Trial reportNature medicine2020
A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia.
Trial report in Nature medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05282277 (Examining the Effects of Estradiol on Neural and Molecular Response to Rewards in Perimenopausal-Onset Anhedonia and Psychosis), which is not on this map. Cited by 150 papers, 6 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Examining the Effects of Estradiol on Neural and Molecular Response to Rewards in Perimenopausal-Onset Anhedonia and Psychosis
Who cites it
150 citing papers in PubMed, 6 syntheses or guidelines pooled it, 220 citations in OpenAlex.
- Pro-dopaminergic pharmacological interventions for anhedonia in depression: a living systematic review and network meta-analysis of human and animal studies.EBioMedicine · 2025Pooled it
- The hierarchical taxonomy of psychopathology and the search for neurobiological substrates of mental illness: A systematic review and roadmap for future research.Journal of psychopathology and clinical science · 2024Pooled it
- A review of the kappa opioid receptor system in opioid use.Neuroscience and biobehavioral reviews · 2024Pooled it
- Charting the proteome landscape in major psychiatric disorders: From biomarkers to biological pathways towards drug discovery.European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology · 2022Pooled it
- Great Expectations: A Critical Review of and Suggestions for the Study of Reward Processing as a Cause and Predictor of Depression.Biological psychiatry · 2021Pooled it
- Assessment of Anhedonia in Adults With and Without Mental Illness: A Systematic Review and Meta-analysis.JAMA network open · 2020Pooled it
- Efficacy and target engagement of dopamine agonist pramipexole for anhedonic depression: a randomized placebo-controlled trial.Nature medicine · 2026Trial
- Computationally Informed Insights Into Anhedonia and Treatment by Kappa Opioid Receptor Antagonism.Biological psychiatry. Cognitive neuroscience and neuroimaging · 2025Trial
- Selective KOR antagonist alters functional patch sizes in individualized brain system: results from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS).Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Trial
- A randomized proof-of-mechanism trial of TNF antagonism for motivational deficits and related corticostriatal circuitry in depressed patients with high inflammation.Molecular psychiatry · 2025Trial
- Sustained effects of repeated levodopa (L-DOPA) administration on reward circuitry, effort-based motivation, and anhedonia in depressed patients with higher inflammation.Brain, behavior, and immunity · 2025Trial
- Efficacy and Safety of Toludesvenlafaxine Hydrochloride Sustained-Release Tablets in Depression With Anhedonia: A Single-Arm, Multicenter Clinical Study.Depression and anxiety · 2025Trial
- A parallel-arm, randomized trial of Behavioral Activation Therapy for anhedonia versus mindfulness-based cognitive therapy for adults with anhedonia.Behaviour research and therapy · 2024Trial
- Efficacy and safety of aticaprant, a kappa receptor antagonist, adjunctive to oral SSRI/SNRI antidepressant in major depressive disorder: results of a phase 2 randomized, double-blind, placebo-controlled study.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Trial
- Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.Biological psychiatry · 2023Trial
- Parsing within & between-person dynamics of therapy homework completion and clinical symptoms in two cognitive behavioral treatments for adults with anhedonia.Behaviour research and therapy · 2023Trial
- Positive affect treatment targets reward sensitivity: A randomized controlled trial.Journal of consulting and clinical psychology · 2023Trial
- Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Trial
- Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.The American journal of psychiatry · 2021Trial
- Navacaprant, a Novel and Highly Selective Kappa Opioid Receptor Antagonist, in Adults With Major Depressive Disorder: A Randomized, Double-Blind Phase 2 Clinical Trial.Journal of clinical psychopharmacologyTrial
90 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
20 authors at 12 institutions in 2 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.