A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia

Andrew D. Krystal, Diego A. Pizzagalli, Moria Smoski, Sanjay J. Mathew, John Nurnberger, Sarah H. Lisanby, Dan Iosifescu, James W. Murrough, Hongqiu Yang, Richard D. Weiner, Joseph R. Calabrese, Gerard Sanacora, Gretchen Hermes, Richard S.E. Keefe, Allen Song, Wayne Goodman, Steven T. Szabo, Alexis E. Whitton, Keming Gao, William Z. Potter

Research output: Contribution to journalArticle


The National Institute of Mental Health (NIMH) ‘fast-fail’ approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13–0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the ‘fast-fail’ approach.

Original languageEnglish (US)
JournalNature Medicine
StateAccepted/In press - Jan 1 2020


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Krystal, A. D., Pizzagalli, D. A., Smoski, M., Mathew, S. J., Nurnberger, J., Lisanby, S. H., Iosifescu, D., Murrough, J. W., Yang, H., Weiner, R. D., Calabrese, J. R., Sanacora, G., Hermes, G., Keefe, R. S. E., Song, A., Goodman, W., Szabo, S. T., Whitton, A. E., Gao, K., & Potter, W. Z. (Accepted/In press). A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia. Nature Medicine. https://doi.org/10.1038/s41591-020-0806-7