the blood.
Oxytocin and Infants
Studies in mouse models of PWS have shown that early administration of oxytocin to newborn mice dramatically improved suckling and survival, and had a long-term impact on social skills. To see if these benefits might also apply to humans, Dr. Tauber and colleagues studied the effects of oxytocin in babies with PWS, in a study published in 2017, The Use of Oxytocin to Improve Feeding and Social Skills in Infants with Prader-Willi Syndrome. Improving feeding ability is important in PWS infants, since aspiration into the lungs and subsequent respiratory problems are common, and can result in life-threatening complications.
This clinical trial, funded by the Hospital University of Toulouse, enrolled 18 infants (age 3 weeks to just under 6 months) who were given oxytocin via nasal spray with differing dosing schedules (every other day, once per day or twice per day) for a week. Feeding (sucking/swallowing) and social behavior were assessed one day prior to the start of treatment, and then again after the last dose. There was no control group, all 18 infants received the treatment. No safety issues were noted. At baseline, all babies had difficulty with feeding (sucking and swallowing) as is typical in PWS. After a week of oxytocin treatment, all of the babies, regardless of oxytocin dose, showed improvements in feeding skills, with 88% of them scoring in the "normal" range for the feeding assessments. Looking at the impact on "social skills" they measured several aspects of facial expression, eye contact and interaction with parents. Measures reflecting social expression, eye contact, and social engagement improved after the oxytocin treatment. Measures of vocalizations and attraction showed no improvement. Finally, all the infants had brain imaging studies before and after oxytocin treatment, and in the ones that had the highest quality images for analysis (n=10), the results suggest that there was improved “connectivity” in a specific brain region (superior orbitofrontal cortex, OFC) after oxytocin treatment. The OFC is important in oral motor skills and in emotional decision making.
When these babies were evaluated later on (at ~2 to 2.5 years old) and compared to toddlers with PWS who had not received oxytocin, their overall growth and body composition was similar. However, more of the children who had been treated with oxytocin were crawling compared to those who had not, possibly reflecting better muscle tone. The authors concluded that a short course of repeated intranasal oxytocin administration improves oral feeding and social skills in infants with PWS. It’s not yet clear if this short-term oxytocin administration will have long-term effects, but this is an area of interest for future studies.
It should be noted that this study was not "placebo controlled" and it’s possible that interventions associated with participating in the study (e.g., additional attention and teaching of feeding skills) may have contributed to improvements. Also, there was no difference in outcome based on dose. Thus it’s not clear if the lowest dose was “enough” or if the optimal dosing has yet to be reached. The findings do however add an important piece to the growing understanding of oxytocin in PWS. An additional study in infants, this one with a placebo control group, has recently been completed at University of Florida the findings of which will further add to the knowledge base. Additional questions to optimize timing, dose, and schedule of oxytocin for PWS need to be explored, and are currently being examined in animal models.
Oxytocin and Method of Delivery
All of these studies reported to date deliver oxytocin intranasally, as a spray in the nose that then crosses the blood-brain barrier to act on oxytocin receptors in the brain — a delivery method that's not necessarily tolerated well by all patients. However, there are also oxytocin receptors in the nose and mouth, located on nerves that carry sensory information from the face and mouth to the brain. A study funded by FPWR is exploring how oxytocin receptors on these neurons may mediate oxytocin's beneficial effects. Using mouse models, Dr. Elizabeth Hammock at Florida State University is studying how the receptors in the nose and mouth respond to oxytocin, and regulate the oral and facial reflexes that are needed for successful feeding and social behavior (Neural Mechanisms of Oxytocin-Enhanced Infant Feeding and Social Behavior Development). Dr. Hammock's team will also investigate how oxytocin therapy may stimulate production of oxytocin in the brain, amplifying the therapeutic effect. These studies may also support the development of a better tolerated, oral form of oxytocin therapy.
Oxytocin Biology and Genetic Variables
Another important effort in this area is underway by Dr. Daniel Driscoll at the University of Florida. His group is working to determine if there are genetic factors contributing to how different individuals with PWS respond to oxytocin therapy. The project is titled Evaluating Factors That May Affect the Efficacy of Intranasal Oxytocin Treatment In PWS.
Specifically, Dr. Driscoll's team will determine if there are genetic variants in the oxytocin pathway among individuals with PWS that might impact how an individual responds to oxytocin therapy. These variants affect how many oxytocin receptors are expressed, how sensitive the receptors are to oxytocin, and how much oxytocin is circulating in the blood. Such differences could help explain why some individuals with PWS respond positively to oxytocin therapy, while others don't seem to benefit. Determining the biological mechanism for "responders" versus "nonresponders" would help inform appropriate dosing, and would guide personalized treatment with oxytocin for individuals with PWS in the future.
Additional Clinical Studies
Finally, leading autism researcher Eric Hollander has investigated the use of oxytocin in autism spectrum disorder and PWS. After an initial, FPWR-funded study (Oxytocin vs. placebo for the treatment of hyperphagia in Prader-Willi syndrome) Dr. Hollander has received funding from the FDA to do an expanded study of the effects of intranasal oxytocin versus placebo in children with PWS, age 5-17 years old. They hypothesize that oxytocin will have a positive effect on hunger (hyperphagia), repetitive behaviors, and social cognition. More details including inclusion/exclusion criteria and contact information can be found here.
As mentioned above, a Phase 3 clinical study of carbetocin, "CARE-PWS" has recently opened in multiple sites across the US and Canada as well. This study will enroll children, age 7-18 years, and examine the effects of intranasal carbetocin on hyperphagia, obsessive compulsive behaviors, and anxiety in PWS. An eight week period comparing a placebo group to those receiving the drug will be followed by a long term phase (more than 1 year) in which all participants can receive carbetocin.
Overall, the use of oxytocin for PWS as a potential therapy remains an exciting area of research. The path forward is likely to be a long and may not always be straight-forward, but the aggregate of the studies completed to date plus those planned should lead to a solid understanding the role of oxytocin in PWS therapeutics, including optimal timing, dose, and short- and long-term effects.
* A final note to families: On behalf of the expert physicians who care for individuals with PWS, please remember that these are early clinical trials. Additional studies are needed to determine if oxytocin is safe in the long term, and if oxytocin shows lasting benefits for infants, children and/or adults with PWS. Oxytocin for PWS is experimental and should not be used outside of a carefully monitored clinical study. Additional clinical trials are planned, and participating in a clinical trial is the best way to safely and efficiently determine whether, how and when oxytocin should be used in PWS. For updated information on PWS clinical trial opportunities and to sign up for a monthly PWS Clinical Trial Alert, visit the PWS clinical trials page.