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Searching for the next Prozac

Research psychiatrists hope revolutionary new drugs will target the causes of the illness, rather than its effects.

May 26, 2003|Benedict Carey | Times Staff Writer

The antidepressant Prozac hit the market 15 years ago and did for depression what Valium had done for anxiety a generation earlier -- made it not only easier to treat but also easier to discuss openly. Similar drugs followed, and millions got better.

Yet as thousands of doctors from around the world convened last week in San Francisco at the American Assn. of Psychiatry's annual meeting, many were looking for news of the next big advance in depression.

The illness affects up to 10% of Americans adults in a year and 8% of adolescents. Doctors write more than 100 million prescriptions a year for Prozac and drugs like it, called selective serotonin reuptake inhibitors. But one-third of patients do not respond to current drugs, and many who do suffer serious side effects. "Anything that works well and doesn't have side effects like weight gain and loss of sexual desire would be huge," said Dr. Elizabeth Koby, a Cleveland psychiatrist. "I think we're all hoping for that."

The meeting featured dozens of reports on chronic low mood, including new evidence on drugs awaiting FDA approval, as well as discussions of novel theories about what causes depression and alternative approaches to treatment. But research psychiatrists said the next revolution in the treatment of depression will come from drugs that attack the cause of the disease rather than its symptoms.

"All of the major drugs we have in psychiatry, including Prozac, grew out of accidental discoveries; we just got lucky," said Dr. Samuel Barondes, director of the Center for Neurobiology and Psychiatry at UC San Francisco and author of "Better Than Prozac" (Oxford, 2003). Barondes said the next generation of antidepressants and other psychiatric drugs will stem from a growing understanding of the genetic causes of mental disease. They will be new classes of drugs rather than fortified or refined versions of the old ones.

One clue to the underlying source of depression, for example, comes from measures of the stress hormone cortisol. Psychiatrists have known for years that many of their depressed patients have high blood levels of cortisol, which is released when the body prepares to fight (or flee) for survival. But in many depressed people, cortisol levels are elevated even when there is no apparent reason for added tension, and some researchers believe that it's this overactive, or abnormal, stress response that may cause depression.

Among the most promising ways to influence this stress response is through a brain chemical known among researchers as Substance P. This chemical is released when people feel pain and is highly concentrated in parts of the brain involved in stress response.

In several studies of animals and in at least one study in depressed patients, an experimental drug has been able to reduce depressive symptoms by blunting the action of Substance P. Although the effect has not proved reliable yet, the drug maker, Merck, is continuing with the research, according to Barondes. "This remains one of the most promising targets" for developing a new class of antidepressants, he said.

There is also good evidence that prolonged depression damages brain cells in the hippocampus, a part of the brain involved in memory and in regulating cortisol levels. If this is true, the disease becomes progressively harder to treat because of physical changes in brain anatomy. "What we think is happening is it's a vicious circle: When the brain is damaged, it's less likely to control this stress response, leading to more damage," said Ron Duman, a Yale University researcher.

Researchers are investigating a protein known as brain-derived neurotrophic factor, or BDNF, which helps the brain shut down the stress response when it's time to relax, studies suggest.

In a study published last year, Duman reported that rats administered BDNF preparations showed significant improvement in measures of depression. There is also evidence that the protein helps the brain regenerate cells, actually repairing areas vulnerable to cortisol-induced injury. Drug researchers are investigating several agents that would enhance BDNF and not only ease symptoms but also reverse the damage already done.

"I think it sounds pretty bad when you hear that you have brain atrophy or some damage from depression," said Duman, "but what we're finding is that these things are reversible. We used to think of the brain as hard-wired, but it's increasingly clear that the circuits and connections are much more malleable and plastic, and it's encouraging to know that even if you've had this disease for a long time, there's hope for complete recovery."

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