Mechanism of Action Underlying Ketamine's Antidepressant Effects: The AMPA Throughput Theory in Patients With Treatment-Resistant Major Depression

Objective Work by our group and others has demonstrated that a single intravenous dose of the glutamatergic modulator ketamine consistently produces rapid (within two hours), robust, and relatively sustained (approximately one to two weeks) antidepressant effects in patients with treatment-resistant major depressive disorder (MDD) and bipolar depression. Although ketamine is an N-methyl-D-aspartate (NMDA) receptor (NMDAR) antagonist, convergent evidence from behavioral, cellular, and molecular ketamine studies supports the theory that enhanced -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity-with a concomitant increase in synaptic plasticity-is critical to its mechanism of antidepressant action and may be the key to developing analogous rapidacting antidepressants. Notably, both animal and human studies indicate that acute, sub-anesthetic ketamine infusion is associated with robust increases in gamma power. Multiple synaptic mechanisms play a role in regulating gamma oscillations, including AMPA receptor (AMPAR)-mediated depolarization and gamma aminobutyric acid (GABA) receptor-mediated inhibition. Ketamine may influence both of these systems, both by silencing GABAergic inhibitory synapses and by increasing glutamate release, thereby activating AMPARs. This clinical translational mechanistic protocol, in parallel with a preclinical study (Bench-to-Bedside Award, NIH), is designed to begin to disentangle the neurobiological underpinnings of ketamine s mechanism of antidepressant action and to develop a cross-species biomarker of target engagement (i.e., gamma power). The study will test the importance of AMPAR throughput by attempting to block the behavioral (i.e., antidepressant), electrophysiological, and biochemical effects of ketamine with an AMPAR antagonist. We first demonstrated in animal models that administering an AMPAR antagonist (NBQX) could block ketamine s antidepressant-like properties, suggesting that AMPAR neurotransmission was involved in these effects. This finding has now been replicated by multiple labs. In the present study, we propose to evaluate whether pre-treatment with perampanel, an AMPAR antagonist, blocks or reduces the acute antidepressant effects of ketamine in patients with treatment resistant depression (TRD). Further, we will examine whether AMPAR activity is important to the continued antidepressant effects of ketamine by examining whether treatment with perampanel blocks or reduces ketamine s continued antidepressant effects. Study Population 70 patients ages 18 to 70 years, with a diagnosis of MDD (without psychotic features) will be recruited for this study. Study Design This is a two-phase pathophysiological study that attempts to understand the mechanism of action of ketamine s antidepressant effects. Phase I includes a medication taper, drug-free period, and baseline testing (e.g. clinical rating scales, sEEG, TMS, MEG). In Phase II, participants will receive an open-label ketamine infusion with a randomized, double-blind, add-on intervention (perampanel vs. placebo). Two to three hours prior to receiving ketamine (0.5 mg/kg), subjects will be randomized into one of three arms. Subjects in Arm 1 will receive perampanel (8 mg p.o.), while those randomized to Arm 2 or Arm 3 will receive matching placebo. On Day 1, the second blinded oral medication will be administered after clinical rating scales are obtained. Subjects randomized to Arm 1 and 3 will receive matching placebo, while subjects randomized to Arm 2 will receive perampanel. sEEG, TMS, and MEG will be obtained again on two more occasions during Phase II. Participants who completed Phase II will also be offered one open-label ketamine treatment, during which they will be assessed for mood symptoms and possible side effects. Outcome Measures The primary outcome measure is the Montgomery-Asberg Depression Rating Scale (MADRS). Hypothesis 1: By Day 1, patients treated with ketamine who are randomized to pre-treatment with a single oral dose of the AMPAR antagonist perampanel will have significantly more depressive symptoms than those who are randomized to pretreatment with placebo, as measured by the MADRS. Hypothesis 2: By Day 2, patients treated with ketamine who were randomized to perampanel on Day 1 will have significantly more depressive symptoms than those who were randomized to placebo, as measured by the MADRS. To acquire data corroborating that ketamine s antidepressant effects are mediated through AMPARs, surrogate plasticity measures will be obtained using sEEG, TMS, and MEG. In addition, blood samples for biomarkers will also be obtained.