Gueorguieva, R. | bioRxiv Science

bioRxiv2023

Ketamine Effects on Energy Metabolism, Functional Connectivity and Working Memory in Healthy Humans

Working memory (WM) is a crucial resource for temporary memory storage and the guiding of ongoing behavior. N-methyl-D-aspartate glutamate receptors (NMDARs) are thought to support the neural underpinnings of WM. Ketamine is an NMDAR antagonist that has cognitive and behavioral effects at subanesthetic doses. To shed light on subanesthetic ketamine effects on brain function, we employed a multimodal imaging design, combining gas-free calibrated functional magnetic resonance imaging (fMRI) measurement of oxidative metabolism (CMRO2), resting-state cortical functional connectivity assessed with fMRI, and WM-related fMRI. Healthy subjects participated in two scan sessions in a randomized, double-blind, placebo-controlled design. Ketamine increased CMRO2 and cerebral blood flow (CBF) in prefrontal cortex (PFC) and other cortical regions. However, resting-state cortical functional connectivity was not affected. Ketamine did not alter CBF-CMRO2 coupling brain-wide. Higher levels of basal CMRO2 were associated with lower task-related PFC activation and WM accuracy impairment under both saline and ketamine conditions. These observations suggest that CMRO2 and resting-state functional connectivity index distinct dimensions of neural activity. Ketamines impairment of WM-related neural activity and performance appears to be related to its ability to produce cortical metabolic activation. This work illustrates the utility of direct measurement of CMRO2 via calibrated fMRI in studies of drugs that potentially affect neurovascular and neurometabolic coupling.

neuroscience↗

bioRxiv2018

Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, Triples the antidepressant Response Rate of Ketamine at 2 Weeks Following Treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trial

BACKGROUNDKetamine exerts rapid and robust antidepressant effects thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine.\n\nMETHODSTwenty-three patients suffering a major depressive episode were randomized to oral rapamycin (6 mg) or placebo, each was followed 2 hours later by ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-[A]sberg Depression Rating Scale (MADRS). Antidepressant response was defined as a MADRS improvement of 50% or more.\n\nRESULTSOver the two-week follow-up, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), reflecting prolonged antidepressant effects post rapamycin+ketamine treatment. At 2 weeks, we found a significantly higher response rate following rapamycin+ketamine (41%) compared to placebo+ketamine (13%, p = 0.04). However, rapamycin pretreatment did not alter the acute effects of ketamine.\n\nCONCLUSIONUnexpectedly, pretreatment with rapamycin prolonged rather than blocked the acute antidepressant effects of ketamine. This observation raises questions about the role of mTORC1 in the antidepressant effects of keta-mine, raises the possibility that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that limit the duration of ketamine effects. The supplementing of ketamine with rapamycin may be a treat-ment strategy for reducing the frequency of ketamine infusions during maintenance treatment.

neuroscience↗