The antidepressant efficacy of subanesthetic-dose ketamine does not correlate with baseline subcortical volumes in a replication sample with major depressive disorder

Abstract

Background This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. Methods Unmedicated subjects with treatment-resistant MDD (n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion). Results Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects (n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers (n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine. Conclusion Baseline subcortical volumes implicated in MDD did not correlate with ketamine’s antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker.

Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis

“…In the exploratory analysis in our sample, baseline volumes of the right thalamus and left Sub head in the hippocampus were positively correlated with changes in MADRS scores, such that patients with relatively larger right thalamus and left Sub head volumes had greater improvements in depressive symptoms following six doses of ketamine. These findings disagreed with the findings of previous studies that showed that patients with smaller pretreatment hippocampal volumes were more likely to achieve better clinical improvements and that smaller left and right thalamic volumes were correlated with the antidepressant response to ketamine in BDNF 66Met allele carriers 18,22 . However, the present findings were in line with those of our previous study that showed that patients with better neurocognitive function, an index that could reflect hippocampal function, may be more likely to benefit from ketamine treatment 24 .…”

“…Abdallah et al 18 tested the pretreatment hippocampal volume in 13 MDD patients who received a single infusion of ketamine and found a smaller left hippocampus volume was correlated with a greater symptom improvement 24 h after the infusion 18 . Niciu and colleagues reported that baseline subcortical volumes were not related to the antidepressant response in 55 unmedicated patients with treatment-resistant depression (TRD) within 24 h of a single infusion of ketamine 22 . However, combined with the brain-derived neurotrophic factor (BDNF) genotype, baseline bilateral thalamic volume was positively correlated with ketamine's antidepressant response in met carriers.…”

“…Hippocampal atrophy was found in flinders sensitive line (FSL) rats, but a single dose of ketamine was able to increase volumes of the hippocampal cornu ammonis (CA)1 and granule cell layer (GCL) regions within 24 h of its infusion 16 . Clinical studies of depression have reported that neural structural plasticity within subcortical regions is associated with ketamine treatment 17 – 22 . Abdallah et al 18 tested the pretreatment hippocampal volume in 13 MDD patients who received a single infusion of ketamine and found a smaller left hippocampus volume was correlated with a greater symptom improvement 24 h after the infusion 18 .…”

The dentate gyrus in depression

“…Notably, preliminary data on the role of fast‐acting antidepressants on mediating changes in the volume of the DG support the idea that antidepressant treatment does not restore the lost volume. A recent study did not identify a correlation between hippocampal volume changes and clinical efficacy of ketamine (Niciu et al, 2017).…”

Adenosinergic-Dopaminergic Signaling in Mood Disorders: A Mini-Review

“…127 These data suggest that a deeper investigation in the regulatory mechanisms of glutamate/GABA balance is of interest, 123,126 and adenosine-dopamine signaling might play an important role, 125 especially considering the glutamate-GABA modulatory effect of both A 2A and D 2 receptors individually. 128,129 The aforementioned findings regarding the A 2A receptor and the D 2 receptor in GABAergic neurons were the first evidence of a possible role of adenosine-dopamine receptors integrated functional control of neuropsychiatric symptoms; however, there is emerging evidence of other heteromers' participation. As the role of the D 3 receptor in mood disorders is being investigated, 69,78,130 the antagonistic modulation of A 2A -D 3 heteromer is proposed as a possible antischizophrenic approach.…”