Prefrontal Connectivity and Glutamate Transmission: Relevance to Depression Pathophysiology and Ketamine Treatment

Abstract

Background Prefrontal global brain connectivity with global signal regression (GBCr) was proposed as a robust biomarker of depression, and was associated with ketamine’s mechanism of action. Here, we investigated prefrontal GBCr in treatment-resistant depression (TRD) at baseline and following treatment. Then, we conducted a set of pharmacological challenges in healthy subjects to investigate the glutamate neurotransmission correlates of GBCr. Methods In study A, we used functional magnetic resonance imaging (fMRI) to compare GBCr between 22 TRD and 29 healthy control. Then, we examined the effects of ketamine and midazolam on GBCr in TRD patients 24h post-treatment. In study B, we acquired repeated fMRI in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction. Results In study A, TRD patients showed significant reduction in dorsomedial and dorsolateral prefrontal GBCr compared to healthy control. In TRD patients, GBCr in the altered clusters significantly increased 24h following ketamine (effect size = 1.0 [0.3 1.8]), but not midazolam (effect size = 0.5 [−0.6 1.3]). In study B, oral lamotrigine reduced GBCr 2h post-administration, while ketamine increased medial prefrontal GBCr during infusion. Lamotrigine significantly reduced the ketamine-induced GBCr surge. Exploratory analyses showed elevated ventral prefrontal GBCr in TRD and significant reduction of ventral prefrontal GBCr during ketamine infusion in healthy subjects. Conclusions This study provides first replication of the ability of ketamine to normalize depression-related prefrontal dysconnectivity. It also provides indirect evidence that these effects may be triggered by the capacity of ketamine to enhance glutamate neurotransmission.

Using Neuroimaging to Decipher the Mechanism of Action of Ketamine: A Pathway to Novel Therapeutics?

“…While the placebo and ketamine conditions were readily distinguished, the oral lamotrigine and oral placebo conditions were indistinguishable. Likewise, degree centrality maps after oral lamotrigine plus IV ketamine were indistinguishable from those after oral placebo plus IV ketamine, in contrast to the present finding by Abdallah et al (3). …”

“…Although the present analysis was restricted to the PFC, it would be interesting to find out whether the original findings of increased GBCr in the posterior cingulate (a default mode network core region) were also replicated. In the present study, Abdallah et al (3) also found that GBCr within the mPFC increased in the 10 subjects scanned 24 hours after ketamine infusion; no significant change in GBCr was observed after the active placebo midazolam. This increase in GBCr, however, did not correlate with clinical improvements after ketamine infusion, although baseline GBCr levels were associated with subsequent changes in mood after both midazolam and ketamine infusions.…”

“…As noted above, mechanistic studies and pharmacologic challenge studies—such as the one by Abdallah et al (3) and the others mentioned herein—are welcome additions to the literature. In particular, Abdallah etal .’s replication of previous work is a commendable contribution to the current replicability crisis across science.…”

“…In this context, mechanistic studies, such as the one performed by Abdallah et al (3) that appears in this issue of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, are not only needed but crucial to antidepressant drug development. Their study had two components.…”

“…In the second substudy, Abdallah et al (3) found reductions in mPFC GBCr in healthy subjects after a single 300-mg dose of oral lamotrigine plus intravenous (IV) saline compared to oral placebo plus IV saline. The authors also noted that oral lamotrigine attenuated the GBCr increase seen after ketamine infusion compared with the oral placebo.…”