Placebo-Controlled Trial of Dextromethorphan in Rett Syndrome

Principal Investigator: SakkuBai Naidu

The overall goal of this study is to counter the effects of increased N-methyl-D-aspartate (NMDA)/glutamate receptors in MeCP2-mutation-positive Rett syndrome (RTT) subjects by use of a placebo-controlled trial of dextromethorphan (DM), an agent known to block the NMDA receptor channels. The drug dose of DM will be 5mg/kg/day as this dose showed optimal results in our previous dose-effect study. We anticipate improved cognition and temperament, and reduced seizure frequency.

RTT is a neurodevelopmental disorder with devastating consequences to both brain and systemic neurons. Despite a prominent 50 percent reduction in the number of synapses, postmortem brain autoradiographic studies demonstrate a striking and disproportionate increase in the number of glutamate/NMDA (N-methyl-D-aspartate) subtype of receptors in the prefrontal cortex, especially in younger patients. DM blocks NMDA receptor channels, which improve some clinical manifestations of RTT (e.g., cognitive and behavioral deficits, seizures) by reducing the excitotoxic damage and preventing the degree of intellectual disability over the long term.

Presently, there is no effective therapy or definitive treatment for RTT, other than palliative care, therefore, our overall specific aim in this biologically-based study is to test the efficacy of DM versus placebo in RTT to block the disproportionate numbers of glutamate/NMDA receptors in the brain and alleviate symptoms. This study holds promise for improved quality of life for girls with RTT, by helping to reduce the degree of functional impairment in this population. Moreover, this study would lend itself to a mode of therapy for other epileptic conditions also associated with glutamatergic excitotoxicity.

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