Psychotropic Drug Development Strategies that Target Neuropsychiatric Etiologies in Alzheimer's and Parkinson's Diseases.

Preclinical Research Neuropsychiatric symptoms are currently recognized as a common burden in patients suffering from Alzheimer's disease (AD), Parkinson's disease (PD), and many other neurodegenerative disorders. Earlier theories positing that these symptoms emerge predominantly in patients with late-stage disease have been largely dismissed. It is now generally accepted that many neuropsychiatric symptoms commonly manifest very early in neurodegenerative disease stages, and in many cases are even considered prodromal indicators. Despite intense research efforts, no reliable drug treatment strategies have been found for the neuropsychiatric symptoms associated with AD and PD. Among the medications commonly used at this stage, many present significant risks for patients in this particular cohort. Transcriptomic tools and proteomic profiling have clearly indicated that neurodegenerative diseases and their associated neuropsychiatric comorbidities are multifactorial in origin. As such, multiple-and in many cases divergent-disease etiologies lead to the neuropsychiatric symptoms associated with AD, PD, and other neurodegenerative disorders. The complexity of these pathways (initiated by a cascade of molecular events that involve several neurotransmitter systems) offer significant challenges to drug discovery efforts aimed at addressing these symptoms. In response to this complexity, a new paradigm has emerged that challenges the widely held assumption that "targeted" drug design is superior to the development of "multi-targeted" drugs as a strategy to address the neuropsychiatric symptoms associated with AD and PD. In this Overview, I offer an overview of drug discovery strategies and investigative drugs currently under development that address multiple CNS etiological targets associated with an array of neuropsychiatric symptoms. Drug Dev Res 77 : 458-468, 2016.