Activation of Central Nervous System Inflammatory Pathways by Interferon-Alpha: Relationship to Monoamines and Depression

• Published in: Biological psychiatry (1969) Vol. 65; no. 4; pp. 296 - 303
• Main Authors: Raison, Charles L., Borisov, Andrey S., Majer, Matthias, Drake, Daniel F., Pagnoni, Giuseppe, Woolwine, Bobbi J., Vogt, Gerald J., Massung, Breanne, Miller, Andrew H.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.02.2009; Elsevier
• Subjects: Adult; Adult and adolescent clinical studies; Antiviral Agents - pharmacology; Biogenic Monoamines - cerebrospinal fluid; Biogenic Monoamines - physiology; Biological and medical sciences; Biomarkers - analysis; Central Nervous System - drug effects; Central Nervous System - pathology; Cerebrospinal fluid; Corticotropin-Releasing Hormone - cerebrospinal fluid; cytokines; Cytokines - cerebrospinal fluid; Depression; Depressive Disorder - cerebrospinal fluid; Depressive Disorder - pathology; Female; Humans; inflammation; Inflammation - cerebrospinal fluid; Inflammation - pathology; Interferon-alpha - pharmacology; Longitudinal Studies; Male; Medical sciences; monoamines; Mood disorders; Neural Pathways - drug effects; Neural Pathways - pathology; Psychiatric Status Rating Scales; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Ribavirin - pharmacology; cytokines; Cerebrospinal fluid; depression; inflammation; monoamines; Mood disorder; Cytokine; Central nervous system; Monoamine; Depression; Activation; Inflammation; Interferon
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2008.08.010

Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established. Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after ∼12 weeks of either no treatment ( n = 12) or treatment with pegylated IFN-alpha 2b ( n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA ( r 2 = −.25, p < .05). These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.