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

Abstract

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. © 2016 Wiley Periodicals, Inc.

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

“…They often have genetic, physiological, neurochemical, degenerative, and inflammatory components, which display variation within the patient group [7,8]. For example, for Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders, multiple-and in many cases divergent-disease etiologies are involved.…”

“…This is likely to lead to development of more targeted treatments, being focused on the underlying causes of the disease as well as its prevention (life-style, diet, etc.). In general, the research focus has shifted from single target toward target networks (systems pharmacology), as networks include the compensatory factors that impact the neuro-PD [7,10,11]. These networks are constructed on basis of integrated genomics, proteomics, and metabolomics data, narrowing down the large number of potential genomicsinformed targets into a fewer number of relevant diseasecausing targets [14,15].…”