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

Abstract

Context: 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.

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 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 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.

Trial registration: clinicaltrials.gov Identifier: NCT00463580.

Figures

Figure 1. Change in HAM-D-17 Scores in TRD Patients Randomly Assigned to Infliximab or Placebo

Using a double-blind, placebo-controlled, randomized design, the change in the 17-item Hamilton Depression Rating Scale (HAM-D-17) was examined in an intent-to-treat MMRM analysis of 60 patients with treatment resistant depression (TRD) administered 3 infusions of the TNF-alpha antagonist infliximab (n=30) or placebo (n=30) at baseline and 2 and 6 weeks of a 12 week trial. There was no main effect of treatment assignment or a treatment by time interaction. However, there was a significant effect of time with both groups exhibiting significant decreases in HAM-D-17 scores across treatment weeks (p=0.01). Depicted is LS Mean (SEM) Change in HAM-D-17 from Baseline to the indicated week using an unstructured covariance matrix with time as a categorical variable.

Figure 2. Relationship between Change in HAM-D-17 Score from Baseline to Week 12 (Infliximab-Placebo) and Log Baseline Plasma hs-CRP in Patients with TRD Treated with Infliximab or Placebo

Based on an interaction between treatment, time and baseline log high sensitivity c-reactive protein (hs-CRP)(p=0.01), the relationship between baseline log plasma hs-CRP and the change in the 17-item Hamilton Depression Rating Scale (HAM-D-17) score from Baseline to Week 12 (Infliximab-Placebo) was examined in 60 patients with treatment resistant depression (TRD) administered 3 infusions of either the TNF-alpha antagonist infliximab (n=30) or placebo (n=30) at baseline and 2 and 6 weeks of a 12 week trial. At plasma concentrations of hs-CRP greater than 4.98 mg/L, the change in HAM-D-17 favored infliximab- versus placebo-treated patients, whereas at plasma concentrations below 4.98mg/L the change in HAM-D-17 favored placebo.

Figure 3. Change in HAM-D-17 Score from Baseline to Week 12 (Infliximab-Placebo) in TRD Patients Subgrouped By Baseline Plasma hs-CRP

To examine the impact of varying levels of baseline plasma high sensitivity c-reactive protein (hs-CRP) on least squares (LS) mean change [± 95% Confidence Interval (CI)] in the 17-item Hamilton Depression Rating Scale (HAM-D-17) score from Baseline to 12 Week (Infliximab-Placebo), the sample of patients with treatment resistant depression (TRD) were subgrouped into all subjects (Overall), all subjects with a baseline hs-CRP >1mg/L (n=45), all subjects with a baseline hs-CRP >3mg/L (n=27) or all subjects with a baseline hs-CRP >5mg/L (n=22). When only considering subjects with a hs-CRP >5mg/L, a 3.1 difference in the HAM-D-17 favoring infliximab was found between infliximab- versus placebo-treated patients.

Figure 4. Change in HAM-D-17 Scores from Baseline to Week 12 in Infliximab- or Placebo-Treated TRD Patients with a Baseline CRP>5 mg/L versus ≤5mg/L

An intent-to-treat MMRM analysis of patients with treatment resistant depression (TRD) administered the TNF-alpha antagonist infliximab or placebo was separately conducted in patients with a baseline high sensitivity c-reactive protein (hs-CRP)>5mg/L (n=22)(Panel A) and those with a baseline hs-CRP ≤5mg/L (n=48)(Panel B). In general, opposite effects of infliximab were found depending on baseline hs-CRP. Subjects with baseline hs-CRP>5 mg/L tended to do better than placebo whereas the opposite effect was seen in subjects with a baseline hs-CRP≤5mg/L. Although there was a main effect of time on change in HAM-D-17 scores in patients with a baseline hs-CRP>5mg/L, there were no effects of treatment assignment or a treatment by time interaction. In addition, no main effects of treatment assignment, time or their interaction were found in subjects with a baseline hs-CRP ≤5mg/L. Depicted is least squares (LS) Mean [standard error of the mean (SEM)] Change in HAM-D-17 from Baseline to the indicated week using an unstructured covariance matrix with time as a categorical variable.

Figure 5. Median Change in Individual HAM-D-17 Items from Baseline to Week 12 in Infiximab- versus Placebo-Treated TRD Patients with Baseline hs-CRP>5mg/L

To determine which symptoms were differentially improved as a function of infliximab treatment, the median change in the 17 items of the Hamilton Depression Rating Scale (HAM-D-17) was plotted. Symptoms of Anxiety-psychic, Retardation, Work and Activities, Suicide and Depressed Mood exhibited greater improvement in infliximab- versus placebo-treated patients with treatment resistant depression (TRD) from Baseline to Week 12 in patients with a baseline plasma high sensitivity c-reactive protein (hs-CRP)>5mg/L.

Figure 6. Percent Treatment Responders in Infliximab- Versus Placebo-Treated TRD Patients with a Baseline hs-CRP≤5mg/L or >5mg/L

Percent Treatment Responders as defined by a ≥50% drop in the 17-item Hamilton Depression Rating Scale (HAM-D-17) at any time during treatment was compared in infliximab- versus placebo-treated patients with treatment resistant depression (TRD) and a baseline plasma high sensitivity c-reactive protein (hs-CRP)≤5mg/L versus >5mg/L as well as the groups combined. Infliximab-treated patients exhibited a higher response rate than placebo when hs-CRP was >5mg/L but a lower response than placebo when hs-CRP was ≤5mg/L. These results did not reach statistical significance (p=0.19). No difference was found between the groups combined (p=1.0).

Figure 7. Change in Plasma hs-CRP Concentrations Across Treatment and as a Function of Treatment Response in Infliximab- versus Placebo-Treated TRD Patients

Plasma high sensitivity c-reactive protein (hs-CRP) was measured across the study in all patients with treatment resistant depression (TRD). Infliximab treatment had a significant main effect on plasma hs-CRP (p