For decades, medications for depression have acted pretty much the same way--by manipulating levels of serotonin and other chemical messengers in the brain. New drugs have offered only modest changes from the old ones.

Now a team of researchers, led by Michael Kaplitt, an associate professor at Weill Cornell Medical College, has proposed a different way to attack depression: by using gene therapy to boost levels of a protein called p11 in an area of the brain called the nucleus accumbens.

"We do believe that the deficiency of this gene in this area of the brain may be one of the underlying root causes of depression, and that addressing that could help improve symptoms," says Kaplitt.

The gene responsible for normal levels of p11 has previously been linked to clinical depression. Kaplitt's new study, published in the current issue of the journal Science Translational Medicine, show that altering levels of this protein in the nucleus accumbens via gene therapy can ameliorate symptoms of depression in mice. A second experiment described in the same paper shows that people diagnosed with depression have lower levels of the protein in this part of the brain.

Roughly 2 to 3 percent of males and 6 to 7 percent of females have severe depression. For about 40 percent of these people, current medications don't fully resolve their symptoms, according to Schahram Akbarian, a psychiatrist and molecular neuroscientist at the University of Massachusetts Medical School. Akbarian was not involved with the new research. Most medications for depression are based on ideas that are now 50 to 60 years old, he says, and the field desperately needs new targets for drug development.

Dozens of genes have been linked to depression in animal models, and major depression in people does run in families, suggesting a genetic component, as well as an environmental one. Previous studies have identified dysfunction of genes involved in serotonin signaling, such as p11, as among the culprits in depression.

Kaplitt and his team focused their research on the nucleus accumbens, which is involved in sensing satisfaction, reward, and pleasure. There is increasing evidence, he says, that this area is dysfunctional in patients with depression.

The researchers found that when they blocked p11 function in their nucleus accumbens in normal mice, the mice showed signs of depression. They drank less sugar water than their healthy counterparts and struggled less when held by the tail, two standards tests of depression in mice. This adds to previous evidence suggesting that p11 in this brain area plays a crucial role in depression. (Depressed mice seem to get less pleasure from this mouse "candy" and quickly give up the fight when they are held by the tail, according to standard research protocol.)

The researchers then took mice bred not to produce p11 and used gene therapy to restore p11 function solely in the nucleus accumbens. As the researchers predicted, these mice no longer showed depressive behaviors.

To assess the role of p11 in human depression, Kaplitt's collaborators at the University of Texas Southwestern Medical Center examined brain tissue from human cadavers, half of whom had been diagnosed with depression when they were alive and half of whom hadn't. Those who had been depressed showed significantly lower levels of p11 in their nucleus accumbens than the healthy controls. "This suggests that human depression is characterized at least in part by deficiency of p11 in this part of the brain," says Kaplitt, who is also a neurosurgeon at New York-Presbyterian Hospital and Weill Cornell Medical Center.

The researchers are now conducting primate studies, injecting p11 into the nucleus accumbens of test animals, to better understand the safety and viability of a p11 treatment for depression in people, he says.

Though research is still preliminary, Kaplitt says he thinks the best way to alter p11 levels in the human brain will be via gene therapy injected directly in the brains of depressed patients. Kaplitt and his colleague and coauthor Brian Alexander hold a patent related to using p11 gene therapy to treat behavioral disorders. Kaplitt also founded and is a paid consultant for the New Jersey-based company Neurologix, which has licensed the intellectual property rights to the treatment technique.

While gene therapy for depression may seem riskier and more invasive than medication, the technology has been shown to be relatively safe in some cases. Similar gene therapy treatments are now being tested in late-stage clinical trials that involve injecting genes into the brains of people with Parkinson's. Altering the therapy to deliver the p11 gene would not be a major stretch, says Kaplitt. And researchers are already experimenting with other invasive treatments for depression, such as deep-brain stimulation, in which an electrode is surgically implanted into the nucleus accumbens to treat severe depression in people who do not respond to medication.

Researchers disagree about whether gene therapy, which is still largely experimental and has been linked to cancer in previous clinical tests, is the best way to target the p11 genes. Akbarian says he'd rather see companies searching their existing compounds for ones that act on p11, not trying gene therapies that bring their own risks. "I don't know why they focused so much on gene therapy," he says. "There is per se no reason to say this is or is not a feasible drug target." While gene therapies are useful for devastating and often fatal neurodegenerative ailments like Parkinson's, Akbarian says, they may not be worth the risk for depression. "To go right away to gene therapy, that's a bit of a stretch," he says.

Kaplitt says gene therapy treatments could reach patients years sooner than new drugs, which would involve finding and developing small molecules that target p11, can get past the blood-brain barrier, and can boost p11 levels in the nucleus accumbens without affecting levels elsewhere in the brain.