Crossing borders in neurodevelopmental disorders: Towards rational treatments and stratified trial designs

Children with neurodevelopmental disorders (NDDs), such as autism spectrum disorder and attention-deficit/hyperactivity disorder, vary greatly in mechanism and clinical presentation. This heterogeneity, however, is largely denied or ignored in trials and has led to a deadlock in treatment development. The aim of this dissertation was to improve this situation by developing stratified trial designs and improving clinical endpoints. We tested these innovations in the context of a novel, mechanism-based treatment option for NDDs. This treatment is based upon the repurposing of the diuretic bumetanide, a chloride importer antagonist. A large body of (pre)clinical evidence has indicated that elevated chloride levels may cause hyperexcitability in the brain, that may be treated by bumetanide in a yet unknown subset of NDDs. The studies tested behavioral, neurocognitive and genetic stratification techniques to find these responsive subsets. We further conducted a parent-driven approach to develop patient reported outcome measures (PROMs) to improve clinical endpoint measurement.

Overall, we found that bumetanide can have a positive effect on behavioral manifestations, such as irritable and repetitive behaviors. Genetic stratification seems especially promising to enhance effectiveness in trial designs. The PROM study showed that the use of generic item banks may be a solution to assess consequences of sensory issues across NDDs as a powerful translational endpoint. In conclusion, these findings highlight the need for a shift from the traditional diagnosis-driven approach to a stratified and etiology-driven approach in NDD clinical trials.