Higher benzodiazepine doses went with non-response to ketamine for depression, above 8 mg diazepam-equivalent
In 47 people with treatment-resistant depression given one ketamine infusion, benzodiazepine doses "were significantly higher in nonresponders (p=0.007)"; a cut-off above 8 mg diazepam-equivalent had sensitivity 80 percent.
Suggestive but preliminary. Not settled. how we score evidence
Caveat on this rating: Small pooled sample from two earlier trials, retrospective analysis, cut-off derived from the same data it is tested on. Association, not proof that the benzodiazepine caused the non-response.
Ketamine, from a clinic or from the street, works on the same brain systems benzodiazepines quiet. This study asked whether the sedative blunts the antidepressant.
Significant findings
Andrashko and colleagues (Frontiers in Psychiatry, 2020) analysed 47 patients with major depression who had not responded to at least one antidepressant and received a single infusion of racemic ketamine, 0.54 mg per kilogram, on top of their existing medication. "Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis."
"The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001)." Patients above that dose had "a significantly worse outcome" on day 3 and day 7.
"The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine's antidepressant effect." A 2015 letter by Frye, Blier and Tye in the Journal of Clinical Psychopharmacology, read for this wave, reported the same pattern under the title "Concomitant benzodiazepine use attenuates ketamine response".
Worth asking
Forty seven patients and a retrospective split, so the cut-off is a hypothesis, not a rule. The direction is consistent across the two reports, and it matters in both settings: a person paying for ketamine treatment while on a moderate benzodiazepine dose may be paying for less effect, and a person using street ketamine on top of a benzodiazepine is combining two sedatives, which the esketamine label in this wave addresses directly. If ketamine treatment is on the table, the question for the clinic is what your benzodiazepine dose is in diazepam-equivalents and whether that changes the plan. Any change to the benzodiazepine is the prescriber's, with a taper; the same drugs cause dangerous withdrawal if stopped abruptly.
Source
The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication — Andrashko V, Novak T, Brunovsky M, Klirova M, Sos P, Horacek J (2020)
Indexed peer-reviewed journal
Read the source: https://doi.org/10.3389/fpsyt.2020.00844
DOI: 10.3389/fpsyt.2020.00844
How this was scored
- Study design
- Cohort study
- Funding
- Funding not disclosed
- Published in
- Indexed peer-reviewed journal
- Sample size
- 47
- Preregistered
- not recorded
- Conflicts disclosed
- not recorded
- Independent of proponent
- not recorded
- Retracted
- No
Read the full scoring rubric, including what it can't tell you.
Published September 21, 2026.
Questions
How strong is the evidence behind this?
veisund rates this source "early signal". Suggestive but preliminary. Not settled. It scores 43 out of 100 on our published rubric. One caveat travels with that badge: Small pooled sample from two earlier trials, retrospective analysis, cut-off derived from the same data it is tested on. Association, not proof that the benzodiazepine caused the non-response. The score is calculated from recorded facts about the source — study design, funding, publication venue, sample size, preregistration — not typed in by an editor.
What is the source for this?
The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication — Andrashko V, Novak T, Brunovsky M, Klirova M, Sos P, Horacek J (2020). Published in: Indexed peer-reviewed journal. DOI: 10.3389/fpsyt.2020.00844. The full source is linked on this page so you can read it yourself.
Who paid for this research, and does that matter?
Study design: Cohort study. Funding: Funding not disclosed. Independence from the proponent is not recorded. Industry sponsorship is one of the most reliably measured biases in medicine, which is why funding carries real weight in the score rather than sitting in a footnote.
Is this medical advice?
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.
This is information to bring to your prescriber, not medical advice and not a reason to change anything on your own. Nothing here is an instruction to stop or reduce a medication. If you are in crisis, call or text 988.