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Abstract
A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose (t36 = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36 = 2.25; P = .03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response (t33 = -2.400; P = .02; slope estimate, -9.85 [95% CI, -18.2 to -1.50]). Although GABA levels correlated with Glx (t33 = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382 to 0.638]), GABA response did not correlate with antidepressant effect. When both ketamine dose and Glx response were included in a mediation analysis model, ketamine dose was no longer associated with antidepressant effect, indicating that Glx response mediated the relationship. Adverse effects were related to blood levels in men only (t5 = 2.606; P = .048; estimated slope, 0.093 [95% CI, 0.001 to 0.186]), but Glx and GABA response were not related to adverse effects. In this study, intravenous ketamine dose and blood levels correlated positively with antidepressant response. The Glx response correlated inversely with ketamine dose and with antidepressant effect. Future studies are needed to determine whether the relationship between Glx level and antidepressant effect is due to glutamate or glutamine. ClinicalTrials.gov Identifier: NCT01558063.
Highlights
GABA levels correlated with Glx (t33 = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382 to 0.638]), GABA response did not correlate with antidepressant effect
When both ketamine dose and Glx response were included in a mediation analysis model, ketamine dose was no longer associated with antidepressant effect, indicating that Glx response mediated the relationship
We previously reported on an open pilot Major depressive disorder (MDD) study that showed, consistent with glutamate increases in rodent studies,[22,23] that ketamine induces an acute increase in ventro-medial prefrontal cortex levels of the combined resonance of glutamate and glutamine (Glx), measured with proton magnetic resonance spectroscopy (1H MRS).[24]
Summary
Major depressive disorder (MDD), a leading cause of disability worldwide,[1] affects more than 16 million adults in the United States,[2] with estimated costs of $210.5 billion in 2010, a 21.5% increase from 2005.3 Response to currently marketed antidepressants generally requires treatment for 6 to 8 weeks,[4] and they are ineffective in 30% to 50% of patients.[5,6] Faster-acting and more effective antidepressants are needed.A single intravenous (IV) subanesthetic dose of ketamine can produce an antidepressant response in hours instead of weeks, even in medication-resistant MDD.[7,8,9,10,11,12,13,14,15,16] Ketamine has antidepressant benefit in both patients with MDD17,18 and those with bipolar depression.[19]. Adverse effects of ketamine include transient depersonalization and derealization, among other psychotomimetic and dissociative symptoms.[20,21] Understanding the mechanism of its rapid-onset antidepressant action may aid identification of alternative medications that can be used orally, have fewer adverse effects, and have less abuse potential
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