For decades, major depressive disorder (MDD) has been treated primarily with medications that influence monoamine neurotransmitters—serotonin, norepinephrine, and dopamine. While SSRIs, SNRIs, and atypical antipsychotics have helped many, a significant portion of individuals with MDD continue to experience partial or inadequate response to treatment. This has driven the need for adjunctive therapies, and in 2025, few investigational agents have captured as much attention as Osavampator (NBI 845).
Osavampator is a selective positive allosteric modulator (PAM) of the AMPA receptor—a novel approach that enhances glutamatergic signaling. It’s different from traditional antidepressants in that it bypasses the monoamine system entirely, working instead to promote neuroplasticity directly at the level of synaptic transmission. This is in contrast to agents like Spravato (esketamine), which indirectly stimulates AMPA activity via NMDA receptor antagonism and is associated with dissociative effects. Osavampator, by contrast, works directly on AMPA receptors without inducing sedation or dissociation.
With its oral, once-daily formulation and a favorable safety profile, Osavampator is being positioned as a highly tolerable and mechanistically distinct adjunctive option for patients who have not found relief with traditional antidepressants alone.
In the Phase 2 SAVITRI trial, Osavampator was studied as an adjunctive treatment in adults with treatment-resistant depression. The primary outcome, reduction in MADRS score at Day 28, showed a statistically significant 4.3-point improvement over placebo, with an effect size of 0.53. By Day 56, this benefit grew to a 7.5-point reduction, corresponding to an effect size of 0.73—one of the strongest results seen in recent adjunctive MDD studies.
Perhaps just as importantly, Osavampator was well tolerated. No serious adverse events were reported, and there were no issues with dissociation, sedation, or other central nervous system effects that commonly complicate glutamatergic treatments.
Compared to other adjunctive treatments like Caplyta, Rexulti, and Abilify, Osavampator shows a competitive and potentially superior profile in both efficacy and tolerability—based on available Phase 2 data.
Caplyta (lumateperone) demonstrated a moderate effect in its adjunctive MDD study, with about a 4.5-point MADRS improvement over placebo and an estimated effect size of 0.56. Notably, Caplyta showed statistically significant results by Day 15 and maintained strong tolerability, with minimal extrapyramidal symptoms or metabolic disruption.
Rexulti (brexpiprazole) had more modest Phase 2 results, with about a 2.3-point MADRS advantage over placebo at Week 6 and an estimated effect size of 0.3 to 0.4. While it remains widely prescribed, Rexulti can be limited by akathisia, weight gain, and insomnia in clinical practice.
Abilify (aripiprazole), also an adjunctive antipsychotic, showed similar modest benefit with a 3.2 to 3.4-point MADRS improvement and a comparable effect size in the 0.3–0.4 range. It carries similar tolerability limitations, including extrapyramidal symptoms, restlessness, and metabolic changes.
Osavampator’s Phase 2 performance—particularly the growing efficacy from Week 4 to Week 8—sets it apart. With an effect size peaking at 0.73 and no sedation, akathisia, or metabolic side effects observed, it stands out as both effective and easy to use.
Osavampator’s mechanism of action also distinguishes it from existing adjunctive therapies. Unlike dopamine partial agonists such as Rexulti and Abilify, which modulate dopaminergic tone and can lead to motor-related side effects, Osavampator enhances glutamatergic transmission by positively modulating AMPA receptors. This directly promotes synaptic plasticity—the same downstream target often cited in ketamine research—without the instability associated with glutamate surges or NMDA inhibition.
Caplyta works via a more diffuse mechanism, modulating dopamine, serotonin, and glutamate. While effective, it is not as targeted in its receptor engagement as Osavampator. Osavampator’s AMPA-specific activity provides a precision mechanism with a clean pharmacological profile—something rarely achieved in psychiatric medications.
Neurocrine launched its global Phase 3 program in January 2025. These placebo-controlled, adjunctive trials are designed to confirm the findings of SAVITRI in a larger and more diverse patient population. Topline data are expected by late 2026 or early 2027. If successful, Osavampator could become the first approved antidepressant that targets AMPA receptors directly—a meaningful shift in how we approach treatment-resistant depression.
In a crowded market of SSRIs, SNRIs, and antipsychotic adjuncts, Osavampator represents a truly novel direction. Its efficacy is among the strongest seen in recent trials, its safety profile is remarkably clean, and its mechanism of action provides an opportunity to break from the limitations of monoamine-based therapy.
If Phase 3 results replicate what we’ve seen in SAVITRI, Osavampator could emerge not just as another tool in the box—but as a first-in-class treatment that redefines how we augment antidepressants. For patients and clinicians alike, that’s a development worth watching closely.
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