title: Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to interferon-alpha-induced changes in the serotonergic system.
abstract: There is now evidence that repeated administration of interferon-alpha (IFN-alpha) to patients with chronic 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 activation of the cytokine network and disturbances in the serotonergic metabolism. The aims of this study were to examine the effects of IFN-alpha-based immunotherapy on the development of depressive symptoms in relation to its effects on plasma tryptophan and kynurenine and serum serotonin (5-HT). Eighteen patients affected by chronic active hepatitis C were treated with IFN-alpha (3-6 million units subcutaneously three to six times a week for 6 months) and had measurements of the previous parameters before starting immunotherapy and 2, 4, 16, and 24 weeks later. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Anxiety (HAM-A) scale, respectively. Immunochemotherapy with IFN-alpha (1) significantly increased the MADRS and HAM-A scores and serum kynurenine concentrations and (2) significantly reduced plasma tryptophan and serum 5-HT concentrations. IFN-alpha-based immunotherapy significantly increased the kynurenine per tryptophan quotient, which estimates the activity of indoleamine 2,3-dioxygenase, the major tryptophan-catabolizing enzyme, which is induced by IFNs. There are significant relationships between the IFN-alpha-induced changes in the MADRS score and serum kynurenine (positive) and 5-HT (negative) concentrations. Immunotherapy with IFN-alpha significantly increases the severity of depressive symptoms. The latter is related to changes in the serotonergic system, such as depletion of serum 5-HT and induction of the catabolism of tryptophan to kynurenine. It is suggested that the IFN-alpha-induced changes in the serotonergic turnover could play a role in the development of IFN-alpha-induced depressive symptoms.
authors.affiliation: Psychiatric Hospital, University La Sapienza, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bonaccorso
authors.forename: Valentina
authors.initials: V
authors.lastname: Marino
authors.forename: Antonella
authors.initials: A
authors.lastname: Puzella
authors.forename: Massimo
authors.initials: M
authors.lastname: Pasquini
authors.forename: Massimo
authors.initials: M
authors.lastname: Biondi
authors.forename: Marco
authors.initials: M
authors.lastname: Artini
authors.forename: Cristiana
authors.initials: C
authors.lastname: Almerighi
authors.forename: Robert
authors.initials: R
authors.lastname: Verkerk
authors.forename: Herbert
authors.initials: H
authors.lastname: Meltzer
authors.forename: Michael
authors.initials: M
authors.lastname: Maes
mesh_terms: D000328:Adult; D003866:Depressive Disorder / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007167:Immunotherapy; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects* / Q000627:therapeutic use; D007737:Kynurenine / Q000097:blood; D008297:Male; D008875:Middle Aged; D010555:Personality Inventory; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins; D012701:Serotonin / Q000097:blood; D014364:Tryptophan / Q000097:blood
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan