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

• Published in: Biological psychiatry : cognitive neuroscience and neuroimaging Vol. 2; no. 7; pp. 566 - 574
• Main Authors: Abdallah, Chadi G., M.D, Averill, Christopher L., B.S, Salas, Ramiro, Ph.D, Averill, Lynnette A., Ph.D, Baldwin, Philip R., Ph.D, Krystal, John H., M.D, Mathew, Sanjay J., M.D, Mathalon, Daniel H., Ph.D., M.D
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2017
• Subjects: Functional MRI; Global brain connectivity; Glutamate; Ketamine; Psychiatry; Rapid-acting antidepressants; Treatment-resistant depression; functional MRI; rapid acting antidepressants; Treatment resistant depression; ketamine; global brain connectivity; glutamate; Functional MRI; Rapid-acting antidepressants; Ketamine; Global brain connectivity; Glutamate; Treatment-resistant depression
• ISSN: 2451-9022; 2451-9030; 2451-9030
• DOI: 10.1016/j.bpsc.2017.04.006

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 ( f MRI) 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 f MRI in 18 healthy subjects to determine the effects of lamotrigine (a glutamate release inhibitor), ketamine, and lamotrigine-by-ketamine interaction. Results In study B, 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.