Inflammation and Treatment-Resistant Depression

Elevated TNF-alpha may be both a biomarker and a treatment target in hard-to-treat depression

STUDY: Wu S et al, Brain Research Bulletin 2026 (in press)

STUDY TYPE: Review

FUNDING: Guangdong Provincial Education Science Planning Project, Guangdong Overseas Distinguished Scholars Program, Natural Science Foundation of Guangdong Province, Medical Scientific Research Foundation of Guangdong Province

Background

Nearly half of patients with treatment resistant depression have inflammation, and this review examines the mechanisms, biomarkers, and anti-inflammatory therapies.

The Study

Patients with treatment-resistant depression consistently show elevated levels of inflammatory markers: CRP, IL-6, IL-1β, and TNF-alpha. These cytokines disrupt serotonin, dopamine, and glutamate signaling, over activate the HPA axis, and impair neuroplasticity.

TNF-alpha is the most specific biomarker. It correlates more strongly with treatment resistance than CRP, and a meta-analysis of four randomized controlled trials found infliximab, an anti-TNF-alpha monoclonal antibody, reduced depressive symptoms in patients with elevated baseline inflammatory markers. The response appears selective: patients with CRP above 5 mg/L, elevated TNF-alpha, or a history of childhood trauma responded; unselected patients did not.

Other anti-inflammatory agents tested in treatment-resistant depression include minocycline, celecoxib, and N-acetylcysteine. Results are mixed, but trend positive when when patients are pre-selected for elevated inflammation.

The author suggests esketamine and ketamine are possibilities, as they have anti-inflammatory mechanisms, but I disagree. Several studies have found inflammation does not predict response to these rapid-acting antidepressants.

Practice Implications

1. CRP is a lost cost test for patients who’ve failed two antidepressants, order as a high sensitivity (hs-CRP).
2. If it’s above 3 mg/L, you’re patient likely has inflammation and will respond better to one of the therapies below (from Difficult to Treat Depression).