Since the discovery of its rapid-acting antidepressant properties, ketamine has helped stimulate a new line of research in the development of rapid-acting antidepressants based on the glutamate and gamma-aminobutyric acid neurotransmitter systems. An intranasal version of the S-enantiomer of ketamine (esketamine) recently received regulatory approval as a therapy for treatment-resistant depression (TRD). Here we review the clinical evidence of esketamine for TRD, challenges to its adoption in clinical practice, and the regulatory requirements imposed by the US Food and Drug Administration (FDA) through a risk evaluation and mitigation strategy (REMS). Brexanolone, an exogenous formulation of allopregnanolone, also recently received FDA approval for the treatment of postpartum depression and is likewise subject to a REMS. Other compounds in late-stage development, including AXS-05 and SAGE-217, are also reviewed.
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