Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms

The placebo effect represents a potent treatment for Major Depressive Disorder (MDD)-placebo response in acute randomized controlled trials (RCTs) of antidepressant medications averages 30%, and meta-analyses have estimated the proportion of medication response attributable to placebo to be 50-75%. Patient expectancy is the mechanism of placebo effects in antidepressant RCTs and has been positively associated with medication response. Determining how expectancy alters the course of MDD could lead to methods of optimizing placebo effects and improving the treatment of MDD. In addition, investigating the neurobiology of placebo effects has the potential to elucidate the pathophysiology of MDD and the mechanisms of action of antidepressant treatments. Brain regions implicated in expectancy and placebo effects comprise prefrontal cortical (PFC) areas, amygdala, insular cortex, rostral anterior cingulate cortex (rACC), and dopaminergic reward pathways in the striatum. Pathological decreases in PFC and striatal function, increases in limbic activity, and disordered connectivity between these regions have all been observed in MDD, and the rostral and dorsal ACC have been repeatedly linked to antidepressant treatment response. Therefore, studying placebo effects offers a window into the functioning of the neural circuits that are disturbed in MDD and improve with effective treatment. The goals of this study are to determine whether expectancy affects the outcome of antidepressant pharmacotherapy and to investigate the neural mechanisms of expectancy effects. These will be accomplished by conducting a clinical trial randomizing adult outpatients with MDD to 8 weeks of treatment in high vs. low expectancy conditions. The high expectancy condition will be open administration of citalopram, while the low expectancy condition will be placebo-controlled administration of citalopram. The neural mechanisms of expectancy will be determined using functional Magnetic Resonance Imaging (fMRI) paradigms to investigate treatment activation differences in brain regions associated with placebo effects and MDD.