May 5, 2006
A recent USA Today sponsored review of the FDA database from 2000 to 2004 found at least 45 deaths in children under 18 with atypical antipsychotics listed as the “primary suspect,” and 1,328 reports of other serious side effects, some life-threatening.
Atypical antipsychotics are a relatively new class of drugs approved by the FDA for the treatment of adult schizophrenia and bipolar disorder. None of the drugs, including Clozaril, Risperdal, Zyprexa, Seroquel, Abilify and Geodon, are approved for children, but doctors continue to prescribe the drugs off-label for unapproved uses.
The FDA’s adverse event reporting system is known to capture only between 1% to 10% of side effects and deaths, which means the true numbers are actually much higher.
Among the 45 deaths, discussed in the May 2, 2006, USA article, at least six were related to diabetes, and other causes ranged from heart and pulmonary problems to choking, liver failure and suicide.
An 8-year-old boy died of cardiac arrest. A 15-year-old boy died of an overdose and a 13-year-old girl experienced diabetic ketoacidosis, a deficiency of insulin. The youngest child was 4, with symptoms that indicated diabetes complications.
The most common adverse reactions reported were:
* A condition known as dystonia, which produces involuntary, and often painful muscle spasms, was the most common side effect with 103 cases.
* Tremors, weight gain, sedation, and other neurological effects with symptoms that varied from slight twitching to full-blown body jerking.
* The neuroleptic malignant syndrome showed up in 41 children, and was the most troubling side effect, according to child psychiatrist Joseph Penn, of Bradley Hospital and Brown University School of Medicine, because it can kill within 24 hours.
Even thought the package inserts for atypicals say their safety and effectiveness with children have not been established, a skyrocketing number of prescriptions are being written for children diagnosed with attention deficit disorder or other behavioral problems, according to a study in the March-April 2006, edition of the journal Ambulatory Pediatrics.
This study found that the number of children prescribed antipsychotic drugs had increased five-fold between 1995 and 2002, to an estimated 2.5 million, which represents an increase from 8.6 for every 1,000 children in the mid-1990s, to nearly 40 in every of 1,000 in 2002.
The researchers analyzed data on children with an average age of 13, who were involved in annual national health surveys involving prescriptions issued during 119,752 doctor visits, and determined that over half of the prescriptions were written for attention deficit or other non-psychotic conditions.
The findings are troublesome “because it looks like these medications are being used for large numbers of children in a setting where we don’t know if they work,” said the study’s lead author, Dr William Cooper, a pediatrician at Vanderbilt Children’s Hospital in Nashville, TN.
Dr Cooper and his colleagues were among the first to investigate the increase in antipsychotic use with children and teens, in a study published in the summer of 2004, that reported that prescriptions for atypicals had doubled among Tennessee children on Medicaid between 1996 and 2001.
Back then they found that 43% of prescriptions were written for ADHD, or a related disorder as the primary diagnosis, and 14% were written for bipolar disorder, and 9% for schizophrenia or other psychotic conditions.
In a later nationwide study, researchers concluded that 6 million prescriptions for atypicals were written for children between 1995 and 2002, and again found that a large percentage of the prescriptions were written with ADHD as the primary diagnosis.
“The bottom line is that we are seeing a huge increase in the use of these medications among children, and we are not sure if they work or if they are safe,” Cooper told WebMD. “These drugs have not been tested for many of the indications that they are being used for.”
Even more disturbing finding was recently reported in a study led by Oregon Health & Science University professor, David Pollack, that revealed that 246 preschool children under the age of 5, who were enrolled in the state-sponsored Medicaid program, were receiving antipsychotic or antidepressant medications.
The review of Medicaid records, reported in the April 2006, Oregon Health News, found that 41% of the preschoolers were prescribed psychiatric drugs for ADD.
Experts say the prospect of children under 5, receiving psychiatric drugs intended for adults is alarming. Also alarming was the finding that about 50% of the prescriptions were written by primary care providers and not psychiatrists.
The study was a collaboration by Oregon’s department of human services, Medicaid program, and the Oregon State University College of Pharmacy.
An equally disturbing report was published in the April 25, 2005, Columbus Dispatch on an investigation of state Medicaid records that found 18 babies ranging from newborn to 3 years-old in Ohio had been prescribed antipsychotic drugs in July 2004.
In another analysis of privately insured children, by the pharmacy benefit manager, Medco Health Solutions, conducted for USA Today, the rate of children, 19 and under, with at least one atypical prescription had increased 80% in the four years from 2001 to 2005. This analysis did not include any children covered by government programs like Medicaid.
The study noted that atypical use among girls was much greater than with boys. The number of girls taking the drugs grew 103% from 2001 to 2005, compared to a 61% increase with boys.
The rate of children treated with atypicals “is growing dramatically faster than the rate for adults,” said Robert Epstein, chief medical officer for Medco, in a press release.
“Doctors need to be judicious when prescribing antipsychotic drugs to children,” Epstein warned. “There is evidence that the risk of diabetes and metabolic disorders from using atypical antipsychotics could be much more severe for pediatric patients than adults,” he said.
“The use of these drugs,” Dr Epstein warned, “can have the pediatric patient trading a behavioral condition for a lifelong metabolic condition that can lead to significant health complications.”
Critics say the increased use of atypicals with children is most troubling because the dangers associated with the drugs, in adults and children, has been evident in the scientific literature since before they came on the market.
In the book, Mad In America, award winning author, Robert Whitaker, reports that one out of every 145 subjects who entered clinical trials for Zyprexa, Risperdal, Seroquel, and Serdolect died. By using the Freedom of Information Act to gain access to FDA data on the drug trials for the atypicals he determined:
1. One in every 145 patients died but the deaths were not mentioned in the scientific literature.
2. The trials were structured to favor the atypicals and most of the reports were discounted by the FDA as being biased.
3. One in every thirty-five patients in Risperdal trials experienced a serious adverse event, defined by the FDA as a life threatening or one that required hospitalization.
4. The atypicals did not demonstrate superior effectiveness or safety over the older antipsychotics.
In addition, persons on atypicals have been found to commit suicide 2 to five times more often than schizophrenics in general. According to Whitaker, “researchers in Ireland reported in 2003 that since the introduction of the atypical antipsychotics, the death rate among people with schizophrenia has doubled.”
For instance, in October 2004, researchers from the Johns Hopkins Children’s Center reported that atypicals were found to trigger insulin resistance in children, a condition that increases the risk of developing type-2 diabetes and heart disease later in life.
Results of the study were presented at October 20, 2004, annual meeting of the American Academy of Child and Adolescent Psychiatry in Washington, DC.
In this study, the research team evaluated 11 children, some overweight and others obese, who gained significant amounts of weight while taking the drugs. Weight gain is a common side effect of the drugs, and is one of the factors that can contribute to insulin resistance.
Insulin resistance is said to occur when muscle, fat, and liver cells do not properly use insulin, which is produced by the pancreas to help cells absorb glucose and provide energy.
When resistance occurs, the pancreas tries to keep up with the demand for insulin by producing more until it eventually cannot keep up with the body’s need for insulin, and then excess glucose builds up in the bloodstream which can lead to an increased risk of developing type-2 diabetes, heart disease, and stroke.
All six children in the study who were on moderate or high doses of one of the atypicals, and three out of 5 children who were on low doses, developed symptoms of insulin resistance.
The evidence in the trial indicating the condition included hypertension, high levels of triglycerides, increased levels of protein in the urine, and low levels of high density lipoprotein cholesterol.
“The insulin resistance seen in these children was greater than what would be expected from weight gain alone, suggesting there is a factor distinct from excess weight that directly induces insulin resistance,” according to the study’s lead author, Mark Riddle, MD, director of the division of child and adolescent psychiatry at the Children’s Center.
Basically to find out how the new atypicals worked in comparison to each other and to determine whether the drugs were worth the cost, the National Institute of Mental Health (NIMH) decided to fund an 18 month study titled, Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).
The results of the study were published in the September 22, 2005, New England Journal of Medicine and revealed that the drugs were barely more effective than no drugs at all.
The study enrolled 1,500 schizophrenic patients from 27 medical centers across the US. Neither the patients nor the doctors knew whether a patient was getting Zyprexa, Seroquel, Risperdal, Geodon, or Trilafon.
The scientists included Trilafon to represent the older generation of antipsychotic drugs.
$44 million later, the CATIE report concluded that the new atypicals “have no substantial advantage” over the old ones.
While Zyprexa turned out to be the most effective, it also had the greatest number of side effects.
The second most effective drug was Trilafon which stunned researchers. “The biggest surprise was that the oldest medication was comparable to at least three of the new medications and not much worse than Zyprexa,” said Dr Jeffrey Lieberman, MD, who led the study.
Scientists involved in designing the study debated on whether to even include Trilafon, according to researcher, Robert Rosenheck, MD. “Many of us thought the question was decided and the old drugs were of no value,” he said in a news conference.
Researcher, Robert Freedman, MD from the University of Colorado, published an editorial to accompany the report in the NEJM.
“No drug provided the majority of patients a treatment that lasted the full 18 months of the study,” he wrote. “Only 36% of the patients receiving the most effective drug completed the trial,” Dr Freedman said.
In the end, 74% of patients elected to seek some other treatment rather than stay on their assigned medication. “The results could be viewed as discouraging,” Dr Freedman wrote.
In what outraged critics are calling a blatant tax dollar funded marketing scheme, on May 1, 2006, the New York Times, revealed that “psychiatric researchers have been experimenting with a bold and controversial treatment strategy: they are prescribing drugs to young people at risk for schizophrenia who have not yet developed the full-blown disorder.”
The findings from the trial, published in the May 2006 American Journal of Psychiatry, “suggest that this preventive approach is more difficult to put into effect – and more treacherous – than scientists had hoped,” the NYTs says.
The study was co-funded by Eli Lilly and the National Institute of Mental Health and involved 60 patients, mostly adolescents, who supposedly scored high on a scale that assesses the risk for psychosis. The scale rates the severity of over a dozen symptoms, that include categories such as grandiosity, suspiciousness, and bizarre thoughts.
From 20 to 45% of people who score high will go on to develop full-blown psychosis, in which the symptoms become extreme, researchers claim.
The trail subjects were divided into 2 groups, with one group receiving drugs and the other placebos.
In the first year of what was slated to be a 2-year trial, five of the 31 patients on medication developed full-blown psychosis, compared to 11 of the 29 subject on placebos.
However, by the end of the first year, more than two-thirds of the patients had quit, making it impossible to interpret any differences between the 2 groups.
The report said that some subjects dropped out without explaining why; others moved; and 10 quit because they either felt the drug was not helping, could not make the appointments or did not like the side effects.
The only undisputable result was that patients taking medication gained an average of 20 pounds, once again verifying a side effect that has been documented for 15 years.
The prices charged for these drugs are over the top and their increased use, along with a few other types of psychiatric drugs, is in large part responsible for the escalating prescription drug costs.
The Medco Health Solution study determined that since 2001, antipsychotic costs for children have increased 196%, or nearly tripled, due to the increase in prescriptions written and the use of the new atypicals with children 97% of the time, rather than the older drugs that sell for only a fraction of prices charged for atypicals
Overall, in 2002, the total sales of antypicals to patients of all ages reached $6.4 billion, making them the fourth-highest-selling class of drugs in the US, according to IMS Health, a company that tracks drug sales.
Two years later in 2004, total sales had jumped more than $2 billion to $8.8 billion, with $2.4 billion of that amount paid by state Medicaid funds, according to the May/June 2005 issue of Mother Jones Magazine.
Schizophrenia drugs account for the biggest share of the $39 billion that states spend each year on prescription drugs.
On October 23, 2005, the San Francisco Chronicle reported that nationwide, “Medicaid programs purchase an estimated 60 to 75 percent of antipsychotic drugs.”
The highest expenditure for California’s Medicaid, was Zyprexa at close to $250 million for the year that ended June 2005. Risperdal and Seroquel, ranked 2nd and 4th in the list of high cost drugs funded by Medicaid.
The costliest per month is Zyprexa, at an average cost of $399.26, according to the California Department of Health Services.
In 2002, the Kentucky Medicaid program ended up with a $230 million deficit and the $36 million bill for Zyprexa was the state’s largest per drug expense.
Judging by third quarter earning reports for 2005, fifteen years of negative studies have had no effect on sales that show:
Seroquel, $706 million, up 32%
Abilify, $206 million, up 58%
Geodon, $148 million, up 18%
Zyprexa, $1.035 billion, up 1%
In a disgusting twist of fate, Zyprexa’s maker, Eli Lilly’s diabetes drugs earned $653 million, up 13% when Zyprexa has consistently been found to be most likely drug to cause weight gain and high blood sugar leading to diabetes.
Risperdal is still Johnson & Johnson’s top-selling drug, and had sales of $916 million in the 3rd quarter, up 23% from the same period a year earlier.
This great news for J&J but translates into 916 fatalities for Risperdal patients, according to estimates by Allen Jones, a former investigator in the Pennsylvania Office of the Inspector General, who says, “my best effort at correlating dollars spent with deaths from drug side effects suggests that people may be dying from side effects from the schizophrenia drugs alone at the rate of at least one death for each one million dollars spent on these drugs.”
“The actual numbers may reflect a much higher death rate,” he warns.
However, experts are predicting that drug company profits might soon take a dive in light of a study published in the September 2005 New England Journal of Medicine, that found that only one atypical worked slightly better than the 40-year-old antipsychotic drug, perphenazine, which only costs about $1.50 a day compared to 10 times that amount for the atypicals.
It is estimated that the Medicaid program overall could save as much as $5.5 billion annually on by switching to perphenazine.
In addition, lawsuits are popping up all over the country filed on behalf of state Medicaid programs charging the drug makers with promoting the off-label use of the atypicals and seeking payment for medical costs billed to Medicaid arising from side effects of the drugs.