**3. Side effect: IFN-induced depression and tryptophan metabolism**

A total of 49 patients (32 males and 17 females; mean age 54.0 ± 2.3 years) suffering from CHC were recruited. **Table 1** shows the clinical characteristics of patients with HCV. In this study, most of patients were treated with recombinant (r) IFN-α 2b or pegylated (PEG)-IFN-α 2b (21 patients (42.9%) received each medicine, respectively). Five patients (10.2%) were treated with natural (n) IFN-α, and others received PEG-IFN-α 2a (2.0%) and rIFN-α 2a (2.0%), individually. All interferons have almost the same efficiency and induce about the same activation of the KYN pathway [36]. No patient had a past record of psychiatric treatment, and all were off from depressive symptoms prior to IFN-α treatment. They did not take any antidepressant medications during the study period. At an average of 104.2 ± 15.8 days after the IFN-α administration, some patients presented with apathy, social isolation tendencies, melancholy, depressed mood, and an intention to stop IFN administration. Patients who felt depressed mood were referred for psychiatric

A Critical Risk Factor for a Major Side Effect of Interferon-Alpha Therapy: Activated Indoleamine…

http://dx.doi.org/10.5772/intechopen.71013

43

**Depression (−) Depression (+)**

"Depression (−)": HCV patients without depression, "Depression (+)": HCV patients with depression following IFN-α

For all HCV patients, blood was collected before the onset of IFN-α therapy, as well as 2 and 4 weeks after the onset of

therapy, and after the end or cessation of therapy. See **Figure 3a** for a detailed blood sampling schedule.\*

**(mean ± SEM)**

1.3 d)

0.2 d)

0.3 d)

± 22.0 d\* ) *t* **df p value**

0.230 48 0.819

0.513 61 0.610

0.952 40 0.347

2.592 46 0.013

*p*<0.05 *versus*

All subjects 30 (male: 20; female:10) 19 (male: 12; female: 7)

therapy [47]. HCV, hepatitis C virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase.

**Time points Depression (−) (mean ± SEM) Depression (+)** 

(a) Before the onset of therapy 1–35 d (6.3 ± 1.8 d) 0–22 d (6.7 ±

(b) 2 w after the onset of therapy 13–15 d (13.8 ± 0.1 d) 12–15 d (13.6 ±

(c) 4 w after the onset of therapy 25–30 d (27.9 ± 0.1 d) 25–29 d (27.6 ±

(d) The period of therapy 167–343 d (252.0 ± 15.7 d) 54–337 d (183.4

**Table 1.** Clinical information for HCV patients undergoing IFN-α therapy.

Age 54.33 ± 2.06 54.0 ± 2.29 HCV genotype 1b 24 (80%) 15 (78.9%) HCV genotype 2a 4 (13.3%) 3 (15.8%) HCV genotype 2b 2 (6.7%) 1 (5.3%) AST 59.43 ± 5.09 57.47 ± 6.45 ALT 82.68 ± 11.36 69.56 ± 8.65

**(a) Clinical characteristics of HCV patients**

**(b) The time points of blood sampling**

Depression (−) [47].

IFN-α has been shown to develop depression in many diseases, not only CHC, but also in melanoma, chronic myelogenous leukemia, and renal cell carcinoma [26]. However, CHC patients may be more susceptible to developing IFN-induced depression than patients with other disorders, possibly due to a baseline 5-HT system dysfunction. Depression in CHC patients may result from changes in platelet 5-HT function, with decreased 5-HT concentrations during CHC infection compensated for by a decrease in reuptake and metabolism [1]. Immune activation, particularly by IFN-γ, affects the catabolism of TRP, a precursor of 5-HT, by inducing expression of IDO1. IDO1 is the first and rate-limiting enzyme that converts TRP to N-formyl-L-kynurenine, which is further metabolized to QUIN (**Figure 2**). IFN treatment of CHC patients results in a decrease in plasma TRP and an increase in plasma KYN [8]. Another clinical study with cancer patients has shown that immunotherapy with IFN-α significantly increases the severity of depressive symptoms, which is related to a depletion of serum 5-HT and induction of the catabolism of TRP to KYN [27]. Thus, TRP catabolism switches from the 5-HT pathway to the KYN pathway, resulting in a decrease in 5-HT levels.

IDO1 is induced by several pro-inflammatory cytokines including IFNs (IFN-α/β, γ), TNF-α, and interleukin 6 (IL-6). It is also widely accepted that IFNs, especially IFN-γ, are essential factors for IDO1 induction since two ISREs and IFN-γ-activated site (GAS) element sequences are found in the 5′-flanking region of the IDO1 gene [28]. Recent preclinical studies in mice have demonstrated that pharmacological inhibition of IDO1 enzymatic activity or genetic deletion of IDO1 abrogates acute and chronic inflammation-dependent behavioral changes induced by peripheral or central administration of lipopolysaccharide (LPS) [29–33]. Additionally, it has been reported that peripheral administration of KYN alone can induce depression-like behavior in rats [34]. In a clinical study, patients receiving IFN-α therapy showed increases in the total Montgomery-Asberg Depression Rating Score (MADRS), an index of depressive symptoms similar to the KYN/TRP ratio; this indicates IDO1 activity and the KYN/KA ratio, which reflects a neurotoxic challenge [35]. These findings suggest that only TRP depletion itself may not be required for the induction of behavioral changes as a result of IDO1 activation; and that KYN and its neuroactive metabolites are more related to cytokine-induced depression-like behaviors than TRP depletion. However, it is still unclear whether direct activation of IDO1 and KYN metabolites plays a definitive role in the induction of depressive symptoms by IFN-α treatment.
