A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers

Charles L Raison, Robin E. Rutherford, Bobbi J. Woolwine, Chen Shuo, Pamela Schettler, Daniel F. Drake, Ebrahim Haroon, Andrew H. Miller

Research output: Contribution to journalArticle

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Abstract

Context: Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent themechanisms of action of conventional antidepressants. Objectives: To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatmentresistant depression and whether an increase in baseline plasma inflammatory biomarkers, including highsensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response. Design: Double-blind, placebo-controlled, randomized clinical trial. Setting: Outpatient infusion center at Emory University in Atlanta, Georgia. Participants : A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n=37) or medicationfree (n=23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. Interventions: Three infusions of the TNF antagonist infliximab (5 mg/kg) (n=30) or placebo (n=30) at baseline and weeks 2 and 6 of a 12-week trial. Main Outcome Measures: The 17-item Hamilton Scale for Depression (HAM-D) scores. Results: No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P =.01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P =.19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P < .05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P < .01). Dropouts and adverse events were limited and did not differ between groups. Conclusions: This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers.

Original languageEnglish (US)
Pages (from-to)31-41
Number of pages11
JournalArchives of General Psychiatry
Volume70
Issue number1
DOIs
StatePublished - Jan 2013

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Treatment-Resistant Depressive Disorder
Randomized Controlled Trials
Tumor Necrosis Factor-alpha
Biomarkers
C-Reactive Protein
Depression
Placebos
Antidepressive Agents
Outpatients
Therapeutics
Cytokines
Infliximab
Antagonist
Randomized Controlled Trial
General Hospitals
Protein
Outcome Assessment (Health Care)
Placebo

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Arts and Humanities (miscellaneous)
  • Medicine(all)

Cite this

A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression : The role of baseline inflammatory biomarkers. / Raison, Charles L; Rutherford, Robin E.; Woolwine, Bobbi J.; Shuo, Chen; Schettler, Pamela; Drake, Daniel F.; Haroon, Ebrahim; Miller, Andrew H.

In: Archives of General Psychiatry, Vol. 70, No. 1, 01.2013, p. 31-41.

Research output: Contribution to journalArticle

Raison, Charles L ; Rutherford, Robin E. ; Woolwine, Bobbi J. ; Shuo, Chen ; Schettler, Pamela ; Drake, Daniel F. ; Haroon, Ebrahim ; Miller, Andrew H. / A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression : The role of baseline inflammatory biomarkers. In: Archives of General Psychiatry. 2013 ; Vol. 70, No. 1. pp. 31-41.
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N2 - Context: Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent themechanisms of action of conventional antidepressants. Objectives: To determine whether inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatmentresistant depression and whether an increase in baseline plasma inflammatory biomarkers, including highsensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response. Design: Double-blind, placebo-controlled, randomized clinical trial. Setting: Outpatient infusion center at Emory University in Atlanta, Georgia. Participants : A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n=37) or medicationfree (n=23) for 4 weeks or more and who were moderately resistant to treatment as determined by the Massachusetts General Hospital Staging method. Interventions: Three infusions of the TNF antagonist infliximab (5 mg/kg) (n=30) or placebo (n=30) at baseline and weeks 2 and 6 of a 12-week trial. Main Outcome Measures: The 17-item Hamilton Scale for Depression (HAM-D) scores. Results: No overall difference in change of HAM-D scores between treatment groups across time was found. However, there was a significant interaction between treatment, time, and log baseline hs-CRP concentration (P =.01), with change in HAM-D scores (baseline to week 12) favoring infliximab-treated patients at a baseline hs-CRP concentration greater than 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration of 5 mg/L or less. Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response (≥50% reduction in HAM-D score at any point during treatment) of 62% (8 of 13 patients) in infliximab-treated patients vs 33% (3 of 9 patients) in placebo-treated patients (P =.19). Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders vs nonresponders (P < .05), and infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to week 12 compared with placebo-treated responders (P < .01). Dropouts and adverse events were limited and did not differ between groups. Conclusions: This proof-of-concept study suggests that TNF antagonism does not have generalized efficacy in treatment-resistant depression but may improve depressive symptoms in patients with high baseline inflammatory biomarkers.

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