Fall 1994 Mission

New drug emerges for manic depression

By Jim Barrett

Susan used to fly every day from Chicago to Los Angeles just to have lunch. Chris was fired from 22 jobs in San Antonio in four years. Ernest shot and killed himself.

Welcome to the world of manic depression where people do unexplainable and tragic things.

Manic depression, or "bipolar disorder," affects an estimated 1 to 2 percent of Americans. They live in a place where the highs are higher and the blues are bluer than anyone would care to experience.

Bipolar sufferers swing from euphoric moods to utter hopelessness. On a manic high, they take risks that endanger their lives. In a dark mood, they are apt to take their own lives.

"Manic depression is a public epidemic and it can be a fatal disease," said Susan Dime-Meenan, a bipolar patient who heads the National Depressive and Manic Depressive Association, an advocacy group in Chicago. She is "Susan," the frequent flier.

"There are more than 2 million Americans who are going to suffer from this illness in any given year. Out of that, 15 percent of the people who go untreated are going to commit suicide," she said.

Psychiatrists can effectively treat bipolar disorder, but fewer than one in three people with the illness receives treatment. The mortality rate is higher than that for many types of cancer and heart disease.

Two obstacles prevail. First, persons with milder or less severe manic states frequently view themselves as unimpaired. Second, the most commonly prescribed medication, lithium, is ineffective for nearly half of manic sufferers. Many others stop taking lithium because of its side effects.

Image Now it appears that a medication with fewer side effects may soon be on the market for bipolar disorder, in part because of an important clinical study led by noted Health Science Center psychiatrist Charles L. Bowden, MD.

The study, published in March in the Journal of the American Medical Association, identified the first successful new treatment for acute mania in 20 years. Valproate, an anticonvulsive drug prescribed for people with epilepsy, proved to be as effective as lithium but with fewer side effects, said Dr. Bowden, a principal investigator in the study. Enrique S. Garza- Trevino, MD, assistant professor of psychiatry, was a co-investigator.

"About 40 percent of patients cannot tolerate lithium, but even among those who can, about a third pay a pretty big price," Dr. Bowden said. "There is good evidence that their creativity is diminished."

Bipolar disorder crosses social and racial lines, but many sufferers are bright, well educated and often richly creative.

"The price lithium patients pay often involves losing some skills they had. That is a higher price than many patients are willing to pay, so they either reduce the dosage or stop taking their medication entirely," he said. Valproate does not produce the dulling effect on the mind that lithium has on some patients, Dr. Bowden said. In addition, the drug does not appear to cause weight gain as often or have the adverse effects on the kidney or thyroid associated with lithium.

Mental health advocates hailed the valproate findings, and academic colleagues praised the study's thoroughness. "This is a definitive study that shows valproate is as effective as lithium in treating bipolar illness," said A. John Rush, MD, a leading psychiatrist from The University of Texas Southwestern Medical Center in Dallas.

Abbott Laboratories, which underwrote the study, is seeking government approval of the drug for bipolar patients. Abbott already markets valproate under the trade name Depakote for use with people with epilepsy.

The reluctance of patients to seek treatment is puzzling because bipolar sufferers usually know something is dreadfully wrong. Such was the case with Dime-Meenan. Before being diagnosed 13 years ago, her mania nearly ruined her court reporting business and home life. She flew from Chicago to Los Angeles 32 times in two months just to have lunch. She spent $27,000 on clothing in one week. "Some of those things sound like fun, right? The 'fun' mania, in my case, just got taken over by a mania that put me in danger," said Dime- Meenan. She became anorexic. Dime-Meenan, who is 4-10, shrank to 68 pounds.

By the '70s, a quest began to understand the biology of depression. Biological psychiatrists focused on metabolic imbalances that affect the amount of neurotransmitters, chemical messengers that transmit electrochemical impulses between brain cells. Indirect evidence emerged that depression is hereditary. "Bipolar disorder is a no- fault disease," said Dr. Bowden. "People don't cause this by sins of omission or commission."

A colleague, James W. Maas, MD, the Hugo A. Auler Professor of Psychiatry, is one of the early researchers in biological psychiatry. Dr. Maas is widely known for his work to identify and measure norepinephrine activity in the brain. Norepinephrine is a key chemical in transmitting messages across synapses in the central nervous system. "We have made more progress in treating mania in the last 30 years than in the entire history of the world," Dr. Maas said. Psychiatrists today can successfully treat up to 90 percent of patients with clinical depression.

But Dr. Maas added: "In terms of understanding depression, the best that can be said is that the hypothesis we had 20 years ago about the cause of depression was too simple-minded."

Researchers thought they would learn the cause of depression by observing the biological effects of antidepressants on the brain, Dr. Maas said. "We now know it's not that simple." Alan Frazer, PhD, another leader in depression research, said, "Everybody is searching for a Holy Grail. My guess is there may be many Holy Grails, that meaning there may be multiple biological reasons why people become depressed."

Dr. Frazer, chairman of the department of pharmacology and a career scientist with the Audie L. Murphy Memorial Veterans Hospital, began his research into antidepressant medications in the early '70s. Part of his work has centered on SSRIs, or "selective serotonin reuptake inhibitors," the most popular of which is Prozac. Developers of Prozac and similar drugs have succeeded in preserving the antidepressant properties of SSRIs while reducing the side effects common with the earlier generations of medications. Those side effects included dry mouth, blurred vision, urinary retention, constipation and dizziness.

The success in using modern medications against mental illnesses has overshadowed psychotherapy, the so-called "talk" therapies. But the biological psychiatrists say psychotherapy is an important adjunct to any drug treatment.

"It is a false dichotomy to counterpose talk therapy and drug therapy. They both work on the brain and the brain is a biological organ," said Alexander L. Miller, MD, professor of psychiatry, who is known for his research in depression and schizophrenia. He also is director of research at San Antonio State Hospital and established its clinical research unit, site of some of Texas' most important psychiatric research since the unit was funded by the legislature in 1989.

"Biochemical events are going on in the brain whenever the person thinks, talks or receives information. Those events can be altered by drugs, but they also can be altered by changing the way information and stimuli get to the brain," Dr. Miller said. He said several psychotherapies are proven to be effective against depression.

Biological psychiatry has established that mental illnesses can be treated medically, but its successes have provoked second thoughts. Questions arise about "cosmetic psychopharmacology," a term coined by Peter Kramer, MD, in his best-seller Listening to Prozac.

Prozac is one of the new, "clean" antidepressants; "clean" because it has fewer side effects than earlier medications. Prozac has been prescribed to 5 million Americans since 1989.

In defense of antidepressants, Dr. Miller said neither Prozac nor any other antidepressants are narcotic nor do they create personality. "You are not changing a person's personality with a drug such as Prozac. Instead a personality emerges that was there all the time, but had a blanket thrown over it," he said.

Antidepressants only help persons with real depression, Dr. Miller said. "Drug dealers on the street aren't selling Prozac. They are selling cocaine or heroin, which have an immediate and dramatic effect on anyone," he said.

Its widespread scope of inquiry has made the Health Science Center one of the nation's major centers for research in manic depression. Dr. Rush, the Dallas psychiatrist, gives much credit to Dr. Bowden. "He is internationally known and he is excellent."

A native of Texas, Dr. Bowden speaks both English and Spanish. He treats patients at two of the Health Science Center's teaching affiliates in San Antonio, University Hospital and University Health Center-Downtown, formerly the Brady/Green Community Health Center.

Dr. Bowden is on the scientific advisory board of the National Depressive and Manic Depressive Association, and travels widely to speak with professional and patients groups. He is named in the latest edition of The Best Doctors in America, and Good Housekeeping listed him in February as one of the nation's 40 top specialists in depression.

"Charles Bowden doesn't only have the curiosity necessary for research and pursuing the ultimate question, he has compassion for the individuals he deals with," Dime-Meenan said. "He has a sense of calmness that makes him especially suited to discussing and treating an illness that's filled with chaos."

Understanding depression is tantamount to conquering it, said Dr. Maas, who added that the public sometimes overlooks the urgency and importance of gaining that understanding:

"Most of us assume the world is sane and that most people behave and feel the same way we do. You have to remind yourself that there are a lot of people who are not that way," he said.

Dr. Frazer predicted that answers are sure to come with modern brain imaging such as positron emission tomography, which is now in use at the Health Science Center's Research Imaging Center. "The brain has been relatively inaccessible to us," he said. "Now, in the next 10 years, some of the key answers are going to come to us."

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