Background: Suicide rates and narcotic overdose have doubled since 2000. At least 30 percent of people with major depression are Treatment-Resistant (TR) and require novel therapeutics. ketamine at low doses has been shown in clinical trials to induce a rapid, short-lived anti-suicide and anti-depressant effect. Objective: To review the potential mechanism of action of ketamines’ alleviation of depressive symptoms from both animal and available human literature. Methods: This is a synthesis of information from papers listed in PUBMED Central. Although not exhaustive, this review highlights the most compelling work in the field related to this remarkable clinical rapid anti-depressant effect. Results: While there have been several theories and with some scientific evidence to date, the conclusion here is that currently, an exact and acceptable mechanism of action (MOA) for ketamines’ rapid anti-depressant effect is not apparent. The MOA of this compound with psychoactive abuse potential at a higher dosage and acute antidepressive effect in the most resistant patients is unknown. Discussion: Possible MOAs reviewed, include dopamine receptor modulation through epigenetic neuroadaptation via specific D1/D2 antagonism, D1 activation using optogenetic stimulation, and the role of D2/D3 availability in the ketamine therapeutic action. Conclusion: Unraveling MOA could guide the development of other unique Psychoplastogens capable of rapidly promoting structural and functional neural plasticity in cases of TR Major Depressive Episodes (MDE) and unipolar Major Depression Disorder (MDD).

These results suggest that the application of transdermal fentanyl patch for a period of 2 h does not produce local peripheral opioid analgesia at the site of patch application.