Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue
Open accessAbstract
Cytokine-induced stimulation of p38 mitogen activated protein kinase (MAPK) has been shown to influence behaviorally-relevant pathophysiologic pathways including monoamine neurotransmission and neuroendocrine function and thus may contribute to behavioral changes that occur during chronic administration of the innate immune cytokine, interferon (IFN)-alpha. Accordingly, in the current study, phosphorylation (activation) of intracellular p38 MAPK in peripheral blood lymphocytes was analyzed by flow cytometry every 2 h for 12 h following the initial injection of IFN-alpha in eleven patients with chronic hepatitis C. Hourly assessments of plasma concentrations of adrenocorticotropic hormone, cortisol and interleukin-6 were also obtained. Symptoms of depression and fatigue were measured at baseline and after 4 and 12 weeks of IFN-alpha treatment. Acute administration of IFN-alpha significantly increased the percentage of lymphocytes staining positive for intracellular phosphorylated p38 (p-p38). IFN-alpha-induced increases in p-p38 were significantly greater in patients that developed clinically significant depressive symptoms [Montgomery-Asberg Depression Rating Scale (MADRS) score≥15] during the first 12 weeks of IFN-alpha treatment. Increases in the percentage of p-p38-positive lymphocytes following the first IFN-alpha injection also highly correlated with depression severity at weeks 4 (r=0.85, p=0.001) and 12 (r=0.70, p=0.018). Similar relationships were observed for fatigue. Examination of relationships between p-p38 induction and factors previously reported to predict IFN-alpha-induced depressive symptoms revealed strong associations of p-p38 with baseline MADRS (r=0.82, p=0.002) and cortisol responses to the initial injection of IFN-alpha (r=0.91, p=0.000). Taken together, these findings indicate that sensitivity of p38 MAPK signaling pathways to immune stimulation is associated with depressive symptoms during chronic IFN-alpha treatment.
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Onset of depression during IFNα treatment is especially likely for patients who exhibit potentiated ACTH, cortisol, and p38 MAPK responses within 12 hr of a first infusion or injection.
“as well as for those who exhibit potentiated adrenocorticotropic hormone, cortisol, and p38 mitogen-activated protein kinase responses within 12 hr of a first infusion or injection”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Felger et al., 2011
Increased p38 MAPK activation in lymphocytes following the initial IFN-alpha injection predicts IFN-alpha-induced depression and fatigue in HCV+ patients.
“Increased p38 MAPK activation (phosphorylation) in lymphocytes following the initial injection of IFN-alpha has predicted IFN-alpha-induced depression and fatigue in HCV+ patients (Felger et al., 2011).”
From Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications (2013) · cites this paper as Felger et al., 2011
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- Authors
- Felger, J. C., Alagbe, O., Pace, T. W. W., Woolwine, B. J., Hu, F., Raison, C. L., & Miller, A. H.
- Affiliations
- Emory University (US)
- Newport Hospital (US)
- Corresponding author
- Miller, Andrew H.
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 25
- Issue
- 6
- Pages
- 1094-1098
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC3116018
- OpenAlex
- W2051892846
- Cited by
- 41
- References
- 27
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 1 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 1 · 2014: 4 · 2013: 8 · 2012: 3
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (K23 MH064619, R01 MH070553)
- Emory Center for AIDS Research (P30 AI050409)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- p38 MAPK, interferon-alpha, depression, fatigue, chronic hepatitis C, peripheral blood lymphocytes, MAPK phosphorylation, cortisol response, ACTH, interleukin-6, innate immunity
- MeSH terms
- Interferon alpha-2, Antiviral Agents, Depression, Drug Therapy, Combination, Fatigue, Humans, Hydrocortisone, Immunity, Innate, Lymphocytes, Phosphorylation, Polyethylene Glycols, Protein Processing, Post-Translational, Recombinant Proteins, Ribavirin, Severity of Illness Index, Time Factors, Interleukin-6, Interferon-alpha, Hepatitis C, Chronic, p38 Mitogen-Activated Protein Kinases
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