Intranasal Esketamine Versus Other Pharmacological Strategies in Treatment-Resistant Depression with High Suicide Risk: A Six-Month Naturalistic Study

Background: Treatment-resistant depression (TRD) poses a major clinical challenge, particularly when accompanied by suicidal behavior. Intranasal esketamine has demonstrated rapid antidepressant effects in TRD, but real-world comparative evidence remains limited. Methods: We conducted a six-month naturalistic prospective cohort study in two Spanish mental health centers, including 62 TRD patients with high suicide risk undergoing fourth-line treatment. Thirty patients received intranasal esketamine and thirty-two alternative pharmacological interventions. Suicidal ideation (C-SSRS), depressive symptoms (HAM-D-17) and functional status (FAST) were assessed at baseline and at 1-, 3- and 6-month follow-ups. Results: Both groups showed significant improvement during follow-up; however, esketamine-treated patients exhibited a faster and greater reduction in suicidal ideation and depressive symptoms than those receiving alternative pharmacological strategies. The number needed to treat to prevent one case of high suicide risk was 1.35. Functional improvement was comparable between groups. Conclusions: In real-world clinical settings, intranasal esketamine was associated with a faster and greater reduction in suicidal ideation and depressive symptoms among TRD patients with high suicide risk, supporting its role as a rapid-acting therapeutic option within comprehensive and closely monitored care.