The Impact of AMPA Receptor Blockade on Ketamine’s Anti-suicidal Effects

The FDA recently approved esketamine for the treatment of individuals with treatment-resistant depression and suicidal ideation. This approval is an important milestone in the development of the first medication for rapidly reducing suicidal ideation. There is increasing evidence that the N-methyl-D-aspartate (NMDA) receptor antagonists esketamine and ketamine can rapidly reduce suicidal ideation, potentially saving many lives. Understanding the neurobiological underpinnings of this discovery would help us better understand the biological bases of suicidality and its potential cures. Translational neuroscience research suggests that the key step to ketamine's anti-depressant effects may be α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA) receptor stimulation. The neurobiological basis of its anti-suicidal properties is unknown. This application proposes the first test of the central hypothesis that AMPA receptor stimulation is critical to ketamine's antidepressant and anti-suicidal properties by employing an FDA-approved AMPA receptor antagonist, perampanel. Subjects will be individuals currently in a major depressive episode with at least passive suicidal ideation. Each subject will receive two ketamine administrations separated by at least three weeks. They will receive perampanel or placebo prior to ketamine administration in a double-blinded, within-subjects counterbalanced design. Suicidal and depressive ideation will be assessed before each ketamine administration. Subjects will be carefully followed for three weeks after each ketamine administration. Individuals will be screened into the study with the Columbia-Suicide Severity Rating Scale and suicidality will be tracked during the trial with a suicide item from the Hamilton Depression Rating Scale, Beck's Scale for Suicide Ideation, and daily suicidal ideation logs. Depression will be assessed with the Hamilton Depression Rating Scale.