Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression

Biol Psychiatry. 2009 Feb 15;65(4):296-303. doi: 10.1016/j.biopsych.2008.08.010. Epub 2008 Sep 18.


Background: 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.

Methods: Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after approximately 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.

Results: 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).

Conclusions: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antiviral Agents / pharmacology
  • Biogenic Monoamines / cerebrospinal fluid
  • Biogenic Monoamines / physiology*
  • Biomarkers / analysis
  • Central Nervous System / drug effects*
  • Central Nervous System / pathology*
  • Corticotropin-Releasing Hormone / cerebrospinal fluid
  • Cytokines / cerebrospinal fluid
  • Depressive Disorder / cerebrospinal fluid
  • Depressive Disorder / pathology*
  • Female
  • Humans
  • Inflammation / cerebrospinal fluid
  • Inflammation / pathology*
  • Interferon-alpha / pharmacology*
  • Longitudinal Studies
  • Male
  • Neural Pathways / drug effects*
  • Neural Pathways / pathology*
  • Psychiatric Status Rating Scales
  • Ribavirin / pharmacology


  • Antiviral Agents
  • Biogenic Monoamines
  • Biomarkers
  • Cytokines
  • Interferon-alpha
  • Ribavirin
  • Corticotropin-Releasing Hormone