Researchers Look at Depression's Chemistry
May 12, 2004
Charleston Daily Mail

Husseini Manji just wants his rats to be happy. But that's not an easy thing to make happen. 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, Md., 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 antidepressants 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, are safer than older antidepressants and have fewer side effects.

But SSRIs work well for only half those who take them. And even when successful, they can sometimes cause gastrointestinal and sexual problems in some patients, including loss of libido.

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

"There's a huge need for new drugs," Columbia University neurobiologist Luca Santarelli said. 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 antidepressants 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," Yale University neuropharmacologist Ron Duman said.

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.

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

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.

Another possible target is glutamate, a neurotransmitter that sends excitatory messages, telling the brain to pay attention. Too much glutamate overstimulates and damages nerve cells, and researchers suspect that this chemical system goes awry in depression. In animal tests, lowering glutamate levels improves depressive behavior and has recently been shown to stimulate neurogenesis.

Manji and his NIMH colleagues are interested in two glutamate blockers used for other ailments. They are memantine, an Alzheimer's drug, and riluzole, which is used for Lou Gehrig's disease.

In a small human trial, riluzole worked "remarkably well" for some depression patients, Manji said. "We're thinking that there may be a subpopulation in whom this may really help," he said.

Scientists are increasingly recognizing that, as the riluzole results suggest, depression is probably not a single disorder, but rather a collection of related subtypes. All depressives feel unhappy and hopeless, but some are agitated and sleepless, and others hardly move and can hardly stay awake.

"It's likely that depression is actually several different biological conditions," said Dr. Dennis Charney, head of depression research at NIMH.

By understanding the neurochemicals that contribute to the disorder, researchers hope to delineate those differences. NIMH is trying to find genetic markers for each subtype.

Researchers at Emory University are focusing on brain scans, trying to pinpoint specific brain circuits affected in various forms of depression. The ultimate goal is to better match drugs with patients. Now, psychiatrists must guess, trying one drug after another until they hit on one that works.

While some researchers try to lower glutamate and stress hormones, others work to boost other neurochemicals that seem to soothe depression. Chief among these is brain-derived neurotrophic factor, a compound that acts as a powerful support system for neurons.

Some researchers, including Yale's Duman, suspect that by triggering neurogenesis and improving overall neuronal health, BDNF can alleviate depression. Current antidepressants also raise BDNF, but they take weeks.

"If we could target (BDNF) more directly, it could be very useful," Manji said.

Roche is looking at the substance and has teamed up with a small biotech company, Memory Pharmaceuticals, to study a drug that could quickly raise brain BDNF levels. The companies are testing the compound on animals.

Manji is also trying another way to boost BDNF: sleep deprivation. Scientists have long known that lack of sleep is a potent and almost immediate antidepressant. Because sleeplessness has obvious side effects, it's not a viable treatment. So Manji and his NIMH colleagues are trying to trick certain brain regions into staying up while the rest of the brain (along with its owner) sleeps.

In an experiment set to begin this spring, scientists will inject sleeping depressives with a BDNF-boosting drug during key sleep periods, when the brain is acutely responsive. If the method works, it could literally cure depression overnight.

"It would be a huge advance," Manji said.

Not all of these ideas will pan out. Antidepressant research is notoriously frustrating. What cheers up rats - even those bred for despair - doesn't always revive unhappy humans. And, because depression is so complex and subjective, what works with one group of humans often fails with another.

But most scientists are confident that some of the research will end up helping patients.

"We're really learning a lot more about what might actually be going on with the illness," Manji said. "Clearly, some things will work and some won't work. But there's every reason to be optimistic."