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.
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