BACKGROUND: Treatment-resistant depression (TRD) remains a major clinical challenge, with inflammation increasingly implicated in its pathophysiology. C-reactive protein (CRP), an accessible biomarker, has emerged as a potential predictor of antidepressant response. While intravenous and intranasal ketamine have shown anti-inflammatory effects, evidence linking inflammation and clinical outcomes remains inconsistent. The effects of subcutaneous (SC) esketamine on CRP and symptom improvement have not been explored.
OBJECTIVE: To investigate whether baseline CRP predicts clinical response, whether SC esketamine reduces CRP in inflamed patients, and whether CRP changes are associated with symptom improvement.
METHODS: This secondary analysis derived from an open-label trial included 22 TRD patients who received seven weekly SC esketamine doses. Patients were stratified by CRP (>1 mg/L = inflammation; ≤1 mg/L = non-inflammation). Depression severity was assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS).
RESULTS: The inflammation group (n = 8) showed significant CRP reductions (week 4: p = 0.005; week 8: p < 0.001); non-inflamed patients showed no significant change. By week 8 (which corresponded to the seventh application), both groups had comparable CRP levels (p = 0.170; 95 % CI [-2.923 to 0.258]). Age, sex, and BMI did not influence CRP changes. Although the inflammation group had greater depressive symptom reduction (ΔMADRS = 15.88 vs. 11.14), this was not statistically significant (p = 0.280). CRP changes did not predict to symptom improvement (p = 0.774).
CONCLUSION: Exploratory findings suggest that patients with elevated baseline CRP showed within-group decreases over time, without clinical correlation. Larger controlled studies with broader immune profiling are needed.
