Investigators Uncover Antidepressant Response Mediator to Ketamine

Matthew Milak, MD

A single subanesthetic dose of ketamine is associated with a rapid antidepressant response in patients with major depressive disorder (MDD). However, the mechanisms of this antidepressant effect have been unclear—despite nasal-spray esketamine (Spravato) being marketed for multiple depressive symptom indications.

A team led by Matthew Milak, MD, and colleagues at Columbia University Medical Center found a link between an increase in ketamine dose and blood level and a suppression of brain glutamate and glutamine (Glx) in the ventro-medial prefontal cortex. They determined that this suppression mediated the relationship between ketamine dose and antidepressant effect.

GABA, a y-aminobutyric acid, had a positive correlation with Glx levels, but the team found there to be no association with clinical improvement.

The investigators enrolled 38 participants. Patietns were a mean age of 38.6, with 23 (60.5%) women, and 25 (65.8%) White. All adults were outpatients experiencing a major depressive episode, but were otherwise physically healthy, and with no history psychotropic medicine usage. Investigators excluded individuals who were not suicidal, in addition to other comorbid factors.

Patients were randomized and assigned 38:5 to receive either ketamine or placebo, respectively. The investigators noted that the disparity between group assignments was due to lack of funding.

Each patient intravenously received 1 ketamine or placebo dose of various levels (maximum 0.5 mg/kg) during a 40-minute proton magnetic resonance spectroscopy scan. This measured Glx and GABA levels in the ventro-medial prefrontal cortex in 13-minute data frames. The investigators measured ketamine and metabolite blood levels after the scan.

Following 24 hours after the ketamine was administered, they assessed clinical improvements using a 22-item version of Hamilton Depression Rating Scale (HDRS-22).

Results showed that there was a positive correlation between ketamine dose and improvements on the HDRS-22 (t₃₆ = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.4-34.11]). There was also a positive relationship between ketamine blood level and HDRS-22 score improvement (t₃₆ = 2.25; P = .03; slope estimate, 0.070 [95% CI, 0.007-0.133]).

Another significant finding revealed a strong association between a low Glx response and increased antidepressant response (t₃₃ = −2.400; P = .02; slope estimate, −9.85 [95% CI, −18.2 to −1.50]).

Although GABA levels positively correlated with Glx (t₃₃ = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382-0.638]), the team did not find it to be associated with clinical improvement (t33 = −1.552; P = .13; slope estimate, −10.67 [95% CI, −24.66 to 3.32]).

When they included ketamine dose and Glx response in a mediation analysis model, they found that dose was no longer associated with antidepressant effect.

This indicates that that the Glx response mediated the relationship between ketamine and clinical improvement.

Using patient BPRS scores to assess psychotomimetic effects, Milak and team determined that adverse effects were related to blood levels in only men (t₅ = 2.606; P = .048; estimated slope, 0.093 [95% CI, 0.001-0.186]).

There was no association between BPRS score and Glx response (t₂₂ = −0.015; P = .99; estimated slope, −0.054 [95% CI, −7.35 to 7.24]).

Addressing further steps for this study, the investigators indicated a need to assess Glx mediation in greater depth.

“Future research should seek to identify the pharmacological effects responsible for Glx response to ketamine, determining if glutamate response accounts for the Glx mediation of antidepressant response, and clarifying the downstream effects of ketamine,” they said.

The study, “Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial,” was published online in JAMA Network Open.