Role of concomitant benzodiazepines, lithium, and lamotrigine in modulating the antidepressant effects of subcutaneous esketamine in patients with treatment-resistant depressive episodes: A retrospective naturalistic study

Ketamine and esketamine have been increasingly used as adjunctive treatments for treatment-resistant depression (TRD), yet evidence on pharmacological interactions with commonly prescribed psychotropic medications remains limited. This study evaluated the association between concomitant lamotrigine, lithium, and benzodiazepine use and antidepressant outcomes during subcutaneous esketamine treatment in patients experiencing treatment-resistant depressive episodes, including unipolar and bipolar depression. We analyzed real-world clinical data from 178 patients treated between 2017 and 2023 at the Esketamine Clinic of the Mood Disorders Program, Universidade Federal de São Paulo. Participants received six weekly subcutaneous esketamine administrations (0.5–1.0 mg/kg), adjusted according to clinical response and tolerability. Changes in Montgomery–Åsberg Depression Rating Scale (MADRS) scores were examined using linear regression and linear mixed-effects models to assess associations between concomitant medication use and outcomes over time. MADRS scores decreased significantly from baseline to endpoint at week 6 ( p < 0.001). Mixed-effects models showed a significant effect of time (β = −2.82 MADRS points per week, p < 0.001), indicating consistent symptom improvement. Concomitant benzodiazepine use was associated with higher MADRS scores across treatment weeks (β = 4.46, 95% CI 0.53–8.39, p = 0.026). Lamotrigine (β = 1.04, p = 0.777) and lithium (β = 1.70, p = 0.343) showed no significant effects, and no medication-by-time interactions were detected. Subcutaneous esketamine was associated with significant symptom reduction. Benzodiazepine use was associated with higher depressive symptom severity during treatment, whereas lamotrigine and lithium were not associated with differential trajectories. Prospective studies are needed to clarify medication-specific interactions. • Benzodiazepine use was associated with higher MADRS scores during treatment. • Lithium and lamotrigine did not significantly impact antidepressant outcomes. • MADRS scores progressively decreased over six weeks of treatment. • Mixed-effects models showed a consistent benzodiazepine-related effect.