Background

Compulsivity is characterized by a repetitive, irresistible urge to perform a behavior, the experience of loss of voluntary control over this intense urge, the diminished ability to delay or inhibit thoughts or behaviors, and the tendency to perform repetitive acts in a habitual or stereotyped manner. Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood (autism spectrum disorder, ASD; obsessive-compulsive disorder, OCD) or adolescence (substance abuse). Our approach integrates clinical data sets for ‘addictive’ (ADHD high risk for substance use), ‘anxious’ (OCD) and ‘stereotypical’ (ASD) compulsive behaviors with highly predictive animal models for new pharmacotherapy.

Objectives

In a series of ‘proof-of-concept’ studies, the cohesion of structural neuroimaging studies (MRI/DTI), neurochemistry (MRS/microdialysis), behavior, genetics (GWAS), proteomics and (Bayesian) machine learning tools in both male and female paediatric clinical populations and behavioral animal models will seek to better understand underlying mechanisms related to glutamate dysfunction in frontostriatal circuits and its remediation/prevention by early intervention studies with glutamate-based (riluzole and memantine) clinically used drugs. The leading drug-based interventions will be tested in pilot Phase IIb-like studies for ‘proof-of-principle’ efficacy in paediatric OCD and ASD populations.

This approach will

1. establish predictive neural, genetic and molecular markers of compulsivity in pediatric populations;
2. provide evidence of disorder modifying pharmacologic strategies as a therapeutic approach;
3. develop a novel animal model for pharmaceutical screening and proof of concept studies;
4. build and valorize a translational biomarker compulsivity database and
5. provide pilot efficacy and safety data in paediatric clinical populations to support future large scale clinical trials according to these strategies.