This project is designed to identify the predictors and targets of response to cytokine antagonism in patients with treatment resistant depression (TRD). The long term objectives are to develop personalized strategies to treat patient populations and symptom domains based on defined pathophysiologic mechanisms related to inflammation. The results of the proposed research will help inform which pathophysiologic domains and therefore which patient populations are most likely to respond to anti-inflammatory strategies including cytokine antagonism in future studies. Up to one third of the ~20 million U.S. adults with major depression are unable to respond to conventional antidepressant therapy, leading to prolonged disability, increased morbidity and mortality and significant economic burden. One pathophysiologic pathway that may contribute to TRD is inflammation. Increased inflammatory markers predict treatment non-response, and clinical factors linked with treatment resistance are associated with increased inflammation. In addition, inflammatory cytokines can sabotage and circumvent mechanisms of action of conventional antidepressant medications. A recently completed NIH-funded, double-blind, placebo-controlled trial (n=60) conducted by our group has shown that 3 infusions of the potent anti-cytokine therapy infliximab (5mg/kg) led to a greater antidepressant response than placebo in TRD patients with high baseline inflammation as reflected by a plasma high sensitivity c-reactive protein >5mg/L (n=22, representing 37% of the sample). Infliximab is a monoclonal antibody that targets the inflammatory cytokine, tumor necrosis factor (TNF)-alpha, which has been shown to be reliably elevated in patients with major depression. As part of the trial, we gathered extensive additional data and samples (which were not part of the original NIH study) including measures of multiple symptom domains, neurocognitive testing, polysomnography, and serial blood samples that can be assayed for kynurenine (KYN) pathway activation and diurnal hypothalamic-pituitary-adrenal (HPA) axis activity. This additional data was collected at baseline, 24 hrs after the first infusion and at Wek 8 of the 12 week trial. In the current study, we propose to assay and analyze these samples and data and use the results to elucidate the pathophysiologic domains that predict and respond to successful infliximab treatment, which represented 50% of infliximab-treated patients (n=15). Based on previous studies of the impact of cytokines on the brain and behavior, we hypothesize that basal ganglia function, sleep, KYN pathway activation and HPA axis activity will be relevant pathophysiologic domains that will predict and respond to acute (within 24 hrs) and chronic administration of infliximab. To test these hypotheses, symptom data, neuropsychological testing, polysomnography and peripheral blood measures of plasma tryptophan, KYN and cortisol will be compared in infliximab vs. placebo responders and non-responders. These data will provide important clues regarding relevant predictors and targets of response to cytokine antagonism and will inform the design of future immune-based therapeutic trials.
There have been increasing efforts to personalize therapy for patients with depression, many of whom end up receiving multiple unsuccessful treatment trials and ultimately populate the ranks of the ~7 million adults in the U.S. who are unable to respond to conventional antidepressant therapy and represent a significant public health concern. Given recent findings that inflammation may contribute to antidepressant treatment non-response, the proposed study plans to use data gathered from a recently completed clinical trial to determine which depressed patients and which depressive symptoms are most likely to respond to a medication that inhibits inflammation and why. This information will help focus future studies and treatments of depressed patients that exhibit increased inflammation and are therefore optimal candidates for anti- inflammatory therapies.
|Weinberger, Jeremy F; Raison, Charles L; Rye, David B et al. (2015) Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. Brain Behav Immun 47:193-200|