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Disturbances of Tryptophan Metabolism and Risk of Depression in HCV Patients Treated with IFN-Alpha

Oxenkrug GF, Turski WA, Zgrajka W, Weinstock JV, Ruthazer R and Summergrad P

Depression is a common side-effect of interferon (IFN)-alpha treatment of hepatitis C virus (HCV) infection and melanoma. Disturbances of tryptophan (TRP) metabolism might contribute to development of IFN-alpha–associated depression due to IFN-alpha-induced activation of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme of TRP– kynurenine (KYN) metabolism. The increased frequency of high producer (T) allele of IFN-gamma (IFNG) (+874) gene, that encodes IFNG production, in depressed patients suggested that increased IDO activity might be a risk factor for depression. The present study assessed KYN/TRP ratio (KTR) as a marker of IDO activity in American Caucasian HCV patients awaiting IFN-alpha treatment. KTR did not differ between 43 patients who did and 37 patients who did not develop depression. TRP concentrations were higher in patients who experienced depression. Odds of development of depression increased with elevation of serum TRP levels from 33% (TRP levels <12000 pmol/ml) to 68% (TRP levels > 16000 pmol/ml). Elevated serum TRP may reflect the impairment of TRP conversion into serotonin in agreement with suggested link between serotonin deficiency and depression. Up-regulation of IDO might be an additional risk factor of IFN-alpha– associated depression. Future studies shall explore the causes of elevated serum TRP in relation to IFN-alpha–associated depression.