Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression

Abstract

Importance: High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.

Objective: To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD).

Design, setting, and participants: In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the µ-opioid receptor-selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect.

Main outcomes and measures: Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding.

Results: Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.

Conclusions and relevance: These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.

Trial registration: clinicaltrials.gov Identifier:NCT02178696.

Conflict of interest statement

Conflict of Interest Disclosures: The authors have no interests to disclose that are or might be perceived to be in conflict with the work reported in this study.

Figures

Figure 1. Experimental Design

Abbreviations: PET: Positron Emission Tomography; i.v.: intravenous; QIDS-16SR: Quick Inventory of Depression Symptomatology; PIDS: Patient's Impression of Depression Severity.

Figure 2. Voxel-by-voxel MOR availability at baseline is positively correlated with depression severity (pre-randomization QIDS-16SR, left) and with antidepressant treatment response (right)

Figure 3. Voxel-by-voxel placebo-induced activation of MOR mediated neurotransmission is associated with placebo-induced improvement in depression symptoms

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Figure 4. Voxel-by-voxel placebo-induced activation of MOR mediated neurotransmission is associated with open-label antidepressant treatment response

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