An Investigation into the Neurobiology of Treatment Response in patients with Major Depression: The Placebo Effect.

Abstract

Recent trends in clinical neuroscience have moved toward identifying neurobiological predictors of antidepressant treatment effects in order to improve overall treatment efficacy in Major Depression, a pervasive and debilitating disorder in which complete remission occurs for only one-third of treatment-seeking patients. However, predictors of placebo effects have largely been overlooked. This is not a small concern: substantial placebo response rates have been documented within antidepressant clinical trials. Hence, neuroimaging predictors of placebo responses may elucidate the neural pathways responsible for depression recovery. Moreover, these predictors may identify patients with a greater susceptibility to placebo effects; in turn, informing patient stratification in antidepressant clinical trials to better distinguish between drug-specific and placebo effects or augment prescribed treatments for patients in clinical settings. This dissertation takes a network-based resting-state functional connectivity (rsFC) approach to investigate predictors of placebo and antidepressant responses with particular focus on the default-mode, salience, and executive networks. This approach allows for consistency with the inherent network organization of the brain and the network-based characterization of depression. Through this investigation, enhanced rsFC of the rostral anterior cingulate (rACC) within the salience network has emerged as a strong predictor of responses to placebo with antidepressant expectations. Furthermore, heightened rACC rsFC within the salience network manifests as a neurobiological pattern differentiating healthy subjects from depressed patients. Finally, in light of evidence that genetic variability within placebo-related pathways modulate placebo treatment outcomes in depression as well as analgesia, where neural and molecular bases of placebo have been extensively mapped, the final chapter of this dissertation observed an effect of genetic polymorphisms within the prepronociceptin gene, an endogenous opioid precursor neuropeptide associated with nociception and depression, on analgesic placebo-induced µ-opioid activation within the rACC and other well-established, placebo-related regions. This effect further corresponded with placebo-associated stress responses and anxiety. These findings enlighten our understanding of the neurobiology behind depression recovery through placebo effects and illustrate the importance of the rACC within antidepressant responses and healthy functioning. Finally, they contribute to a growing database of potential clinical neuroimaging and genetic markers of placebo responses which may substantially benefit therapeutic care in depression.