Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Pharmacology and Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
2 papers in the library · 56 citations · publishing 2024-2025
Major depressive disorder (MDD) is better understood not as a serotonin deficit but as inflexibility in cognitive and emotional brain circuits that creates a persistent negativity bias. Effective treatments—including conventional antidepressants, ketamine, psychedelics, psychotherapy, and neuromodulation—work by enhancing neuroplasticity, restoring synaptic, network, and behavioral function to enable adaptive cognitive and emotional processing. The article provides accessible language and metaphors for clinicians and researchers to communicate this updated framework to patients and the public, aiming to improve understanding and trust.
A single dose of (2R,6R)-hydroxynorketamine (HNK), a metabolite of ketamine, rapidly strengthens weakened synapses in a rat model of treatment-resistant depression. In plasticity-deficient Wistar Kyoto rats, (2R,6R)-HNK boosted glutamatergic transmission, restored long-term potentiation (LTP), and reversed deficits in hippocampal-dependent memory. The drug selectively increased activity of CA1 pyramidal neurons during novelty exploration and restored spatial recognition memory reliant on Schaffer collateral pathways. Prior spatial learning partially blocked LTP in control rats, a pattern mirrored in LTP-impaired rats where spatial learning deficits were reversed by (2R,6R)-HNK. The findings indicate that (2R,6R)-HNK promotes adaptive synaptic changes at impaired synapses, improving cognitive function.