Rapastinel
Also known as: GLYX-13, GLYX‑13, NRX-1074, Rapastinel, Thr-Pro-Pro-Thr-NH2
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Summary
Rapastinel (GLYX‑13, NRX‑1074) is a synthetic tetrapeptide under investigation as a rapid‑acting antidepressant. It belongs to the class of NMDA‑receptor modulators and is being studied for use in major depressive disorder, especially treatment‑resistant forms. The compound is administered intravenously or subcutaneously in clinical trials, but it is not yet approved for any indication.
Mechanism of Action
Rapastinel acts as a positive allosteric modulator at the glycine‑binding site of NMDA receptors, enhancing NMDA‑mediated calcium influx rather than blocking the channel. This modest NMDA activation is thought to increase downstream AMPA‑receptor activity, trigger brain‑derived neurotrophic factor (BDNF) release, and stimulate mTORC1 signaling, thereby promoting synaptic plasticity and rapid antidepressant effects.
What the Research Shows
Evidence for rapastinel comes mainly from early‑phase clinical trials and mechanistic studies. A Cochrane review identified only one randomized trial of rapastinel among 64 glutamate‑modulator studies, describing the evidence as limited and of low certainty. Other reviews note that rapastinel has reached late‑stage development and that preclinical work shows rapid antidepressant‑like effects with a favorable side‑effect profile. Overall, the data suggest potential efficacy but remain insufficient to draw firm conclusions.
Reported Benefits
Preliminary findings indicate rapastinel may produce a rapid reduction in depressive symptoms, possibly within hours to days, and could be effective in patients who have not responded to conventional antidepressants. Mechanistic data suggest it shares the beneficial downstream pathways of ketamine (BDNF and mTORC1 activation) while lacking the severe dissociative or psychotomimetic effects reported for ketamine.
Limitations of the Evidence
The clinical evidence base is very small—only a single small trial has been reported, and the overall certainty of effect is low. Long‑term efficacy, optimal dosing, and comparative effectiveness versus existing treatments have not been established. Consequently, rapastinel remains investigational, and larger, well‑controlled studies are needed to confirm its therapeutic value.
Safety Considerations
Early reports describe rapastinel as well‑tolerated, with no severe adverse events observed in the limited trials, contrasting with the dissociative side effects of ketamine. However, the safety profile is not fully characterized; rare or delayed adverse effects may emerge with broader use. Ongoing studies are required to define contraindications and monitoring requirements.
How It Is Administered
Rapastinel is administered by injection, either intravenously or subcutaneously, in the investigational setting. Formulations are peptide solutions suitable for parenteral use. Dosing regimens have varied across trials, but no standardized therapeutic dose has been established for clinical practice.
Routes of Administration
Goals & Uses
- Treatment-resistant depressionPsychiatryLow
- Rapid antidepressant effectPsychiatryLow
- Major Depressive DisorderDepressionModerate
- Synaptic plasticity enhancementNeuroscience / ResearchModerate
- Major Depressive Disorder (MDD) treatmentPsychiatry / AntidepressantModerate
Contraindications
- History of psychotic disordersPsychiatricModerate
- Known hypersensitivity to rapastinel or excipientsAllergyHigh
Adverse Effects
- HeadacheNeurologicCommonPain in the head or upper neck
- Transient hypertensionCardiovascularUncommon
- NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
- Dissociative symptomsPsychiatric/NeurologicalRare
- Infusion site reactionsLocalUncommon
- DizzinessNeurologicCommonFeeling faint, lightheaded, or unsteady
Drug Interactions
- Other NMDA receptor modulators (e.g., ketamine, memantine)Moderate
- Antidepressants (SSRIs, SNRIs, MAOIs)Low
- MemantineLow
- KetamineModerate
Population Constraints
- Severe renal or hepatic impairmentOrgan FunctionRelative
- PregnancyReproductive SafetyRelative
- Pediatric patientsAgeRelative
- Pregnant womenReproductiveRelative
Regulatory Status
- European UnionInvestigationalClinical trials ongoing; no EMA approval
- United StatesInvestigationalUnder clinical investigation; not FDA‑approved
- United KingdomInvestigationalBeing evaluated in UK clinical studies
Investigational drug; not approved for any indication in the US, EU or UK.
Evidence & Sources
- Journal ArticleHighDean RL, et al.2021-01-01T00:00:00.000000Z
- Journal ArticleModerateFreudenberg F, et al.2025-01-01T00:00:00.000000Z
- Journal ArticleModerateWitkin JM, et al.2018-01-01T00:00:00.000000Z
- Journal ArticleModerateHenter ID, Park LT, Zarate CA Jr2021-01-01T00:00:00.000000Z
- Journal ArticleModerateWitkin JM, et al.2019-01-01T00:00:00.000000Z
- Journal ArticleModerateWang YT, et al.2022-01-01T00:00:00.000000Z
Frequently Asked Questions
What makes rapastinel different from ketamine?
Rapastinel is a positive allosteric modulator of NMDA receptors, whereas ketamine is an NMDA antagonist. Rapastinel appears to produce antidepressant effects without the dissociative or psychotomimetic side effects that are common with ketamine, based on early trial data.
Is rapastinel approved for treating depression?
No. Rapastinel is currently an investigational compound and has not received regulatory approval for any indication.
How quickly might rapastinel work?
Preclinical and early clinical studies suggest a rapid onset of antidepressant effect, potentially within hours to a few days after a single dose, although definitive timing data are limited.
What are the known side effects?
Limited trial data report no severe adverse events, and the compound seems to lack the dissociative symptoms seen with ketamine. Comprehensive safety information is still pending further research.
Who might benefit from rapastinel?
Patients with major depressive disorder, especially those who have not responded to standard antidepressants (treatment‑resistant depression), are the primary target population in current investigations.
What is Rapastinel?
Rapastinel (GLYX‑13, NRX‑1074) is a synthetic tetrapeptide under investigation as a rapid‑acting antidepressant. It belongs to the class of NMDA‑receptor modulators and is being studied for use in major depressive disorder, especially treatment‑resistant forms. The compound is administered intravenously or subcutaneously in clinical trials, but it is not yet approved for any indication.
What is Rapastinel used for?
Rapastinel is educationally associated with: Treatment-resistant depression, Rapid antidepressant effect, Major Depressive Disorder, Synaptic plasticity enhancement, Major Depressive Disorder (MDD) treatment. Educational only — not medical advice.
How is Rapastinel administered?
Recorded routes of administration: Intravenous, Subcutaneous.
What are the potential side effects of Rapastinel?
Reported adverse effects include: Headache, Transient hypertension, Nausea, Dissociative symptoms, Infusion site reactions, Dizziness. This list is not exhaustive — consult a qualified clinician.
Who should avoid Rapastinel?
Recorded contraindications: History of psychotic disorders, Known hypersensitivity to rapastinel or excipients. Consult a qualified clinician before use.