A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia
Open accessAbstract
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.
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The KOR JNJ-67953964 increased VTA activation relative to placebo during reward anticipation.
“Indeed, the KOR JNJ-67953964 was found to increase VTA activation relative to placebo during reward anticipation”
From Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions (2021) · cites this paper as [24]
The group receiving JNJ-67953964 showed reduced anhedonic symptoms relative to controls.
“The group receiving JNJ-67953964 showed reduced anhedonic symptoms relative to controls.24”
From Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions (2021) · cites this paper as [24]
A randomized proof-of-mechanism trial investigated κ-opioid antagonists as treatment for anhedonia symptoms.
“A recent randomized proof-of-mechanism trial24 investigated κ-opioid antagonists (KOR) as treatment for anhedonia symptoms.”
From Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions (2021) · cites this paper as [24]
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References 78 · Cited by 227
Research works printed but not linked: 2
- [55]Cohen J Statistical Power Analysis for the Behavioral Sciences. Routledge (1988).
- [66]Andersson JLR, Jenkinson M, Smith S. Non-linear registration, aka Spatial normalisation FMRIB technical report TR07JA2 FMRIB Centre, Oxford, United Kingdom. 2007.
- Authors
- 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.
- Affiliations
- Duke University (US)
- Harvard University (US)
- Michael E. DeBakey VA Medical Center (US)
- National Institute of Mental Health (US)
- NYU Langone Health (US)
- Icahn School of Medicine at Mount Sinai (US)
- Duke Clinical Research Institute (US)
- Case Western Reserve University (US)
- Yale University (US)
- Baylor College of Medicine (US)
- The University of Sydney (AU)
- Corresponding author
- Krystal, Andrew D.
- ORCID
- Venue
- Nature Medicine
- Published
- 2020-03-30
- Volume
- 26
- Issue
- 5
- Pages
- 760-768
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC9949770
- OpenAlex
- W3013097214
- Cited by
- 227
- References
- 78
- Citations by year
- 2026: 27 · 2025: 28 · 2024: 48 · 2023: 38 · 2022: 27 · 2021: 36 · 2020: 22
- FWCI
- 14.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (HHS-N271-2012-000006-I, R37 MH068376)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- anhedonia, target engagement, reward anticipation, mood disorders, anxiety disorders, early drug development
- MeSH terms
- Proof of Concept Study, Adult, Anxiety Disorders, Benzamides, Central Nervous System Agents, Double-Blind Method, Female, Humans, Male, Middle Aged, Narcotic Antagonists, Pyrrolidines, Time Factors, Treatment Outcome, Receptors, Opioid, kappa, Mood Disorders, Anhedonia
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