Skyler Child

Introduction. Major depressive disorder (MDD), i.e. major depression, is a complex mental disorder that affects more than 16% of the world population with an estimated annual toll of $326.2 billion.^1,2 Unlike diseases characterized by biological markers, it is diagnosed via subjective symptoms, including loss of will, dysphoria, and anhedonia.¹ While many efficacious FDA-approved drugs treat MDD, the majority of patients do not achieve remission via monotherapy.¹ Ketamine, a dissociative anesthetic, has recently exhibited rapid antidepressant effects in patients with treatment resistant MDD.^3,4 While the mechanism is not elucidated, hydroxynorketamines (HNKs), which are prominent metabolites found in circulation shortly after ketamine administration, may participate in the antidepressant effects.⁴ Attributed for the anesthetic and negative hallucinogenic effects, inhibition of the N-methyl-D-aspartate (NMDA) receptor by ketamine and associated metabolites is speculated to play a role in its antidepressant efficacy.³ Methods. Rodent models were used to test antidepressant effects of ketamine and HNKs via conditioned avoidance (CA), forced swim test (FST), and novelty suppressed feeding test.^5,6,8 Protein transcription via eEF2 pathway in mouse brains were studied via eEF2K knockout mice.⁶ Mouse embryos and human induced pluripotent stem cell cultures of dopamine neurons, identified with anti-tyrosine hydroxylase antibody, were used to study drug structural plasticity effects on neuron soma area, primary dendrite number, and dendrite length.⁷ Cultures were pretreated with inhibitors of BDNF, mTOR, NMDA, AMPA, and D3R to analyze their role in ketamine induced structural plasticity.⁷ Interaction of HNKs and NMDA receptor were studied with HNK treatment followed by LD₉₉ of NMDA.⁸ In clinical trial, MDD patients were treated with ketamine infusion and intervals of serum analysis of ketamine metabolites and simultaneous depression rating scale.⁹ Results. One study found only ketamine, not HNKs, exhibited antidepressant effects with CA via fewer failed escape attempts (P<0.0001).⁵ Furthermore, clinical trials correlated HNKs to worse antidepressant effect.⁹ However, ketamine and HNKs both induced increased structural plasticity in dopamine neuron cell cultures via increased dendrite length (both P<0.0001).⁷ In (2R,6R)-HNK treated mice, antidepressant response was exhibited via decreased immobility time during FST one hour after treatment (P<0.01).⁸ These mouse brains exhibited measured increased expression of mature BDNF (P<0.01) and increased phosphorylation of mTOR (P<0.05).⁸ Conclusions. Both ketamine and HNKs enhance signaling in pathways increasing dopamine neuron structural plasticity, but HNKs have variable results determining their antidepressant efficacy.^5,7-9 While NMDA receptor blockade may participate in ketamine’s antidepressant efficacy, HNKs which lack this blockade were not administered directly in clinical trial.^7-9

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