Tryptophan: The key to boosting brain serotonin synthesis in depressive illness

Abstract

It has been proposed that focusing on brain serotonin synthesis can advance antidepressant drug development. Biochemical aspects of the serotonin deficiency in major depressive disorder (MDD) are discussed here in detail. The deficiency is caused by a decreased availability of the serotonin precursor tryptophan (Trp) to the brain. This decrease is caused by accelerated Trp degradation, most likely induced by enhancement of the hepatic enzyme tryptophan 2,3-dioxygenase (TDO) by glucocorticoids and/or catecholamines. Induction of the extrahepatic Trp-degrading enzyme indolylamine 2,3-dioxygenase (IDO) by the modest immune activation in MDD has not been demonstrated and, if it occurs, is unlikely to make a significant contribution. Liver TDO appears to be a target of many antidepressants, the mood stabilisers Li(+) and carbamazepine and possibly other adjuncts to antidepressant therapy. The poor, variable and modest antidepressant efficacy of Trp is due to accelerated hepatic Trp degradation, and efficacy can be restored or enhanced by combination with antidepressants or other existing or new TDO inhibitors. Enhancing Trp availability to the brain is thus the key to normalisation of serotonin synthesis and could form the basis for future antidepressant drug development.

Tryptophan pathway alterations in the postpartum period and in acute postpartum psychosis and depression

“…Lastly, we did not investigate the correlation between the tryptophan pathway and cortisol or sex-steroids. Although the two systems are known to interact (Badawy, 2013), a single measurement would not have been informative in this highly fluctuating hormonal period.…”

The tryptophan utilization concept in pregnancy

“…IDO is induced mainly by interferon-γ [5,6] and to a lesser extent by interferon-α [7] and its activity can be modulated by both pro- and anti-inflammatory cytokines and mediators in various ways (for references, see [8]). The resultant decrease in [Trp] after IDO induction by interferon-γ is thought to underlie the antiparasitic, antibacterial and antiproliferative actions of this major cytokine [9,10].…”

“…This suggests a mild degree of immune activation during the third trimester, which should be contrasted with the huge neopterin elevations of 300% to 600% in conditions of heightened immune activation, such as human immunodeficiency virus infection [39,40]. Under these latter conditions and also when liver TDO is strongly induced by glucocorticoids, the decrease in plasma total [Trp] never exceeds 30% [8]. It is therefore unlikely that a modest maternal immune activation in pregnancy can decrease maternal plasma total [Trp] to any significant extent, if at all.…”

The influence of physical exercise and leisure activity on neuropsychological functioning in older adults

“…Another hypothesis that is related to these alterations is that during physical exercise, the distribution of tryptophan, which is a precursor amino acid for serotonin, is altered by lipolysis, which causes a growing concentration of free fatty acids in the plasma, dislocating tryptophan from albumin-binding sites, and thus raising the levels of free tryptophan that is responsible for synthesizing serotonin (Badawy 2013). There could also be an increase in the reception and oxidation of branchedchain amino acids by the muscles during exercise, and as a result, the bloodstream concentration of these amino acids could be reduced.…”