Why Ketamine Helps Fight Depression

Last year, neuroscientists at the National Institute of Mental Health (NIMH) made headlines with a surprising result. They found that a single dose of ketamine–an anesthetic and club drug known as special K–could relieve depression in some patients in a matter of hours, rather than in the six or more weeks it typically takes for existing antidepressants to kick in. What’s more, the drug was successful in a group that is usually extremely difficult to treat: patients who had failed to find relief after trying multiple antidepressant medications.

Because of its hallucinogenic side effects, ketamine is unlikely to become a widely used antidepressant. But now researchers think they have discovered how ketamine exerts its fast-acting effect. Several pharmaceutical companies are already developing compounds that target this mechanism, one of which will be tested at the NIMH within the next few months.

“In studying ketamine’s effects, we may be heading down a path that leads us to treatments that might help the large numbers of depressed people who remain symptomatic despite available antidepressant treatments,” says John Krystal, a neuroscientist at Yale University who also studies ketamine.

Ketamine is an anesthetic approved by the Food and Drug Administration. It is also widely abused because it produces hallucinations and can trigger an out-of-body experience at higher doses. By understanding the mechanism underlying ketamine’s antidepressant qualities, scientists hope to be able to develop novel compounds that mimic the beneficial effects without the accompanying hallucinations.

In the brain, ketamine blocks a receptor known as the NMDA receptor, which plays a key role in brain signaling. But according to a new study by Husseini Manji, Carlos Zarate, and their colleagues at NIMH, that’s just one part of the drug’s biochemical influence. Blocking this receptor actually boosts the activity of another receptor, known as the AMPA receptor. This boost appears to be crucial for the drug’s antidepressant effects: when the researchers blocked the AMPA receptors before administering ketamine to mice, the drug no longer stopped depressive behavior in an animal model of the disease. The findings were published last month in the journal Biological Psychiatry.

The findings add to a growing body of evidence showing that compounds that trigger AMPA receptors eliminate depressive behavior in animal models of the disorder. While no such compounds have been tested yet in clinical trials for depression, several companies are developing molecules that target AMPA receptors for disorders including schizophrenia, Alzheimer’s disease, and attention deficit/hyperactivity disorder (ADHD) and trials for Alzheimer’s and ADHD are underway. Zarate and his colleagues are now planning a clinical trial of one such compound for depression.

While scientists don’t yet know exactly how ketamine works so quickly against depression or why it seems to be effective in a broader group of patients than currently available antidepressants are, they hypothesize that it boosts production of an important growth factor in the brain known as brain-derived neurotrophic factor. Popular antidepressants, such as Prozac, also boost this growth factor, but only after a complex series of chemical reactions. AMPA activation may circumvent this process, acting much more quickly.

Directly targeting AMPA receptors may also bypass the drug’s psychotic side effects, says Jeff Witkin, a neuroscientist at Lilly Research Labs, in Indianapolis. That’s because the hallucinatory component of ketamine’s effects is driven specifically by NMDA receptors, rather than by AMPA receptors.

“In any other illness of depression’s magnitude, patients aren’t expected to just accept that their treatments won’t start helping them for weeks or months,” said NIMH director Thomas R. Insel in a statement released by NIMH. “The value of our research on compounds like ketamine is that it tells us where to look for more-precise targets for new kinds of medications that can close the gap.”