When psychiatrists write a prescription for a typical antidepressant such as Zoloft or Paxil, they don't expect their patients to show much improvement for a few weeks. Clinical trials, however, have shown that low doses of a drug known as ketamine, which is used at higher doses as an anesthetic and is taken recreationally as a hallucinogen (sometimes called "Special K"), can ease the symptoms of depression within hours. Now, scientists have figured out how ketamine works in the brain. In the process, they've uncovered a new molecular pathway involved in clinical depression.
Neuroscientist Lisa Monteggia and her colleagues at the University of Texas Southwestern Medical Center in Dallas began their work on ketamine by verifying what other scientists have shown: 30 minutes after receiving a dose of ketamine, mice prone to depression show an easing of their symptoms. When put in a tub of water, mice considered depressed quickly give up escape attempts and instead float motionless. After receiving ketamine treatment, such mice swim for a longer period of time in the water.
Monteggia's team then moved toward understanding how the drug affects the brain. Scientists already knew that ketamine binds to, and blocks, a receptor in the brain called NMDAR, which triggers its anesthetic effects, so Monteggia's group used other compounds to block NMDARs in mice. As the water test revealed, the animals depression once again lessened, so the researchers knew that ketamine's antidepressant effects also depended on NMDAR. Next, the team studied how levels of certain proteins in the brain changed when mice were given ketamine. Blocking NMDARs with other compounds turns off production of some proteins, but ketamine causes the neurons to make more of a protein called BDNF (brain-derived neurotrophic factor), the researchers report online today in Nature. The findings suggest a new set of molecules that ketamine and NMDAR affects, and that means a new set of molecules involved in depression.
"There was no precedent for this," Monteggia says. "We had no idea why blocking an NMDAR would produce protein." There are two ways of activating NMDARs. Some turn on when the specific neurons fire to accomplish a task—be it learning, memorizing, or thinking. But other NMDARs are activated simply as background noise in the brain. Ketamine, the researchers showed, doesn't block the brain from activating NMDARs when it's using them to send a specific message. But it does block them from creating that background noise. Although scientists have long known about the brain's spontaneous level of background nerve firing, Monteggia's study is the first to suggest a link between such background noise and depression.
"What we're suggesting is that this background activity is important," Monteggia says. She says that the link between spontaneous nerve firing and depression could also explain why electroconvulsive therapy (also known as "electroshock therapy") eases depression--perhaps ECT and ketamine reset the background brain activity. Furthermore, Monteggia's group identified a new molecule that carries out NMDARs' effects on spontaneous brain activity. When the researchers activate this protein, called eEF2, in mice, they see the same fast-acting antidepressant action. A drug that targets eEF2 instead of NMDARs could treat depression, Monteggia says.
Carlos Zarate, a psychiatrist at the National Institute of Mental Health, in Bethesda, Maryland, who led many of the initials studies of ketamine as an antidepressant, says that the study goes far in uncovering a new pathway involved in depression. "It brings about a new series of targets for drugs that has not been pursued at all."
Although ketamine is used for short-term depression treatment in humans, its potential for abuse keeps doctors from prescribing it for the long term. A drug that targets the ketamine pathway in another way could offer antidepressants without the same potential for abuse. The next questions, Zarate says, are whether eEF2 is a safe drug target in humans and what other pathways are involved in depression.