TNF Antagonist Infliximab for Treatment-Resistant Depression: The Role of Baseline Inflammatory Biomarkers

Increased concentrations of inflammatory biomarkers predict antidepressant nonresponse, and inflammatory cytokines can sabotage and circumvent the mechanisms of action of conventional antidepressants.

Objectives
To determine whether:
- Inhibition of the inflammatory cytokine tumor necrosis factor (TNF) reduces depressive symptoms in patients with treatment-resistant depression and
- Whether an increase in baseline plasma inflammatory biomarkers, including high-sensitivity C-reactive protein (hs-CRP), TNF, and its soluble receptors, predicts treatment response.

Design Double-blind, placebo-controlled, randomized clinical trial.

Participants A total of 60 medically stable outpatients with major depression who were either on a consistent antidepressant regimen (n = 37) or medication-free (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 > 5 mg/L and favoring placebo-treated patients at a baseline hs-CRP concentration < 5 mg/L.
- Exploratory analyses focusing on patients with a baseline hs-CRP concentration greater than 5 mg/L revealed a treatment response 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.