Research paperPersistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: A randomized control study

•The persistent antidepressant effect of a low-dose ketamine infusion was mediated by increased activation in the SMA and dACC.•The higher increase in dACC activation was related to the reduction in depressive symptoms after ketamine infusion.•A single optimal low-dose ketamine infusion facilitated the glutamatergic neurotransmission in the SMA and dACC.

BackgroundA single low-dose ketamine infusion exhibited a rapid antidepressant effect within 1 h. Despite its short biological half-life (approximately 3 h), the antidepressant effect of ketamine has been demonstrated to persist for several days. However, changes in brain function responsible for the persistent antidepressant effect of a single low-dose ketamine infusion remain unclearMethodsTwenty-four patients with treatment-resistant depression (TRD) were randomized into three groups according to the treatment received: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and normal saline infusion. Standardized uptake values (SUVs) of glucose metabolism measured through 18F-FDG positron-emission-tomography before infusion and 1 day after a 40-min ketamine or normal saline infusion were used for subsequent whole-brain voxel-wise analysis and were correlated with depressive symptoms, as defined using the Hamilton Depression Rating Scale-17 (HDRS-17) scoreResultsThe voxel-wise analysis revealed that patients with TRD receiving the 0.5 mg/kg ketamine infusion had significantly higher SUVs (corrected for family-wise errors, P = 0.014) in the supplementary motor area (SMA) and dorsal anterior cingulate cortex (dACC) than did those receiving the 0.2 mg/kg ketamine infusion. The increase in the SUV in the dACC was negatively correlated with depressive symptoms at 1 day after ketamine infusionDiscussionThe persistent antidepressant effect of a 0.5 mg/kg ketamine infusion may be mediated by increased activation in the SMA and dACC. The higher increase in dACC activation was related to the reduction in depressive symptoms after ketamine infusion. A 0.5 mg/kg ketamine infusion facilitated the glutamatergic neurotransmission in the SMA and dACC, which may be responsible for the persistent antidepressant effect of ketamine much beyond its half-life.