Contributed by Dr Janice L. Forster, IPWSO Clinical Scientific Advisory Board; Child and Adolescent Psychiatrist in private practice in Pittsburgh, PA who specializes in Developmental Neuropsychiatry.
Dr. Jeremy Veenstra VanderWeele presented an overview of autistic spectrum disorder (ASD) and discussed the complexity of developing biomarker-based therapeutics that produce change in behavioral domains in complex syndromes. He spoke about potential targets of interventions from genes to proteins to networks that are developmentally expressed to impact neurons, synapses, specific brain regions and interconnecting circuits in the brain. He described how difficult it is at times to determine whether changes that are observed or measured to occur during treatment are actually due to the treatment intervention. He discussed medication trials in complex syndromes that were effective and not effective. Risperidone, which improves irritability/agitation, hyperactivity/defiance, and stereotypic behavior in ASD, is offset by side effects of weight gain, extrapyramidal signs, and metabolic changes leading to insulin resistance. A similar drug, lurasidone, was ineffective. A trial of citalopram to target stereotypic behavior in ASD was ineffective, but produced side effects of mood activation in 50% of study participants. Overall, when co-morbid disorders are attached to ASD, treatment response is diminished and side effects are more likely to occur. All of this experience of developing drug treatments for autism can be applied to PWS.
Dr. Eric Hollander and his colleague Dr. Bonnie Taylor presented their preliminary findings about an 8 week, double blind placebo controlled trial of oxytocin in PWS. This study defined target symptoms of repetitive behaviors using the Repetitive Behavior Scale and Yale Brown Obsessive Compulsive Scale, disruptive behaviors using the Aberrant Behavior Checklist-Irritability domain, and social communication using the Aberrant Behavior Checklist-Social Withdrawal domain and the Social Responsiveness Scale. These assessment tools worked well. The data obtained were preliminary findings as the study had not concluded, and the blind had not been broken. None the less, they presented the data as responders and nonresponders, even though they did not know who was actually receiving the oxytocin. This drew criticism from both parents and scientists. This presentation was a reminder of the value of placebo controlled studies and the importance of understanding placebo response in PWS.
Sleep was a theme explored in animal models (Necdin, Magel2, and SNORD116 deficient mice) during the scientific conference. Technology now allows for sleep studies, similar to those performed in humans, to be studied in mice. These animal models are contributing to our understanding of the genetic underpinnings of disrupted sleep in PWS (increased sleep cycles, increased fragmentation of REM sleep with intrusions into daytime, and impaired timing of anticipatory behaviors) and whether there are medications that can rescue these abnormalities. One must be careful to realize that these findings occur in specific genetic models of PWS and may not be generalizable to humans. During the pre-conference workshop, which occurred on Wednesday, there was a discussion about the impact of both disrupted sleep and abnormalities of wakefulness and their impact on cognition, mood and behavior in PWS. In the scientific session Dr. Holger Stark presented his studies in Europe using histamine 3 receptor antagonists to enhance alertness in narcolepsy and Parkinson's disease. With a favorable side effect profile, he was optimistic that this class of medications might be helpful in PWS.
Finally, there were some fascinating presentations regarding diets and pathways to obesity in all of us. Dr. Mark Friedman presented Hyperphagia: Cause or Consequence of obesity. He described evidence of abnormalities of fatty acid oxidation in liver cells, leading to increased deposition of fat, increased glycogen storage, decreased available energy, resulting in hyperphagia. For them, high carbohydrate diets promote lipid synthesis and storage while inhibiting fatty acid oxidation and mobilization. These individuals have a decreased ketone response to a fast and intolerance of low carbohydrate, calorie restricted diets. They require diets with higher fats and lower carbs but not calorie restriction. His work debunks the myth that obese people are fat because they eat too much.