The new ‘5-HT’ hypothesis of depression: Cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression

Abstract

This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well.

Introduction

The bioactive neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is derived from the essential amino acid tryptophan. The synthesis of 5-HT in the brain is highly dependent on the bio-availability of tryptophan in the plasma (Fernstrom, 1983). Catabolism via the oxidative or the so-called kynurenine pathway may divert tryptophan from the 5-HT synthetic route. This pathway, shown in Fig. 1, is the major catabolic route for tryptophan degradation. Ultimately, catabolism of tryptophan leads to the synthesis of nicotinamide and generation of energy via the glutarate pathway. The first step of this pathway, conversion of tryptophan to kynurenine is rate-limiting. Two enzymes catalyze this first step: tryptophan 2,3-dioxygenase (TDO, tryptophan pyrolase EC 1.13.11.11) and indoleamine 2,3-dioxygenase (IDO, EC 1.13.11.52), both leading to kynurenine.

Following induction of IDO or TDO, by stimuli to be discussed, various metabolites are formed from tryptophan, particularly, kynurenine, kynurenic acid, xanthurenic acid, and quinolinic acid (see Fig. 1). These tryptophan catabolites (TRYCATs) have multiple effects, e.g. they may act as pro- or antioxidants, are neurotoxic or neuroprotective, may induce apoptosis, and are depressogenic and anxiogenic (Lapin, 2003, Mackay et al., 2006). Since along this pathway many TRYCATs are formed that all have significant (patho)physiological effects, we label this pathway the TRYCAT pathway instead of the classical term kynurenine pathway or other terms, such as quinolinic acid or IDO pathway. The TRYCAT pathway may be activated through TDO that is stimulated by glucocorticoids, or through IDO that is stimulated by pro-inflammatory cytokines, lipopolysaccharides (LPS) and free radicals.

Early antidepressant drugs like iproniazid, imipramine and selective 5-HT reuptake inhibitors (SSRIs) suggested a role for biogenic monoamines, their receptors and transporters in the etiology of mood disorders, the so-called 5-HT hypothesis of depression (Coppen, 1967, Maes and Meltzer, 1995). This ‘5-HT hypothesis of depression’ considered that a diminished synthesis of 5-HT, and hence central diminished stimulation of various 5-HT receptors, e.g. 5-HT1A, 5-HT2C, 5-HT3 etc., and hyposerotonergic activity is associated with the onset of depression (Maes and Meltzer, 1995).

There is now abundant evidence that depression is accompanied by hyperactivity of the hypothalamic–pituitary–adrenal (HPA)-axis, as indicated by increased levels of glucocorticoid levels (Carroll, 1980), and systemic inflammation and cell-mediated immune activation, with increased production of pro-inflammatory cytokines (Maes, 1993, Maes, 1995, Maes, 2008, Maes, 2010). Consequently, these factors would be expected to induce TDO and IDO, respectively, leading to lowered plasma tryptophan in depression.

The aims of the present paper are to review whether a) the lowered availability of plasma tryptophan in depression is caused by increased HPA-axis activity or to systemic inflammation or cell-mediated immune activation, neither or both; b) TDO and/or IDO activation is associated with clinical depression; c) tryptophan depletion and/or the production of TRYCATs are associated with the onset of depression; and d) the same pathways can be detected in animal models of depression. Finally, we review the molecular pathways that may account for the detrimental effects of TRYCAT formation and novel drug targets in the TRYCAT pathway.