Rapastinel
Rapastinel (GLYX-13), intravenous NMDA receptor glycine site partial agonist tetrapeptide
Written by Aaron CuhaReviewed Sep 2026
Also known as: GLYX-13
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.
Overview
Rapastinel is a four amino acid peptide that acts at the glycine site of the NMDA receptor as a functional partial agonist. It was developed by Naurex and then Allergan as a rapid acting antidepressant without ketamine's dissociative effects. That was the promise, and the early data supported it: in a randomised, placebo controlled proof of concept trial, a single intravenous dose of 5 or 10 mg/kg reduced Hamilton depression scores within 2 hours in 116 people who had not responded to a standard antidepressant, with the effect lasting about a week and no psychotomimetic side effects. Doses of 1 and 30 mg/kg did nothing, an inverted U dose response that is a known warning sign in drug development.
The phase 3 programme that followed was large and it is fully reported, though only on the trial registry, never in a journal. Three acute adjunctive trials (RAP-MD-01, 02 and 03) randomised 465, 658 and 429 people with major depression to weekly intravenous rapastinel or placebo on top of their existing antidepressant. On the primary endpoint, change in MADRS total score at 3 weeks, placebo fell 5.0, 4.9 and 4.1 points and rapastinel 450 mg fell 4.7, 5.4 and 5.1 points: differences of 0.3 (p = 0.65), 0.5 (p = 0.58) and 1.0 (p = 0.24) in favour of nothing in particular. A 1,304 person relapse prevention trial found no difference in time to relapse (p = 0.53 and 0.46 for the two dosing schedules). Four further phase 3 trials in monotherapy were terminated in July 2019 with the sponsor's reason recorded as a business decision to stop the programme. Roughly 3,900 people were enrolled in phase 3 in total, not counting a 617 person long term safety extension.
Rapastinel was never approved and its development has ended. Its value on this site is as the clearest example in the catalogue of a rapid acting antidepressant mechanism that looked convincing in 116 people and disappeared in 1,500.
Mechanism of action
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 evidence
Extensive. Roughly 3,900 people were enrolled in phase 3 alone, not counting a 617 person long term safety extension, and the three pivotal acute trials, the relapse prevention trial and the terminated monotherapy trials all have results or termination reasons posted by the sponsor on ClinicalTrials.gov. The results are null. No phase 3 result was ever published in a journal.
- Proof of concept (2015): 116 adults with treatment resistant depression, single intravenous dose. 5 and 10 mg/kg reduced HAM-D17 at days 1 to 7 with onset within 2 hours; 1 and 30 mg/kg did not. Naurex funded.
- RAP-MD-01 (NCT02932943): 465 enrolled. MADRS change -4.7 versus -5.0 placebo at 3 weeks, difference 0.3, p = 0.65.
- RAP-MD-02 (NCT02943564): 658 enrolled. MADRS change -4.8 (225 mg), -5.4 (450 mg), -4.9 (placebo); p = 0.89 and 0.58.
- RAP-MD-03 (NCT02943577): 429 enrolled. MADRS change -5.1 versus -4.1, difference -1.0, p = 0.24.
- Relapse prevention (NCT02951988): 1,304 enrolled, 52 weeks. No difference in time to first relapse, p = 0.53 and 0.46.
- Monotherapy phase 3 programme: four trials totalling 1,082 enrolled terminated July 2019, sponsor's reason recorded as a business decision to stop the program; one further trial withdrawn.
- Driving study (2022): 107 healthy adults. Rapastinel 900 and 1,800 mg did not impair simulated driving; ketamine did. Allergan funded.
- Earlier phase 2 (NCT01234558): 115 participants, single intravenous dose in treatment resistant depression, completed 2012, no results posted.
What this does not tell you: The phase 3 data answer the efficacy question for weekly intravenous rapastinel added to an antidepressant, and the answer is no separation from placebo. What they cannot tell you is why the 116 person trial looked so different: the proof of concept dosed by weight and found an inverted U, the phase 3 used a fixed 450 mg dose, and no published analysis reconciles the two. The registry results are the sponsor's own tabulations, never peer reviewed. Nothing here says anything about oral or intranasal rapastinel, which have never been studied in people, or about cognition in healthy people, which no trial measured.
Reading the research record
Rapastinel is the compound to read when someone tells you a small positive trial settles a question. Naurex funded the 116 person proof of concept and published it; Allergan, of which Naurex became an affiliate, funded a phase 3 programme of ten registered trials and several thousand participants. That programme is exactly what should happen after a promising early result, and it produced a clear answer. The registry results posted in late 2019 and 2020 show placebo adjusted differences of 0.3, 0.5 and 1.0 MADRS points in the three acute trials and no difference in relapse. The monotherapy trials were stopped in July 2019 with the reason business decision to stop the program recorded on each record.
Two features of the record deserve stating. First, the phase 3 results exist only on ClinicalTrials.gov. The sponsor met its legal posting obligation and never published a paper, so the failure is documented in a primary source but is invisible to anyone who only searches the journal literature, where the last human efficacy paper on rapastinel is the positive 2015 proof of concept. Second, the driving study, published in 2022 after the programme had ended, is a genuine and well run finding about a drug nobody will take: it shows rapastinel did not impair driving where ketamine did, which was the whole safety rationale for the molecule. Rapastinel itself is finished, and vials sold under the name GLYX-13 are of a compound whose own sponsor concluded, at a cost of several thousand participants, does not separate from placebo.
The evidence, charted
Fig. 1 · evidence composition
7of 7 citations (100%) are in people
Every citation cited here is Human work; no other study type is cited on this page. This count is of our own citation list and understates any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 4 distinct years, 2015 to 2022, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human2015
Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent
116 adults with major depression who had not responded to at least one antidepressant in the current episode, randomised to a single intravenous dose of 1, 5, 10 or 30 mg/kg or placebo. The 5 and 10 mg/kg doses reduced HAM-D17 scores from day 1 through day 7, with onset within 2 hours on the Bech-6; 1 and 30 mg/kg did not. No psychotomimetic effects. Funded by Naurex, the developer.
Journal of Psychiatric Practice - Human2016
A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder, RAP-MD-01 (NCT02932943)
Phase 3, 465 enrolled, weekly intravenous rapastinel 450 mg or placebo added to an antidepressant. Posted results: MADRS change at 3 weeks of -4.7 on rapastinel versus -5.0 on placebo, least squares mean difference 0.3 (95% CI -1.07 to 1.72), p = 0.65. Sponsor funded; results posted October 2019, never published in a journal.
ClinicalTrials.gov, Naurex / Allergan - Human2016
A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder, RAP-MD-02 (NCT02943564)
Phase 3, 658 enrolled, rapastinel 225 mg, 450 mg or placebo weekly. Posted results: MADRS change at 3 weeks of -4.8 (225 mg), -5.4 (450 mg) and -4.9 (placebo); p = 0.89 for 225 mg versus placebo and p = 0.58 for the 450 mg comparison. Sponsor funded; results posted December 2019.
ClinicalTrials.gov, Naurex / Allergan - Human2016
A Study of Rapastinel as Adjunctive Therapy in Major Depressive Disorder, RAP-MD-03 (NCT02943577)
Phase 3, 429 enrolled, rapastinel 450 mg or placebo weekly. Posted results: MADRS change at 3 weeks of -5.1 versus -4.1, least squares mean difference -1.0 (95% CI -2.70 to 0.68), p = 0.24. Sponsor funded; results posted November 2019.
ClinicalTrials.gov, Naurex / Allergan - Human2016
A Study of Rapastinel as Adjunctive Therapy in the Prevention of Relapse in Patients With Major Depressive Disorder (NCT02951988)
Phase 3, 1,304 enrolled, 52 week double blind relapse prevention with rapastinel 450 mg weekly, every two weeks, or placebo. Posted results: no difference in time to first relapse, p = 0.53 (every two weeks) and p = 0.46 (weekly). Suicidal ideation was recorded in 17, 25 and 23 participants respectively. Sponsor funded; results posted March 2020.
ClinicalTrials.gov, Naurex / Allergan - Human2018
Study of Rapastinel as Monotherapy in Patients With MDD (NCT03560518)
Phase 3 monotherapy trial, 439 enrolled, terminated in July 2019. Sponsor's stated reason: business decision to stop the program. Three further phase 3 trials (NCT03614156, 363 enrolled; NCT03668600, 230; NCT03675776, 50) were terminated with the same wording and one (NCT03855865) was withdrawn before enrolling.
ClinicalTrials.gov, Naurex / Allergan - Human2022
A randomized, multicenter trial assessing the effects of rapastinel compared to ketamine, alprazolam, and placebo on simulated driving performance
107 healthy adults, five period crossover: rapastinel 900 and 1,800 mg intravenously did not impair simulated driving compared with placebo (p > 0.5), while ketamine 0.5 mg/kg did (p = 0.0001) for at least 105 minutes. Funded by Allergan; several authors were Allergan employees.
Clinical and Translational Science
Frequently asked questions
Did rapastinel fail its phase 3 trials?
Yes, and the results are public. In RAP-MD-01, 02 and 03, the MADRS depression score at 3 weeks fell by 4.7 to 5.4 points on rapastinel and 4.1 to 5.0 on placebo; the placebo adjusted differences were 0.3, 0.5 and 1.0 points with p values of 0.65, 0.58 and 0.24. The 1,304 person relapse prevention trial also found no difference. These figures come from the sponsor's own results postings on ClinicalTrials.gov; no journal paper was ever published.
But the early trial was positive?
It was. In 116 people, a single intravenous dose of 5 or 10 mg/kg reduced depression scores within 2 hours for about a week, with no dissociative effects, and doses of 1 and 30 mg/kg did nothing. That result did not reproduce at scale. The discrepancy between the two has never been explained in a publication.
Was rapastinel safer than ketamine?
On the one measure that was tested head to head, yes: in 107 healthy volunteers, rapastinel at 900 and 1,800 mg intravenously did not impair simulated driving, while ketamine 0.5 mg/kg did for at least 105 minutes. No psychotomimetic effects were reported in any rapastinel trial. Being free of ketamine's side effects is not the same as sharing its antidepressant effect, and the phase 3 trials show it did not.
Is GLYX-13 sold as a nootropic worth anything?
No human study has measured cognition or mood in healthy people taking rapastinel, and every human trial used intravenous dosing. A tetrapeptide taken by mouth or nose has not been studied in people at all. The one large dataset that exists shows no effect on depression at the dose the sponsor chose.