Shorter to be effective: subanesthetic-dose ketamine infusion reduces the global and regional path length of brain functional connectivity in patients with treatment-resistant depression and suicidal ideation

Psychopharmacology (Berl). 2026 May 22. doi: 10.1007/s00213-026-07089-6. Online ahead of print.

ABSTRACT

BACKGROUND: Studies have demonstrated that subanesthetic-dose ketamine may modulate the functioning of specific depression-related brain regions, particularly the anterior cingulate cortex and prefrontal cortex. However, how subanesthetic-dose ketamine alters the global and regional graph theory metrics of resting-state functional connectivity in patients with treatment-resistant depression (TRD) and strong suicidal symptoms remains unclear.

METHODS: We conducted a randomized, double-blinded, resting-state functional magnetic resonance imaging clinical trial in patients with TRD and strong suicidal symptoms. These patients received either subanesthetic-dose ketamine (0.5 mg/kg, n = 21) or midazolam (0.045 mg/kg, n = 22). Neuroimaging was performed before infusion and on day 3 after infusion. A graph theory analysis was conducted to calculate global and regional metrics after infusion.

RESULTS: Compared with the midazolam group, the ketamine group exhibited a substantially lower mean global path length after infusion. Specifically, in patients who received subanesthetic-dose ketamine treatment, the regional path lengths were decreased in key depression-related brain regions such as the anterior cingulate cortex, posterior cingulate cortex, supplementary motor area, superior parietal lobule, and superior frontal gyrus.

DISCUSSION: Decreased global and regional path lengths suggest improved network integration following subanesthetic-dose ketamine treatment in patients with TRD and strong suicidal symptoms. Further studies are required to validate our findings.

PMID:42168548 | DOI:10.1007/s00213-026-07089-6