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Laura Sanders, Frame of mind

A new generation of antidepressants could help patients feel better faster

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SN Prime | January 28, 2013 | Vol. 3, No. 4

People talk a lot about speeding up drug development. But for some problems, they should also focus on speeding up the drugs. For brain disorders like depression, the medicines prescribed by doctors can take weeks or months to kick in. (And even after the long wait, the number of people who experience complete turnarounds is surprisingly low.)

The idea that a disorder — even a complicated brain disorder — can be quickly reversed isn’t so outrageous. We have drugs that bring down high blood pressure within minutes, shrink inflamed airways instantaneously and stop an allergic reaction in its tracks. Why should drugs for the brain be any different?

New work from neuroscientists and psychiatrists shows that, in theory, depression too can be turned off fast. Hitting the right target can jolt the brain out of melancholy, recent experiments with mice suggest. And new results on people are promising, too. The anesthetic drug ketamine and other compounds like it could be prototypes for antidepressants that work in hours instead of weeks.

Recent experiments show that the potential is there. Using a technique that makes a nerve cell fire or remain silent by stimulating it with laser light, researchers were able to switch depression symptoms on and off in mice. By puppeteering a small group of carefully chosen nerve cells in the brain, the scientists both created and destroyed signs of despair in the rodents. Activate these cells and signs of depression — like giving up in a swimming challenge and eschewing sugar water — disappeared. Curb the cells’ activity, though, and the mice slipped into melancholy, exhibiting behaviors similar to symptoms experienced by depressed people.

Of course, mice that drink less sugar water are a far cry from people with major depressive disorder, who may be suffering from a constellation of symptoms brought on by a complex mix of genetics and environment. But these rodent results, described online December 13 in Nature, are a big deal because they illuminate the parts of the brain that help regulate mood.

And the best part? All of this action happened within minutes of flipping the light switch. The findings show that the brain harbors mood wiring that can be quickly turned on or off, says Ming-Hu Han of Mount Sinai School of Medicine in New York City. Han, who coauthored one of the new studies, says that understanding these sorts of fast switches might help scientists develop drugs that can instantly counteract depression in people.

Ketamine may already hit one of these switches. But the drug is far from the perfect anti-depressant. Even at low doses, it can cause sensations of floating, separation from physical senses and other hallucinations. This psychoactive effect is also what earned ketamine its cred as a street drug. Known as “Special K,” the substance is used at clubs to induce out-of-body experiences.

The discovery that ketamine can quickly reverse depression in people has raised the bar for other antidepressant drugs, writes Carlos Zarate, a depression researcher at the National Institute of Mental Health in Bethesda, Md. Scientists should no longer settle for drugs that take weeks to work, he says. And Zarate is putting this sentiment into action.

He and his colleagues recently tested an experimental drug that’s thought to act like ketamine, but without the hallucinatory side effects. Like ketamine, this drug, called AZD6765, taps into the brain’s glutamate system. Glutamate is a messenger molecule that tells nerve cells to get excited and start firing off signals. That’s a completely different mechanism from the most common class of antidepressants currently in use, which work by changing levels of the chemical messenger serotonin.

Eighty minutes after a single IV infusion of AZD6765, about a third of 22 depressed volunteers felt better, briefly. The positive effects lasted for only about half an hour. The success rate beat that of a placebo, but it’s lower than the success rate of ketamine, which in the same study produced improvements in about half of volunteers.

The trial was small, and the results were modest. But these 22 patients had particularly pernicious forms of depression that couldn’t be touched with other methods. In addition to taking other drugs, about half of the volunteers had previously undergone electroconvulsive therapy, to no avail.

So finding anything that helps even just a little bit is a big deal. AZD6765 might not be the panacea for depression, but it, and other drugs like it, may offer valuable clues about how to turn the disease around. Fast.

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