Marco Pignatelli

Assistant Professor of Psychiatry WashU Medicine

Thursday 17th September 2026

Panel Discussion: Ketamine & Rapid Acting Antidepressants: Plasticity, Metabolites & the Next Generation of Therapeutic Innovation

10:30 am

What emerging preclinical and clinical data reveal about ketamine induced synaptic plasticity as a unifying mechanism for rapid antidepressant effects
The role of ketamine metabolites, including HNKs, in disentangling efficacy from dissociation and informing more targeted drug design
Progress toward non dissociative and next generation ketamine derived therapies, and how these may reshape safety, scalability, and patient access
Lessons from S-ketamine on regulatory pathways, payer expectations, and commercial adoption; and what this means for the broader psychedelic and rapid acting psychiatry landscape

Thursday 17th September 2026

Circuit Level Mechanisms of Ketamine’s Antidepressant Action: From Stress Induced Nucleus Accumbens Atrophy to Plasticity Driven Rescue of Motivation

1:30 pm

Describe how chronic stress produces profound effort related deficits and structural atrophy in D1 medium spiny neurons of the nucleus accumbens, a hub of reward computation, and how these circuit changes map onto anhedonia in depression
Explain how a single ketamine administration, assessed after the drug has fully cleared, induces lasting synaptic plasticity that restores activity in NAc D1 MSNs and rescues stress driven motivational impairments
Highlight how ketamine re engages two stress sensitive excitatory pathways (medial prefrontal cortex NAc and hippocampus NAc), each contributing complementary but distinct roles in restoring reward seeking behavior
Outline next steps to translating these circuit findings to humans using functional connectivity and morphometric data analyses as a biomarker of antidepressant treatment outcome