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

Patrícia Cavalcanti-Ribeiro, Lara Carvalho Araújo Melo De Souza, Vagner Deuel O de Tavares, Raíssa Nóbrega de Almeida, Nicole Bezerra de Medeiros Lima, Kaike Thiê da Costa Gonçalves, Eduardo Igor Torquato Cardoso Lopes, Raynara Bolcont, Aldielyson Jorge Cavalcanti de Brito, Marcelo Falchi-Carvalho, Emerson Arcoverde, Dráulio Barros de Araújo, Fernanda Palhano-Fontes, Nicole Leite Galvão‐coelho

Journal of Affective Disorders March 15, 2026 DOI: 10.1016/j.jad.2025.120877 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Secondary analysis of an open-label trial Peer reviewed
Sample size 22
Population Patients with treatment-resistant depression
Intervention subcutaneous esketamine
Dose seven weekly doses
Duration 8-week intervention
Topics Depression Esketamine Ketamine
Keywords Antidepressant response C-reactive protein Inflammation Subcutaneous administration
Key findings Patients with elevated baseline CRP showed significant within-group reductions in CRP over time, but these changes did not correlate with depressive symptom improvement.

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.

Comparable studies

Other non-randomized and open-label trials on esketamine for depression, most cited first.

Study Year Design Participants
Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression Adults (≥ 18 years) with treatment-resistant depression 2020 Phase 3, open-label, multicenter, long-term study n = 802
Long-Term Safety and Maintenance of Response With Esketamine Nasal Spray in Participants With Treatment-Resistant Depression: Interim Results of the SUSTAIN-3 Study Adults with treatment-resistant depression 2023 Open-label, long-term extension study n = 1,148
Safety and efficacy with esketamine in treatment-resistant depression: long-term extension study. Adults with treatment-resistant depression who participated in ≥1 of 6 phase 3 parent... 2025 Open-label, single-arm long-term extension study n = 1,148
Efficacy and Safety of Intranasal Esketamine in Patients With Treatment-Resistant Depression and Comorbid Chronic Post-traumatic Stress Disorder: Open-Label Single-Arm Pilot Study Patients with treatment-resistant major depressive disorder and comorbid post-traumatic... 2022 Open-label, single-arm, retrospective pilot study n = 11
Rapid and long-lasting effects of subcutaneous esketamine on suicidality: An open-label study in patients with treatment-resistant depression. Treatment-resistant depressive patients 2024 Open-label clinical trial n = 18

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