title: [New developments on the serotonin hypothesis of depression:  shunt of tryptophan].
abstract: Since the late 1960s, the serotonin deficiency, as demonstrated in major depression, was related to an increased activity of the liver enzyme tryptophan-pyrrolase stimulated by an excess of circulating corticosteroids, which would shift the metabolism of tryptophan from serotonin to kynurenine production. The finding that the kynurenine causes different effects in central nervous system suggested that an up-regulation of the tryptophan-kynurenine pathway determined not only a deficiency of serotonin, but could also play a role in the development of anxiety, psychotic symptoms and cognitive impairment associated with depression. This review aims to evaluate the different hormonal and genetic factors regulating the metabolism of tryptophan via kynurenine, and to highlight how this metabolic pathway may be involved in depression pathogenesis. Rate-limiting enzymes of kynurenine formation are two: tryptophan 2,3-dioxygenas (TDO) activated by stress hormones, and indoleamine 2,3-dioxygenase (IDO), activated by proinflammatory cytokines. The increased expression of the genes that produce inflammatory cytokines (interferon-gamma and tumor necrosis factor alpha) would determine a genetic predisposition to develop depression by up-regulating the IDO pathway, while environmental stressors would activate TDO via hormonal activation. Therefore, it can be reasonably assumed that the pathway of tryptophan-kynurenine represents one of the main melting points of the interaction between genetic and environmental factors involved in the pathophysiology of depression, as well as new targets for future antidepressant strategies.
authors: Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotechnologie, Università di Pisa, Italy. dmarazzi@psico.med.unipi.it
authors: Donatella
authors: D
authors: Marazziti
authors: Stefano
authors: S
authors: Baroni
authors: Michela
authors: M
authors: Picchetti
authors: Armando
authors: A
authors: Piccinni
authors: Stefano
authors: S
authors: Silvestri
authors: Liliana
authors: L
authors: Dell'Osso
mesh_terms: D016207:Cytokines / Q000502:physiology; D003863:Depression / Q000209:etiology*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D055495:Neurogenesis; D010913:Pituitary-Adrenal System / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D016207:Cytokines; D012701:Serotonin; D014364:Tryptophan