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 DOI: 10.1016/j.jad.2026.121721 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 178 |
| Population | Patients with treatment-resistant depressive episodes (unipolar and bipolar depression) treated at a mood disorders clinic |
| Intervention | subcutaneous esketamine |
| Dose | 0.5-1.0 mg/kg |
| Duration | 6-week intervention |
| Topics | Depression Esketamine Ketamine |
| Keywords | Benzodiazepine Lamotrigine Lithium Madrs Real-world evidence |
| Key findings | Concomitant benzodiazepine use was associated with higher depressive symptom severity during subcutaneous esketamine treatment, while lamotrigine and lithium showed no significant association with outcomes. |
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.
Comparable studies
Other observational and cohort studies on esketamine for depression, most cited first.
Citations in the library
Cites 11
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Single-dose infusion ketamine and non-ketamine N-methyl-D-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories Psychological Medicine February 12, 2016
and 6 more in the library