Experimental Drug PA 915 Delivers Rapid, Lasting Antidepressant Effects in Stressed Mice

A single dose of the experimental drug PA 915 rapidly eased depression– and anxiety-like behaviors in stressed mice. The benefits lasted up to eight weeks, suggesting a potential new path for rapid-acting antidepressants.

Key Points

• A single dose of PA 915 produced fast-onset, eight-week antidepressant effects in multiple mouse chronic stress models.
• Unlike classic antidepressants, PA 915 improved mood and cognition without inducing hyperactivity, cognitive side effects, or dependency.
• While promising in mice, these preclinical studies still require human studies to test safety and efficacy.

Study at a Glance

• Journal & Date: Molecular Psychiatry, 2025 (online ahead of print). PubMed Abstract
• Study Design & Population: Mouse experiments using chronic stress paradigms, including social defeat stress, corticosterone exposure, and isolation, to model depressive- and anxiety-like behaviors.
• Primary Outcomes: Rapid rescue of depressive and anxiety behaviors, normalization of cognition, and reduced corticosterone activity; effects lasted up to eight weeks after a single dose, with no changes in healthy control mice.

What’s New vs Prior Evidence

Traditional antidepressants take weeks to work and often require continuous dosing, leaving many patients without timely relief. In recent years, ketamine has gained attention as a rapid-acting option, but it carries risks of dissociation, short duration, and abuse potential. PA 915 stands out by offering both a rapid onset and an extended duration after just one dose, at least in mice. It improved cognition, reduced anxiety behaviors, and did not trigger motor agitation or addictive responses. If such results could be replicated in humans, PA 915 would represent a breakthrough in redefining what “fast-acting antidepressant” means.

Expert Comment

Carlos Zarate Jr., MD, Chief of the Experimental Therapeutics & Pathophysiology Branch at the U.S. National Institute of Mental Health, is a leading authority on rapid-acting antidepressants. He explains:

“The pursuit of fast-acting, durable antidepressants has gained urgency with the rise of ketamine therapies, but their risks remain significant. PA 915 is exciting because it demonstrates both a rapid onset and extended duration of effect after a single dose in mice. It works via PAC1 receptor antagonism, a novel pathway distinct from NMDA antagonism or monoaminergic modulation. Its clean behavioral profile (no cognitive or motor side effects) is especially encouraging. But mouse results often fail to translate to humans, so we must view this as a first step, not an endpoint. We need to understand its mechanism better and test safety, tolerability, and efficacy in well-designed clinical trials. If any of that holds true, PA 915 could significantly expand our therapeutic toolkit.”

Who Could Benefit

• Patients with treatment-resistant depression, where existing options are inadequate.
• Clinicians seeking alternatives to ketamine or psychedelics that combine rapid relief with safer profiles.
• Neuroscience researchers, gaining a new experimental tool to probe stress and mood pathways.
• Pharma developers, exploring PAC1 receptor antagonists as next-generation antidepressant candidates.

Limitations & Uncertainties

• All evidence so far comes from mice; human brains may respond very differently.
• The long-term safety profile of PAC1 receptor antagonism is not yet known.
• Mouse behavioral tests only approximate human depression and cannot capture its full complexity.
• The PAC1 receptor is involved in multiple systems, raising the possibility of unexpected off-target effects.
• Translation to humans will require careful dose-finding, toxicology, and phased clinical trials.

What Happens Next

Researchers are now working to replicate the results in additional preclinical labs and refine dosing strategies. Toxicology studies are needed to confirm that blocking the PAC1 receptor is safe over time and does not impair other brain functions. If successful, the next milestone would be early-phase human trials to test whether the rapid and durable effects seen in mice hold up in patients.

Summary

PA 915 is a new experimental drug that lifted depression-like symptoms in stressed mice within hours after just one dose. The improvements lasted for two months and came without common side effects such as agitation or memory problems. It’s still early research, but scientists hope that this compound could eventually inspire faster, longer-lasting treatments for depression.

Glossary

• PA 915: An experimental small-molecule drug that blocks the PAC1 receptor, tested for antidepressant effects in mice.
• PAC1 Receptor: A brain receptor involved in stress and mood regulation; blocking it may reduce depression-like behaviors.
• Chronic Stress Models: Laboratory techniques (e.g., social defeat stress, corticosterone treatment) used to mimic depressive symptoms in animals.
• Rapid-Acting Antidepressant: A treatment that begins working within hours or days instead of weeks.
• Corticosterone: A stress hormone in rodents, equivalent to cortisol in humans, often elevated in depression models.

References

1. Shintani, Y., Hattori-Takahashi, A., Tokuhara, I., Koike, T., & Hongo, H. (2025). Rapid and long-lasting antidepressant effects of the pituitary adenylate cyclase-activating polypeptide receptor antagonist PA-915 in chronic stress mouse models of anxiety and depression. Molecular Psychiatry.
2. PubMed. (2025). Rapid and long-lasting antidepressant-like effects of PA-915 in stressed mice. National Library of Medicine. https://pubmed.ncbi.nlm.nih.gov/40908362/
3. Nature. (2025, June 20). Experimental drug delivers long-lasting antidepressant effects in mice. Nature News. https://www.nature.com/articles/s41380-025-03209-4