The Potential Role of Infliximab, a TNF Inhibitor, in Treatment-Resistant Depression
Infliximab (Remicade; Janssen Biotech), a monoclonal antibody ordinarily used to treat autoimmune diseases such as rheumatoid arthritis, may have utility in treating patients with treatment-resistant depression (TRD), who have failed to respond to conventional antidepressant therapy. Study of this agent for depression has been stimulated by an increasing focus on inflammation as a hypothesized pathophysiologic mechanism that might contribute to treatment resistance in depression.
There is a bidirectional relationship between inflammation and TRD. A number of inflammatory biomarkers (including inflammatory cytokines such as tumor necrosis factor [TNF], acute phase proteins, chemokines, and adhesion molecules) have been found to be reliably elevated in depressed patients and have been associated with increased likelihood of poor response to conventional antidepressants.1,2 Conversely, psychosocial stressors and other disorders linked to poor treatment response have been associated with increased inflammation.2 Given the disturbing estimate that one-third of depressed patients fail to respond to conventional antidepressant treatment,3 it is critical to investigate newly emerging insights into the pathophysiology of treatment resistance, such as inflammation, which might inform development of novel therapeutic agents.
Raison et al. investigated whether inhibition of TNF reduces depressive symptoms in patients with TRD. They also explored whether an increase in baseline plasma inflammatory biomarkers (including high-sensitivity C-reactive protein [hs-CRP], TNF, and its soluble receptors) predicts treatment response.4
The researchers randomized 60 medically stable outpatients with moderate treatment resistance, as determined by the Massachusetts General Hospital Staging Method, to receive either three infusions of the TNF-antagonist infliximab (N=30) or placebo (N=30) over a 12-week period. The primary outcome measure was improvement on the 17-item Hamilton Scale for Depression (HAM-D).
The researchers found no overall difference in change of HAM-D scores between treatment groups over time; however, there was a significant effect of time, with HAM-D scores significantly decreasing from baseline to end of treatment in both groups (P=0.01)
Based on these results, the researchers conducted more in-depth exploratory analyses to investigate whether baseline levels of inflammation appeared to play a role in treatment response. Several important findings emerged.
- Infliximab was superior to placebo in reducing HAM-D scores by >50% at any point during treatment in participants with high baseline concentrations of hs-CRP (>5mg/L) versus those with lower concentrations (<5mg/L). Infliximab-treated patients with higher baseline hs-CRP levels experienced a treatment response rate of 62%, compared to 33% in the placebo group (P=0.19). On the other hand, placebo was superior for participants with lower baseline concentrations.
- Baseline concentrations of TNF and its soluble receptors were significantly higher in infliximab-treated responders, versus nonresponders (P<0.05).
- Infliximab-treated responders exhibited significantly greater decreases in hs-CRP from baseline to Week 12, compared with placebo-treated responders (P<0.01).