Novel multi-modal methodology to investigate placebo response in major depressive disorder.

The neurobiological mechanisms underlying the placebo phenomenon in patients with major depressive disorder (MDD) remain largely unknown. The progressive rise in rates of placebo responses within clinical trials over the past two decades may impede the detection of a true signal and thus present a major obstacle in new treatment development. Understanding the mechanisms would have several important implications, including (1) identifying biomarkers of placebo responders (thereby identifying those individuals who could benefit therapeutically from such interventions), (2) opening new avenues for manipulating such mechanisms to maximize symptom reduction, and (3) refining treatments with approaches that decrease (in clinical trials) or increase (in clinical practice) the placebo response. Here we investigated the research question: is the dopaminergic system one of the neurobiological underpinnings of the placebo response within MDD? Inspired by preclinical and clinical findings that have implicated dopamine in the occurrence, prediction, and expectation of reward, we hypothesized that dopaminergic activity in the mesolimbic system is a critical mediator of placebo response in MDD. To test this hypothesis, we designed a double-blind, placebo-controlled, sequential parallel comparison design clinical trial aimed at maximizing placebo antidepressant response. We integrated behavioral, imaging, and hemodynamic probes of mesocorticolimbic dopaminergic pathways within the context of manipulations of psychological constructs previously linked to placebo responses (e.g., expectation of improvement). The aim of this manuscript is to present the rationale of the study design and to demonstrate how a cross-modal methodology may be utilized to investigate the role of reward circuitry in placebo response in MDD.

Interpersonal Trauma Effects on Adolescent Depression: The Moderating Role of Neurophysiological Responses to Positive Interpersonal Images.

Trauma exposure is associated with a heightened risk for depression and such risk is thought to vary based on the type of traumatic events (e.g., interpersonal, including abuse and domestic violence, or non-interpersonal, including accidents or natural disasters). Depression is often accompanied by altered emotional reactivity, and the late positive potential (LPP) serves as a reliable neurophysiological measure of sustained attention towards emotional stimuli, raising questions regarding the role of the LPP in moderating trauma effects on depression. We conducted a cross-sectional study of 201 adolescents aged 14-17 years (61.2% female) who were oversampled for current depression and elevated risk of depression based on maternal history. Clinical interviews were conducted to assess diagnoses and lifetime trauma exposure, and participants reported on current depressive symptoms. Electroencephalogram (EEG) was continuously recorded while participants completed a previously validated interpersonal emotional images task. Cumulative trauma (CT) and interpersonal trauma (IPT) were both associated with greater depressive symptoms, but non-interpersonal trauma (NIPT) was not significantly related to depressive symptoms. The association between IPT and depressive symptoms was moderated by the LPP to positive interpersonal images, such that IPT-exposed adolescents with blunted neural responses to such images showed the greatest symptoms. This result was specific to IPT, and the LPP to threatening interpersonal images did not significantly moderate the effects of IPT on depressive symptoms. These findings highlight the unique effects of interpersonal trauma on depressive symptoms and elucidate a potential vulnerability linking trauma exposure to depression risk among adolescents.