Targeting of Glutamatergic Pathway for Management of Treatment Resistant Depression

In this episode, Dr Anita Clayton and experts discuss targeting of glutamatergic pathway for TRD.

Dr. Citrome contextualized the evolution of antidepressant treatment by noting that decades of pharmacotherapy have focused almost exclusively on increasing monoamines — serotonin, norepinephrine, and dopamine — at the synapse, with atypical antipsychotics simply modulating those same pathways. Targeting glutamate signaling represents a fundamentally different and more upstream approach.

Glutamate plays a critical role in synaptogenesis and neuroplasticity, and preclinical evidence translated to human studies has established its involvement in depression. By acting on NMDA receptors and increasing AMPA receptor activity, these agents initiate a downstream cascade that promotes synaptogenesis — essentially helping to rebuild neural connections disrupted by depression.

Two glutamatergic agents are currently available. Esketamine nasal spray, approved in 2019 for TRD and in 2020 for MDD with acute suicidal ideation, acts directly on NMDA receptors. The oral combination of dextromethorphan-bupropion, approved in 2022, works similarly — with dextromethorphan performing the primary NMDA receptor modulation, along with sigma-1 receptor activity, while bupropion enhances its bioavailability.

In the next episode, “Factors Guiding Treatment Selection in Treatment Resistant Depression,“ panelists discuss how treatment selection in TRD should be guided by patient preference, logistics, and clinical profile, while highlighting the rapid onset and functional impact of glutamatergic therapies as compelling reasons to consider them earlier in treatment.