Table I. Three ways of conducting phase 1 studies. MTD, maximal tolerated dose; PK, pharmacokinetics; PD, pharmacodynamics; BBB, blood-brain barrier. *Basic PD includes BBB crossing, minimal active dose, dose effect, and non-central nervous system (CNS) PD. **Basic PD without BBB crossing. ***Refined PD (model): proof of concept, minimal active dose, dose effect, and non-CNS PD.

	Classic	curent (usual)	Echanced
Single-dose study
Population	Young, healthy volunteers	Young, healthy volunteers	Young, healthy volunteers
Design	Parallel, double-blind, vs placebo	Parallel, double-blind, vs placebo	Parallel, double-blind, vs placebo
Objectives	Safety/tolerability (MTD) PK	Safety/tolerability (MTD) PK Basic PD* PK/PD relationships	Safety/tolerability (MTD) PK Basic PD* PK/PD relationships
Repeated-dose study
Population	Healthy volunteers	Healthy volunteers	Healthy volunteers
Design	Parallel, double-blind, vs placebo	Parallel, double-blind, vs placebo	Grossover, double-blind, vs placebo
Objectives	Safety/tolerability (MTD) PK	Safety/tolerability (MTD) PK Basic PD* PK/PD relationships	Safety/tolerability (MTD) PK Basic PD* PK/PD relationships
Next step
Population	Patients	Health volunteers	Patients
Design	Parallel, double-blind, vs placebo	Grossover, double-blind, vs placebo	Parallel, double-blind, vs placebo
Objectives	Safety Efficacy	Refined PD PK/PD relationships	Safety Efficacy