Ketamine response biomarker may help tailor antidepressant treatments
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Ketamine dose and blood level appeared closely related, and both were significantly associated with antidepressant benefit, according to results of a randomized clinical trial published in JAMA Network Open.
“We sought to find a biomarker that related to the degree of clinical improvement because that could guide clinicians, provide brain biological validity to the treatment effect and be a guide to find other fast-acting antidepressants whose potential could be assessed by their capacity to have this same effect on the biomarker,” J. John Mann, MD, Paul Janssen Professor of Translational Neuroscience (in psychiatry and in radiology), told Healio Psychiatry. “By the degree of that effect relative to ketamine’s effect, a prediction could be made of how good an antidepressant this new drug could be without having the need to treat a single depressed patient. Of course, this would be a screening tool only, since each new drug will have to undergo testing in a randomized controlled clinical trial before FDA approval for use.”
Results of previous studies suggested a single IV subanesthetic ketamine dose may result in an antidepressant response in hours rather than weeks, even among patients with medication-resistant major depressive disorder. Thus, gaining insight into the mechanism of its fast-acting antidepressant action could help researchers identify alternative medications that can be used orally, have less abuse potential and have fewer adverse effects, according to Mann and colleagues.
In the current study, the investigators included 38 psychotropic medication-free, physically healthy adult outpatients who were in an MDD-related major depressive episode but who were not actively suicidal. Participants were given one dose of ketamine or placebo via IV during 40 minutes of a proton magnetic resonance spectroscopy scan measuring ventro-medial prefrontal cortex brain glutamate and glutamine (Glx) and -aminobutyric acid (GABA) levels in 13-minute data frames. The researchers measured clinical improvement according to the 22-item Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine administration, and they measured ketamine and metabolite blood levels after the scan.
Results showed a positive correlation between HDRS-22 score improvement and ketamine dose and blood level, with a lower Glx response linked to a better antidepressant response. GABA levels were not correlated with antidepressant effect, despite their correlation with Glx. Ketamine dose or blood level were no longer associated with antidepressant effect when the researchers included both ketamine dose and Glx response in a meditation analysis model, indicating the role of Glx response in mediating the relationship. Glx and GABA response were not linked to adverse effects; however, adverse effects were associated with blood levels in men only.
“The side effects are not related to antidepressant effect or to the effects on Glx or GABA, and so it appears it should be possible to design a drug that works as well as ketamine for depression but does not have a psychotomimetic effect,” Mann told Healio Psychiatry.