Novel Antidepressant Compounds From the Pipeline at ASCP

CONFERENCE REPORTER

From the American Society of Clinical Psychopharmacology Annual Meeting, John Miller, MD, highlighted 3 investigational compounds with novel mechanisms of action for major depressive disorder.

Miller described the first agent as the first drug in psychiatry to operate through an epigenetic mechanism—specifically, inhibition of a SIRT6 enzyme involved in histone acetylation, which regulates gene transcription without altering the underlying genetic sequence.¹ A striking feature of the early data was a sex-specific treatment effect: the drug demonstrated robust efficacy in women but not in men, a finding Miller described as "very compelling" and potentially indicative of a specific biological mechanism relevant to depression.

The second compound, ALT-203, is a histamine 3 receptor antagonist. Miller distinguished the clinical effects of prohistaminergic stimulation—wakefulness, attention, and alertness—from the sedation and weight gain associated with antihistamine agents, explaining that blocking the histamine 3 autoreceptor disrupts a feedback loop and produces a histaminergic surge.² Early studies suggested efficacy for improving arousal and cognitive performance, though the agent remained in early development.

The third compound is an AMPA receptor positive allosteric modulator. Miller situated this mechanism within the glutamatergic antidepressant landscape, noting that ketamine, esketamine, and dextromethorphan act upstream via NMDA receptor antagonism, producing a glutamate surge that activates the AMPA receptor. By targeting AMPA directly, this class of agents bypasses NMDA and avoids associated adverse effects like dissociation, sedation, and hypertension, while still driving downstream synaptogenesis and neuroplasticity relevant to antidepressant response.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Volunteer Consulting Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Dai W, Qiao X, Fang Y, et al. Epigenetics-targeted drugs: current paradigms and future challenges. Signal Trans Targeted Ther. 2024;9:332.

2. Shen L, Guo Y, Ferreira de Silva M, et al. ALTO-203, a novel histamine H# inverse agonist, increase sucrose preference in dopamine-depleted rats. 2025. Accessed May 27, 2026. https://altoneuroscience.com/wp-content/uploads/2025/04/SOBP2025_ALTO203_Sucrose_Preference_final.pdf