Infliximab for Treatment-Resistant Depression

About one third of depressed patients fail to respond to conventional antidepressant medication. It is believed that inflammation is a possible mechanism that contributes to this treatment resistance. A number of inflammatory biomarkers (including inflammatory cytokines, acute phase proteins, chemokines, and adhesion molecules) have been found to be reliably elevated in depressed patients and have been associated with a decreased likelihood of response to conventional antidepressants.

Given the association of inflammatory cytokines with treatment resistance, there has been interest in testing whether inhibiting inflammatory cytokines might be used as therapy for treatment-resistant depression (TRD). One inflammatory cytokine, tumor necrosis factor (TNF), has been reliably shown to be elevated in depressed patients.

The investigators wished to determine whether inhibition of the inflammatory cytokine TNF reduces depressive symptoms in patients with TRD 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.

The study [JAMA Psychiatry. 2013;70(1):31-41] was a single-site, parallel-group, randomized, double-blind trial of infliximab versus placebo for antidepressant nonresponders with major depression. A total of 60 medically stable outpatients who were on a consistent antidepressant regimen (n=37) or off antidepressant therapy for at least 4 weeks prior to baseline (n=23), had moderate severity of depression, and had experienced moderate resistance to treatment were enrolled in the study.

Half of the patients were selected to receive infliximab (n=30) and the other half received placebo (n=30). All patients reported to the infusion center in the Emory Division of Digestive Diseases on 3 separate occasions (baseline, 2 weeks, and 6 weeks) to receive an infusion of either infliximab (5 mg/kg) or placebo over 120 minutes.

The primary end point was change in depression severity as measured by the 17-item Hamilton Rating Scale for Depression (HAM-D) score. Additional end points included treatment response, defined as a ≥50% reduction in HAM-D score at any point during the study, and remission, which was considered a HAM-D score of ≤7 at the end of treatment (week 12). Secondary end points included the Clinical Global Impression Scale–Severity score.

Of the 60 patients randomly assigned, 27 in the infliximab group and 28 in the placebo group completed all 3 infusions. In total, 90% of the participants completed all 12 weeks of the trial (29/30 participants in the placebo group [97%] and 25/30 participants in the infliximab group [83%]). No differences in change in HAM-D scores over time were found between treatment groups (t58=0.10), nor was there a significant interaction between treatment and time (t305=0.86). There was a significant effect of time, with HAM-D scores decreasing from baseline to end of treatment (t305=2.53; P=.01). When the baseline hs-CRP concentration (log-linear and quadratic terms) was entered into the model, there was a significant interaction among treatment, time, and log hs-CRP concentration (t302=2.65; P=.01).

To identify the critical threshold for the influence of baseline hs-CRP concentration, change in HAM-D from baseline to week 12 (infliximab minus placebo) in relation to log hs-CRP concentration was analyzed. A baseline hs-CRP concentration >5 mg/L was found to be the point at which infliximab-treated patients began to exhibit a greater decrease in HAM-D scores than placebo-treated patients. Similar results were found for the Clinical Global Impression Scale–Severity score.

For participants with a baseline hs-CRP concentration >5 mg/L, however, the treatment response rate was 62% (8 of 13 participants) in the infliximab group and 33% (3 of 9 participants) in the placebo group. Regarding the effect of infliximab and placebo on hs-CRP concentrations across treatment, there was a significant effect of treatment (t57=2.25; P=.03), but no effect of time (t433=0.10) and no treatment X time interaction (t433=0.27). Infliximab was found to lead to a significant reduction in hs-CRP concentrations compared with placebo at all visits beyond baseline (P<.05).