Esketamine: the first glutamatergic drug for the management of treatment- resistant depression

Intranasal esketamine has been recently approved by the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment-resistant depression in adults and will be soon clinically available also in Italy. Esketamine is the (S) enantiomer of ketamine, a non-competitive N-Methyl-D-aspartate (NMDA) glutamate receptor antagonist, introduced in clinics as anesthetic and analgesic since over 50 years ago. Due to its dissociative properties and abuse/misuse potential, ketamine is also widespread used at high dose as recreational drug.
Accumulating clinical studies demonstrated that the off-label use of low-dose ketamine infusion in severe depressed treatment-resistant patients produces a rapid and sustained antidepressant effect, with only transient and mild dissociative side effects. Although short/medium-long efficacy and safety of repeated intranasal esketamine has been demonstrated in well-powered clinical studies, few is still known about the cellular/molecular mechanisms underlying its nonpareil antidepressant effect. Therefore, if on one hand long-term benefit/risk assessment with careful monitoring of cognition and behavior are still missing, the in-depth study of fast antidepressant effect, together with the search of alternative drugs acting on the same targets, are required.
Overall, despite the limitations and some skepticism of part of the scientific community, esketamine can be considered the first drug approved as rapid-acting antidepressant, with a new mechanism of action implying the direct modulation of glutamate transmission and neuroplasticity.