Esketamine: the first glutamatergic drug for the management of treatment- resistant depression
October 1, 2020 DOI: 10.36118/pharmadvances.03.2020.02 via OpenAlex
Summary
Intranasal esketamine has been approved for treatment-resistant depression in adults and is soon to be available in Italy. It is the (S) enantiomer of ketamine, which acts as a non-competitive NMDA glutamate receptor antagonist. Clinical studies show that low-dose ketamine infusions can produce rapid antidepressant effects with mild side effects. However, long-term safety and cognitive impacts are still not fully understood, highlighting the need for further research into its mechanisms and alternative treatments.
Study at a glance
| Population | adults with treatment-resistant depression |
|---|---|
| Key finding | Esketamine is considered the first drug approved as a rapid-acting antidepressant, directly modulating glutamate transmission and neuroplasticity. |
Abstract
Intranasal esketamine has been recently approved by both 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.