The understanding of the neurobiological processes leading to major depressive disorder (MDD) is an active
field of research in the scientific community. For years, the alteration of monoamine neurotransmission, in particular serotonin
(5-HT), has been considered the most significant pathophysiological mechanism of the disorder. However, biological
data supporting the postulated MDD-related monoamine alterations have been inconclusive, and the use of monoaminergic
antidepressants has not yielded the expected results. In the last few years, it has been demonstrated that inflammatory
pathways have a significant role in the pathophysiology of MDD. According to the cytokine hypothesis, the
disorder would be due to a stress-related increased production of cytokines, including interleukins, tumor necrosis factor-α
and interferon- α and γ. These, in turns, would cause the activation of the indoleamine 2,3 dioxygenase (IDO), with subsequent
production of tryptophan (TRP) catabolites along the IDO pathway (TRYCATs) and decreased availability of
TRP and 5-HT. Besides monoamines, other molecular mechanisms, as those within the inflammatory pathways, should be
taken into account in the attempt to clarify the pathophysiology of MDD and to improve its treatment.
Keywords: Cytokines, Indoleamine 2, 3 dioxygenase (IDO), inflammation, major depressive disorder (MDD), serotonin (5-
HT), stress, tryptophan catabolites along the IDO pathway (TRYCATs).
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