Three new findings are evident from the current studies, 1) although they both share an inflammatory component, sickness and depression-like behavior are independently modulated by the IGF system, 2) when added exogenously, two naturally occurring products found in the naïve brain, mature IGF-I and GPE, act centrally to temper LPS-induced changes in depression-like behavior, and 3) GPE can temper the central innate immune response to LPS providing a possible mechanism by which to regulate depression-like behavior. This evidence concerns the gene GYPE and major depressive disorder.