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EVALUATING HEPATIC EFFECTS OF SERIAL KETAMINE INFUSIONS FOR TREATMENT-RESISTANT BIPOLAR DEPRESSION

Gabrielle Lovell — Shreya Vasudeva1, Diana Orsini1, Sara Di Luch1, Danica Johnson1, Nelson Rodrigues1, Rodrigo Mansur2, Roger S. McIntyre2, Joshua D. Rosenblat2 1University of Toronto, 2University Health Network Gabrielle Lovell, University of Toronto

2026 ASCP Annual Meeting

Background

Ketamine has been identified as a promising treatment for treatment resistant depression (TRD) demonstrating rapid and robust antidepressant effects. Concerns from regulatory agencies have emerged regarding the risk of hepatotoxicity of prolonged ketamine use after identifying cases of liver impairment, typically following ketamine for chronic pain treatment or misuse. Bipolar disorder (BD) is associated with higher rates of hepatic impairment, however, the risk of hepatic dysfunction following serial ketamine infusions in BD remains unknown.

Methods

In a double-blinded, randomized controlled trial (RCT) (KET-BD, NCT05004896), participants with a diagnosis of treatment-resistant bipolar depression (TRBD) received four infusions over two weeks of either intravenous ketamine (0.5 - 0.75mg/kg) or an active placebo (midazalom; 0.02-0.03 mg/kg). Liver function tests (i.e., aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), C-reactive protein (CRP), albumin, total protein, bilirubin) were conducted at baseline and following an acute course of treatment (primary endpoint; Day 14). The results of 62 participants were analyzed.

Results

In the ketamine group, 9.7% (n = 6) of participants demonstrating normal liver function ranges at baseline developed transaminitis by Day 14 (elevation of AST/ALT), with no participants exceeding 2x the upper limit of normal (ULN). In the midazolam group, 1.6% (n = 1) of participants demonstrating normal liver function at baseline developed transaminitis. One participant had > 2x ULN ALT at primary endpoint and another participant had > 2x ULN CRP at primary endpoint, however both participants had elevated ALT or CRP respectively at baseline, and were in the midazolam group. For both albumin and total protein, 6.5% (n=2) from the ketamine group and 3.2% (n=1) from the midazolam group were within the normal range at baseline but elevated at primary endpoint, however no participants exceeded 2x ULN. No patients demonstrated elevated bilirubin levels at any point in the trial.

Conclusion

To our knowledge, this is the largest analysis of hepatotoxicity of ketamine in the context of BD treatment. Based on these findings, four repeated doses of intravenous ketamine may result in transaminitis, however impaired liver function was not demonstrated, as suggested by bilirubin levels remaining in normal range. With the rise of repeated and prolonged dosing methodologies in clinical trials and clinical practice, these results contribute to a greater understanding of the risk profile associated with ketamine treatment. Given how commonly transaminitis was observed, routine liver monitoring is merited with serial ketamine infusions.

Learning Objective 1: Evaluate evidence of hepatic injury and/or impaired hepatic function from the largest RCT investigating serial intravenous ketamine infusions in a treatmentresistant bipolar depression

Learning Objective 2: Describe the need for evidence quantifying the risk for hepatotoxicity related to ketamine treatment for patients with treatment resistant bipolar depression

References

: Hsu JH, Chien IC, Lin CH. Increased risk of chronic liver disease in patients with bipolar disorder: A population-based study. General Hospital Psychiatry. 2016;42:54-59. Thakkar, B.; Wu, G.Y. Ketamine Hepatotoxicity: An Underappreciated Cause of Liver Damage - Analysis by RUCAM. Journal of Clinical and Translational Hepatology 2025, 13, 524–531,