( 2R,6R )-hydroxynorketamine exerts mGlu 2 receptor-dependent antidepressant actions
Panos Zanos, Jaclyn N. Highland, Brent W. Stewart, Polymnia Georgiou, Carleigh Jenne, Jacqueline Lovett, Patrick J. Morris, Craig J. Thomas, Ruin Moaddel, Carlos A. Zarate, Todd D. Gould
Proceedings of the National Academy of Sciences March 13, 2019 DOI: 10.1073/pnas.1819540116 via OpenAlex
Summary
A single subanesthetic dose of ketamine produces rapid (within hours) and sustained antidepressant effects, unlike standard antidepressants that take months and fail in about 30% of patients. The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant candidate with fewer adverse effects. Using behavioral, genetic, pharmacological approaches and EEG measurements, the study found that antidepressant-relevant actions of (2R,6R)-HNK involve metabotropic glutamate receptor subtype 2 (mGlu2) signaling and identified high-frequency EEG oscillations as a marker of rapid antidepressant responses. The findings suggest clinical trials combining subtherapeutic doses of mGlu2 receptor inhibitors with ketamine or (2R,6R)-HNK for depression treatment.
Study at a glance
| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Topics | Ketamine |
| Keywords | Antidepressant Metabotropic receptor Pharmacology Metabotropic glutamate receptor |
| Citations | 153 |
| Key finding | The antidepressant-relevant actions of (2R,6R)-HNK converge with mGlu2 receptor signaling, and high-frequency EEG oscillations are a marker associated with rapid antidepressant responses. |
Abstract
Significance Despite available medications for depression, currently approved antidepressants take months to exert therapeutic effects, and ∼30% of patients remain treatment resistant. In contrast, a single subanesthetic dose of ketamine exerts rapid (within hours) and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite ( 2R , 6R )-hydroxynorketamine [( 2R , 6R )-HNK] is a rapid-acting antidepressant candidate with limited adverse effects compared with ketamine. Using behavioral, genetic, and pharmacological approaches and EEG measurements, we determined that the mechanism underlying antidepressant-relevant actions of ( 2R , 6R )-HNK converges with metabotropic glutamate receptor subtype 2 (mGlu 2 ) receptor signaling and identified high-frequency EEG oscillations as a marker associated with rapid antidepressant responses. Our data support the use of individually subtherapeutic doses of mGlu 2 receptor inhibitors with ketamine or ( 2R , 6R )-HNK in clinical trials for the treatment of depression.