Glutamatergic Modulators for Major Depression from Theory to Clinical Use.

Glutamate signaling has emerged as a promising target for treating major depressive disorder (MDD), a chronic condition where standard monoamine antidepressants often have delayed effects and low remission rates. This narrative review describes how glutamate dysregulation is linked to depression, based on preclinical evidence and the rapid improvement seen with ketamine in a proof-of-concept trial. While many NMDA-targeted therapies have been investigated in phase 2 or 3 trials, most were discontinued. However, two glutamate-targeted antidepressants are now FDA-approved: nasal esketamine (Spravato) for treatment-resistant depression and MDD with suicidal ideation, and oral dextromethorphan-bupropion (Auvelity) for MDD in adults. These approvals highlight glutamate's role and offer new treatment options.

Study at a glance

Abstract

Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2 decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato®) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan-bupropion (AXS-05, Auvelity® extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants.