Thread by @sanilrege

🧵What are the differences between Ketamine and Memantine - 🚨1/7

Both are NMDA antagonists - But with different clinical effects.

Here’s why 👇

1/ Receptor selectivity

-Memantine → preferentially blocks extrasynaptic NMDARs (excitotoxic signalling)

-Ketamine → blocks synaptic + extrasynaptic NMDARs

- Ketamine is non-selective (muscarinic, monoaminergic, opioid effects → psychotomimetic profile)

2/ Affinity & channel behaviour

- Memantine: moderate affinity, fast unblocking, activity-dependent

- Ketamine: higher affinity, longer channel occupancy

Clinical relevance :
Memantine disengages during normal synaptic activity → good tolerability.

Ketamine’s longer occupancy contributes to dissociation and perceptual effects.

3/ NR2 subunit preference

- Memantine → GluN1/NR2A (LTP, prolonged glutamate exposure)

- Ketamine → GluN1/NR2B (LTD, brief glutamate bursts)

→ Memantine acts during pathological glutamate ‘flooding’

→ Ketamine acts during normal signalling bursts

4/ Calcium homeostasis

-Memantine stabilises Ca²⁺-dependent desensitised state

-Ketamine disrupts Ca²⁺ regulation (PMCA inhibition → glutamate surge)

5/ Network effect

-Ketamine disinhibits pyramidal neurons (via GABA interneurons) → glutamate surge → antidepressant effect

-Memantine does not do this

6/ Duration of binding

- Ketamine stays in channel longer → dissociation/sedation

- Memantine brief occupancy → cognitive tolerability

7/ Summary 🚨

👉Memantine dampens sustained, pathological NMDAR activity while preserving normal transmission → good tolerability; used in dementia and as adjunct where glutamatergic overactivity is suspected.

👉Ketamine transiently disrupts physiological NMDAR signalling via interneuronal disinhibition → rapid antidepressant effect with dissociative/psychotomimetic features.

I’ve covered all the above and more in the article below

psychscenehub.com/psychinsights/…