Perampanel (Fycompa) and Ketamine Therapy | Tovani Health
Fycompa (Perampanel) — AMPA receptor antagonist (anticonvulsant)
Verdict at Tovani Health
Direct AMPA antagonism may blunt ketamine's antidepressant cascade; evaluate individually.
Perampanel alongside ketamine requires individual evaluation, and not for the usual sedation reason. Perampanel is a selective non-competitive AMPA receptor antagonist. Ketamine's antidepressant effect depends on a downstream AMPA-mediated cascade triggered by NMDA blockade — AMPA activation is what drives the BDNF release and synaptogenesis underlying ketamine's effect. A direct AMPA antagonist may therefore meaningfully attenuate ketamine's antidepressant response, more so than any other psychiatric medication interaction we cover. Perampanel also carries an FDA black-box warning for serious psychiatric and behavioral reactions independent of ketamine.
If you take Fycompa regularly and are considering at-home ketamine therapy, the combination is depends on your specific situation. This page covers the brief pharmacologic context and what we do at intake.
How Fycompa interacts with ketamine
Perampanel selectively and non-competitively antagonizes AMPA-type glutamate receptors. Ketamine's antidepressant mechanism is hypothesized to require AMPA activation downstream of NMDA blockade (the Duman / Krystal / Aan het Rot framework). Direct AMPA antagonism therefore has a stronger theoretical concern than the indirect GABAergic mechanisms (benzos, valproate) we already flag for response blunting.
What we do at intake
Disclose dose, indication, and duration of therapy. Patients on perampanel for refractory epilepsy should not stop it; we discuss whether KAP is the right augmentation given the mechanism interaction.
Bottom line
Perampanel alongside ketamine requires individual evaluation, and not for the usual sedation reason. Perampanel is a selective non-competitive AMPA receptor antagonist. Ketamine's antidepressant effect depends on a downstream AMPA-mediated cascade triggered by NMDA blockade — AMPA activation is what drives the BDNF release and synaptogenesis underlying ketamine's effect. A direct AMPA antagonist may therefore meaningfully attenuate ketamine's antidepressant response, more so than any other psychiatric medication interaction we cover. Perampanel also carries an FDA black-box warning for serious psychiatric and behavioral reactions independent of ketamine.
Frequently Asked Questions
Will perampanel completely block ketamine from working?
Not block, but it has the most direct mechanism of attenuation among any psychiatric drug we cover. The actual clinical magnitude in humans isn't quantified — the concern is based on the underlying pharmacology. We discuss honestly whether the trade-off makes sense for your situation.
Ready to find out if at-home ketamine fits your situation?
We’ll note that you’re on Fycompa (Perampanel) at intake. The eligibility check takes 5 minutes and gives you an honest answer about whether at-home ketamine fits your specific situation.
FL and NJ residents only. Benjamin Soffer, DO — Tovani Health.
Sources
The verdict and clinical guidance on this page are based on the following peer-reviewed literature and FDA prescribing information.
- Pharmacodynamic Interactions Between Ketamine and Psychiatric Medications Used in the Treatment of Depression. Veraart JKE, Smith-Apeldoorn SY, et al.. International Journal of Neuropsychopharmacology. 2021. PMID: 34170315
Clinically reviewed
Reviewed by Benjamin Soffer, DO on May 19, 2026. Dr. Soffer is a board-certified physician (American Board of Internal Medicine) licensed in Florida and New Jersey, prescribing at-home ketamine therapy through Tovani Health.
This page is general information about how this medication interacts with at-home ketamine therapy at Tovani Health. It is not a substitute for medical advice from your prescribing physician about your specific situation. Always discuss medication changes with the doctor who prescribed them.