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