CNS drug development is rapidly evolving to meet the unique and changing demands of the fields of psychiatry and neurology. Phase I studies are traditionally focused on determining the safety, tolerability, and pharmacokinetics of a new molecular entity in young healthy volunteers: first in a single ascending dose (SAD) study and then in a multiple ascending dose (MAD) study. The use of an adaptive design to examine data and modify the study in real time may also promote time- and cost-efficient identification of novel molecular entities (NMEs) that have the characteristics necessary to be successful in confirm stages of drug development research. This chapter discusses how use of biomarkers as surrogate endpoints can be incorporated into early clinical trials to determine if a drug modulates the appropriate targets, which enhances the likelihood of demonstrating efficacy in the confirm phase of clinical testing.

This chapter focuses on drug development for psychiatric as opposed to other central nervous system (CNS) indications such as neurological conditions, pain, and sleep. It provides an overview of how CNS drug development has evolved over its relatively short history of perhaps 50-100 years as well as to provide some sense of how it might evolve in the not-too-distant future. Chlorpromazine and other phenothiazine molecules were synthesized around the turn of the last century and some were initially used to treat pinworm infestation. However, chlorpromazine over the last 50 years has come to play a pivotal role in the modern era of clinical psychopharmacology. CNS drug development principally focused on serotonin selective reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors SNRIs, atypical antipsychotics, and cholinesterase inhibitors. The current development of drugs for Alzheimer's and other neurodegenerative diseases could be a model for how future CNS drug development might proceed.

This chapter focuses on the challenges presented by therapeutic targets in the central nervous system (CNS), the manner in which animal models have and can be used to support the translation of therapeutic biologies to the human CNS, the blood brain barrier (BBB), and the uncertainties of CNS drug exposures. It also addresses how these challenges can be met and the associated risks of CNS therapeutic development mitigated. Animal CNS disease models are unique tools that have led to a significant increase in the number of potential new therapeutic targets and an improved understanding of the biologies underlying disease processes. Development of pharmacodynamic (Pd) biomarkers for CNS drug development should be a high priority. Pd biomarkers are used in Phase 1, 2, and 3 studies, although most commonly in Phase 1 and 2 studies.