Open AccessImaging the effect of ketamine on synaptic density (SV2A) in the living brain
Author(s) -
Sophie Holmes,
Sjoerd J. Finnema,
Mika Naganawa,
Nicole DellaGioia,
Daniel Holden,
Krista Fowles,
Margaret T. Davis,
Jim Ropchan,
Paul Emory,
Yunpeng Ye,
Nabeel Nabulsi,
David Matuskey,
Gustavo A. Angarita,
Robert H. Pietrzak,
Ronald S. Duman,
Gerard Sanacora,
John H. Krystal,
Richard E. Carson,
Irina Esterlis
Publication year - 2022
Publication title -
molecular psychiatry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.071
H-Index - 213
eISSN - 1476-5578
pISSN - 1359-4184
DOI - 10.1038/s41380-022-01465-2
Subject(s) - ketamine , antidepressant , neuroscience , psychology , major depressive disorder , medicine , psychiatry , hippocampus , cognition
The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [ 11 C]UCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects.