Rethinking MDD Through Glutamate and Neuroplasticity

Although treatment for major depressive disorder (MDD) has traditionally centered on monoaminergic antidepressants, approximately one-third of patients may not respond adequately to these agents, prompting growing interest in alternative pharmacologic targets. 

In this conversation, Michael Asbach, DMSc, PA-C, Clinical Editor, Psych Congress Journal, explores key concepts from his Psych Congress 2026 session, “Could Glutamatergic Modulation be the Keystone of Durable Change in Treatment-Resistant Depression?” Asbach discusses the limitation of traditional monoaminergic agents, explores the connection between glutamatergic signaling and neuroplasticity, and explains why conceptualizing depression as more than a chemical imbalance may lead to better care for patients with MDD.

• About one-third of patients may have treatment-resistant depression (TRD), while monoaminergic agents may require 6-8 weeks to show benefit and can cause sexual dysfunction, weight gain, and sleep disturbance. 
• Glutamate plays a critical role in learning, adaptation, and neuroplasticity, and disrupted glutamatergic signaling may contribute to impaired adaptive processes and structural brain changes in depression.
• Conceptualizing depression as dysfunction of systems, circuits, and synaptic plasticity rather than solely monoamine deficiency may provide additional targets for understanding and treating MDD.

Michael Asbach, DMSc, PA-C: My name is Mike Asbach. I'm a psych PA and I serve as the associate medical director at Dent Neurologic Institute. I'm also a proud member of the Psych Congress Steering Committee and serve as a clinical editor of Psych Congress Journal.

Psych Congress Network: What limitations of traditional monoaminergic antidepressants have driven interest in glutamatergic treatment targets? 

Asbach: As clinicians, we're very familiar with the role of monoaminergic agents for depression. This has been the standard of treatment for decades. And yet, as clinicians, we probably are also quite familiar with the shortcomings or limitations that come with monoamine therapy: Some patients don't respond. Depending on the research, about a third of patients may be treatment resistant, meaning that even after multiple lines of therapy with a monoamine agent, the depression hasn't gotten better. 

Oftentimes when we use monoamine agents, the results may take time, 6-8 weeks before we truly can see benefit. There's always been a bit of a paradox because we know that a selective serotonin reuptake inhibitor (SSRI) will immediately raise serotonin levels and yet the antidepressant effect often lags by several weeks if not several months. 

Additionally, monoamine agents may have side effects that are intolerable. Sexual dysfunction, weight gain, sleep disturbance are all things that as clinicians we've had to deal with many of our patients. 

A lot of these shortcomings are why we have so much excitement for glutamate modulation. Glutamate offers an opportunity to maybe get a little bit closer to the origin of depression.

Glutamate plays a critical role within the brain in learning and adaptation. Our understanding of depression continues to evolve away from neurotransmitter deficiency or chemical imbalance but rather looking at this in terms of systems and circuits. When we look at the role of glutamate within the brain, we know that it plays a critical role in modulating neuroplasticity.

Our brains are incredibly complex and throughout life there's adaptation that occurs. Pathways within the brain that we use a lot get reinforced and we call this long-term potentiation. Pathways that don't get used a lot may be pruned back and we call this long-term depression. 

It's critical for glutamate to play a role in how we modulate this neuroplastic process. Unfortunately, in depression, the role of glutamate can get thrown off. Those adaptive signals may not occur the way that they should, and this may lead to alterations and structural changes within the brain that lead to the depressive cascade. 

This is why we're so excited for glutamate, not only just as a potential treatment, but also as a major step forward in our understanding of how depression affects the brain at a neurobiologic level.

PCN: What does it mean to describe MDD as a disorder of synaptic plasticity rather than simply a disorder of monoamine deficiency? 

Asbach: As we evolve our understanding of MDD, we've moved away from the idea of this as just a chemical imbalance or deficiency. Let's be honest, looking backwards, the idea of MDD as a serotonin deficiency was probably too simple. And we knew that. 

Moving forward, we don't think of MDD just as an imbalance of a neurotransmitter or a chemical issue, but rather a dysfunction of systems and circuits. 

When we move to our understanding of depression as a problem of neuroplasticity, meaning the brain's adaptive mechanisms have been thrown off and are not functioning the way that they should, it also changes our perspective on how we can target treatment and how we can bring the brain back online. 

Our brains are incredible and the ability to adapt and make changes throughout our lifetime is a critical feature. This is the underlying basis of neuroplasticity. When our brains are thrown off, our ability to adapt and respond to changes is no longer happening the way that it should. We may see changes in the brain that lead to less neuronal connection, less dendritic opportunities to connect and have good synapses.

This also offers us an opportunity to better understand treatments that may restore or bring the brain back online.

Michael Asbach, DMSc, PA-C, is a doctorally trained Physician Assistant and Associate Medical Director at the DENT Neurologic Institute in Buffalo, New York. He earned his Master’s in Physician Assistant Studies from Daemen University and his Doctor of Medical Science from A.T. Still University. He also holds the Psychiatry Certificate of Added Qualification from the National Commission on Certification of Physician Assistants.

A nationally recognized educator and CME speaker, Dr. Asbach specializes in treatment-resistant depression, bipolar disorder, and emerging psychiatric therapies. He holds a faculty appointment with Shenandoah University’s Doctor of Medical Science program, teaches across multiple universities, serves on the Psych Congress Steering Committee, and is a co-chair of the Psych Congress PA Institute annual meeting.

© 2026 HMP Global. All Rights Reserved.
 
Any views and opinions expressed above are those of the author(s) and do not necessarily reflect the views, policy, or position of the Psych Congress Network or HMP Global, their employees, and affiliates.