Ketamine modulates NMDA receptors and glutamate transmission for treatment-resistant depression and other psychiatric disordersKetamine Shows Potential for Treatment-Resistant Depression and Anxiety

Frontiers in Medicine Published October 1, 2026 DOI ↗ Editorial oversight: Dr. Ji-eun Park, MD · Brain, Mind & Pain

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Key Takeaway

Note that ketamine acts as an NMDA receptor antagonist to modulate glutamate and BDNF for various psychiatric conditions.

This systematic review synthesizes the pharmacological mechanisms, network-level effects, and clinical applications of ketamine. The scope includes its use in anesthesia, treatment-resistant depression, pain management, PTSD, anxiety disorders, and bipolar disorder. The review identifies ketamine as an antagonist of NMDA receptors, which triggers heightened glutamate transmission, AMPA receptor activation, increased BDNF expression, synaptogenesis, and mTOR pathway signaling.

At the network level, the review indicates that ketamine alters activity within large-scale brain circuits, including the default mode network. These findings suggest a multi-faceted pharmacological profile that may contribute to its clinical utility in various psychiatric and neurological conditions.

Limitations noted by the authors include fragmented research originating from different fields. Despite these gaps, the review addresses clinical and ethical considerations, including safety, monitoring, and the potential for telehealth prescribing of oral and sublingual formulations. The findings provide a basis for understanding the pharmacological basis of ketamine's effects, though clinical application remains subject to ongoing research.

How this fits prior evidence

This systematic review addresses a gap in understanding the pharmacological mechanisms of ketamine for psychiatric conditions. It expands upon prior evidence regarding the neurofunctional mechanisms of MDD and BD, and the management of PTSD. While prior evidence noted that ketamine does not significantly reduce pain scores or total opioid consumption in traumatic chest injuries, this review focuses on its broader clinical applications, including anxiety disorders and bipolar disorder.

A systematic review of 106 articles looked at how ketamine affects the brain and its use in various medical conditions. The review focused on how the drug interacts with brain receptors and its potential applications for patients who do not respond well to standard treatments.

Researchers found that ketamine acts as an antagonist of NMDA receptors. This process triggers several biological responses, including increased glutamate transmission and the activation of AMPA receptors. These actions are linked to increased BDNF expression and the growth of new synapses in the brain. The drug also appears to alter activity within large-scale brain circuits, such as the default mode network.

While the review notes that ketamine is used for anesthesia and pain, it also highlights its role in treating treatment-resistant depression, PTSD, anxiety disorders, and bipolar disorder. Because the research is currently fragmented across different fields, the evidence is not yet uniform. Patients should discuss these findings with a doctor to understand the specific risks and clinical applications for their own health.

What this means for you:

Ketamine may help with treatment-resistant depression and anxiety by changing brain chemistry and signaling.

Common questions

What conditions can ketamine be used to treat?

Ketamine is being studied and used for several conditions, including treatment-resistant depression, post-traumatic stress disorder (PTSD), anxiety disorders, and bipolar disorder. It is also commonly used for anesthesia and the management of pain.

How does ketamine work in the brain?

Ketamine works as an antagonist of NMDA receptors. This triggers heightened glutamate transmission and AMPA receptor activation. These processes are linked to increased BDNF expression, synaptogenesis, and mTOR pathway signaling, which can alter activity in large-scale brain circuits.

Is the research on ketamine for mental health conclusive?

The research is currently described as fragmented across different fields. While it shows potential for treating various mental health conditions, the evidence is not yet unified, and patients should consult a medical professional regarding specific treatments.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedOct 2026

View Original Abstract ↓

Ketamine has progressed from solely being an anesthetic agent to a drug of rising clinical and research interest due to its distinctive pharmacological properties. Its dissociative properties and rapid-acting antidepressant effects have made it a prominent area of investigation across many medical and psychiatric applications. This systematic review examines ketamine’s history, mechanisms of action, clinical uses, and significant challenges. A systematic search of PubMed, SCOPUS, PsycINFO, and other sources, generated peer-reviewed publications that addressed the history of ketamine, its pharmacology, clinical applications, recreational use, safety considerations, and societal consequences. Overall, 106 articles were identified for inclusion in this study. At the receptor level, ketamine is an antagonist of NMDA receptors that triggers a number of downstream effects ranging from heightened glutamate transmission, AMPA receptor activation, increased BDNF expression, synaptogenesis, and mTOR pathway signaling. At the network level, it alters activity within large-scale brain circuits including the default mode network, affecting cognition, mood, and perception. Clinically, ketamine is used for anesthesia, treatment-resistant depression, and pain, with off-label uses for PTSD, anxiety disorders, and bipolar disorder. The review also examines current challenges related to ketamine’s recreational use, associated risks, sociocultural factors, and key clinical and ethical considerations, including safety, monitoring, and telehealth prescribing of oral and sublingual formulations. It integrates previously fragmented research from anesthesiology, neuroscience, pharmacology, psychiatry, and public health, consolidates clinical and ethical guidance, identifies critical gaps in current knowledge, and proposes directions for future research.

Ketamine modulates NMDA receptors and glutamate transmission for treatment-resistant depression and other psychiatric disordersKetamine Shows Potential for Treatment-Resistant Depression and Anxiety

How this fits prior evidence

Common questions

Study Details

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Ketamine modulates NMDA receptors and glutamate transmission for treatment-resistant depression and other psychiatric disordersKetamine Shows Potential for Treatment-Resistant Depression and Anxiety

How this fits prior evidence

Common questions

More on Depression

Study Details

PETRUSHKA decision-support tool reduced treatment discontinuation and improved symptoms in major depressive disorder

The Algorithm That Helps Doctors Pick the Right Antidepressant for You

Clinical research that matters. Delivered to your inbox.

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