TABLE 2.

Problems and solutions for clinical trial failures of therapies targeting the impact of inflammation on the brain

	Methodologic Issues
Sample
Problem	Heterogenous populations with a limited percentage of patients with high inflammation
Solution	Enrich populations for high and/or low inflammation with a priori defined inflammation status at baseline
Design
Problem	Randomized, double-blind, placebo-controlled clinical trial with no stratification
Solution	Match/mismatch design with patients stratified by inflammation status—drug targeting inflammation should only show efficacy in high-inflammation group Randomized, double-blind, placebo-controlled trial with stratification on inflammation or conducted solely on patients with high inflammation
Target engagement
Problem	No measure of inflammatory or brain endpoint to establish drug effect on the target
Solution	Predetermined inflammatory markers in brain or periphery that establish that the drug has engaged the target
Outcome variables
Problem	Overall symptom severity
Solution	Outcome variables tied to the known biologic effects of inflammation on behavior (e.g., anhedonia, psychomotor slowing, anxiety)