dna with genetic materials

Antipsychotic-induced Weight Gain in Autism Spectrum Disorder [IDDRC Research Project]

Principal Investigators - Lea Davis, Ph.D. (Genetics), Sharon Davis, M.S. (Bioinformatics), and Mark Wallace, Ph.D. (Hearing and Speech Sciences)

Specific Aims

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder that affects as many as 1 in 59 individuals and is defined by difficulties in social communication, repetitive behaviors, and restricted interests. Along with or due to these core deficits, children with ASD often have behavior problems such as aggression, irritability, self-injury, anxiety, and obsessive-compulsive behaviors. These behavior challenges are often the most limiting and interfering aspect ofASD. Indeed, disruptive behaviors, such as aggression, tantrums, and self-injury, occurs in 20-50% of individuals with ASD and severely affects their quality of life and community inclusion.

Targeting these problems with behavioral and/or pharmacological treatments are the major focus of ASD interventions. While behavioral interventions have been shown to be effective, significant barriers and lack of efficacy in some people leads to the use of pharmacological intervention, often with atypical antipsychotics (ATAP) such as risperidone or aripiprazole. These two ATAPs are FDA approved to treat severe behavior disturbances such as aggression and irritability in ASD, and while ATAPs can be effective, these drugs are associated with increased weight gain, with a high risk of developing obesity (up to 40%) and metabolic syndrome.

This effect on weight has the potential to result in long term health issues such as diabetes, associated cardiovascular complications, and stroke. Cumulatively, the high prevalence of ASD, use of ATAP, and the development of obesity (and its significant associated comorbidities) represents a large public health issue. Thus, there is a pressing need to improve the clinical approach of using ATAP in ASD.

Successful development of predictors of ATAP-induced weight gain in ASD and comparison of weight gain between the two commonly used ATAP in ASD would provide the framework for improved clinical care including reduced ATAP induced weight gain and, ultimately, facilitate precision care for people with ASD and disruptive behaviors. Critically, it would provide the platform for developing precision care approaches more broadly for those with IDD. There are three aims:

  1. Aim 1. Develop an electronic medical record (EMR) based predictive model of ATAP-induced weight gain in ASD.
    Currently, little is known about predictors of ATAP induced weight gain in ASD. Researchers will use an existing large de-identified EHR database at Vanderbilt to develop and validate a predictive model for ATAP induced weight gain in all people with ASD and determine if these models also apply to children with ASD. Models will be built using robust machine learning models (e.g. neural networks, random forests) combined with sophisticated regression and will include EHR-features clinically relevant to obesity, as well as clinical features of general interest related to ASD, such as the number of emergency room visits or behavioral therapy services as predictors. Additionally, we will determine if incorporation of genetic features (from Aim 2) improve model performance. Robust predictive models could improve clinical ASD care by inclusion in clinical decision support systems, with subsequent evaluation of real-world benefit.

  2. Aim 2. Identify pharmacogenetic risk factors associated with ATAP-induced weight gain in ASD.
    While pharmacogenetic studies have identified genetic risk factors associated with ATAP induced weight gain in adults, evidence exists that ATAP induced weight gain is influenced by different genetic features in children compared to adults. To date, only a few pharmacogenetic studies of ATAP induced weight gain in children with ASD have been conducted. To address this knowledge gap, researchers are conducting genome-wide association studies using the largest uniformly genotyped and phenotyped sample of ATAP exposed individuals to date to identify pharmacogenetic risk factors of ATAP induced weight gain. Subsequent sensitivity analysis will be performed on the restricted ASD cohort to determine if any genetic associations are significantly different between the ASD subset and the pooled sample. The identification of pharmacogenetic risk factors could then be used to guide pragmatic trials to determine if the information can better inform a clinician on treatment to develop precision, or personalized, medication use in ASD.

  3. Aim 3. Compare rates of ATAP-induced weight gain in ASD between two FDA-approved ATAPs.
    There is limited evidence regarding the differential risk of ATAP induced weight gain between the two ASD-approved ATAPs, aripiprazole and risperidone. Researchers will conduct a randomized pragmatic clinical trial within the context of standard care to evaluate weight at 3 months (primary outcome) after aripiprazole or risperidone treatment initiation in ATAP-naïve individuals with ASD. As an exploratory analysis, researchers also will evaluate efficacy via an EMR embedded caregiver reported outcome. The trial will directly compare rates of ATAP induced weight gain between the two ASD-approved ATAPs, explore the feasibility of using a caregiver report as an outcome metric, and serve as a platform to conduct other pragmatic trials more broadly, both in ASD and for other IDDs.