Naltrexone modulates contextual processing in depression

Abstract

Context, the information surrounding an experience, can significantly alter the meaning and the affective responses to events. Yet the biological mechanisms through which context modulate experiences are not entirely understood. Here, we hypothesized that the µ-opioid system-extensively implicated in placebo effects, a clinical phenomenon thought to rely on contextual processing-modulates the effects of contextual information on emotional attributions in patients with depression. To test this hypothesis, 20 unmedicated patients with depression completed a randomized, double-blind, placebo-controlled, crossover study of one dose of 50 mg of naltrexone, or placebo immediately before completing two sessions of the Contextual Framing fMRI task. This task captures effects of valenced contextual cues (pleasant vs. unpleasant) on emotional attribution (the rating of subtle emotional faces: fearful, neutral, or happy). Behaviorally, we found that emotional attribution was significantly moderated by the interaction between contextual cues and subtle emotional faces, such that participants' ratings of valenced faces (fearful and happy), compared to neutral, were more negative during unpleasant, compared to pleasant context cues. At a neural level, context-induced blood-oxygen-level-dependent responses in the ventromedial prefrontal cortex, the dorsal anterior cingulate, the dorsolateral prefrontal cortex, and the lateral orbitofrontal cortex, significantly moderated the effects of context on emotional attribution, and were blunted by naltrexone. Furthermore, the effects of naltrexone on emotional attribution were partially abolished in more severely depressed patients. Our results provide insights into the molecular alterations underlying context representation in patients with depression, providing pivotal early data for future treatment studies.

Trial registration: ClinicalTrials.gov NCT04322526.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Study design: participants completed a randomized, double-blind, placebo-controlled, crossover study of one dose of naltrexone 50 mg, or matching placebo.

a, b Contextual framing fMRI task: Participants were first presented with an emotionally salient contextual image (from IAPS) for 2 s (context phase), followed by an ambiguous face to be rated as either positive or negative in 3 s (emotion and rating phase). Note: the examples of contextual images were replaced with similar copyright-free images from the website in order to comply with the IAPS usage agreement.

Fig. 2. Contextual effects on emotional attribution.

Behavioral contextual effects (a) are moderated by depression severity (b) and naltrexone (c).

Fig. 3. Neural contextual effects.

a Neural contextual framing neural effects (pleasant > unpleasant). b Behavioral contextual effects are moderated by vmPFC BOLD responses.

Fig. 4. Naltrexone modulation of neural contextual effects.

a Naltrexone-induced modulation of contextual effects (pleasant > unpleasant) during the contextual framing task: the administration of one single dose of naltrexone was associated with significant decreases in BOLD responses in the vmPFC and the bilateral lOFC. b, c Naltrexone differentially reduced the effect of context on emotional attribution in participants with reduced vmPFC responses, whereas it enhanced the effect of context in emotional attribution in participants with high lOFC/dlPFC responses.