Molecular psychiatry
December 1, 2024
Chloe E Page, C Neill Epperson, Andrew M Novick et al.
54 citations
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.
Cell reports
May 21, 2025
Lace M Riggs, Sage Aronson, Ta-Chung M Mou et al.
2 citations
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.
British journal of pharmacology
July 1, 2019
Panos Zanos, Jaclyn N Highland, Xin Liu et al.
In mice, (R)-ketamine's metabolism to (2R,6R)-hydroxynorketamine (HNK) enhances its antidepressant-relevant actions. A deuterated form of (R)-ketamine that blocks this metabolism had less potency in antidepressant-sensitive behavioral tests, while (2R,6R)-HNK itself produced dose-dependent sustained antidepressant effects. However, (R)-ketamine also caused NMDA receptor-mediated adverse effects—including locomotor stimulation, conditioned-place preference, prepulse inhibition deficits, and motor incoordination—at sub-anaesthetic doses, with about half the potency of racemic ketamine. These findings indicate that while antidepressant-relevant effects occur at lower doses, there is a potential risk for sensory dissociation and abuse liability at higher doses.