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.
Ketamine enters the NMDA channel on a dendrite when the channel is open (and calcium ions flow in, dragging ketamine with them). When the top of the channel closes, much like the Venus flytrap plant closing and trapping an insect inside, much of the ketamine gets trapped in the channel, and the block persists or builds. Most of the ketamine (82%) is trapped in this way and interferes with normal glutamate functions.
Drugs that block the NMDA receptors vary in the rates at which they get trapped in the channel. Drug researchers would like to find a blocker that gets trapped at a low rate, so that only quickly firing neurons are blocked and normal low-level activity is left unperturbed. Among already developed drugs, ketamine is trapped at 82%, dizocilpine or MK801 (which is not used clinically due to its side effects) at 76%, the anti-Alzheimer’s drug memantine at 70%, and the anticonvulsant remacemide at 64%.
In the case of AZD6765, only 52% to 59% of the drug gets trapped in the NMDA receptor. AZD6765 has rapid-onset antidepressant effects like ketamine, but induces no minor dissociative symptoms or psychosis. Following initial exploration, it is now being tested in larger, more rigorous placebo-controlled antidepressant trials of 8 and 12 weeks duration, which include multiple infusions.
As a general trend, many large pharmaceutical companies have recently been drastically reducing their research into neuropsychiatric drug development. In the past they often spent hundreds of millions of dollars on the development of a potential central nervous system psychotropic drug that often didn’t even make it to market. Now, for example, AstraZeneca has trimmed its central nervous system drug development program from over 300 scientists to about 30. However, the potential of NMDA receptor blockers make this area of drug development appear promising, and Quirk and his remaining colleagues believe they are on the right track with AZD6765.
