Low-dose ketamine modulates brain entropy in treatment-resistant depression: Results from two neuroimaging clinical trials.

Abstract

Background: Several studies have reported entropy reductions in regions of the brain associated with affective-regulatory and reward- and motivation-related processes in patients with major depressive disorder. However, whether low-dose ketamine modulates this reduction remains unclear.

Methods: We analyzed resting-state functional magnetic resonance imaging data from two single-infusion low-dose ketamine trials. Data at baseline and 3 days after infusion were analyzed. In Trial 1, patients with treatment-resistant depression were randomized to receive 0.2 or 0.5 mg/kg ketamine or normal saline. In Trial 2, patients with treatment-resistant depression and suicidal ideation were randomized to receive either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. Sample entropy was calculated from the spontaneous blood oxygenation level-dependent time series of 166 regions of interest defined by the automated anatomical labeling atlas 3.

Results: In Trial 1, increased brain entropy was observed in the gyrus rectus, cerebellar vermis I/II, substantia nigra, red nucleus, and bilateral locus coeruleus after low-dose ketamine infusion. In Trial 2, the ketamine group exhibited higher brain entropy in the left amygdala compared with the midazolam group.

Discussion: Low-dose ketamine rapidly increases brain entropy (from baseline to day 3) in frontolimbic, cerebellar, and ascending neuromodulatory regions, including the gyrus rectus, cerebellar vermis I/II, substantia nigra, red nucleus, bilateral locus coeruleus, and left amygdala. Changes in brain entropy after low-dose ketamine infusion may be associated with its rapid antidepressant and antianhedonic effects, although this relationship requires further investigation.