Trial reportBiological psychiatry. Cognitive neuroscience and neuroimaging2021
μ Opioid Antagonist Naltrexone Partially Abolishes the Antidepressant Placebo Effect and Reduces Orbitofrontal Cortex Encoding of Reinforcement.
Trial report in Biological psychiatry. Cognitive neuroscience and neuroimaging, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers, 1 of them a synthesis 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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
5 citing papers in PubMed, 1 synthesis or guideline pooled it, 6 citations in OpenAlex.
- Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review.The international journal of neuropsychopharmacology · 2022Pooled it
- Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study.Nature medicine · 2025Trial
- Expectancy-Mood Neural Dynamics Predict Mechanisms of Short- and Long-Term Antidepressant Placebo Effects.Biological psychiatry. Cognitive neuroscience and neuroimaging · 2025Trial
- Opioids diminish the placebo antidepressant response: Observational post hoc findings from a randomized controlled ketamine trial.Journal of affective disorders · 2025Trial
- The opioid system in depression.Neuroscience and biobehavioral reviews · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundLike placebo analgesia, the antidepressant placebo effect appears to involve cortical and subcortical endogenous opioid signaling, yet the mechanism through which opioid release affects mood remains unclear. The orbitofrontal cortex (OFC)-which integrates various attributes of a stimulus to predict associated outcomes-has been implicated in placebo effects and is rich in μ opioid receptors. We hypothesized that naltrexone blockade of μ opioid receptors would blunt OFC-dependent antidepressant placebo effects.
methodsTwenty psychotropic-free patients with major depressive disorder completed a randomized, double-blind, placebo-controlled crossover study of 1 oral dose of 50 mg of naltrexone or matching placebo immediately before completing 2 sessions of the antidepressant placebo functional magnetic resonance imaging task. This task manipulates placebo-associated expectancies and their reinforcement while assessing expected and actual mood improvement.
resultsBehaviorally, manipulations of antidepressant placebo expectancies and their reinforcement had positive, interactive effects on participants' expectancy and mood ratings. The high-expectancy condition recruited the dorsolateral and ventrolateral prefrontal cortex, as well as dorsal attention stream regions. Interestingly, increased dorsolateral and ventrolateral prefrontal cortex brain responses appeared to attenuate the antidepressant placebo effect. The administration of 1 oral dose of naltrexone, compared with placebo, partially abolished the interaction of the expectancy and reinforcement manipulation on mood and blocked reinforcement-induced responses in the right central OFC.
conclusionsOur results show preliminary evidence for the role of μ opioid central OFC modulation in antidepressant placebo effects by positively biasing the value of placebo based on reinforcement and enhancing subsequent hedonic experiences.
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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.