JAMA Psychiatry
Could targeting inflammation unlock new options for difficult-to-treat depression?
Clinical Takeaway: In patients with treatment-resistant depression and elevated inflammatory markers, IL-6 inhibition with tocilizumab showed signals of benefit across depression, fatigue, and anxiety measures, supporting larger trials of immunotherapy-guided psychiatry.
Up to 30% of patients with depression may have low-grade systemic inflammation, raising the possibility of precision treatment approaches that target immune pathways rather than neurotransmitters alone.
A proof-of-concept randomized clinical trial suggests that blocking interleukin-6 (IL-6) signaling may improve symptoms in patients with difficult-to-treat depression linked to low-grade inflammation.
Researchers enrolled 30 adults with moderate-to-severe depression despite antidepressant treatment, elevated high-sensitivity C-reactive protein (hs-CRP ≥0.3 mg/dL on 2 tests), and prominent somatic symptoms. Participants received either a single IV infusion of the IL-6 receptor antagonist tocilizumab (8 mg/kg) or placebo and were followed for 4 weeks.
Although the study wasn’t powered to show statistical significance, patients receiving tocilizumab demonstrated greater stepwise improvement over time in overall depression severity, somatic symptoms, fatigue, anxiety, and quality of life. By day 28, remission rates were 53.9% with tocilizumab vs. 31.3% with placebo, while treatment response rates were 46.2% vs. 18.8%, respectively. The estimated number needed to treat was 5 for remission and 4 for response.
Fatigue appeared particularly responsive, and symptom-level analyses suggested benefits for low energy, concentration difficulty, appetite changes, agitation, pessimism, and feelings of worthlessness. No serious adverse events or treatment discontinuations were reported.
Investigators also found that higher baseline hs-CRP — but not IL-6 levels — tracked with greater improvement, suggesting CRP testing may help identify patients most likely to benefit from anti-inflammatory strategies.
“These findings suggest that the IL-6 or IL-6 receptor pathway could be a new treatment target for inflammation-linked depression,” the authors wrote, while emphasizing that larger and longer trials are needed to confirm efficacy.
Source: Foley EM, et al. (2026, May 20). JAMA Psychiatry. Interleukin 6 as a Treatment Target for Depression: A Proof-of-Concept Randomized Clinical Trial