Association Between Placebo-Activated Neural Systems and Antidepressant Responses

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 PARTICIPANTSIn 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 [ 11 C]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 MEASURESChanges in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of μ-opioid receptor binding. RESULTSHigher 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

A Novel Strategy to Identify Placebo Responders: Prediction Index of Clinical and Biological Markers in the EMBARC Trial

“…However, other factors such as gender and age, while significant in venlafaxine versus placebo studies [18], did not replicate in a meta-analysis by Holmes et al [19]. The neurobiological basis of the placebo response is characterized by an increase in the metabolic activity of the frontal and striatal cortical regions [20] and increased endogenous opioid release in the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala [21,22]. The placebo response has also been linked to increased baseline resting state functional connectivity of the rostral anterior cingulate cortex (rACC) within the salience network [23] and to increased pretreatment rACC activity in 2 EEG studies [24,25].…”

“…The placebo response has also been linked to increased baseline resting state functional connectivity of the rostral anterior cingulate cortex (rACC) within the salience network [23] and to increased pretreatment rACC activity in 2 EEG studies [24,25]. Previous studies of neuroimaging biomarkers of placebo response have been limited by small sample sizes and a lack of comparison with other clinical and biobehavioral markers [21,23]. Despite extensive research to characterize placebo responders, a set of clinical and objective predictors and tools to filter out this subgroup from clinical trials has yet to be agreed upon and implemented.…”

Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: Implications for anhedonia, anxiety and treatment response

“…Here we used positron emission tomography (PET) and the D 2/3 selective radiotracer [ 11 C]raclopride to examine the relationships among D 2/3 receptor availability, symptoms of anhedonia, and the response to antidepressants and placebo treatments. For this purpose, we utilized a design identical to one recently utilized to examine endogenous opioid mechanisms of the placebo response in MDD (Peciña et al, 2015). In the present report, we also aimed to dissect the motivational and consummatory components of the overall anhedonia construct (Treadway and Zald, 2011), using two different self-reported questionnaires: the Apathy Evaluation Scale (motivational anhedonia) (Marin et al, 1991) and the Snaith-Hamilton Pleasure Scale (SHAPS) (consummatory anhedonia) (Snaith et al, 1995).…”

Implications of a Biosignature Study of the Placebo Response in Major Depressive Disorder

“…One could envision that the definition of stage 1 placebo nonresponders in SPCD trials could be augmented by the absence of a modulation of μ-opioid neurotransmission in response to placebo exposure among patients with MDD during the first stage. In summary, the findings of the study by Peciña and colleagues 1 have important clinical and clinical trial method implications and certainly warrant further studies.…”