Head to head
PE-22-28 against Rapastinel
Two rapid-acting antidepressant peptides, one experimental and one that finished the job. Rapastinel reduced depression scores within hours in a 116 person trial and then failed three pivotal phase 3 trials in about 1,500 people, with placebo-adjusted MADRS differences of 0.3, 0.1 and 1.0 points.
Column A
PE-22-28PE-22-28 (spadin analogue)
An experimental peptide studied for rapid antidepressant effects and neurogenesis by blocking a potassium channel in the brain.
Column B
RapastinelRapastinel (GLYX-13), intravenous NMDA receptor glycine site partial agonist tetrapeptide
An intravenous tetrapeptide antidepressant that reduced depression scores within hours in a 116 person trial, then failed three pivotal phase 3 trials totalling about 1,500 people: placebo-adjusted differences on the MADRS of 0.3, 0.1 and 1.0 points, none significant. Allergan stopped the programme in July 2019.
Side by side, on the facts we can check
| Attribute | PE-22-28 | Rapastinel |
|---|---|---|
| Category | Nootropic & CNS | Nootropic & CNS |
| FDA status | Not FDA-approved; experimental | Not FDA approved. Phase 3 programme in major depressive disorder failed its primary endpoints (results posted on ClinicalTrials.gov 2019 to 2020) and was stopped by the sponsor in July 2019. No further development. |
| Half-life | Short | Not reported |
| Molecular weight | ~800 Da | Not reported |
| Mechanism | Blocks the TREK-1 potassium channel, which is implicated in mood regulation, producing rapid antidepressant-like effects in animals. | In people, what is established is that a single intravenous dose of 5 or 10 mg/kg reduced depressive symptoms for about a week in a 116 person trial, that weekly 450 mg doses produced no separation from placebo in three phase 3 trials, and that doses of 900 and 1,800 mg did not impair simulated driving in 107 healthy volunteers where ketamine 0.5 mg/kg did. Whether rapastinel modulates NMDA receptor signalling in a human brain has not been shown directly. In animals and cells, rapastinel binds the NMDA receptor at or near the glycine co-agonist site and acts as a functional partial agonist, enhancing NMDA mediated currents at low concentrations and reducing them at high ones, which is the proposed explanation for the inverted U dose response seen in both rodents and the human proof of concept. Rodent studies report rapid increases in synaptic protein synthesis and long lasting antidepressant-like behaviour after a single dose, similar to ketamine but without ketamine's channel block. In a 2022 rodent study it also accelerated loss of morphine withdrawal signs and blunted relapse to drug seeking. |
| Human studies cited | 0 | 7 |
| Legal status, US | Not approved; research use only | Investigational, not approved |
Frequently asked questions
What is the difference between PE-22-28 and Rapastinel?
PE-22-28: An experimental peptide studied for rapid antidepressant effects and neurogenesis by blocking a potassium channel in the brain. Rapastinel: An intravenous tetrapeptide antidepressant that reduced depression scores within hours in a 116 person trial, then failed three pivotal phase 3 trials totalling about 1,500 people: placebo-adjusted differences on the MADRS of 0.3, 0.1 and 1.0 points, none significant. Allergan stopped the programme in July 2019.
Which has stronger research evidence, PE-22-28 or Rapastinel?
This database does not grade compounds. It counts what was run in people: 0 of the 2 studies cited on the PE-22-28 profile were human work, against 7 of 7 for Rapastinel. Those counts are of our own citation lists and understate any larger literature, and neither is a recommendation.
Are PE-22-28 and Rapastinel FDA-approved?
PE-22-28: Not FDA-approved; experimental. Rapastinel: Not FDA approved. Phase 3 programme in major depressive disorder failed its primary endpoints (results posted on ClinicalTrials.gov 2019 to 2020) and was stopped by the sponsor in July 2019. No further development..
Reviewed Sep 2026. This page sets two published records side by side. It is educational, it is not medical advice, and it contains no dosing protocols or recommendations for personal use.