Deuteration may reduce the efficacy of dextromethorphan in treating agitation in Alzheimer’s disease

Agitation is one of the most prevalent neuropsychiatric symptoms leading to institutionalization in individuals with Alzheimer's disease (AD) dementia. It is associated with poor outcomes, including reduced functional ability, reduced quality of life, accelerated disease progression, increased mortality, and significant economic burden. Following an initial report demonstrating the strong efficacy of a combination of dextromethorphan and the CYP2D6 inhibitor quinidine, several follow-up development efforts have explored this approach. Axsome Therapeutics has reported positive results in three out of four clinical trials evaluating AXS-05, a combination of dextromethorphan with another CYP2D6 inhibitor, bupropion. In contrast, Otsuka's AVP-786, a combination of deuterated dextromethorphan and quinidine, has yielded predominantly negative results. It is widely believed that deuteration alters a molecule's pharmacokinetic properties without affecting its pharmacodynamics. However, in our patch-clamp experiments, deuteration resulted in a 16-fold increase in IC50 for dextrorphan and about two-fold increase for dextromethorphan at NMDA receptors containing the NR2D subunit. Thus, based on both clinical data and emerging pharmacological evidence, we hypothesize that AVP-786 failed to demonstrate efficacy in treating agitation in AD dementia due to the negative impact of deuteration on dextromethorphan's pharmacodynamic properties.