86 0271-0749/02/2201-0086/0 Journal of Clinical Psychopharmacology Vol. 22, No. 1 Copyright © 2002 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. There is now evidence that repeated administra- tion of interferon- (IFN-) to patients with chro- nic active hepatitis and cancers induces depressive symptoms. There is also evidence that induction of the cytokine network modulates the serotonergic system and that major depression is related to acti- vation of the cytokine network and disturbances in the serotonergic metabolism. The aims of this study were to examine the effects of IFN-–based immu- notherapy on the development of depressive symp- toms in relation to its effects on plasma tryptophan and kynurenine and serum serotonin (5-HT). Eigh- teen patients affected by chronic active hepatitis C were treated with IFN- (3–6 million units subcuta- neously three to six times a week for 6 months) and had measurements of the previous parameters be- fore starting immunotherapy and 2, 4, 16, and 24 weeks later. Severity of depression and anxiety were measured with the Montgomery–Asberg De- pression Rating Scale (MADRS) and the Hamilton Rating Scale for Anxiety (HAM-A) scale, respec- tively. Immunochemotherapy with IFN- (1) signif- icantly increased the MADRS and HAM-A scores and serum kynurenine concentrations and (2) sig- nificantly reduced plasma tryptophan and serum 5- HT concentrations. IFN-–based immunotherapy significantly increased the kynurenine per trypto- phan quotient, which estimates the activity of in- doleamine 2,3-dioxygenase, the major tryptophan- catabolizing enzyme, which is induced by IFNs. There are significant relationships between the IFN-–induced changes in the MADRS score and serum kynurenine (positive) and 5-HT (negative) concentrations. Immunotherapy with IFN- signifi- cantly increases the severity of depressive symp- toms. The latter is related to changes in the sero- tonergic system, such as depletion of serum 5-HT and induction of the catabolism of tryptophan to kynurenine. It is suggested that the IFN-–induced changes in the serotonergic turnover could play a role in the development of IFN-–induced depres- sive symptoms. (J Clin Psychopharmacol 2002;22: 86–90) I MMUNOTHERAPY WITH interferon- (IFN-) is used for treating patients with chronic hepatitis C. 1 IFN- is a cytokine with potent antiviral and antiproliferative ef- fects. 2 The adverse effects of IFN-–based immunother- apy, which appear after several weeks, comprise major depression and depressive symptoms, such as expressed and unexpressed sadness, irritability, insomnia, loss of appetite, asthenia, loss of interest, slowness, anxiety, so- cial withdrawal, and lack of concentration. 1 There is now evidence that major depression is asso- ciated with an activation of the inflammatory response system (IRS), as indicated by (1) increased numbers of peripheral blood neutrophils, monocytes, and activated T cells; (2) increased plasma concentrations of positive acute phase proteins (APPs), such as haptoglobin, and decreased plasma concentrations of negative APPs, such as albumin and transferrin; and (3) increased production of proinflammatory cytokines, such as interleukin-1 (IL- 1), IL-6, and IFN-. 3, 4 IRS activation and administration of proinflammatory cytokines may induce depressive symptoms through Increased Depressive Ratings in Patients With Hepatitis C Receiving Interferon-–Based Immunotherapy Are Related to Interferon-–Induced Changes in the Serotonergic System STEFANIA BONACCORSO, MD*†‡, VALENTINA MARINO, MD*, ANTONELLA PUZELLA, MD*, MASSIMO PASQUINI, MD*, MASSIMO BIONDI, MD, PHD, PROF*, MARCO ARTINI, MD§, CRISTIANA ALMERIGHI, MD§, ROBERT VERKERK, RT HERBERT MELTZER, MD, PROF,‡, AND MICHAEL MAES, MD, PHD, PROF†‡ *Psychiatric Hospital, University La Sapienza, Rome, Italy; †Department of Psychiatry, University Hospital of Maastricht, Maastricht, the Netherlands; ‡Department of Psychiatry, Vanderbilt University, Nashville, Tennessee; §Department of Hepatology, I Medical Clinic, University La Sapienza, Rome, Italy; Department of Medical Biochemistry, University of Antwerp, Belgium Received June 30, 2000; accepted after revision March 26, 2001. Address requests for reprints to: Michael Maes, MD, PhD, Depart- ment of Psychiatry and Neuropsychology, University Hospital of Maastricht, Postbus 5800, 6202 AZ Maastricht, The Netherlands. Ad- dress e-mail to: crc-mh@online.be.