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

Abstract

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 (MDD). Accumulating evidence have repeatedly shown reduced PFC GBCr in MDD, an abnormality which appears to normalize following ketamine treatment.

Methods: Fifty-six unmedicated participants with MDD were randomized to intravenous placebo (normal saline; n = 18), ketamine (0.5mg/kg; n = 19) or lanicemine (100mg; n = 19). PFC GBCr was computed using time series from functional magnetic resonance imaging (fMRI) scans that were completed at baseline, during infusion, and 24h post-treatment.

Results: Compared to placebo, ketamine significantly increased average PFC GBCr during infusion (p = 0.01) and 24h post-treatment (p = 0.02). Lanicemine had no significant effects on GBCr during infusion (p = 0.45) and 24h post-treatment (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 24h post-treatment (corrected p < 0.05). Exploratory vertex-wise analyses examining the relationship with depression improvement showed positive correlation with GBCr in the dorsal PFC during infusion and 24h post-treatment, but negative correlation with GBCr in the ventral PFC during infusion (uncorrected p < 0.01).

Conclusions: In a randomized placebo-controlled approach, the results provide the first evidence in MDD of ketamine-induced increases in PFC GBCr during infusion, and suggests that ketamine's rapid-acting antidepressant properties are related to its acute effects on prefrontal connectivity. Overall, the study findings underscore the similarity and differences between ketamine and another N-methyl-D-aspartate receptor (NMDAR) antagonist, while proposing a pharmacoimaging paradigm for optimization of novel rapid-acting antidepressants prior to testing in costly clinical trials.

Figure 1.

The effects of the study drugs on average prefrontal global connectivity. Compared to placebo, ketamine significantly increased PFC GBCr during infusion (a) and at 24-h posttreatment (b). PFC GBCr changes during and following lanicemine did not significantly differ from PFC GBCr changes in the placebo group (a and b). Delta PFC GBCr (time point minus baseline) values are the estimated marginal means covarying for study site and baseline depression severity; p values reflect the results of the time effect within each group (i.e., during/post infusion vs. baseline); and *(p < 0.05) and n.s. (p > 0.05) reflect the comparison of delta PFC GBCr between groups (i.e., drug vs. placebo). PFC: prefrontal cortex; GBCr: global brain connectivity with global signal regression.

Figure 2.

The effects of ketamine on prefrontal global connectivity during infusion. Compared to placebo, ketamine significantly increased GBCr in the red/yellow clusters.

Figure 3.

The effects of ketamine on prefrontal global connectivity at 24-h posttreatment. Compared to placebo, ketamine significantly increased GBCr in the red/yellow clusters.

Figure 4.

Statistical maps examining the correlation between percentage improvement of depression and GBCr changes during infusion of ketamine (uncorrected p ≤ 0.01). Compared to placebo, treatment response—as measured by the Beck Depression Inventory at 24-h posttreatment—is associated with increased GBCr in the dorsal PFC (red/yellow), but reduced GBCr in the ventral PFC (blue).

Figure 5.

Statistical maps examining the correlation between percentage improvement of depression and GBCr changes at 24-h posttreatment with ketamine (uncorrected p ≤ 0.01). Compared to placebo, treatment response—as measured by the Beck Depression Inventory at 24-h posttreatment—is associated with increased GBCr in the dorsal PFC (red/yellow).