How Ketamine Works
Pick an explanation.
The Non-Nerdy Answer
The Non-Nerdy Answer: Ketamine works by helping to “reboot” our brain. Through a process of stimulating rapid neuron proliferation, growth, and increased connectivity between neurons, ketamine is able to help break up the rigidity of many of the practiced negative thought patterns and behaviors that we have ingrained in ourselves over long periods of time through our depression and traumas. It leaves the patient feeling more optimistic and hopeful. It also works through allowing the patient to more easily think positively and engage with life to implement changes that support healthy thoughts and behaviors.
The Nerdy Answer
Ketamine works in a unique manner to other psychiatric medications in that it does not appear to work by directly targeting the monoaminergic neurotransmitter system (serotonin, norepinephrine, dopamine). Ketamine acts as a N-Methyl-D-Aspartate Receptor (NMDAR) antagonist. This action has signal cascading effects that continue in the brain long after the medication is out of the system. Specifically, increases glutamate neurotransmission by both increased glutamate release and increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression. This causes secondary release of brain-derived neurotrophic factor (BDNF) and extracellular regulated kinases (ERK) signaling which then stimulates mammalian target of rapamycin (mTOR). MTOR is a kinase that causes protein translation and via a complex signaling path, leads to increased synaptogenesis, increased density of synapses, which leads to increased structural connectivity between neurons, particularly those in the pre-frontal cortex.
Proposed mechanism of ketamine’s antidepressant action, whereby ketamine, through a blockade of tonic GABAergic inhibition (1), causes a surge in glutamate release and cycling (2). The resulting increased glutamatergic transmission through AMPA receptors (whose surface expression may be independently upregulated by the suppression of spontaneous NMDAR-mediated neurotransmission) (3) leads to increased BDNF-dependent (4) levels of synaptogenesis (5) that ultimately contribute to the rapid and sustained antidepressant effects.
(Neuropsychopharmacology (2015) 40, 259-267; doi:10.1038/npp.2014.261)