Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression

Background: Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states. Methods: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined. Results: A reduction in Montgomery-Asberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t.5.18, P< .0001, FDR-corrected), right temporal pole (t.4.97, P< .0001, FDR-corrected), right parahippocampal gyrus (t=5.80, P..001, FDR-corrected), and left lateral occipital cortex (t=4.73, P..03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results. Conclusions: These preliminary results suggest that the lib might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.