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.
João Paulo Atidio, Rodrigo Simonini Delfino, Igor Saque Garios, Camila Serra Galdino Farias De Brito, Yuri Padilha Gerheim, Gustavo Magalhães De Almeida E Vasconcelos, Rodrigo Piloto, Mateus Dadamos Ferro, Rogério Onofre Pereira De Souza Júnior, Juliana Canada Surjan, Acioly L T Lacerda
Journal of affective disorders August 1, 2026 Peer reviewed DOI: 10.1016/j.jad.2026.121721 via PubMed
Summary
Subcutaneous esketamine treatment significantly reduced depressive symptoms in patients with treatment-resistant depression, as indicated by decreased Montgomery-Åsberg Depression Rating Scale (MADRS) scores over six weeks. However, concomitant benzodiazepine use was linked to higher MADRS scores, suggesting worse outcomes, while lamotrigine and lithium did not show significant effects on symptom trajectories. The study highlights the need for further research on medication interactions.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 178 |
| Population | patients with treatment-resistant depression receiving subcutaneous esketamine |
| Key finding | Esketamine treatment was associated with significant symptom reduction, but benzodiazepine use correlated with higher depressive symptom severity. |
Abstract
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.