A fresh look at depression

Research: New approaches promise better treatments for the ailment that affects 20 million Americans.

May 02, 2004|By David Kohn | David Kohn,SUN STAFF

Husseini Manji just wants his rats to be happy. But that's not easy to do. Many have been genetically engineered to be fretful and melancholic, to give up easily when faced with problems.

But Manji is determined; he gives his disheartened rodents a range of experimental drugs, including one that lowers chemicals released during stress and another that strengthens the brain's neuronal support system.

Manji isn't an overenthusiastic animal lover. He's a psychiatrist at the National Institute of Mental Health who knows that if he can get his rats to be more curious, or swim longer in a pool of deep water, he might eventually be able to help some of the 20 million Americans suffering from depression.

Manji, 44, is part of a new wave in depression research. Using fresh insights into how this often-devastating disease harms the brain, he and others are developing innovative drugs.

These new approaches go far beyond current treatments, most of which work by increasing levels of the neurotransmitter serotonin. Over the past decade, researchers have linked depression to other neurochemicals and have found evidence that structural defects in the brain might play a role.

"What we're working on here is to come up with something completely different, that will be much better," Manji said.

He helps oversee NIMH's extensive depression research program. In labs spread over several floors of a brick building on the Bethesda campus of the National Institutes of Health, Manji and his colleagues examine depression from a variety of angles. In addition to rats, they study genes, neurons, primates and humans.

The most commonly used anti-depressants are drugs such as Prozac, which increase brain levels of serotonin, a chemical that has powerful effects on mood, anxiety, and cognition. Introduced 17 years ago, these drugs, known as selective serotonin reuptake inhibitors (SSRIs), are safer than older anti-depressants and have fewer side effects.

But SSRIs work well for only half of those who take them. And even when successful, they regularly cause gastrointestinal and sexual problems, including loss of libido. Last month, the FDA warned that SSRIs might cause suicidal thoughts, particularly in children.

Another limitation is that a quarter of the 6 million Americans who take anti-depressants aren't helped by any medicines, whether SSRIs or their predecessors.

"There's a huge need for new drugs," said Columbia University neurobiologist Luca Santarelli. He is one of many scientists working on drugs that stimulate the growth of new nerve cells in key parts of the brain.

Studies in animals and humans have shown that this neuronal sprouting, as it is called, can lift depression. Known as neurogenesis, this recently discovered phenomenon could play a crucial role in the next wave of medicines.

"This could be the key to treating depression," said Princeton University psychologist Barry Jacobs, a leading proponent of the neurogenesis theory.

Current anti-depressants stimulate neurogenesis in the hippocampus - a brain region involved in mood and anxiety - but do so indirectly and slowly. These drugs typically take three to six weeks to improve mood, an eternity for a deeply depressed person, particularly someone who is suicidal. Santarelli and others are looking for molecules that trigger neurogenesis without such a lag.

The search has spurred scientists to examine relatively overlooked neurochemicals. "People have realized that serotonin doesn't explain the whole story of depression," said Yale University neuropharmacologist Ron Duman.

Many researchers have focused on stress hormones. Released when animals are under pressure, these chemicals help put the body and brain on alert. Many depressed people have high stress hormone levels, and scientists think these compounds could trigger the disease. This theory has received a recent boost from studies finding that excess stress hormones can shrink the hippocampus, the opposite of neurogenesis.

For some people, depression might be "a stress response that gets stuck in the `on' position," said NIMH researcher Dr. Philip Gold, who is studying a drug that lowers brain levels of the key stress chemical corticotropin-releasing hormone (CRH).

Gold thinks the compound, known as antalarmin, might work especially well in melancholic depression, a subtype in which patients are overagitated and anxious.

Reducing side effects

Several pharmaceutical companies are also working on anti-CRH compounds. Because these drugs and the Prozac class of medicines work by different neurochemical pathways, they aren't likely to have the sexual and digestive side effects, and might work faster, scientists say.

"We think it has legs," said Jim Cassella, head of clinical research at Neurogen Corp., a Connecticut biotech company working on a CRH antagonist. The company hopes to begin human trials next year.

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