Progress in Neuro-Psychopharmacology and Biological Psychiatry
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
Research highlights
► Induction of the tryptophan catabolite (TRYCAT) pathway is associated with the onset of depression. ► Activation of IDO and TDO may induce this pathway and increase the synthesis of detrimental TRYCATs. ► IDO is induced by proinflammatory cytokines, TDO by glucocorticoids, both increased in depression. ► Activation of IDO and TDO deplete plasma tryptophan and consequently brain 5-HT. ► The TRYCAT pathway is new drug target in depression.
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.
Section snippets
Plasma tryptophan and brain 5-HT
5-HT synthesis depends on the dietary intake of tryptophan; tryptophan circulates in the blood with a major fraction loosely bound to albumin (around 70–90%), whereas the remaining circulates as free tryptophan (Curzon and Sarna, 1984, Fernstrom, 1984, Yuwiler et al., 1977). Tryptophan is actively transported over the brain blood barrier via the large chain amino acid transporter and thus has to compete with other amino acids like tyrosine, valine, leucine, isoleucine and phenylalanine for
Cell-mediated immune activation and oxidative and nitrosative stress (O&NS) pathways
In this section we will briefly review the key components of the inflammatory response, cell-mediated immunity, O&NS, and translocation of LPS from gram negative bacteria because these factors play a role in depression and are related to IDO activation.
Inflammatory responses are a self-defense mechanism that is triggered following various insults and consist of cellular and humoral responses, and complement and cytokine cascades (Burdette et al., 2010). Primary cell-derived mediators of the
Lower plasma tryptophan
There are several reports that plasma tryptophan is significantly reduced in depressed patients, as shown by lowered plasma free and total tryptophan and tryptophan/CAA ratio (DeMyer et al., 1981, Joseph et al., 1984, Møller, 1985, Maes et al., 1987a, Maes et al., 1987b, Maes et al., 1990f, Maes et al., 1991b, Maes et al., 1991c, Cowen et al., 1989). The plasma tryptophan concentrations following ingestion of large doses of tryptophan, either as an oral load or intravenously, are significantly
Systemic inflammation, cell-mediated immunity and O&NS in depression
The systemic inflammatory response in depression is indicated by key findings such as increased levels of pro-inflammatory cytokines, like IL-1β, IL-6 and TNFα, and increased plasma concentrations of positive APPs, like haptoglobin, and lowered levels of negative APPs, like albumin and transferrin (Maes et al., 1991a, Maes et al., 1992b, Maes, 1993, Maes, 1995, Song et al., 1994, Myint et al., 2005). There is also evidence for CARS in depression, as exemplified by increased serum levels of
Increased IDO activity in clinical depression
The first paper reporting on increased TRYCAT levels in depression and anxiety dates back from 1979. Thus, Hoes (1979) observed an increased excretion of xanthurenic acid, one of the TRYCATs, in 24 h urine (following ingestion of 5 g tryptophan) in anxiety but not in depression. Increased induction of TDO by glucocorticoids was considered to be the mechanistic explanation for this finding. Hoes and Sijben (1981) detected that during antidepressive treatment the normalization in xanthurenic acid
IDO: a shift in hypothesis from tryptophan and 5-HT depletion towards the detrimental effects of TRYCATs
In 2002–2005, we proposed a shift in the 5-HT hypothesis of depression, i.e. not only tryptophan and the consequent 5-HT depletion is related to the onset of depression, but also the detrimental effects of some TRYCATs (Maes et al., 2002, Bonaccorso et al., 2002, Wichers and Maes, 2004, Myint and Kim, 2003, Wichers et al., 2005). This novel hypothesis was based on the findings that IDO activation and the consequent production of TRYCATs are more strongly related to the development of affective
Lowered 5-HT and effects of tryptophan
There are many studies that examined brain 5-HT metabolism in animal models of depression. For example, in a genetic rat model, i.e. Flinders Sensitive Line (FSL) rats plasma concentrations of free tryptophan were not significantly lowered, whereas the synthesis of 5-HT in the brain was significantly reduced, e.g. in raphe nuclei, nucleus accumbens, cingulate and frontal cortex, hippocampus, amygdala, and thalamus (Hasegawa et al., 2006). In mice using the forced-swimming and open-field test,
Immune effects through tryptophan depletion
IDO activation is a key component in the immunoregulatory mechanisms that are involved in for example infection, autoimmunity, trauma, transplantation, neoplasia and pregnancy. Its role in infectious and autoimmune disorders is now well established (Eggers et al., 2004, Murr et al., 2001, Huengsberg et al., 1998, Kwidzinski et al., 2005, Bertazzo et al., 1999). Early reports show that IFNγ-induced IDO activation functions as an antimicrobial mechanism in infectious diseases (Pfefferkorn and
IDO induction, O&NS pathways and mitochondria
Early studies show that IDO uses SAR as a co-substrate. This is quite unique as superoxide dismutase (SOD, EC 1.15.1.1) is the only other enzyme using SAR as a substrate. The induction of xanthine oxidase (EC 1.1.3.22) by IFNγ, generating SAR, fuels the enzymatic reaction. In normal circumstances, superoxide dismutase is the main enzyme eliminating SAR but in situations of excessive oxidative stress by SAR and induction of IDO and xanthine oxidase by pro-inflammatory cytokines, IDO may
The neuroexcitatory, neurotoxic and neurodegenerative effects of TRYCATs
There is now some evidence that depression is accompanied by neurodegenerative processes and decreased neurogenesis. Structural brain changes have been observed in depressed patients in hippocampus, amygdala, prefrontal cortex, anterior cingulate and basal ganglia (Campbell and MacQueen, 2006). Stockmeier et al. (2004) reported on cellular changes in the postmortem hippocampus and neuronal and glial cell modifications. Most research in this area has been focused on the detrimental effects of
Conclusions
Lower plasma tryptophan frequently occurs in depression. Lowering the plasma levels of tryptophan in humans or depressed patients in remission may cause the reoccurrence of depressive symptoms probably through a reduction of central 5-HT and energy metabolism. Lowered plasma tryptophan in depressive states may be the consequence of a) cell mediated immune activation and inflammation through IDO activation by pro-inflammatory cytokines, such as IFNγ, IL-6 and TNFα; LPS and oxidative stress; b)
The IDO pathway as a novel drug target in depression
The data in clinical depression and in animal models reviewed here lend support to the thesis that IDO activation in depression may result in both detrimental and beneficial effects. Therefore, direct inhibitors of IDO are less likely to be useful drugs because these treatments could abrogate the antiproliferative and antioxidative effects of IDO activation which probably constitute a negative feedback loop that downregulates the activated inflammatory and oxidative pathways. This contrasts the
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