Although there are other proposed downstream mechanisms by which it could exert antidepressant effect, ketamine is best defined as a NMDA receptor antagonist. Perampanel (Fycompa), an AMPA receptor antagonist, was approved for use in the adjunct treatment of epilepsy in 2012 despite motor-impairing effects at higher doses. Modulating metabotropic glutamate receptors (mGluRs) might circumvent the side effects of ion channel blockage. mGluR agonists have been studied in schizophrenia, and mGluR antagonists, in depression, so far with mixed results. Allopregnanolone (FDA approved for postpartum depression) is an example of a neurosteroid analog.

Publication reference : Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 2018; 23: 801-11
Reference URL: https://pubmed.ncbi.nlm.nih.gov/29532791/