Immunotherapy with interferon-alpha (IFN-α) induces neuropsychiatric side effects, most notably depression. One of the presumed pathophysiological mechanisms is an effect on tryptophan metabolism. As tryptophan is the precursor of serotonin, decreased availability of tryptophan to the central nervous system could result in serotonin deficiency. Tetrahydrobiopterin (BH(4)) is a cofactor for one of the enzymes synthesizing serotonin. We conducted an exploratory study into the serum concentrations of large neutral amino acids (AA), biopterin (BIOP) and neopterin (NEOP), of 67 patients with high-risk melanoma, who were either treated with two different doses of IFN-α or were part of an observation-only control group. We found evidence for IFN-α to decrease concentrations of all AA except phenylalanine. The decrease in tryptophan concentration was most prominent and consistent. These changes persisted throughout a year of maintenance treatment. Concentrations of NEOP rose sharply, whereas, those of BIOP did not change. Except for the increase in NEOP and the increase in the ratio between phenylalanine (PHE) and tyrosine (TYR), no support for derangement in BH(4) metabolism was found. The increase in the ratio between PHE and TYR suggests inhibition of the enzyme phenylalanine hydroxylase. Patients with IFN-α induced anxiety and depression had higher pretreatment concentrations of NEOP. Changes in tryptophan metabolism may play a role in the pathophysiology of the neuropsychiatric side effects of IFN-α, and further research into the predictive potential of NEOP is warranted.

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Keywords Amino acids, Biopterin, Depression, Interferon-alpha, Melanoma, Neopterin, Tryptophan
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Journal Psychiatry Research
van Gool, A.R, Fekkes, D, Kruit, W.H.J, Mulder, P.G.H, ten Hagen, T.L.M, Bannink, M, … Eggermont, A.M.M. (2003). Serum amino acids, biopterin and neopterin during long-term immunotherapy with interferon-alpha in high-risk melanoma patients. Psychiatry Research, 119(1-2), 125–132. doi:10.1016/S0165-1781(03)00113-6