Clinical Edge

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Relationship between ketamine dose and blood level with antidepressant response

Key clinical point: Ketamine suppression of glutamate and glutamine (Glx) in the ventro-medial prefrontal cortex mediated the relationship of ketamine dose and level with antidepressant effect but was unrelated to psychotomimetic side effects.

Major finding: Injected dose of ketamine and ketamine blood level both had a positive relationship with clinical improvement. There was a negative relationship between ketamine dose and Glx and with GABA.

Study details: This randomized clinical trial involved 38 patients with major depressive disorder.

Disclosures: The authors reported receiving grants from the National Institute of Mental Health.


“Intravenous ketamine has been highly utilized in the last few years off-label for treatment resistant depression (TRD) and nasal esketamine more so recently after FDA approval. This study by Milak et al. interestingly attempts to further delineate why ketamine is effective in rapidly lowering depressive symptoms. Increased dosing and resultant increased blood levels predicted response per usual. Interestingly, downstream changes in glutamate/glutamine in the prefrontal cortex had the greatest predictability of clinical response even when doses were lower. In picking candidates for ketamine intervention, perhaps at some point a test dose measuring this initial downstream glutamate/glutamine change might help predict which patients will fully remit their TRD symptoms after a full course of treatment? Ketamine/esketamine are expensive cash-based or insurance-based treatments, where interventionalists may need to spend much time on prior authorizations or patients spend their income in the absence of coverage for several weeks of treatment. It might be easier to authorize a single test treatment if there is a better predictive value of who will ultimately respond…ideally full insurance coverage would follow, or patients would know they have better odds of responding if they pay cash for a full treatment course.”

Thomas L. Schwartz, MD

Senior Associate Dean of Education, Interim Chair/Professor of Psychiatry

SUNY Upstate Medical University


Milak, M, et al. JAMA Netw Open. 2020;3(8):e2013211. doi:10.1001/jamanetworkopen.2020.13211