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

In a small open-label trial of 22 patients with treatment-resistant depression who received seven weekly subcutaneous doses of esketamine, those with elevated baseline C-reactive protein (CRP > 1 mg/L) showed significant reductions in CRP by week 4 and week 8, while patients without inflammation showed no change. By week 8, CRP levels in both groups were comparable. Although the inflammation group had a greater average reduction in depression severity (15.88 points on the MADRS scale versus 11.14 points), this difference was not statistically significant, and changes in CRP did not predict symptom improvement. Larger controlled studies are needed.

Study at a glance

Abstract

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.