Think twice before pairing benzos with esketamine/ketamine
STUDY: Atidio JP et al, J Affect Disord 2026; doi:10.1016/j.jad.2026.121721
STUDY TYPE: Retrospective naturalistic study
FUNDING: Independent
Background
Some studies suggest benzodiazepines interfere with ketamine’s antidepressant effects, blunting the glutamate surge by raising GABA tone. This study of esketamine (Spravato) looks further into that, along with lithium and lamotrigine, which may interact with the ketamines through glutamatergic their effects.
The Study
This retrospective study analyzed 178 adults with treatment-resistant unipolar or bipolar depression treated with weekly subcutaneous esketamine (0.5–1.0 mg/kg) for six weeks at a Brazilian academic mood disorders clinic. Researchers used linear mixed-effects models to assess how concomitant benzodiazepines, lithium, or lamotrigine affected depression trajectories over time.
Remission was nearly half as common in benzodiazepine users (19%) versus non-users (29%) at week 6. Two-thirds of the cohort took benzodiazepines, and they carried higher depression (MADRS) scores throughout treatment (β = +4.46 points, p = 0.026), though the rate of improvement over time was similar to non-users. Lithium and lamotrigine had no meaningful effect on outcomes.
Limitation: Non-randomized, retrospective study, so confounding by indication is a possibility. Patients on benzos were likely sicker and more anxious to begin with.
Practice Implications
- Despite the limitation, this study is consistent with the known mechanism and with earlier studies of benzo-ketamine.
- Ketamine and esketamine treats benzo withdrawal, making a rapid taper before starting the ketamines a feasible strategy – as described in our podcast interview with Kyle Greenway, founder of the Montreal Model for ketamine-assisted psychotherapy.
- For lithium and lamotrigine, this study offers reassurance: don’t stop them.
— Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
What’s Your Take? Share in Comments
- How do you manage benzos with ketamines?
- Have you seen interactions with the ketamines and other meds?
One comment
Idriss
April 11, 2026 at 1:12 pm
Thank you very much for this article. We’ve discussed that on multiple occasions even at the level of international conferences that combining benzodiazepine, in particular long-acting benzodiazepine with esketamine, this opposing the efficacy of one another. Benzodiazepines dampen the esketamine plasticity and the synaptogenesis. Unfortunately, some patients have severe anxiety disorder and TRD patients always have co-morbid generalized anxiety disorder, so some patients already were on chronic benzos before they start esketamine and many times we tried to omit these benzos, but they relapsed into a severe anxiety despite that esketamine treats both conditions, depression and anxiety, but unfortunately, for some patients, we cannot wean them from the benzodiazepines and unfortunately they continue to benefit partially from the treatment.