Antidepressant and antisuicidal effects of ketamine on the functional connectivity of prefrontal cortex-related circuits in treatment-resistant depression: A double-blind, placebo-controlled, randomized, longitudinal resting fMRI study

Background: Increasing evidence suggests that infusion of a subanesthetic dose of ketamine exerts antidepressant and antisuicidal effects in patients with treatment-resistant depression (TRD). Aims: In this investigation, we used the resting functional connectivity magnetic resonance imaging (fcMRI) to determine the effects of ketamine on the functional connectivity (FC) of prefrontal cortex (PFC)-related circuits in patients with TRD. Methods: Forty-eight patients with TRD were recruited and randomly divided into three groups on the basis of ketamine infusion dose: 0.5 mg/kg (standard dose), 0.2 mg/kg (low dose), or normal saline (a placebo infusion). Resting functional MRI data and clinical data were recorded at the baseline and on the third day after ketamine infusion treatment. Results: The standard-dose group showed a reduction in the FC of the left dorsal anterior cingulate cortex (dACC) and right dorsolateral (dl)PFC with the other frontal regions. The low-dose group demonstrated a more pervasive reduction of FC in the bilateral dACC with other frontal and parietal regions. A negative correlation was observed between the reduction in suicidal ideation and the reduction in the FC between the left dACC and right ACC regions in the standard-dose group, whereas a positive correlation was observed between the reduction in suicidal ideation and the increase in the FC between the right dlPFC and left superior parietal region in the low-dose group. Conclusions: Our results support the hypothesis that PFC-related circuit modulation is crucial to the antidepressant and antisuicidal effects of the ketamine infusion treatment.