Sara Reardon in Nature:
The anaesthetic ketamine — a hallucinogenic club drug also known as Special K — has tantalized researchers who are seeking new ways to treat depression. The drug can lift a person’s mood in hours, even when depression is severe. But several ‘ketamine-like’ medications have failed to alleviate depression in clinical trials over the past decade. Now, some researchers think they know why. Emerging evidence suggests that scientists have misunderstood how ketamine fights depression. So they might have attempted to mimic the wrong biological mechanism when designing drugs to improve mood while avoiding the disorienting ketamine high. On 20 May, researchers at a meeting of the Society of Biological Psychiatry in San Diego, California, will present results suggesting that some of ketamine’s power comes from its ability to affect brain cells called glia, which support neurons. Their finding adds to recent studies contradicting a long-held idea that the drug works mainly by blocking proteins called NMDA receptors, on the surface of brain cells, which transmit signals between those cells.
At the upcoming meeting, a team led by neuroscientist Mark Rasenick of the University of Illinois at Chicago will report on tests of antidepressant drugs in cultured rat glial cells. All of the drugs that the researchers studied caused a cluster of proteins to shift position in the glial cells’ membranes, signalling to the cells to form new connections with their neighbours. But ketamine produced this effect in 15 minutes, as compared to 3 days for conventional antidepressants. Moreover, drugs that block NMDA receptors but are not antidepressants did not show the effect at all. This suggests that ketamine’s ability to bind to NMDA receptors might not be its primary weapon against depression. Rasenick’s team is not the first to suggest a different target for ketamine. A paper published in Nature in May 2016 concluded that one of ketamine’s breakdown products — not the drug itself — probably lifted depression in mice1. And this compound affected cell proteins called AMPA receptors, instead of NMDA receptors.