Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resistant depression

Differential expression of genes related to glucose and lipid metabolism predicts response to TNF antagonism in treatment resistant depressed patients. The tumor necrosis factor (TNF) antagonist infliximab was recently found to reduce depressive symptoms in patients with increased baseline inflammation as reflected by a plasma C-reactive protein concentration > 5. mg/L. To further explore predictors and targets of response to infliximab, differential gene expression was examined in peripheral blood mononuclear cells from infliximab responders (n=. 13) versus non-responders (n=. 14) compared to placebo at baseline and 6. h, 24. h, and 2. weeks after the first infliximab infusion. Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. One-hundred-forty-eight gene transcripts were significantly associated (1.2-fold, adjusted p≤. 0.01) with response to infliximab and were distinct from placebo responders. Transcripts predictive of infliximab response were associated with gluconeogenesis and cholesterol transport, and were enriched in a network regulated by hepatocyte nuclear factor (HNF)4-alpha, a transcription factor involved in gluconeogenesis and cholesterol and lipid homeostasis. Of the 148 transcripts differentially expressed at baseline, 48% were significantly regulated over time in infliximab responders, including genes related to gluconeogenesis and the HNF4-alpha network, indicating that these predictive genes were responsive to infliximab. Responders also demonstrated inhibition of genes related to apoptosis through TNF signaling at 6. h and 24. h after infusion. Transcripts down-regulated in responders 2. weeks after infliximab were related to innate immune signaling and nuclear factor-kappa B. Thus, baseline transcriptional signatures reflective of alterations in glucose and lipid metabolism predicted antidepressant response to infliximab, and infliximab response involved regulation of metabolic genes and inhibition of genes related to innate immune activation.