Breaking Through Trauma and Depression: How Glutamate May Hold the Key

As a psychiatric provider, one of the hardest parts of my work is meeting people who’ve tried treatment after treatment for depression—only to feel little or no relief. I see the frustration, the exhaustion, and the self-blame that can come when antidepressants don’t seem to work. If this sounds familiar, please know this: it’s not your fault, and you are not alone.

We’ve known for a long time that standard antidepressants, like SSRIs, don’t work for everyone. For many people, depression treatment can feel like trial and error, with long waits to see if a medication might help. Meanwhile, depression continues to drain energy, cloud focus, and strain relationships, often taking a toll on physical health as well.

Why Trauma Can Make Depression More Stubborn

One group I see struggling most are those with depression linked to trauma—especially people who have lived through childhood adversity, neglect, or abuse. Research is showing that depression connected to trauma may actually function a bit differently in the brain and body than depression without trauma.

For example, people with trauma-related depression often experience:

• More severe symptoms, including higher risk for suicidal thoughts or behaviors.

• Cognitive difficulties, like slower processing, trouble concentrating, or problems with planning.

• Greater sensitivity to stress, linked to changes in brain development, inflammation, and metabolism.

  
  

We also know that inflammation plays a big role here. People with trauma-related depression often have higher levels of inflammatory markers in their blood—things like CRP, IL-6, and TNF-α. This inflammation seems to interfere with the brain’s chemistry, blunting the effects of medications that focus mainly on serotonin.

Looking Beyond Serotonin: The Role of Glutamate

Traditionally, antidepressants have targeted serotonin, norepinephrine, or dopamine. But another important player in the brain has been gaining attention: glutamate.

Glutamate is the brain’s main “on switch,” the chemical messenger that helps neurons talk to each other. But when trauma and inflammation disrupt this system, things can go haywire. The result? Overstimulation of certain brain receptors, toxic stress on brain cells, and reduced levels of BDNF—a protein that supports brain repair and resilience.

In other words, inflammation may be short-circuiting the brain’s ability to adapt and heal.

A New Frontier: Glutamatergic Treatments

This is where things get exciting. Newer treatments called glutamatergic modulators aim to rebalance this system. Instead of only tweaking serotonin, these treatments work more directly on glutamate pathways, and some also reduce inflammation.

Here are a few examples I discuss with patients:

• Ketamine and Esketamine (Spravato®): Fast-acting treatments that target NMDA receptors, with strong results in treatment-resistant depression.

• Auvelity: oral combination of dextromethorphan and bupropion that modulates glutamate.

• Vortioxetine (Trintellix®): A multimodal antidepressant that affects serotonin and glutamate, with evidence of benefit in trauma-related depression.

• Lamotrigine: Often thought of as a mood stabilizer, also believed to modulate glutamate release.

• D-cycloserine: An antibiotic as well as a NMDA receptor partial agonist, still being studied.

  
  

Why This Matters for You

These aren’t one-size-fits-all solutions, but they’re expanding our toolkit. If antidepressants haven’t helped you in the past, it may mean your depression has a different biological fingerprint—and needs a different approach.

The future of psychiatry is moving toward personalized medicine—matching treatments not just to symptoms, but to your biology, history, and lived experience. For those living with trauma-related depression, glutamatergic treatments are giving us new reasons for hope.

My Takeaway for Patients

• Trauma-related depression is real, and it often responds differently than other types.

• Inflammation and glutamate imbalances may explain why traditional antidepressants don’t always help.

• Newer treatments like ketamine/esketamine, vortioxetine, and lamotrigine may offer relief when other options haven’t worked.

Research is still evolving, but we’re learning more every day—and that means better, more tailored care for you.

Tammy Johnson, PMHNP has a passion for working with immigrant and underserved communities stemming from her personal background and years spent volunteering with Hispanic, Asian, and rural populations. She is an active supporter of the ACLU. In her free time she is a devoted animal lover and proud mom of two dogs and a cat.

References: 

Teopiz KM, Lo HKY, Lakhani M, Kwan ATH, Lim PK, Zhang M, Wong S, Le GH, Swainson J, Cao B, Dri C, Ho R, Valentino K, McIntyre RS. Should glutamatergic modulators be considered preferential treatments for adults with major depressive disorder and a reported history of trauma? Conceptual and clinical implications. CNS Spectr. 2025 May 26;30(1):e61. doi: 10.1017/S1092852925100278. PMID: 40415673.

Williams LM, Debattista C, Duchemin A-M, Schatzberg AF, Nemeroff CB. Childhood trauma predicts antidepressant response in adults with major depression: data from the randomized international study to predict optimized treatment for depression. Transl Psychiatry 2016;6(5):e799. 

Wang S-K, Feng M, Fang Y, et al. Psychological trauma, posttraumatic stress disorder and trauma-related depression: A mini-review. World J Psychiatry 2023;13(6):331–9. 11. 

Zagaria A, Fiori V, Vacca M, Lombardo C, Pariante CM, Ballesio A. Inflammation as a mediator between adverse childhood experiences and adult depression: A meta-analytic structural equation model. J Affect Disord 2024;357:85–96.