The investigators will use the NMDAR antagonist Ketamine combined with the AMPAR antagonist perampanel to test the following hypotheses:~Primary Hypotheses:~Perampanel pre-treatment will attenuate Ketamine's reduction of suicidal ideation as assessed 24 hours after drug infusion with a well-established suicidal ideation inventory that has been shown to be sensitive to Ketamine's anti-suicidal effects.~Perampanel pre-treatment will attenuate the antidepressant response to Ketamine as assessed 24 hours after drug infusion with the Hamilton Depression Inventory, a well-established depression inventory used extensively to test Ketamine treatment effectiveness.~Exploratory: Perampanel pre-treatment reduces the anti-suicidal effect of Ketamine directly as well as indirectly through depression symptom remission.~Eligibility will be determined by psychiatric interview, rating scales and questionnaires, and a complete physical exam with electrocardiogram and labs. Individuals found eligible will receive perampanel or placebo, in counterbalanced order, 2.5 hours before a standard, subanesthetic Ketamine infusion (0.5 mg/kg over 40 minutes). Ketamine infusions will be at least three weeks apart and individuals will complete follow-up assessments.
The purpose of this study is to test the hypothesis that the anti-depressant and anti-suicidal effects of the N-methyl-D-aspartate receptor (NMDAR) antagonist Ketamine is critically dependent on stimulation of Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid receptors (AMPAR).