German composer Robert Schumann led a life of extreme ups and downs. In 1833, at the age of 23, he attempted suicide; in 1840, he experienced a period of inexplicable, great elation. Then in 1844 he fell into another deep depression, with another "up," or "manic," period five years later. In 1853, his mental illness forced him to resign as musical director of the Dusseldorf Symphony Orchestra, and a year later, he tried to kill himself by jumping into the Rhine River. He was rescued and placed in an asylum, where he died two years later of self-imposed starvation.
Some of Schumann's musical compositions noticeably reflect his dramatic mood swings. One account of the composition "Carnaval" describes the part called Florestan as the product of an "emotional, impulsive, stormy extrovert," yet attributes another portion, called Eusebius, to a "quiet introspective dreamer."
Robert Schumann suffered from manic-depressive illness, also known as bipolar disorder. This condition affects 1 percent of the U.S. population at some time in their lives. Periods of expansive, hyperactive thinking and behavior with elevated mood occur in sharp contrast to periods of extreme despair and sadness. Either phase can greatly disrupt a person's life.
Other gifted artists, writers, poets, and composers who suffered from manic-depressive illness include Walt Whitman, Cole Porter, Tennessee Williams, Mark Twain, Edgar Allen Poe, Sylvia Plath, and Vincent van Gogh. The incidence among creative people is 10 to 20 times greater than that of the general population, according to Kay Redfield Jamison, professor of psychiatry at Johns Hopkins University School of Medicine, who has studied manic-depressive illness and its effects on the creative community.
But bipolar disorder also makes plenty of regular folk miserable. Two million people in the United States have the condition, and researchers estimate that a third of them receive no treatment. Untreated, the suicide rate is 15 percent.
For many years, the standard treatment for manic-depressive illness has been lithium, a pure chemical sold under many brand names, including Carbolith, Duralith, Lithobid, Lithizine, Eskalith, and Lithane. It is the best-studied drug to treat manic-depressive illness, and is effective not only in the acute treatment of mania, but also in long-term prevention of relapses.
While effective in many people, lithium also brings significant side effects to some. In May 1995, FDA approved the anti-seizure drug Depakote (divalproex sodium) for a new use: short-term treatment of manic-depressive illness. It is not yet known whether the drug is effective in preventing relapses over the long term.
"This is a different bullet in the armamentarium against this illness. It has been widely used to treat mania for years. What's new is clinical trial evidence showing that it's efficacious," says Steven Hardeman, consumer safety officer at FDA's division of neuropharmacological drugs.
Depakote has been approved in the United States to treat seizures since 1983. The formulation has since been altered slightly to minimize gastrointestinal side effects. The drug may be helpful for some of the 30 to 40 percent of people with manic-depressive illness who do not respond to lithium.
Eighteen-year-old Melissa Kluth, who lives in upstate New York, has been taking Depakote to treat manic-depression for a few months. While her experience may not run true for all persons who try Depakote, Kluth, who, never took lithium, says she feels like a new person. "When I'm off the medication, if you say anything to me, I get angry. I scream and yell and kick and throw chairs. When I'm on the medication, I'm fine; nothing bothers me," she says.
Depakote and lithium treat the mania portion of bipolar illness. Jack Gorman, M.D., deputy director of the New York State Psychiatric Institute, describes mania's distinctive symptoms: "The patient becomes very hyperactive. He or she doesn't sleep, and doesn't need to sleep. Thoughts race, and they talk very, very fast. They may be hypersexual and spend huge amounts of money. They get in all kinds of trouble, fights, even car accidents. Most people are diagnosed in their early 20s after having a few depressive episodes, and then a manic one."
To diagnose manic-depressive illness, a psychiatrist compares a patient's symptoms with the diagnostic criteria for the disorder in the fourth (1994) edition of the Diagnostic and Statistical Manual of the American Psychiatric Association. DSM-IV distinguishes two variants. Bipolar I consists of major depression and mania. Bipolar II includes major depression and a milder form of mania called hypomania. The manual classifies manic-depressive illness as a "mood disorder," a designation that also includes altered mood due to a medical condition or taking a mood-altering substance.
In diagnosing manic-depressive illness, sometimes psychiatrists also consult scales and behavioral assessment tests that are more commonly used in clinical studies. These tools help assess signs such as elevated mood, diminished need for sleep, excess energy and activity, grandiosity (feeling that one can do anything), racing thoughts, poor judgment, irritability, and fast speech.
As is the case for many mental illnesses, the causes of manic-depression aren't at all clear, although there are inherited components. Yale University professor of psychiatry Joel Gelernter, M.D., describes the causes of manic-depressive illness as "utterly unknown" in an editorial in the May 1995 issue of the American Journal of Human Genetics. But in some cases, the condition, or susceptibility to it, appears to be inherited. A flurry of research reports in 1987, 1994, and 1996 trace the illness to specific chromosomes in a few very large families, but different studies point to different chromosomes. This indicates that there may be several ways to inherit the condition.
Twin studies--another way of looking for genetic clues--also suggest an inherited tendency to manic-depressive behavior. Several studies show that if one identical twin has the illness, chances are from 70 to 100 percent that the other twin does, too. Among identical twins reared apart, the probability of both suffering from manic-depressive illness is two-thirds, suggesting an inherited predisposition that persists even when identical twins are raised in very different environments. Among fraternal twins, who, unlike identical twins, are no more closely related genetically than are any two siblings, the chance that the second twin is affected is only 20 percent.
A Tale of Two Drugs
Drug treatment for manic-depressive illness has a long and fascinating history. Lithium's effects on manic-depressive illness were discovered by chance in 1949 by an Australian physician named John Cade. He used lithium to treat gout in hamsters, and they calmed down. "They would sit and be quiet instead of running around their cages," says Paul Keck, M.D., associate professor of psychiatry and pharmacology at the University of Cincinnati College of Medicine.
Tests on humans in Australia in the 1960s showed that lithium alleviated symptoms of mania. After additional clinical tests focusing on safety aspects, including, according to Keck, its toxicity when used as a salt substitute, FDA approved lithium in 1971 for treating manic episodes of manic-depressive illness.
Meanwhile, researchers were noticing that brain activity is similar in seizure disorders and in mania, giving rise to the idea that seizure medications might also relieve symptoms of mania.
"Valproic acid was discovered in the 1960s by a French psychiatrist to benefit people with manic-depressive illness, but for reasons that are not understood, that research was not followed up. Then, in the mid-1980s in the United States, people got re-interested in it for treating bipolar disorder," says Keck.
Adds Gorman, "Robert Post [M.D.], at the National Institute of Mental Health used the seizure medication Tegretol (carbamazepine) to treat lithium-refractive patients. He combined lithium and Tegretol, and the response was excellent. So the work was extended to other anticonvulsants, and people decided to test valproic acid."
These observations led to two studies. One, published in the January 1991 issue of the Archives of General Psychiatry,, compared valproic acid to a placebo. Another, published in the January 1992 issue of the American Journal of Psydchiatry, compared valproic acid to lithium. Both found valproic acid to be promising. Then the Journal of the American Medical Association published a study in the March 23/30, 1994, issue, comparing all three regimens--valproic acid, lithium, and placebo.
The Depakote Mania Study Group, led by Charles L. Bowden, M.D., of the department of psychiatry at the University of Texas Health Science Center in San Antonio, carried out the study. They randomly assigned 179 patients at nine participating university hospitals to one of the three treatments. Neither the patients nor the physicians knew which patients were receiving lithium, Depakote or placebo. This approach, called a double-blind study, lessens the likelihood of either a patient or a physician expecting a certain response and thus obscuring the investigation's results or conclusions.
The study continued for only 21 days for two reasons. First, previous work had shown that 21 days is sufficient for symptom relief. Second, the researchers did not want to subject patients receiving placebo to their symptoms longer than was necessary to see results. Several participants in each group dropped out because either the treatment's side effects or the illness' symptoms were intolerable.
The researchers concluded that both drugs were similarly effective in lessening manic symptoms and both were markedly superior to placebo. The percentage of patients experiencing a greater than 50 percent improvement, as judged by rating scales, was 49 percent for lithium, 48 percent for Depakote, and 25 percent for placebo.
The researchers said they also found that:
* fewer people dropped out who were receiving Depakote than the other two options
* Depakote worked in several patients on whom lithium had previously shown no effect
* Depakote relieved symptoms in the most severe type of manic-depression, called the rapid-cycling form because mood swings occur more frequently.
Depakote and lithium have different side effect profiles, which a physician considers in prescribing one or the other for a particular patient. Side effects indicating too high a dose of lithium include trembling hands, nausea, weight gain, and frequent urination.
Depakote's side effects include nausea, vomiting, sleepiness, and dizziness. The physician labeling of Depakote carries a boxed warning about potentially fatal liver problems with the drug. Using either lithium or Depakote requires periodic blood monitoring to ensure that the dosage is therapeutic, but not toxic.
Valproic acid is known to cause birth defects in offspring of women who take the drug while pregnant. Specific birth defects linked to Depakote include poor growth, small head, developmental delay, and several distinctive facial characteristics, such as a short and broad nose, small teeth, flattened midface area, and a thin upper and thick lower lip. A more serious effect is increased risk of spina bifida, a birth defect in which the spinal column does not close completely, leading to a lesion on the newborn's back and loss of feeling from the point of the lesion down.
In the general population, spina bifida occurs in fewer than 1 in 1,000 births. Among women exposed to Depakote, it occurs in 1 to 2 in 100. The defect occurs during the fourth week of gestation--often before a woman realizes that she is pregnant.
It is unclear whether lithium can cause birth defects. In studies conducted in the early 1970s, lithium was found to be associated with birth defects, specifically a rare heart defect called Ebstein's anomaly. However, Lee Cohen, M.D., a psychiatrist at Massachusetts General Hospital, and co-workers from other institutions reported in the Jan. 12, 1994, issue of the Journal of the American Medical Association, that these studies were not well-controlled. These researchers concluded that the risk was far less than had been thought.
They reevaluated four more recent studies, involving a total of 207 children with Ebstein's anomaly. None of the mothers had taken lithium. Based on these results, Cohen's team suggests that some pregnant women with severe manic-depressive illness might be able to continue lithium treatment without great risk to the fetus. The researchers suggest that obstetricians take these revised risks into account when determining whether a specific woman should continue using lithium during pregnancy.
Treatment can radically improve the life of a person suffering from manic-depressive illness. One of the most frustrating aspects of this disorder, patients say, is the delay until they are diagnosed. Sometimes young people endure years of punishment for bad behavior, followed by misdiagnosis, before discovering that their mood swings are part of a chronic but on-again off-again illness. Finding an effective treatment is an enormous relief, to them and their families.
This is what happened for Melissa Kluth, who says, "I'm 18, and I think I've had manic-depression all my life. When I was younger, an allergist said it was attention deficit disorder, so I was put on Ritalin to treat that. But when I became a teenager, in the eighth grade, I became suicidal. This past February, I just couldn't deal with it. I just wasn't myself." Since her psychiatrist put her on Depakote, Kluth says, she feels more like a "normal" person on the brink of adulthood--and looks forward to a much brighter future.
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