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08. NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine

Published on July 1, 2025 Certification expiration date: July 1, 2028

Scott R. Beach, M.D.

Associate Professor of Psychiatry - Harvard Medical School - Massachusetts General Hospital

Key Points

NMDA antagonists like amantadine and memantine are considered third-line treatments for catatonia after benzodiazepines and ECT.
NMDA antagonists can be used as monotherapy for catatonia but are most commonly employed as augmentation to benzodiazepines.
Despite a 91% response rate in some cases, ketamine is not recommended for catatonia due to its unpredictability and potential to worsen symptoms.

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Slides and Transcript

Slide 1 of 13

In the next section, we’re going to be exploring NMDA antagonists in the management of catatonia.

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 1 of 13

Slide 2 of 13

We talked the last time about the fact that NMDA antagonists like memantine and amantadine are generally considered third-line treatment strategies after benzodiazepines and ECT. The British guidelines really sort of upheld this recommendation noting that when first-line therapies for catatonia are either unavailable, cautioned, ineffective or only partly effective, a trial of an NMDA receptor antagonist such as amantadine or memantine should be considered.

References:

Rogers, J. P., Oldham, M. A., Fricchione, G., Northoff, G., Ellen Wilson, J., Mann, S. C., Francis, A., Wieck, A., Elizabeth Wachtel, L., Lewis, G., Grover, S., Hirjak, D., Ahuja, N., Zandi, M. S., Young, A. H., Fone, K., Andrews, S., Kessler, D., Saifee, T., Gee, S., … David, A. S. (2023). Evidence-based consensus guidelines for the management of catatonia: Recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology, 37(4), 327–369. https://doi.org/10.1177/02698811231158232

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 2 of 13

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Slide 3 of 13

In addition to the British guidelines, we also have a 2024 review on the use of NMDA antagonists to help guide us. In that review, amantadine had been used in at least 27 cases of catatonia, and memantine had been used in at least 20 cases. So we’re gaining more robust data about the use of these medications. Most of the cases had schizophrenia as an underlying diagnosis, and rapid resolution was achieved with NMDA antagonists in some cases.

References:

Lee, J. H., & Suzuki, J. (2024). N-methyl-d-aspartate (NMDA) receptor antagonists for treatment of catatonia in adults: Narrative review. General Hospital Psychiatry, 91, 60-65. https://doi.org/10.1016/j.genhosppsych.2024.09.005

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 3 of 13

Slide 4 of 13

A case series of amantadine also highlighted the use in patients with comorbid catatonia and delirium. So the evidence continues to suggest that amantadine and memantine should be the next line strategies if benzodiazepines are not fully effective and ECT is not available, for example.

References:

Lee, J. H., & Suzuki, J. (2024). N-methyl-d-aspartate (NMDA) receptor antagonists for treatment of catatonia in adults: Narrative review. General Hospital Psychiatry, 91, 60-65. https://doi.org/10.1016/j.genhosppsych.2024.09.005

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 4 of 13

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Slide 5 of 13

NMDA antagonists are most commonly added in or used as augmentation for benzodiazepines though there are reports of their use as monotherapy as well.

References:

Lee, J. H., & Suzuki, J. (2024). N-methyl-d-aspartate (NMDA) receptor antagonists for treatment of catatonia in adults: Narrative review. General Hospital Psychiatry, 91, 60-65. https://doi.org/10.1016/j.genhosppsych.2024.09.005

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 5 of 13

Slide 6 of 13

The other agent that has garnered some interest with regard to catatonia that is also an NMDA antagonist is ketamine. Ketamine is a really interesting one because it’s been associated with lysing catatonia in some reports but it has also been associated with inducing or worsening catatonia in other reports.

References:

Evanoff, A. B., Baig, M., Taylor, J. B., & Beach, S. R. (2023). Ketamine: A practical review for the consultation-liaison psychiatrist. Journal of the Academy of Consultation-Liaison Psychiatry, 64(6), 521–532. https://doi.org/10.1016/j.jaclp.2023.06.001
Gouzoulis-Mayfrank, E., Heekeren, K., Neukirch, A., Stoll, M., Stock, C., Obradovic, M., & Kovar, K. A. (2005). Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry, 38(6), 301–311. https://doi.org/10.1055/s-2005-916185

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 6 of 13

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Slide 7 of 13

As a reminder, an older study showed that nine healthy volunteers receiving ketamine all developed dose-dependent psychomotor poverty, poverty of speech, apathy, and withdrawal, and six of those individuals displayed catatonia-like motor phenomenon including posturing. So it’s pretty clear that ketamine can cause catatonia and catatonic-like symptoms.

References:

Gouzoulis-Mayfrank, E., Heekeren, K., Neukirch, A., Stoll, M., Stock, C., Obradovic, M., & Kovar, K. A. (2005). Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry, 38(6), 301–311. https://doi.org/10.1055/s-2005-916185

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 7 of 13

Slide 8 of 13

But there was also a recent review of 25 cases of patients receiving ketamine for catatonia as a treatment that showed a 91% response rate and a 55% remission rate.

References:

Caliman-Fontes, A. T., Vieira, F., Leal, G. C., Carneiro, B. A., Quarantini-Alvim, Y., Andrade, T. V., Mello, R. P., Gadelha, A., Lacerda, A. L. T., & Quarantini, L. C. (2024). Ketamine for catatonia: A novel treatment for an old clinical challenge? A systematic review of the evidence. Schizophrenia Research, 271, 355–370. https://doi.org/10.1016/j.schres.2024.07.055

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 8 of 13

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Slide 9 of 13

I’ve talked to some experts on ketamine about kind of how they make sense of this, and they’ve pointed out that one way to think about this is to consider the fact that ketamine is an extremely dirty medication, with actions at multiple receptors including NMDA receptors, opioid receptors, dopamine, serotonin, norepinephrine, cholinergic, and GABA receptors.

References:

Caliman-Fontes, A. T., Vieira, F., Leal, G. C., Carneiro, B. A., Quarantini-Alvim, Y., Andrade, T. V., Mello, R. P., Gadelha, A., Lacerda, A. L. T., & Quarantini, L. C. (2024). Ketamine for catatonia: A novel treatment for an old clinical challenge? A systematic review of the evidence. Schizophrenia Research, 271, 355–370. https://doi.org/10.1016/j.schres.2024.07.055

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 9 of 13

Slide 10 of 13

They believe that the response of catatonia to ketamine may depend on the underlying psychiatric illness, and may also depend on the dose of ketamine. They pointed out that ketamine acts on the same site of the NMDA receptor, the open channel, as memantine and amantadine, but with a much higher binding affinity. And in that way, it’s actually similar to PCP which also acts on the open channel with a higher affinity. And we know from older literature that PCP like ketamine can also induce or worsen catatonia.

References:

Caliman-Fontes, A. T., Vieira, F., Leal, G. C., Carneiro, B. A., Quarantini-Alvim, Y., Andrade, T. V., Mello, R. P., Gadelha, A., Lacerda, A. L. T., & Quarantini, L. C. (2024). Ketamine for catatonia: A novel treatment for an old clinical challenge? A systematic review of the evidence. Schizophrenia Research, 271, 355–370. https://doi.org/10.1016/j.schres.2024.07.055

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 10 of 13

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Slide 11 of 13

For these reasons, I personally would be quite hesitant about using ketamine in catatonic patients just because of its unpredictability, and I would err much more on the side of using amantadine or memantine which now have more cases of success and no indication that they cause or worsen catatonia.

References:

Caliman-Fontes, A. T., Vieira, F., Leal, G. C., Carneiro, B. A., Quarantini-Alvim, Y., Andrade, T. V., Mello, R. P., Gadelha, A., Lacerda, A. L. T., & Quarantini, L. C. (2024). Ketamine for catatonia: A novel treatment for an old clinical challenge? A systematic review of the evidence. Schizophrenia Research, 271, 355–370. https://doi.org/10.1016/j.schres.2024.07.055

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 11 of 13

Slide 12 of 13

To summarize, some key points from this section: NMDA antagonists should be considered either as monotherapy or augmentation when benzodiazepines and ECT are ineffective, partly effective or cannot be used. Amantadine has been used more commonly than memantine in the case report literature though both have been used dozens of times at this point.

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Slide 13 of 13

Reports are emerging of success using ketamine but it continues not to be recommended because of the potential to worsen catatonia, and that may be related to the dirtiness of the agent compared to other NMDA antagonists.

NMDA Antagonists for Catatonia Management: Amantadine, Memantine, and Ketamine Slide 13 of 13

Next Section

09. Other Pharmacologic Strategies for Catatonia: Zolpidem, Bromocriptine, and Cariprazine

Learning Objectives:

After completing this activity, the learner will be able to:

Recognize the clinical features of catatonia using validated assessment tools.
Implement evidence-based pharmacologic interventions for catatonia.
Identify and manage medical complications associated with catatonia.

Original Release Date: July 1, 2025

Expiration Date: July 1, 2028

Expert: Scott Beach, M.D.

Medical Editor: Flavio Guzmán, M.D.

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None of the faculty, planners, and reviewers for this educational activity have relevant financial relationships to disclose during the last 24 months with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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