From the Guidelines
Antagonism of N-methyl-D-aspartate (NMDA) receptors can produce therapeutic effects, but also causes significant side effects, and its use should be carefully considered based on the specific clinical context and the most recent evidence available, such as the study by 1. When NMDA receptors are antagonized, calcium influx into neurons is prevented, reducing neuronal excitation and potentially protecting against excitotoxicity. This mechanism is utilized by medications like ketamine, memantine, and dextromethorphan.
Key Points to Consider:
- NMDA receptor antagonism can lead to anesthesia, analgesia, and potential neuroprotection.
- Side effects include dissociation, hallucinations, and memory impairment.
- High doses can cause a state resembling schizophrenia with thought disorders and perceptual abnormalities.
- Chronic NMDA receptor blockade may lead to upregulation of receptors and potential neurotoxicity in certain brain regions.
Clinical Applications:
- Ketamine is used for anesthesia and depression, with typical doses ranging from 0.5-1 mg/kg IV.
- Memantine is used for Alzheimer's disease, starting at 5 mg daily and titrating to 10 mg twice daily.
- Dextromethorphan is used for cough, with a typical dose of 30 mg orally every 6-8 hours.
Recent Evidence:
- A 2025 study published in Alzheimer's and Dementia 1 found that memantine was associated with small improvements in measures of cognitive function in individuals with vascular dementia.
- The balance between therapeutic benefits and adverse effects depends on the specific antagonist, dosage, and duration of treatment, highlighting the need for careful consideration and monitoring in clinical practice, as noted in studies such as 1, 1, and 1.
From the FDA Drug Label
Ketamine hydrochloride, a racemic mixture of ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The mechanism of action is primarily due to antagonism of N-methyl-D-aspartate (NMDA receptors) in the central nervous system.
The antagonism of N-methyl-D-aspartate (NMDA) receptors by ketamine results in a dissociative anesthetic state characterized by:
- Profound analgesia
- Normal pharyngeal-laryngeal reflexes
- Normal or slightly enhanced skeletal muscle tone
- Cardiovascular and respiratory stimulation
- Occasional transient and minimal respiratory depression 2
From the Research
Antagonism of NMDA Receptors
The antagonism of N-methyl-D-aspartate (NMDA) receptors has been studied in various contexts, including the treatment of major depressive disorder (MDD) and schizophrenia.
- NMDA receptor antagonists, such as ketamine, have been shown to have rapid antidepressant effects in patients with treatment-resistant MDD and bipolar disorder 3, 4, 5.
- The response rate for ketamine ranged from 25% to 85% at 24 hours post-infusion and from 14% to 70% at 72 hours post-infusion, with generally mild adverse effects 3.
- NMDA receptor antagonists have also been implicated in the treatment of schizophrenia, with ketamine having been used as a model of schizophrenia in animals and humans 6.
- However, the use of NMDA receptor antagonists in schizophrenia is limited due to the risk of exacerbating psychotic symptoms 6.
Mechanisms of Action
The mechanisms of action of NMDA receptor antagonists are complex and involve the modulation of glutamatergic transmission.
- Ketamine, for example, functions as a channel blocker of the excitatory glutamate-gated NMDA receptors, displaying compelling fast-acting and sustained antidepressant effects for treatment-resistant depression 4.
- The signalling pathway of ketamine-mediated antidepressant effects involves the glutamate hypothesis of depression, which suggests that dysfunction of glutamatergic transmission is associated with the pathology of depression 4.
Therapeutic Implications
The antagonism of NMDA receptors has significant therapeutic implications for the treatment of MDD and other conditions.
- The development of novel therapeutic drugs that target the NMDA receptor system, such as ketamine, memantine, and AZD6765, offers new hope for the treatment of treatment-resistant depression 3, 5.
- However, further research is needed to fully understand the mechanisms of action of NMDA receptor antagonists and to develop safer and more effective treatments for MDD and other conditions 5, 7.