A retrospective study of 153 patients with severe treatment-resistant depression found that twice-weekly IV ketamine over 4–5 weeks led to faster and greater symptom reduction than intranasal esketamine, with overall tolerability similar. IV ketamine produced significant improvement after the first session, while IN esketamine’s effects emerged after the second. Final depression scores decreased 49.8% with IV ketamine versus 39.5% with IN esketamine. Dropout rates and side effects were comparable, highlighting both as valuable neuropsychiatric tools.