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

ABSTRACT: High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD).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.Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding.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?

SUBMITTER: Pecina M

PROVIDER: S-EPMC4758856 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Peciña Marta M Bohnert Amy S B AS Sikora Magdalena M Avery Erich T ET Langenecker Scott A SA Mickey Brian J BJ Zubieta Jon-Kar JK

JAMA psychiatry 20151101 11

<h4>Importance</h4>High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.<h4>Objective</h4>To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD).<h4>Design, setting, and participants</h4>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 ...[more]

PMID: 26421634

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Project description:ContextThe high percentage of failed clinical trials in depression may be due to high placebo response rates and the failure of standard statistical approaches to capture heterogeneity in treatment response.ObjectiveTo assess whether growth mixture modeling can provide insights into antidepressant and placebo responses in clinical trials of patients with major depression.DesignWe reanalyzed clinical trials of duloxetine to identify distinct trajectories of Hamilton Scale for Depression (HAM-D) scores during treatment. We analyzed the trajectories in the entire sample and then separately in all active arms and in all placebo arms. Effects of duloxetine hydrochloride, selective serotonin reuptake inhibitor (SSRI), and covariates on the probability of following a particular trajectory were assessed. Outcomes in different trajectories were compared using mixed-effects models.SettingSeven randomized double-blind clinical trials of duloxetine vs placebo and comparator SSRI. Patients A total of 2515 patients with major depression.InterventionsDuloxetine and comparator SSRI. Main Outcome Measure Total score on the HAM-D.ResultsIn the entire sample and in the antidepressant-treated subsample, we identified trajectories of responders (76.3% of the sample) and nonresponders (23.7% of the sample). However, placebo-treated patients were characterized by a single response trajectory. Duloxetine and SSRI did not differ in efficacy, and compared with placebo they significantly decreased the odds of following the nonresponder trajectory. Antidepressant responders had significantly better HAM-D scores over time than placebo-treated patients, but antidepressant nonresponders had significantly worse HAM-D scores over time than the placebo-treated patients.ConclusionsMost patients treated with serotonergic antidepressants showed a clinical trajectory over time that is superior to that of placebo-treated patients. However, some patients receiving these medications did more poorly than patients receiving placebo. These data highlight the importance of ongoing monitoring of medication risks and benefits during serotonergic antidepressant treatment. They should further stimulate the search for biomarkers or other predictors of responder status in guiding antidepressant treatment.

Dataset Information

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

Publications

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

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