Dataset Information

μ Opioid Antagonist Naltrexone Partially Abolishes the Antidepressant Placebo Effect and Reduces Orbitofrontal Cortex Encoding of Reinforcement.

ABSTRACT:

Background

Like 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.

Methods

Twenty 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.

Results

Behaviorally, 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.

Conclusions

Our 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.

SUBMITTER: Pecina M

PROVIDER: S-EPMC8419202 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

μ Opioid Antagonist Naltrexone Partially Abolishes the Antidepressant Placebo Effect and Reduces Orbitofrontal Cortex Encoding of Reinforcement.

Peciña Marta M Chen Jiazhou J Lyew Thandi T Karp Jordan F JF Dombrovski Alexandre Y AY

Biological psychiatry. Cognitive neuroscience and neuroimaging 20210306 10

<h4>Background</h4>Like 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-dependen ...[more]

PMID: 33684624

Similar Datasets

Project description:Supratherapeutic doses of methylphenidate activate μ-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed μ-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention-deficit/hyperactivity disorder (ADHD). We conducted a 6-week, double-blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to ~1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH. Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (χ² = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (χ² = 0.22, P = .64) of SODAS-MPH treatment. Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential. ClinicalTrials.gov identifier: NCT01673594.

Dataset Information

μ Opioid Antagonist Naltrexone Partially Abolishes the Antidepressant Placebo Effect and Reduces Orbitofrontal Cortex Encoding of Reinforcement.

Background

Methods

Results

Conclusions

Publications

μ Opioid Antagonist Naltrexone Partially Abolishes the Antidepressant Placebo Effect and Reduces Orbitofrontal Cortex Encoding of Reinforcement.

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