Neuropsychopharmacology reportsAug 29, 2025

Lack of Improvement with Ketamine in Hard-to-Treat Bipolar Depression

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 28, 2026

Abstract

Essence

In treatment-resistant bipolar depression, ketamine nonresponse was associated with heavier psychiatric comorbidity burden and prior benzodiazepine use.

Evidence

This was a post hoc analysis of a naturalistic 4-week ketamine study in 35 patients given intravenous or oral dosing, with 14 of 35 classified as nonresponders.

Caveat

The findings are preliminary because the sample was small, nonrandomized, and post hoc, and no individual comorbidity or baseline suicidality significantly predicted response.

Simplified

OBJECTIVES: Ketamine is a prototypical rapid-acting antidepressant for treatment-resistant bipolar depression (TRBD), yet many patients do not achieve a meaningful response. This study explored features of ketamine nonresponse in TRBD.

METHODS: In a post hoc analysis of a naturalistic study, 35 TRBD patients received a four-week ketamine regimen (intravenous 0.5 mg/kg or oral 2.0/2.5 mg/kg). Response was measured using the Montgomery-Åsberg Depression Rating Scale, and baseline sociodemographic and clinical features were compared between responders and nonresponders.

RESULTS: Fourteen patients (40%) were nonresponders. They had a higher median number of psychiatric comorbidities (2 vs. 1; p = 0.0366), were more likely to have any psychiatric comorbidity (78.6% vs. 33.3%; p = 0.0153), and had greater prior benzodiazepine use (64.3% vs. 23.8%; p = 0.0332). No significant links emerged between individual comorbidities or baseline suicidality and response.

CONCLUSION: Ketamine demonstrates a favorable safety and tolerability profile for short time use in TRBD regardless of isolated baseline characteristics, although a more severe comorbidity burden and benzodiazepine use appear to be associated with nonresponse.

TRIAL REGISTRATION: NCT04226963 and NCT05565352.