Recent Developments in Pharmacotherapy of Depression: Bench to Bedside.

For 70 years depression treatment was limited by the monoamine hypothesis until the approval of the S-enantiomer of ketamine, an NMDA receptor blocker with rapid antidepressant and antisuicidal effects. Dextromethorphan, another NMDA receptor antagonist, has also been approved for depression in combination with bupropion. The GABA-A receptor modulator brexanolone has shown relatively rapid antidepressant efficacy. However, clinical utility is compromised by high drug costs, mandatory monitoring requirements, parenteral administration, lack of insurance coverage, COVID-19 effects on healthcare systems, and psychopharmacology training gaps. This narrative review analyzes the clinical pharmacology of recently approved antidepressants and barriers to bench-to-bedside translation. Overall, meaningful advances have not reached many depressed patients, including those with treatment-resistant depression who might benefit most.

Study at a glance

Abstract

For the last 70 years, we did not move beyond the monoamine hypothesis of depression until the approval of the S-enantiomer of ketamine, an N-methyl-D-aspartate (NMDA) receptor blocker and the first non-monoaminergic antidepressant characterized by rapid antidepressant and antisuicidal effects. A similar profile has been reported with another NMDA receptor antagonist, dextromethorphan, which has also been approved to manage depression in combination with bupropion. More recently, the approval of a positive allosteric modulator of GABA-A receptors, brexanolone, has added to the list of recent breakthroughs with the relatively rapid onset of antidepressant efficacy. However, multiple factors have compromised the clinical utility of these exciting discoveries in the general population, including high drug acquisition costs, mandatory monitoring requirements, parenteral drug administration, lack of insurance coverage, indirect COVID-19 effects on healthcare systems, and training gaps in psychopharmacology. This narrative review aims to analyze the clinical pharmacology of recently approved antidepressants and discuss potential barriers to the bench-to-bedside transfer of knowledge and clinical application of exciting recent discoveries. Overall, clinically meaningful advances in the treatment of depression have not reached a large proportion of depressed patients, including those with treatment-resistant depression, who might benefit the most from the novel antidepressants.