Benzodiazepines May Blunt Esketamine

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

1. Despite the limitation, this study is consistent with the known mechanism and with earlier studies of benzo-ketamine.
2. 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.
3. For lithium and lamotrigine, this study offers reassurance: don’t stop them.