Chapter 6 Depression and neuroprogression: Sirtuins and mitochondria as crucial hubs George Anderson and Michael Maes Introduction Historically, major depressive disorder (MDD) has been variously conceptual- ized, including as cognitive, psychoanalytical, and biological, with treatment ap- proaches being thereby derived. In experimental studies, treatment success has been little greater than that of placebo, suggesting that there is an urgent need for reframing the conceptualization of the nature of MDD, with more targeted and efective treatments based on this (1). A growing body of recent research on the biological underpinnings of MDD has shown a role for increased oxidative and nitrosative stress (O&NS) and immuno-infammatory processes. As well as direct efects on cells, O&NS and immune-infammation drive changes in other efector pathways, including proinfammatory cytokine-induced indoleamine 2,3-dioxygenase (IDO), which takes tryptophan away from serotonin synthesis by driving it to the production of tryptophan catabolites (TRYCATs), such as kynurenine and kynurenic acid (KYNA). Such TRYCATs have direct efects on neuronal activity and survival (1). Evidence indicates that such neuroregulatory TRYCATs may be diferentially expressed in diferent brain regions, thereby driving altered patterning of interarea neuronal activity (1). Stress, particularly via the stress hormone cortisol, may also contribute to TRYCAT production by activating tryptophan 2,3-dioxygenase (TDO), which, similar to IDO, drives tryptophan away from serotonin synthesis to TRYCAT production. Tese processes are therefore important mediators of the plethora of data showing lowered levels of serotonin in MDD. It should also be noted that serotonin is a necessary precursor for the sequential synthesis of N-acetylserotonin (NAS) and melatonin, with lowered activation of the melatonergic pathway being increasingly appreciated as a signifcant change in a host of medical conditions, including MDD (2). OUP UNCORRECTED PROOF – FIRSTPROOFS, Mon Oct 08 2018, NEWGEN Kapczinski220618MEDUK_MSC.indd 77 08-Oct-18 6:50:57 PM