Inflammatory response to repeated subcutaneous esketamine in treatment-resistant depression: The role of baseline...

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.

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.

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).

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).

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.