Introduction. Treatment Resistant Depression (TRD) affects 1% of individuals in the US and 30% of depressed patients1. Patients with treatment resistant depression are those who have been unsuccessful with treatment from two different classes of antidepressants for a sufficient duration of time and dosage2. Treatment for these patients is lacking, however Ketamine has become an area of interest due to its rapid acting antidepressant effects. Ketamine has clinically been used as an anesthetic in the past, however studies have shown its potential as an antidepressant1. Ketamine is an open channel blocker of the N-methyl-D-aspartate receptor (NMDAR), however the exact mechanism resulting in Ketamine’s antidepressant actions remains uncertain3. Methods. To determine the antidepressant effects of ketamine, a 10mg/kg dose of ketamine was injected and the mice were tested in a forced swim test (FST). Immobility time, which is characterized as minimal movement that keeps the animal’s head above the water, was scored by a trained observer3. The immobility time is representative of the time it takes to reach depression. The two enantiomers, R and S Ketamine, were measured followed by Ketamine’s metabolite, hydroxynorketamine (HNK), to compare antidepressant effects. To confirm that HNK is responsible for the effects, the C6 position was deuterated and the effects were measured. Results. The (S) enantiomer is a more potent inhibitor of NMDAR, but the (R) had greater antidepressant effects suggesting there is an alternative NMDA independent mechanism. The antidepressant actions of ketamine involve α-amino-3-hydroxy-5- methyl-4-isoxazole propionic acid (AMPA) receptor activation by (2R,6R)-HNK3. When binding to AMPA receptors occurs, an increase in intracellular calcium results in the release of brain-derived neurotrophic factor (BDNF). This causes downstream signaling of mammalian target of rapamycin (mTOR), which results in an increase in synaptogenesis4. This restores the connectivity between the medial prefrontal cortex and hippocampus in the brain of depressed patients. Confirmation of HNK’s effects is indicated by the lack of effect from the deuterated Ketamine. Conclusions. The underlying mechanism responsible for the antidepressant effects are independent of NMDA inhibition, which was previously thought to be responsible. By using AMPA receptors to activate downstream signaling pathways and synaptic transmission, a new option will be available for the long term treatment of depression4. Utilizing this knowledge and continuing research of the cellular mechanism underlying the effects of HNK will close treatment gaps for those with TRD5.
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- Feifel, D., Malcolm, B., Boggie, D., & Lee, K. (2017). Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. Journal of Affective Disorders,221, 283-288. doi:10.1016/j.jad.2017.06.043
- Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G.I.,Gould, T. D. (2016). NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature,533(7604), 481-486. doi:10.1038/nature17998
- Koike, H., & Chaki, S. (2014). Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behavioural Brain Research,271, 111-115.doi:10.1016/j.bbr.2014.05.065
- Shirayama Y, Hashimoto K. Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine. Int J Neuropsychopharmacologyl. 2017;21(1):84–88.doi:10.1093/ijnp/pyx108