Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1

Abstract

Depression is known to occur frequently in chronic hepatitis C viral (HCV) patients receiving interferon (IFN)-α therapy. In this study, we investigated whether indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan (TRP) metabolism plays a critical role in depression occurring as a side effect of IFN-α therapy. Increases in serum kynurenine (KYN) and 3-hydroxykynurenine (3-HK) concentrations and in the ratios of KYN/TRP and 3-HK/kynurenic acid (KA) were much larger in depressive HCV patients than in non-depressed patients following therapy. Furthermore, transfection of a plasmid continuously expressing murine IFN-γ into normal mice significantly increased depression-like behavior. IFN-γ gene transfer also resulted in a decrease in serum TRP levels in the mice while KYN and 3-HK levels were significantly increased in both serum and frontal cortex. Genetic deletion of IDO1 in mice abrogated both the increase in depression-like behavior and the elevation in TRP metabolites' levels, and the turnover of serotonin in the frontal cortex after IFN-γ gene transfer. These results indicate that the KYN pathway of IDO1-mediated TRP metabolism plays a critical role in depressive symptoms associated with IFN-α therapy.

Figure 1. Changes in the levels of serum TRP and its metabolites in HCV patients undergoing IFN-α therapy.

(a) The Y axis shows TRP, KYN, KA, and 3-HK concentrations in HCV patients at 2 and 4 weeks after the onset of therapy, expressed as a percentage of the concentration before IFN-α therapy. (b) Serum KYN/TRP and 3-HK/KA ratios in HCV patients are shown as a percentage of values before IFN-α therapy. Rectangles indicate non-depressive HCV patients [Depression (−)]; circles indicate HCV patients with depressive symptoms [Depression (+)]. Each data point represents the mean ± SEM of values obtained from n = 30 depression (−) patients and n = 19 depression (+) patients. ^*p < 0.05, ^***p < 0.001 versus before the onset of IFN-α therapy, ^#p < 0.05, ^##p < 0.01 versus depression (−) patients. Detailed statistical analyses are in Tables 2 and 3.

Figure 2. Abnormal behavior in a forced swimming test after IFN-γ gene transfer in mice.

The open bar shows control plasmid (empty pCpG-mcs vector)-injected mice [IFN-γ transfected (−) mice]; closed bar shows mice received the pCpG-Muγ plasmid, which continuously expresses murine IFN-γ [IFN-γ-transfected (+) mice]. (a) Locomotor activity and rearing of IFN-γ-transfected (+) and (−) mice in a novel environment in an open field test. (b) Short-term memory in a Y-maze test for the two groups of mice. Alternation behavior and total arm entries were measured in an 8 min session. (c) Immobility of IFN-γ-transfected (+) and (−) mice in a forced swimming test. Each column represents the mean ± SEM (n = 9–16). *p < 0.05 versus IFN-γ-transfected (−) mice.

Figure 3. Changes in the levels of TRP and its metabolites in the serum and frontal cortex of mice after IFN-γ gene transfer.

TRP-KYN metabolite concentrations were determined in the serum (a) and the frontal cortex (b) of mice at 28 days after IFN-γ-gene transfer. The open bar shows IFN-γ-transfected (−) mice, and the closed bar shows IFN-γ-transfected (+) mice. Each column represents the mean ± SEM (n = 15–20). **p < 0.01, ***p < 0.001 versus IFN-γ-transfected (−) mice.

Figure 4. Effects of IDO1 gene-deficiency on depressive behavior, changes in TRP metabolism, serotonin levels and serotonin turnover in the mouse frontal cortex after IFN-γ-gene transfer.

(a) A forced swim test was performed 28 days after IFN-γ-gene transfer in wild type mice and IDO1 K.O. mice. The Y axis shows % value of immobility time in IFN-γ-transfected (+) mice, compared with the time (100%) in IFN-γ-transfected (−) mice. Actual immobility times in IFN-γ-transfected (−) and (+)/wild type mice were 118.9 ± 162.1 and 160.9 ± 137.0 sec, respectively. While, actual immobility times in IFN-γ-transfected (−) and (+)/IDO1 K.O. mice were 188.1 ± 78.0 and 146.5 ± 171.0 sec, respectively (n = 8–15). The level of TRP metabolites (b) and the amount of 5-HT, 5-HIAA, and 5-HIAA/5-HT ratio as an index of serotonin turnover (c) in the frontal cortex of mice at 28 days after IFN-γ-gene transfer (n = 6–15). The open bar shows wild type; the closed bar, IDO1 K.O. mice. IFN-γ-transfected (−) mice were injected with the control plasmid (pCpG-mcs), and IFN-γ-transfected (+) mice were injected with the IFN-γ-expressing pCpG-Muγ plasmid. Each column represents the mean ± SEM. *p < 0.05, ***p < 0.001 versus IFN-γ-transfected (−) wild type mice, ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 versus IFN-γ-transfected (+) wild type mice.