Background: This case series describes the combined use of electroconvulsive therapy (ECT) and intranasal esketamine (ESK)—2 rapidly acting, evidence-based options for treatment-resistant depression (TRD). Each can leave residual symptoms or early relapse. Whether concurrent use confers more durable benefit remains unclear. Methods: We followed 4 adults (50 to 72 y) with severe TRD who had shown partial or waning benefit to ECT or ESK alone. During acute treatment, bilateral ECT (2 to 3 sessions/wk) was paired with ESK (28 to 84 mg, 1 to 2 doses/wk) on non-ECT days. Over 24 weeks, ECT was tapered individually to every 1 to 3 weeks while ESK continued weekly or fortnightly, with schedules adjusted to course and tolerability. MADRS, ECT cadence, and adverse events were documented every 4 weeks. Results: Two response profiles emerged. In 2 patients, adding the complementary modality to partial monotherapy produced sustained improvement: ESK added to ongoing ECT reduced MADRS from 36→18 (−50%), and ECT during ongoing ESK reduced MADRS from 35→22 (−37%). In 2 maintenance-ECT responders, adding ESK produced improvements from 42→16 (−62%) and 36→6 (−83%), allowing ECT intervals to extend from weekly to every 14 to 21 days. Mean symptom reduction was 58%; no relapses occurred over 24 weeks. Adverse events were mild and transient—brief dissociation (3/4) and post-ictal confusion (2/4); no serious events occurred. Conclusions: In this naturalistic series, combined ECT+ESK was feasible and associated with sustained symptom improvement, wider ECT spacing, and potentially lower cognitive burden. Findings are hypothesis-generating, support prospective controlled trials to define sequencing, dosing, and safety.
López-Rodríguez et al. (2026) studied this question.