Interferon-alpha–induced changes in tryptophan metabolism

Abstract

Background

Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-α therapy.

Methods

Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-α treatment and continuing for the first 12 weeks of IFN-α therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-α treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity.

Results

Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-α therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressant-free patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients.

Conclusions

The results suggest that reduced TRP availability plays a role in IFN-α–induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-α, attenuates the behavioral consequences of IFN-α–mediated TRP depletion.

Introduction

Major depression frequently develops in medically ill patients who are administered cytokine therapies for infectious diseases or cancers. For example, it has been shown that the rate of major depression in patients with malignant melanoma receiving high-dose interferon (IFN)-α is almost 45% (Musselman et al 2001). Despite an increasing appreciation of cytokine-induced depressive syndromes, the mechanisms involved remain to be elucidated. In a recent study, cancer patients undergoing IFN-α and/or interleukin-2 therapy exhibited significant decreases in serum concentrations of tryptophan (TRP) and the ratio of TRP to large neutral amino acids (namely tyrosine, phenylalanine, leucine, isoleucine, valine) that correlated with increased depression scores (Capuron et al 2002b). These findings suggested that the development of depressive symptoms during cytokine therapy might be mediated, at least in part, by TRP depletion.

Tryptophan is the precursor of serotonin (5HT), which is believed to play a prominent role in the neurobiology of mood disorders (see for review Malone and Mann 1993, Owens and Nemeroff 1994). Tryptophan availability is the rate-limiting step in the synthesis of 5HT. Reductions in blood TRP concentrations are associated with reduced 5HT availability within the central nervous system (CNS), and TRP depletion has been associated with the induction of depressive relapse in vulnerable patients Delgado et al 1994, Moore et al 2000, Moreno et al 2000. Moreover, drug-free depressed patients have been reported to exhibit reduced plasma TRP concentrations compared with normal control subjects Deakin et al 1990, Lucca et al 1992, Maes et al 1994, Ressler and Nemeroff 2000, Song et al 1998. Conversely, drugs that block the reuptake of 5HT, namely the selective serotonin reuptake inhibitors (SSRIs), and thereby increase 5HT availability within the CNS, are well known to be effective treatments for major depression (Tollefson and Rosenbaum 1998).

The pathways by which IFN-α and/or interleukin-2 induce peripheral TRP depletion during cytokine therapy are unknown but may involve activation of the enzyme, indoleamine-2,3-dioxygenase (IDO). IDO catalyzes the rate-limiting step of TRP conversion into kynurenine (KYN) and then quinolinic acid (Byrne et al 1986), thereby reducing the availability of TRP for conversion into 5HT (Figure 1). In vivo, the activity of IDO is reflected by the relative plasma or serum concentrations of KYN and TRP. Indeed, the ratio of KYN/TRP is considered to be an estimate of IDO activity, independent of baseline TRP concentrations (Widner et al 2000). IDO can be induced in a variety of immune cells, such as monocyte-derived macrophages and microglia, by inflammatory cytokines, including, most notably, IFNs (Mellor and Munn 1999). Consistent with IDO induction by IFNs, decreased plasma TRP concentrations and a high KYN/TRP ratio have been found to correlate with concentrations of neopterin in patients with infectious diseases Fuchs et al 1990, Fuchs et al 1991. Neopterin, a pteridine derived from guanosine triphosphate, is released from human monocytes and macrophages upon stimulation with IFNs, especially IFN-γ, and is therefore considered a marker of activated cell-mediated immunity (Murr et al 2002). Release of neopterin by IFN-stimulated immune cells is initiated at the expense of biopterin synthesis, a co-factor of several monooxygenase reactions, including tryptophan-5-hydroxylase (Widner et al 2000). Interestingly, increased concentrations of neopterin and IFN-γ, together with a lower availability of L-TRP, have been described in patients with major depression (Maes et al 1994).

In a recent report, patients treated with IFN-α for chronic hepatitis C were found to exhibit evidence of increased IDO activity, including reduced TRP concentrations, increased KYN concentrations, and an increased KYN/TRP ratio. Although these patients also exhibited a corresponding increase in depressive symptoms (Bonaccorso et al 2002), the relationship between TRP metabolism and the development of specific depressive symptoms was not reported. Moreover, the impact of antidepressant treatment was not examined.

Recent work by our group has shown that the antidepressant paroxetine, a 5HT and norepinephrine reuptake inhibitor (Gilmor et al 2002), was effective in preventing the development of major depression, especially its mood and cognitive features, in patients receiving high-dose IFN-α therapy for malignant melanoma Capuron et al 2002a, Musselman et al 2001. The mechanisms by which paroxetine prevents depressive symptoms in IFN-α–treated patients remain obscure. One possibility is that paroxetine may influence the effect of IFN-α on IDO activity and TRP metabolism, either directly or indirectly through an effect on the activation of relevant immune cells. Indeed, recent data indicate that antidepressants, most notably tricyclics, but also SSRIs, may inhibit inflammatory immunologic responses Kubera et al 2001, Pellegrino and Bayer 2000.

To further examine the relationships among TRP metabolism, immune cell activation, and the development and treatment of depressive symptoms during IFN-α therapy, we measured TRP, KYN, and neopterin in placebo- and paroxetine-treated patients undergoing high-dose IFN-α therapy for malignant melanoma.