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Stanford Report, September 10, 2003

Improved drug therapy found for children predisposed to bipolar disorder


Children with psychiatric problems who also have a high risk of developing bipolar disorder respond well to a mood-stabilizing drug, according to a study that is the first to examine the drug’s effect on children predisposed to bipolar disorder. Medical center researchers say determining the correct medication for these children is crucial because standard drug therapies, such as antidepressants and stimulants, may in fact trigger manic episodes, exacerbating their underlying condition.

In a study published recently in the Journal of Clinical Psychiatry, the researchers found that more than three-quarters of these at-risk children showed improvement in their mood or behavioral disorders after receiving a drug called divalproex. The drug, used to treat mania in adults, essentially "cools off the brain," said Kiki Chang, MD, assistant professor of psychiatry and behavioral sciences at the School of Medicine and a psychiatrist at Lucile Packard Children’s Hospital.

Bipolar disorder affects 2.2 million Americans, who experience extreme and debilitating highs and lows. Children known as "bipolar offspring" — who have a parent with bipolar disorder but have not yet developed the disorder themselves — and who suffer from other psychiatric problems are more likely to develop the disease.

Researchers studied 23 bipolar offspring between the ages of 6 and 18 who had attention-deficit/hyperactivity disorder or ADHD, depression or other mood disorders. These children showed signs of depression or mania but did not meet the criteria for bipolar I or II disorder, though they were considered at risk. Previous studies have estimated that bipolar offspring have up to a 24 percent chance of developing the disease, and ADHD might be a predictor.

Researchers evaluated patients at the start of the trial, assessing them for manic and depressive symptoms and determining the severity of their conditions. After stopping any current medications, the children took divalproex for 12 weeks and underwent periodic re-evaluations. While there was no placebo control group, researchers monitored the participants for a relatively long time, said Chang, first author of the paper.

Of the study participants, 78 percent were "very much improved" or "much improved" in their mood or behavioral disorders and 82 percent showed at least a 50 percent decrease in their ratings of depressive or manic symptoms. Children with depression responded dramatically to the medication after as little as one week of treatment.

"What was most surprising was how quickly the patients responded and that patients with depression responded so well to divalproex," Chang said. While traditional drugs are effective for most children, they can lead to an earlier onset of a manic episode for children at risk of bipolar disorder. The trick then becomes to determine which children are likely to be predisposed to the illness.

Chang and his colleagues in the Stanford Pediatric Bipolar Disorders Program are conducting separate studies investigating the genetics and brain physiology of bipolar offspring to search for indicators. The scientists are also designing

another divalproex experiment with a placebo component and will conduct a study monitoring these children to determine if, and when, they develop bipolar disease. They will also investigate non-drug interventions, such as family-focused therapies. "Our goal is to identify these children early for treatment and perhaps prevention," he said. "If we can prevent bipolar disease in childhood, we can prevent later treatment resistance and future complications like substance abuse, poor work and school performance, and even suicide."

It is possible that divalproex not only relieves the mood and behavioral problems of bipolar offspring but also delays or prevents the onset of the disorder, Chang noted. Studies of the drug in cell cultures and mice suggest that it can help protect the brain, but such studies have not been done in humans.

For now, though, Chang hopes to alert psychiatrists to the possibility that children predisposed to bipolar disorder will respond poorly to standard medications for other mood and behavior disorders and that there are alternative treatment options. "We want to raise awareness about these kids and the idea that perhaps they will be better treated with mood stabilizers," he said.

Co-authors are Kimberly Dienes, research assistant; Christine Blasey, PhD, research psychologist; Nancy Adleman, graduate student; Terence Ketter, MD, associate professor of psychiatry and behavioral sciences; and Hans Steiner, MD, professor of psychiatry and behavioral sciences.

The research was supported by grants from Abbott Laboratories, which makes divalproex; the National Alliance for Research on Schizophrenia and Depression; and the Klingenstein Third Generation Foundation.

Looking for predictor, team studies bipolar disease in parents, children (3/5/03)