Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study

Abstract

Background: Multiple lines of evidence support a role for the glutamatergic system in the pathophysiology of major depressive disorder (MDD). Ketamine, an N-methyl-D-aspartate antagonist, rapidly improves depressive symptoms in individuals with treatment-resistant depression. The neural mechanisms underlying this effect remain unknown.

Methods: In this preliminary study, 20 unmedicated participants with treatment-resistant MDD underwent positron emission tomography to measure regional cerebral glucose metabolism at baseline and following ketamine infusion (single dose of .5mg/kg intravenous over 40minutes). Metabolic data were compared between conditions using a combination of region-of-interest and voxelwise analyses, and differences were correlated with the associated antidepressant response.

Results: Whole-brain metabolism did not change significantly following ketamine. Regional metabolism decreased significantly under ketamine in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices of the right hemisphere. Metabolism increased postketamine in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices. Improvement in depression ratings correlated directly with change in metabolism in right superior and middle temporal gyri. Conversely, clinical improvement correlated inversely with metabolic changes in right parahippocampal gyrus and temporoparietal cortex.

Conclusions: Although preliminary, these results indicate that treatment-resistant MDD subjects showed decreased metabolism in the right habenula and the extended medial and orbital prefrontal networks in association with rapid antidepressant response to ketamine. Conversely, metabolism increased in sensory association cortices, conceivably related to the illusory phenomena sometimes experienced with ketamine. Further studies are needed to elucidate how these functional anatomical changes relate to the molecular mechanisms underlying ketamine's rapid antidepressant effects.

Figure 1

Region placement of the habenula on a representative subject. Medial thalamic region of interest (ROI) is also visible.

Figure 2

Coronal image sections obtained with a statistical parametric map of t-values software (SPM5) (Wellcome Department of Imaging Neuroscience, London, UK) illustrating key findings from voxelwise analysis of ketamine-induced metabolic changes in a group of individuals with treatment-resistant major depressive disorder (MDD; N=20). The color bar designates the corresponding voxel t-statistic value. Clusters are overlaid on a canonical single subject image, with t-maps thresholded to show only the relevant cluster. (A) Glucose metabolism decreased in the right habenula. The peak voxel from the habenula cluster in the voxelwise analysis shown here is located at coordinates 6, −32, 4 (x, y, z). This voxelwise finding corresponds with the finding in the region of interest (ROI) analysis of a significant decrease in the right habenula ROI following ketamine infusion (Table 2). (B) Decreased metabolism in the right insula was the most robust (i.e., peak t-value) finding in the voxelwise analysis (Table 4).