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
This retrospective naturalistic study (n=178) examined whether benzodiazepines, lithium or lamotrigine altered the antidepressant effects of subcutaneous esketamine in people with treatment-resistant depression. Depression scores fell over six weeks, but benzodiazepine use was linked to higher symptom levels during treatment, while lithium and lamotrigine were not.
Authors
- Atidio, J. P.
- Delfino, R. S.
- Garios, I. S.
Published
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Research Summary of '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'
Blossom's Take
Interactions with other medications (antidepressants, benzos, etc.) are something that is understudied in psychedelics. With two decades of real-world use of ketamine, we gather valuable data on this interaction. Conclusions don't fully generalise to other psychedelics but this research provides a template for further research into this topic.
Introduction
Major depressive disorder remains a major source of disability, and a substantial proportion of patients do not achieve remission after multiple adequate antidepressant trials, leaving a persistent need for faster and more effective treatments. Ketamine and esketamine have attracted attention because they can reduce depressive symptoms rapidly through mechanisms that differ from conventional monoaminergic antidepressants. However, many patients receiving these treatments also take other psychotropic medicines, and it is still unclear whether commonly used agents such as benzodiazepines, lamotrigine, and lithium alter esketamine’s antidepressant effects. Atidio and colleagues aimed to evaluate whether concomitant benzodiazepine, lamotrigine, or lithium use was associated with different antidepressant outcomes during a course of subcutaneous esketamine in patients with treatment-resistant depressive episodes. The study specifically examined whether these medications changed the trajectory of Montgomery-Åsberg Depression Rating Scale (MADRS) scores over time in a real-world clinical cohort including both unipolar and bipolar depression. The paper addresses a practical gap in routine care, where esketamine is often used alongside other psychotropic drugs and where evidence on potential medication interactions is limited, particularly for the subcutaneous route of administration.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Atidio, J. P., Delfino, R. S., Garios, I. S., de Brito, C. S. G. F., Gerheim, Y. P., de Almeida e Vasconcelos, G. M., Piloto, R., Ferro, M. D., de Souza Júnior, R. O. P., Surjan, J. C., & Lacerda, A. L. (2026). 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. Journal of Affective Disorders, 121721. https://doi.org/10.1016/j.jad.2026.121721
References (1)
Papers cited by this study that are also in Blossom
Fond, G., Loundou, A., Macgregor, A. et al. · Psychopharmacology (2014)
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