Low-dose ketamine modulates brain entropy in treatment-resistant depression: Results from two neuroimaging clinical trials.
Ying-Jay Liou, Li-Kai Cheng, Wei-Chen Lin, Tung-Ping Su, Li-Fen Chen, Pei-Chi Tu, Cheng-Ta Li, Ya-Mei Bai, Shih-Jen Tsai, Mu-Hong Chen
Journal of Affective Disorders October 26, 2026 DOI: 10.1016/j.jad.2026.122673 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Secondary analysis of two randomized controlled trials Peer reviewed |
|---|---|
| Population | Patients with treatment-resistant depression (Trial 1) and patients with treatment-resistant depression and suicidal ideation (Trial 2) |
| Interventions | Ketamine Midazolam Normal saline |
| Dose | 0.2 or 0.5 mg/kg ketamine; 0.045 mg/kg midazolam |
| Duration | Single infusion, with data analyzed at baseline and 3 days after infusion |
| Measures | Sample entropy |
| Topics | Depression Esketamine Ketamine |
| Keywords | Amygdala Brain entropy Clinical trial Locus coeruleus Low-dose ketamine |
| Key findings | Low-dose ketamine increased 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. The authors suggest these entropy changes may be associated with ketamine's rapid antidepressant and antianhedonic effects, though they state this relationship requires further investigation. |
Abstract
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. 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. 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. 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.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.