Rapastinel (GLYX-13)

Rapastinel, formerly known as GLYX-13, is an investigational drug that was studied as a potential rapid-acting antidepressant and cognitive enhancer.
It showed promise in early-phase trials for treatment-resistant depression (TRD) and as an adjunct to traditional antidepressants, with a single intravenous dose demonstrating rapid antidepressant effects (within hours) that lasted for about a week. However, its Phase III trials failed to meet primary efficacy endpoints and its development for major depressive disorder was discontinued. While rapastinel itself is no longer in active development, its mechanism inspired ongoing research into glycine-site NMDA modulators for depression and cognitive disorders.

Rapastinel is a NMDA receptor modulator that acts as a partial agonist at the glycine site of the NMDA receptor. Unlike ketamine, which is a non-competitive NMDA receptor antagonist, rapastinel modulates the receptor in a way that is believed to promote synaptic plasticity without causing dissociative or hallucinogenic side effects.

While direct human studies on cognition are limited, rapastinel’s NMDA modulation could theoretically improve prefrontal cortex (PFC) function, which is critical for attention and executive control. NMDA receptors in the PFC regulate working memory and cognitive flexibility, both impaired in ADHD and ASD.

Unlike full NMDA antagonists (i.e., ketamine), rapastinel’s partial agonism may provide a more balanced enhancement of glutamatergic signaling without overexcitation or toxicity. Rapastinel increases brain-derived neurotrophic factor (BDNF), promoting synaptic growth in regions like the hippocampus and PFC. Moreover, it is hypothesized that it may prime neurons for synaptic strengthening without causing excessive depolarization, which further distinguishes it from ketamine.

In rodent studies, rapastinel improved fear extinction learning and spatial memory, suggesting NMDA receptor-dependent plasticity enhancements.

A 2014 study (Burgdorf et al., Neuropsychopharmacology) found that rapastinel enhanced long-term potentiation (LTP) in the hippocampus, a key process in memory formation.

While no clinical studies have tested rapastinel specifically for ADHD or Austism Spectrum Disorder (ASD), its mechanism of action suggest that it might be helpful in the treatment of those conditions.

Given that ADHD involves dysregulated dopamine and glutamate signaling in the PFC, rapastinel’s NMDA modulation could indirectly normalize dopamine release by improving cortical glutamate function. Since NMDA receptors are critical for sustained attention and impulse control, rapastinel might help where stimulants (e.g., methylphenidate) are ineffective or poorly tolerated. It seems to be more likely to produce substantial improvement for people with primarily inattentive subtype. could experience more benefits. Unlike traditional ADHD medications, it would carry neither abuse potential nor cardiovascular risks. Yet, its long-lasting, delayed onset might not address acute focus demands.

As some ASD models suggest hypo- or hyper-NMDA activity, leading to synaptic imbalance, rapastinel’s modulatory effect could potentially help stabilize signaling. Also, rapastinel improved social recognition memory in rodents, suggesting potential for ASD-related social deficits. Enhanced fear extinction observed with this compound could help with rigid behaviors and anxiety, highly prevalent in ASD. NMDA modulation might normalize sensory gating, which is often disrupted in ASD (hyper- and hyposensitivity).

That said, ASD is highly heterogenous and therefore variable effects are to be expected. As seen with memantine, rapastinel could theoretically lead to overstimulation in some individuals.

Benefits of taking rapastinel

• boost in mood;

• lessened anxiety;

• improved memory and learning;

• ehanced executive function;

• improved social recognition memory;

• better focus and alertness;

• increased neuroplasticity;

• decreased behavioral rigidity;

• possible aid in the treatment of ADHD and ASD.

Side effects

Rapastinel has been found to be well-tolerated.

The only side effect reported was brief periods of dizziness.

Dosage

While its original route of administration was intravenous, extrapolations can be made based on known rapastinel’s bioavailability. And so, its intranasal dose would range from 5 to 20 mg. When dosed orally, as much as 50-200 mg might be required in order to experience equivalent benefits.

During the initial 1-2 week period (“loading phase”) rapastinel would be used every day (single dose), which is necessary to induce synaptic changes. Subsequently, based on observed response, it should be taken once or twice a week (“maintenance phase”).