Depression Response to Fast-Acting Treatments: Inflammation and Reward Mechanisms

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PROJECT SUMMARY/ABSTRACT High inflammation is a biological characteristic associated with poorer response to antidepressant medication. Anhedonia, representing a facet of reward system dysfunction, is a common symptom of depression, and also predicts poor therapeutic response. Recent literature suggests that these variables (one biological, the other behavioral) are linked. However, no research has simultaneously addressed whether both of these dimensional characteristics—higher inflammation and greater reward deficits—impact depression treatment outcome, with consideration of levels at baseline as well as dynamic, longitudinal changes following treatment. Electroconvulsive therapy (ECT) and ketamine both elicit robust and rapid antidepressant response in patients with severe and treatment resistant depression. Thus, these treatment modalities are ideal for testing dynamic links between inflammation, behavioral constructs of reward, and treatment outcomes within a relatively short time frame. Furthermore, contrary to inflammation predicting poor outcome to antidepressant pharmacotherapy, our preliminary data show that higher baseline inflammation (as indexed by interleukin [IL]-6) predicts better treatment response to ECT (n=29, p=0.01). Moreover, ketamine has also been theorized to be more effective for depressed patients with high inflammation, and some initial clinical results support this hypothesis. However, data are sparse, inflammatory assessments are limited, and at least one ketamine study has failed to replicate earlier results. Notably, reward deficits have not been formally evaluated as a predictor of response to ECT nor ketamine. We have the unique opportunity to leverage a large funded U01 study, “Perturbation of the treatment resistant depression connectome by fast-acting therapies” (PI Narr, U01 MH110008, 09/16-05/20) to investigate relationships between inflammation, reward processes, and treatment outcome, within and across ECT and ketamine. Neither inflammation nor a comprehensive assessment of reward processes are examined in the parent grant. The goals of this proposal are thus unique and do not overlap with those of the U01. Here, we propose to comprehensively capture a vertically integrated assessment of inflammation including systemic levels, upstream cellular production, and transcription factor activation, and to evaluate both reward motivation and reward responsiveness via behavioral tasks and self-report. Our central hypothesis is that inflammation will link with deficits in reward, and will impact treatment outcome. Determination of differences in treatment response based upon linked clinical phenotypes and inflammatory profiles would be ground-breaking, informing more effective personalized treatment strategies for depressed patients with elevated inflammation. This K23 integrated training and research program is designed to prepare the candidate to become a clinical translational depression researcher, with expertise in psychoneuroimmunology, reward processes, and the study of interventions at this interface, to improve personalized treatment strategies for this highly prevalent disorder.