Functional Measurements of Central Nervous System Drug Effects in Early Human Drug Development

Abstract An important objective of early development of drugs for neurobehavioral conditions is to demonstrate a drug-related central nervous system (CNS) effect. For this, functional measurements are often performed in healthy volunteers. However, many available CNS tests are unable to show significant and reproducible effects, even for established neuropsychiatric drugs. This chapter systematically evaluates a wide range of neuropsychological and neuroendocrine measurements for their sensitivity to drugs with established CNS effects and for their applicability in development. For most CNS measurements, drug effects are highly variable between studies. Some effects however seem to be closely related to an underlying pharmacological effect. Most support for such pharmacological effect measures comes from pharmacokinetic/pharmacodynamic modeling. Some of these tests are linked to a specific pharmacological mechanism. This includes prolactin increase for D2 receptor inhibition and saccadic peak velocity reductions for GABA-A receptor agonism. Pharmacological effect measures can provide essential information on CNS-active drugs: penetration of the blood-brain barrier, binding and activity at the target, concentration dependence of the effect, and impact on (neuro)physiological processes that are relevant for therapeutic or adverse effects. These data are important for the prediction of therapeutic effect range, the safety window, the selection of dosing regimens, and the pharmacological profile of the compound.