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San Francisco Gate
Drug report barred by FDA
Scientist links antidepressants to suicide in kids

Rob Waters, Special to The Chronicle
Sunday, February 1, 2004

A scientist at the Food and Drug Administration has been barred from publicly presenting his finding that several leading antidepressants may increase the risk of suicidal behaviors among children, according to sources inside the FDA.

FDA medical officer Andrew Mosholder was to present his report Monday at an FDA advisory hearing in Washington that promises to be a contentious affair involving competing medical experts and parents whose children took their own lives while on the medications.

A senior FDA official said the study wouldn't be presented because it wasn't "finalized." But critics fear that the agency's action indicates it is not prepared to take stronger action against the drugs, despite warnings about their possible effects on children.

Mosholder had been asked by the agency to perform a safety analysis of antidepressants after reports emerged this summer of high rates of suicidal behavior among children enrolled in clinical trials for Paxil, Effexor and other antidepressants.

Mosholder, a child psychiatrist, reviewed data from 20 clinical trials involving more than 4,100 children and eight different antidepressants. His preliminary analysis, according to two FDA sources familiar with the report's contents, concluded that there was an increased risk of suicidal behavior among children being treated for depression with Paxil and several other antidepressants.

An initial agenda for Monday's hearing listed Mosholder and his findings, but his presentation was removed from a revised agenda, and Mosholder was told that he could not present his findings at the hearing, one FDA official, who wished to remain anonymous, told The Chronicle.

According to the official, in early January, Russell Katz, director of the division of neuropharmacological drug products, called Mosholder in for a meeting. "He told him that he was sorry, but he wasn't going to be able to present (his report) because he had reached a conclusion and therefore was biased," the official said.

Mosholder declined several requests to be interviewed and was not made available despite repeated requests to FDA's press office. Katz was unavailable to comment on the charges.

In a telephone interview Friday with The Chronicle, Anne Trontell, deputy director of the agency's Office of Drug Safety, who is Mosholder's direct supervisor, said the analysis would not be presented because it had not yet been approved within her office.

"The consult on that is not finalized. It's not a final document within the Office of Drug Safety," Trontell said.

However, Trontell said that at Monday's hearing, Mosholder would provide a rundown of reports of suicidal behavior received by the agency from doctors and other professionals.

While Mosholder's safety analysis report may eventually be completed and made public, some FDA insiders fear that withholding it from Monday's hearing indicates that the agency may be siding with the pharmaceutical industry in its long-running battle with critics of antidepressants.

"Why is the agency sitting on its hands and acting as if there isn't a risk when their own scientists have looked at the data and concluded that there is?" one FDA official remarked.

The use of antidepressants and other psychiatric medication among children has more than tripled in recent years and now approaches adult usage rates, according to a January 2003 study in the Archives of Pediatric and Adolescent Medicine. Study author Julie Zito, an associate professor of pharmacy and medicine at the University of Maryland, estimates that more than 1 million American children used antidepressants in 2000.

Advocates of the drugs argue that they are imperfect but necessary weapons against a rising tide of mental illness among children.

Last month, a task force of the American College of Neuropsychopharmacology released its own preliminary review of published studies on antidepressants and suicide and stated it found no statistically significant increase in suicide attempts among children taking the drugs.

"The most likely explanation for the episodes of attempted suicide while taking SSRIs (selective serotonin reuptake inhibitors) is the underlying depression, not the SSRIs," said Graham Emslie, a child psychiatrist and researcher at the University of Texas Southwestern Medical Center in Dallas.

But critics, including consumer advocates and mental health professionals contend, based on other studies, that the drugs are often ineffective and sometimes dangerous and that the FDA has failed to vigorously investigate the risks and protect children's safety.

"The FDA is shielding the industry," said Vera Sharav, president of the Alliance for Human Research Protection, a consumer advocacy group.

Mosholder's analysis appears to be similar to the conclusions reached by British regulators, who told doctors in December to stop prescribing Paxil, Zoloft, Effexor and three other antidepressants to children because of an apparent "increased rate of self-harm and suicidal thoughts."

British regulators took action against Paxil in early June after new data presented to U.S. and British authorities showed that children taking the drug were nearly three times as likely to consider or attempt suicide as children taking placebos.

Later that month, the FDA issued a similar warning, urging doctors not to prescribe Paxil to children and announced that it would conduct a detailed review of pediatric trials of Paxil. The review was subsequently broadened to include seven other antidepressants, including top sellers Prozac, Zoloft and Effexor.

In October, the agency wrote to physicians to "call to (their) attention" reports of suicide among children in antidepressant trials. The agency did not, however, urge doctors to stop prescribing the drugs.

Several current and former FDA staff members interviewed by The Chronicle said the dispute over Mosholder's report highlights a lack of assertiveness within the agency over safety issues. They spoke of a split between the Office of Drug Safety -- Mosholder's office -- and the FDA's drug-reviewing divisions.

As an example, they cite a hearing last March on a rheumatoid arthritis drug, Arava, which had generated numerous reports of adverse effects, including nine deaths, after being approved by the FDA.

Members of the Office of Drug Safety, who had prepared a 37-page safety report, were present at the hearing but were not allowed to speak. A representative of the FDA division that originally approved the drug, along with the pharmaceutical company that makes the drug, did most of the talking.

A documentary crew from the PBS series Frontline filmed the meeting and afterward, in the hallway, caught up with David Graham, a senior epidemiologist with the Office of Drug Safety. The producers had been denied previous requests to interview Graham, but the government scientist gave a brief interview without permission.

"We had a different perspective, and we really weren't given an opportunity to present our side of the story," Graham, on camera, told the producers. "And the people who did present, the reviewing division and the company, you know, they didn't see a problem. This was a very hostile process. And let's just leave it at that."

Paul Stolley, a professor and former chairman of the department of epidemiology at the University of Maryland, spent a sabbatical year as a senior consultant in the Office of Drug Safety in 2000 and 2001. While there, he recalls, he tussled with agency managers over the safety of Lotronex, a drug used to treat irritable bowel syndrome, a chronic but usually not serious disease.

Stolley said his investigation uncovered high rates of negative side effects, including a number of deaths, among patients using the drug and led the company to withdraw the drug from the market.

A few months later, over Stolley's objections, the agency allowed the drug back on the market with a "risk management" program aimed at educating patients and doctors about the drug's risks. Stolley said he was excluded from internal FDA meetings on the issue.

"I'm worried about the agency," he says. "I didn't expect people to think I was right just because I was very senior. What I did expect was a vigorous debate and instead of having a vigorous debate, they made a policy decision and then excluded me."

Rob Waters' article, "A Suicide Side Effect? What parents aren't being told about their kids' antidepressants," appeared in the Jan. 4 edition of The Chronicle Magazine. E-mail him at robw001@pacbell.net.

Children's drug is more potent than cocaine

Jean West
Sunday September 9, 2001
The Observer

The children's drug Ritalin has a more potent effect on the brain than cocaine, a study has found.
Using brain imaging, scientists have found that, in pill form, Ritalin - taken by thousands of British children and four million in the United States - occupies more of the neural transporters responsible for the 'high' experienced by addicts than smoked or injected cocaine. The research may alarm parents whose children have been prescribed Ritalin as a solution to Attention Deficit Hyperactive Disorder.

The study was commissioned to understand more about why Ritalin - which has the same pharmacological profile as cocaine - is effective in calming children and helping them concentrate, while cocaine produces an intense 'high' and is powerfully addictive.

In oral form, Ritalin did not induce this intense psychological 'hit'. But Dr Nora Volkow, psychiatrist and imaging expert at Brookhaven National Laboratory, in Upton, New York, who led the study, said that injected into the veins as a liquid rather than taken as a pill, it produced a rush that 'addicts like very much'. Interviewed in last week's Journal of the American Medical Association newsletter, she said: 'They say it's like cocaine.'

Even in pill form, Ritalin blocked far more of the brain transporters that affect mood change and had a greater potency in the brain than cocaine. Researchers were shocked by this finding. A normal dose administered to children blocked 70 per cent of the dopamine transporters. 'The data clearly show the notion that Ritalin is a weak stimulant is completely incorrect,' said Volkow. Cocaine is known to block around 50 per cent of these transporters, leaving a surfeit of dopamine in the system, which is responsible for the hit addicts crave. But now it is known that Ritalin blocks 20 per cent more of these auto-receptors.

'I've been almost obsessed about trying to understand [Ritalin] with imaging,' said Volkow. 'As a psychiatrist I sometimes feel embarrassed [about the lack of knowledge] because this is by far the drug we prescribe most frequently to children.'

However, it was still not clear why a drug that has been administered for more than 40 years was not producing an army of addicted schoolchildren. Volkow and her team concluded that this was due to the much slower process of oral ingestion. It takes around an hour for Ritalin in pill form to raise dopamine levels in the brain. Smoked or injected, cocaine does this in seconds.

Dr Joanna Fowler, who worked with Volkow on the project, said: 'All drugs that are abused by humans release large quantities of dopamine. But dopamine is also necessary for people to be able to pay attention and filter out other distractions.'

But opponents of Ritalin, labelled a 'wonder drug' and a 'chemical cosh', believe it may be addictive and has dangerous side-effects. Moreover, many believe ADHD is a fraudulent title for a non-existent condition once put down to the exuberance of youth. Professor Steve Baldwin, a child psychologist from Teesside University, who died this year in the Selby rail crash, campaigned against Ritalin. He pointed out similarities between the drug and amphetamines as well as cocaine.

Mandy Smith of Banff in Scotland has a son of eight who was prescribed Ritalin for nine months. 'I am astonished the British Government have allowed this drug to be prescribed,' she said. 'It can destroy people's lives. My son was a changed person when he took Ritalin. He was suicidal and depressed.'

Janice Hill, of the Overload Support Network, a charity for parents of children with behavioural problems, said: 'Now we have thousands of children in Scotland taking a drug that is more potent than cocaine. What does it take before the situation is thoroughly investigated?'

A spokeswoman for Novartis, which makes Ritalin, said: 'Ritalin is available as tablets only. It should only be initially prescribed by a doctor who is a specialist in child behavioural disorders and should always be used and monitored under strict medical supervision.'