Ketamine, but Not the NMDAR Antagonist Lanicemine, Increases Prefrontal Global Connectivity in Depressed Patients

Background Identifying the neural correlates of ketamine treatment may facilitate and expedite the development of novel, robust, and safe rapid-acting antidepressants. Prefrontal cortex (PFC) global brain connectivity with global signal regression (GBCr) was recently identified as a putative biomarker of major depressive disorder. Accumulating evidence have repeatedly shown reduced PFC GBCr in major depressive disorder, an abnormality that appears to normalize following ketamine treatment. Methods Fifty-six unmedicated participants with major depressive disorder were randomized to intravenous placebo (normal saline; n = 18), ketamine (0.5 mg/kg; n = 19), or lanicemine (100 mg; n = 19). PFC GBCr was computed using time series from functional magnetic resonance imaging scans that were completed at baseline, during infusion, and at 24-h posttreatment. Results Compared to placebo, ketamine significantly increased average PFC GBCr during infusion ( p = 0.01) and at 24-h posttreatment ( p = 0.02). Lanicemine had no significant effects on GBCr during infusion ( p = 0.45) and at 24-h posttreatment ( p = 0.23) compared to placebo. Average delta PFC GBCr (during minus baseline) showed a pattern of positively predicting depression improvement in participants receiving ketamine ( r = 0.44; p = 0.06; d = 1.0) or lanicemine ( r = 0.55; p = 0.01; d = 1.3) but not those receiving placebo ( r = −0.1; p = 0.69; d = 0.02). Follow-up vertex-wise analyses showed ketamine-induced GBCr increases in the dorsolateral, dorsomedial, and frontomedial PFC during infusion and in the dorsolateral and dorsomedial PFC at 24-h posttreatment ( corrected p