New Route To Treat Depression

A NEW TARGET for treating depression, discovered by researchers in Iowa, may offer an alternative to current antidepressants, which target other mechanisms to treat the condition.

"The mechanism issue is important because if a patient doesn't respond to one drug, the chances of them responding to another drug that works through the same mechanism are low," says John A. Wemmie, who led the research team. Wemmie is an associate professor of psychiatry and neurosurgery at the University of Iowa and a staff physician and researcher at the Iowa City Veterans Affairs Medical Center.

Wemmie's team focused on a biochemical pathway involving acid-sensing ion channel (ASIC) proteins expressed by neurons. ASICs are activated by protons that are believed to act as neurotransmitters (C&EN, Jan. 14, 2008, page 10). Wemmie and his colleagues concentrated on the ASIC1a class of these ion channels, which are abundant in regions of the brain associated with mood.

The research group had previously shown in mice that ASIC1a activity is associated with anxiety, which often accompanies depression. In the new work, the researchers showed that mice lacking the gene for ASIC1a were less susceptible than normal mice to depression caused by stress. In a second experiment, the researchers treated normal mice with A-317567, an experimental ASIC inhibitor that Abbott Laboratories has been studying for pain treatment. Wemmie's team reports that blocking ASIC1a in this way produced antidepressant effects in the animals (J. Neurosci. 2009, 29, 5381).

"If we find ways to block the channels or to manipulate pH in ways that will inhibit ASIC activation in people," Wemmie says, "this may provide a novel opportunity to reduce depression in patients."

"The development of antidepressants that act on other molecular targets in the brain would be a major breakthrough," comments pharmacologist John F. Cryan, who studies the treatment of depression at University College Cork, in Ireland, but is not affiliated with the Iowa work. A new treatment paradigm might help the more than one-third of patients for whom current antidepressants aren't particularly effective, he adds.