Developing Rapid Onset Antidepressant Drugs That Act at the NMDA Receptor
For several years, researchers have been exploring potential rapid-acting treatments for unipolar and bipolar depression. Intravenous ketamine has the best-replicated results so far. A slow infusion of ketamine (0.5mg/kg over 40 minutes) produces a rapid onset of antidepressant effects in only a few hours, but the improved mood lasts only 3-5 days.
Ketamine blocks the receptors of the main excitatory neurotransmitter in the central nervous system, glutamate. Glutamate is released from nerve endings and travels across the synapse to receptors on the next cell’s dendrites. There are multiple types of glutamate receptors at the dendrites, and ketamine blocks one called the NMDA receptor, which allows calcium ions to enter the cell.
Some downsides to ketamine are the brief duration of its effectiveness and its dissociative side effects. The search is on for other drugs that are free from these side effects and that could extend the duration of rapid-onset antidepressant effects.
At the 2012 meeting of the International Congress of Neuropsychopharmacology (CINP), Mike Quirk of the pharmaceutical company AstraZeneca reviewed data on the intricacies of the glutamate NMDA receptor blockade and discussed the potential of AZD6765, an NMDA receptor blocker he and his colleagues have been researching.
The more the NMDA receptor is blocked, the more psychomimetic it becomes, meaning it produces hallucinations and delusions. For example, phencyclidine (PCP or angel dust) is a potent NMDA receptor blocker and psychosis inducer. For antidepressant purposes, a less complete or less persistent NMDA receptor blockade is desired. Read more
