Fig. 1: Th1 dominance in depression and its amelioration by ketamine.

A A diagram comparing M1 and M2 type macrophages. M1 macrophages are activated by pro-inflammatory signals, including LPS, Th1 cytokines (IFNγ, TNFα) and Th1 cell surface proteins (CD40L). M2 macrophages are activated by Th2 cytokines (IL-4, IL-10, IL-13, IL-21) and by ketamine. M1 macrophages produce pro-inflammatory cytokines, as well as nitric oxide (NO) and neurotoxic kynurenine and reactive oxygen species and thus mediate the Th1 response. Ketamine causes the polarisation of monocytes to M2 macrophages. This acts to promote the release of anti-inflammatory TGFβ, IL-10 and ornithine. It also reduces monocyte differentiation to M1 macrophages, hampering the effects of Th1 dominance. B A schematic showing the possible causes of Th1 dominance in patients with treatment-resistant depression and the downstream consequences of this excessive Th1 immune activation. Indoleamine 2,3-dioxygenase (IDO) activation is central to inflammation-induced depression via its effects on tryptophan metabolism and generation of neurotoxicity. IDO-mediated changes in tryptophan metabolism reduce serotonin, as does phosphorylation of serotonin transporters (SERT). Brain-derived neurotrophic factor (BDNF) exacerbates the negative effects of IDO activation on hippocampal volume by reducing hippocampal neurogenesis, as does nuclear factor kappa B (NFkB) induction.