Abstract
Twenty-four hours after administration, ketamine exerts rapid and robust antidepressant effects that are 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. Twenty patients suffering a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo 2 h prior to the intravenous administration of 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–Åsberg Depression Rating Scale (MADRS). Rapamycin pretreatment did not alter the antidepressant effects of ketamine at the 24-h timepoint. Over the subsequent 2-weeks, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), suggesting a prolongation of the antidepressant effects of ketamine by rapamycin. Two weeks following ketamine administration, we found higher response (41%) and remission rates (29%) following rapamycin + ketamine compared to placebo + ketamine (13%, p = 0.04, and 7%, p = 0.003, respectively). In summary, single dose rapamycin pretreatment failed to block the antidepressant effects of ketamine, but it prolonged ketamine’s antidepressant effects. This observation raises questions about the role of systemic vs. local blockade of mTORC1 in the antidepressant effects of ketamine, provides preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration.
Highlights
INTRODUCTION Ketamine is anN-methyl-D-aspartate receptor (NMDAR) antagonist that exerts rapid and robust antidepressant effects [1, 2]
The antidepressant effects may emerge within hours of a single dose, but without additional ketamine doses, relapse typically occurs in 3–14 days [3,4,5]
Ketamine and its metabolites are believed to exert antidepressant effects primarily by inducing a prefrontal glutamate neurotransmission surge leading to activation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs), which increases brain-derived neurotrophic factor (BDNF) levels, enhances stimulation of TrkB receptors, activates the mechanistic target of rapamycin complex 1, and produces synaptogenesis [6,7,8,9]
Summary
INTRODUCTION Ketamine is anN-methyl-D-aspartate receptor (NMDAR) antagonist that exerts rapid and robust antidepressant effects [1, 2]. Ketamine and its metabolites are believed to exert antidepressant effects primarily by inducing a prefrontal glutamate neurotransmission surge leading to activation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs), which increases brain-derived neurotrophic factor (BDNF) levels, enhances stimulation of TrkB receptors, activates the mechanistic target of rapamycin complex 1 (mTORC1), and produces synaptogenesis [6,7,8,9]. A single infusion of rapamycin into the medial prefrontal cortex (PFC) prior to ketamine injection in rodents was reported to block the neuroplasticity and antidepressant-like effects of ketamine [10, 16]. Following an experimental paradigm derived from animal research [10, 16], we aimed to demonstrate in patients the observation that rapamycin blocks the antidepressant-like effects of ketamine [10, 16]
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