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

Peciña, Marta; Chen, Jiazhou; Lyew, Thandi; Karp, Jordan F.; Dombrovski, Alexandre Y.

doi:10.1016/j.bpsc.2021.02.009

Cited by 5 publications

(21 citation statements)

References 89 publications

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“…After de-duplication, we screened 3286 titles and abstracts, 234 full-text articles were obtained, and 16 records met inclusion criteria ( Figure 1 ). Twelve studies were of patients with depression utilizing the following imaging modalities: ASL ( Cooper et al, 2019 ), fMRI ( Sikora et al, 2016 ; Pecina et al, 2018 ; Zilcha-Mano et al, 2019 ; Chin Fatt et al, 2020 ; Fan et al, 2020 ; Greenberg et al, 2020 ; Chin Fatt et al, 2021b ; Chin Fatt et al, 2021a ; Peciña et al, 2021 ), and PET ( Mayberg et al, 2002 ; Pecina et al, 2015 ). Four studies were in patients with social anxiety disorder (SAD) utilizing PET ( Furmark et al, 2008 ; Faria et al, 2012 ; Faria et al, 2014 ) and fMRI ( Faria et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“…Two studies by Pecina et al (2018 , 2021 ) attempted to manipulate trial-by-trial antidepressant expectancies through a “simulated neurofeedback” task. In brief, this task involved 6 runs of 12 trials, where each trial began with a timer cue reflecting an anticipation period prior to either receiving or not receiving a “rapid-acting antidepressant” infusion (in reality, normal saline).…”

Section: Resultsmentioning

confidence: 99%

“…Naltrexone was also associated with reduced activity in the right orbitofrontal cortex during positive sham neurofeedback (max t = 5.64, cluster size = 334 voxels, P < .001). Greater naltrexone-induced reductions in orbitofrontal cortex activity during positive sham neurofeedback correlated with higher expectancy during the “antidepressant” condition (b = .40, P < .01) ( Peciña et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…The results of our quality assessment are summarized in Figures 2 and 3 . Most studies (10, 62.5%) were rated as “some concerns.” For most, this was due to the lack of a preregistered analysis plan, which meant practices such as dichotomizing treatment groups or the use of “small volume correction” might represent selective reporting ( Mayberg et al, 2002 ; Furmark et al, 2008 ; Faria et al, 2012 , 2014 , 2017 ; Peciña et al, 2015 , 2018 , 2021 ; Sikora et al, 2016 ). In addition, we had concerns regarding missing data for 3 studies ( Pecina et al, 2015 ; Sikora et al, 2016 ; Chin Fatt et al, 2021a ).…”

Section: Resultsmentioning

confidence: 99%

“…Activity in dorsolateral prefrontal cortex (dlPFC) correlated with placebo response in many studies ( Mayberg et al, 2002 ; Faria et al, 2014 ; Peciña et al, 2018 , 2021 ; Cooper et al, 2019 ; Chin Fatt et al, 2020 , 2021b ; Fan et al, 2020 ). This region is reliably activated by placebo analgesia and is thought to be important in generating placebo-related expectancies ( Atlas and Wager, 2014 ; Wager and Atlas, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review

Huneke

Aslan

Fagan

et al. 2022

International Journal of Neuropsychopharmacology

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Background The mechanisms underlying placebo effects of psychotropic drugs remain poorly understood. We carried out the first systematic review of functional neuroimaging correlates of placebo response in adults with anxiety/depressive disorders. Methods We systematically searched a large set of databases up to February 2021 based on a pre-registered protocol (PROSPERO CRD42019156911). We extracted neuroimaging data related to clinical improvement following placebo or related to placebo mechanisms. We did not perform a meta-analysis due to the small number of included studies and significant heterogeneity in study design and outcome measures. Results We found 12 relevant studies for depressive disorders and four for anxiety disorders. Activity in the ventral striatum, rostral anterior cingulate cortex and other default mode network regions, orbitofrontal cortex, and dorsolateral prefrontal cortex correlated with placebo antidepressant responses. Activity in regions of the default mode network, including posterior cingulate cortex, was associated with placebo anxiolysis. There was also evidence for possible involvement of the endogenous opioid, dopamine and serotonin systems in placebo antidepressant and anxiolytic effects. Conclusions Several brain regions and molecular systems may be involved in these placebo effects. Further adequately powered studies exploring causality and controlling for confounders are required.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review

Huneke

Aslan

Fagan

et al. 2022

International Journal of Neuropsychopharmacology

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Dynamic Feedback Between Antidepressant Placebo Expectancies and Mood

et al. 2023

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ImportanceDespite high antidepressant placebo response rates, the mechanisms underlying the persistence of antidepressant placebo effects are still poorly understood.ObjectiveTo investigate the neurobehavioral mechanisms underlying the evolution of antidepressant placebo effects using a reinforcement learning (RL) framework.Design, Setting, and ParticipantsIn this acute within-patient cross-sectional study of antidepressant placebos, patients aged 18 to 55 years not receiving medication for major depressive disorder (MDD) were recruited at the University of Pittsburgh between February 21, 2017, to March 1, 2021.InterventionsThe antidepressant placebo functional magnetic resonance imaging task manipulates placebo-associated expectancies using visually cued fast-acting antidepressant infusions and controls their reinforcement with sham visual neurofeedback while assessing expected and experienced mood improvement.Main Outcomes and MeasuresThe trial-by-trial evolution of expectancies and mood was examined using multilevel modeling and RL, relating model-predicted signals to spatiotemporal dynamics of blood oxygenation level–dependent (BOLD) response.ResultsA bayesian RL model comparison in 60 individuals (mean [SE] age, 24.5 [0.8] years; 51 females [85%]) with MDD revealed that antidepressant placebo trial-wise expectancies were updated by composite learning signals multiplexing sensory evidence (neurofeedback) and trial-wise mood (bayesian omnibus risk &lt;0.001; exceedance probability = 97%). Placebo expectancy, neurofeedback manipulations, and composite learning signals modulated the visual cortex and dorsal attention network (threshold-free cluster enhancement [TFCE] = 1 − P &gt;.95). As participants anticipated antidepressant infusions, learned placebo expectancies modulated the salience network (SN, TFCE = 1 – P &gt;.95), positively scaling with depression severity.Conclusions and RelevanceResults of this cross-sectional study suggest that on a timescale of minutes, antidepressant placebo effects were maintained by positive feedback loops between expectancies and mood improvement. During learning, representations of placebos and their perceived effects were enhanced in primary and secondary sensory cortices. Latent learned placebo expectancies were encoded in the SN.

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