Nonresponse to Ketamine in Treatment‐Resistant Bipolar Depression

Ketamine is a fast-acting antidepressant for treatment-resistant bipolar depression, but about 40% of patients do not respond. Among 35 patients receiving a four-week ketamine regimen, nonresponders had more psychiatric comorbidities (median 2 vs. 1) and were more likely to have any psychiatric comorbidity (78.6% vs. 33.3%) and prior benzodiazepine use (64.3% vs. 23.8%). Individual comorbidities and baseline suicidality were not linked to response. Ketamine remains safe and well-tolerated for short-term use, but a heavier comorbidity burden and benzodiazepine use may predict nonresponse.

Study at a glance

Abstract

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.