Our hearts go out to them: Bias in pharma-funded research for psychoactive drugs

In the final months of Rebecca Riley's life in Hull, Massachusetts, a school nurse said the little girl was so weak she was like a "floppy doll." The preschool principal had to help Rebecca off the bus because the 4-year-old was shaking so badly.

Rebecca — who had been diagnosed with attention deficit hyperactivity and bipolar disorder, or what used to be called manic depression — died Dec. 13, 2006 of an overdose of prescribed drugs. Rebecca was found dead on the floor of her parents' bedroom wearing only a pink pull-up diaper and gold-stud earrings, on top of a pile of clothes, magazines and a stuffed brown bear.

According to the medical examiner, Rebecca died of a combination of Clonidine, a blood pressure medication Rebecca had been prescribed for ADHD; Depakote, an antiseizure and mood-stabilizing drug prescribed for the little girl's bipolar disorder; a cough suppressant; and an antihistamine. The amount of Clonidine alone in Rebecca's system was enough to be fatal, the medical examiner said.

The two brand-name prescription drugs are approved by the Food and Drug Administration for use in adults only, though doctors can legally prescribe them to youngsters, and do so frequently.



Rebecca's death has inflamed a long-running debate in psychiatry. Some psychiatrists believe bipolar disorder, which was traditionally diagnosed in adolescence or early adulthood, has become a trendy diagnosis in young children.

"As a clinician, I can tell you it's just very difficult to say whether someone is just throwing tantrums or has bipolar disorder," said Dr. Oscar B. Bukstein, a child psychiatrist and associate professor at the University of Pittsburgh.

Marcia Angell's comments are particularly insightful. They'll appear in the forthcoming NY Review of Books in the issue of Jan. 15, 2009:

Some of the biggest blockbusters are psychoactive drugs. The theory that psychiatric conditions stem from a biochemical imbalance is used as a justification for their widespread use, even though the theory has yet to be proved. Children are particularly vulnerable targets. What parents dare say "No" when a physician says their difficult child is sick and recommends drug treatment? We are now in the midst of an apparent epidemic of bipolar disease in children (which seems to be replacing attention-deficit hyperactivity disorder as the most publicized condition in childhood), with a 40-fold increase in the diagnosis between 1994 and 2003.

Take the case of Dr. B., widely reported in Boston recently, about a professor of psychiatry at Harvard Medical School and chief of pediatric psychopharmacology at a major Harvard teaching hospital. Thanks largely to him, children as young as two years old are now being diagnosed with bipolar disorder and treated with a cocktail of powerful drugs, many of which were not approved by the Food and Drug Administration (FDA) for that purpose and none of which were approved for children below ten years of age.

Legally, physicians may use drugs that have already been approved for a particular purpose for any other purpose they choose, but such use should be based on good published scientific evidence. That seems not to be the case here. The doctor's own studies of the drugs he advocates to treat childhood bipolar disorder were, as the New York Times summarized the opinions of its expert sources, "so small and loosely designed that they were largely inconclusive."

In June, Senator Grassley revealed that drug companies, including those that make drugs he advocates for childhood bipolar disorder, had paid Dr. B. $1.6 million in consulting and speaking fees between 2000 and 2007. Two of his colleagues received similar amounts. After the revelation, the president of the hospital and the chairman of its physician organization sent a letter to the hospital's physicians expressing not shock over the enormity of the conflicts of interest, but sympathy for the beneficiaries: "We know this is an incredibly painful time for these doctors and their families, and our hearts go out to them."

Rebecca's case has lots of blame to go around, and many factors were involved. At this time, we can be sure of few things. Three things seem clear:

1. The consulting and speaking fees seem like a lot of money – enough to influence the doctor's judgment.

2. In the gray zone of the proper selection and dosage of psychoactive drugs for children, where the FDA has not specifically approved their use, we need research to be as pure, as unbiased, as possible.

3. Drug companies now own the right to cherry-pick the findings and the studies they fund, and they do so.

My opinion is that we must make doctors fully free to publish the results of their studies, and let the chips fall where they may. If so, more negative results of the usefulness of psychoactive drugs will probably be published. Currently, the drug companies often suppress such findings, e.g., as was done in half of studies of anti-depressants, according to a January 2008 article in the New England Journal of Medicine. If all such studies are published, doctors will be more skeptical of the value of these drugs, and are likely to prescribe them less frequently. We have to ask ourselves whether insisting, through government regulation, that doctors have this freedom to decide what to publish, and whether requiring doctors to disclose their research funding sources and amounts, would have saved the lives of Rebecca and other children.

Advice: Try to tighten your state’s requirements for disclosure of drug research studies and free rights for doctors to publish all research they perform.

Thanks to Helen Haskell and to Marcia Angell. Thanks also to the Associated Press for their article on March 23, 2007.