2.5 Million US Children Prescribed Antipsychotics_ FDA ADHD–ADR Review

The Associated Press reports that a newly released study by Dr. William Cooper of Vanderbilt Children’s Hospital found that two and half million children in the U.S. are being prescribed antipsychotics annually. Tthat’s 40 out of every 1,000 children are being exposed to highly toxic drugs that have never been approvedd for use in children.  The drugs damage the central nervous system,  the metabolic system, trigger hyperglycemia, acute weight gain, diabetes, cardiac arrest, cognitive impairment, and are linked to insulin suppression in children. The drugs carry Black Boxes–but that does not seem to deter psychiatry from prescribing these drugs anyway.

These drugs diminish the quality of these children’s lives, possibly forever. Do  these children’s lives have no value?
It is clear that drug manufacturers and their financially dependent health care professionals have put their financial interests above concern for the safety and welfare of children.
These reckless and irresponsible off-label drug prescribing practices have been shielded by a complicit FDA  whose officials bear equal responsibilty for facilitating a massive crime against children’s mental and physical health.

Regulators’ approval of ever more toxic drugs and drug patches — without regard for the long-term consequences the drugs are likely to cause– has resulted in catastrophic drug-induced harm.

A long overdue review by the FDA and the manufacturers of psychostimulant drugs used to treat children labeled as ADHD, a controversial unvalidated diagnosis, is a stunning confirmation of these drugs’ hazardous effects in children.

The review found almost 1,000 reports of psychosis or mania possibly linked to the drugs — which included Adderall, Concerta, Ritalin and Strattera — from Jan. 1, 2000, through June 30, 2005. The reports were pulled from the FDA’s database and from the drug companies themselves.  Executive Summaries of the reports submitted by FDA medical safety officers of their analysis of adverse event reports in clinical trials and in post-marketing reports follow the AP report about the abusive prescribing of antipsychotic drugs for children.

“The most important finding of this review is that signs and symptoms of psychosis or mania, particularly hallucinations, can occur in some patients with no identifiable risk factors, at usual doses of any of the drugs currently used to treat ADHD."

“A substantial proportion of psychosis-related cases were reported to occur in children age ten years or less, a population in which hallucinations are not common. The occurrence of such symptoms in young children may be particularly traumatic and undesirable, both to the child and the parents. The predominance in young children of hallucinations, both visual and tactile, involving insects, snakes and worms is striking, and deserves further evaluation. Positive rechallenge (i.e., recurrence of symptoms when drug is re-introduced) is considered a hallmark for causality assessment of adverse events. Cases of psychosis related events which included a positive rechallenge were identified in this review for each of the drugs included in this analysis.”

Prescribing antipsychotic drugs for children will go down in the annals of medicine as one of the greatest crimes against children—as these drugs diminish the quality of their lives, possibly forever.

The astounding evidence provided for the first time to an FDA Advisory Committee underscores the fact that ADHD is both a gateway to prescribed psychoactive drugs, but also a gateway for major mental illness induced by those very drugs. 

The evidence also appears to support our observation that the underlying cause that has led a US. diagnostic aberration—"the Bipolar Child"–(not witnessed anywhere else in the world) is an effect of the drugs millions of children are being prescribed recklessly.  Amphetamines and psychostimulants, SSRI antidepressants, and the most toxic of all the psychoactive drugs, antipsychotics, all may induce mania, psychosis, hostility, aggression, suicidal and homicidal behavior.

FDA Advisory meeting:  Hilton Washington DC North /The Ballrooms 620 Perry Pkwy. Gaithesburg, MD at 7:30 AM -6:00 PM  Tel: 1-301-977-8900  FAX: 1-301-977-3450

Public Comments begin at 1:00 P.M

Unfortunately, there is no Metro close to the hotel. Shady Grove on Red line is closest. A shuttle from the Hilton to Shady Grove. It leads one to wonder why the FDA doesn’t see fit to accommodate the public when convening a public meeting?

 
Contact: Vera Hassner Sharav
veracare@ahrp.org
 
~~~~~~~~~~~
http://www.nytimes.com/aponline/national/AP-Psychiatric-Drugs-Kids.html
 
March 16, 2006
More Kids Are Getting Anti – Psychotic Drugs
Antipsychotics for kids up fivefold, study says

By LINDSEY TANNER
The Associated Press

CHICAGO (AP) — Soaring numbers of American children are being prescribed anti-psychotic drugs — in many cases, for attention deficit disorder or other behavioral problems for which these medications have not been proven to work, a study found.

The annual number of children prescribed anti-psychotic drugs jumped fivefold between 1995 and 2002, to an estimated 2.5 million, the study said. That is an increase from 8.6 out of every 1,000 children in the mid-1990s to nearly 40 out of 1,000.
But more than half of the prescriptions were for attention deficit and other non-psychotic conditions, the researchers said.
The findings are worrisome ”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 lead author Dr. William Cooper, a pediatrician at Vanderbilt Children’s Hospital.

The increasing use of anti-psychotics since the mid-1990s corresponds with the introduction of costly and heavily marketed medications such as Zyprexa and Risperdal. The packaging information for both says their safety and effectiveness in children have not been established.
Anti-psychotics are intended for use against schizophrenia and other psychotic illnesses.

However, attention deficit disorder is sometimes accompanied by temper outbursts and other disruptive behavior. As a result, some doctors prescribe anti-psychotics to these children to calm them down — a strategy some doctors and parents say works.

The drugs, which typically cost several dollars per pill, are considered safer than older anti-psychotics — at least in adults — but they still can have serious side effects, including weight gain, elevated cholesterol and diabetes.
Anecdotal evidence suggests similar side effects occur in children, but large-scale studies of youngsters are needed, Cooper said.
The researchers analyzed data on youngsters age 13 on average who were involved in annual national health surveys. The surveys involved prescriptions given during 119,752 doctor visits. The researchers used that data to come up with national estimates.

Cooper said some of the increases might reflect repeat prescriptions given to the same child, but he said that is unlikely and noted that his findings echo results from smaller studies.
The study appears in the March-April edition of the journal Ambulatory Pediatrics.
Heavy marketing by drug companies probably contributed to the increase in the use of anti-psychotic drugs among children, said Dr. Daniel Safer, a psychiatrist affiliated with Johns Hopkins University, who called the potential side effects a concern.

Safer said a few of his child patients with behavior problems are on the drugs after they were prescribed by other doctors. Safer said he has let these children continue on the drugs, but at low doses, and he also does periodic tests for high cholesterol or warning signs of diabetes.

Dr. David Fassler, a University of Vermont psychiatry professor, said more research is needed before anti-psychotics should be considered standard treatment for attention deficit disorders in children.
”Given the frequency with which these medications are being used, there’s no question that we need additional studies on both safety and efficacy in pediatric populations,” Fassler said.
 
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http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210B-Index.htm

Psychiatric Adverse Events Associated with Drug Treatment of ADHD:
Review of Postmarketing Safety Data
Kate Gelperin, M.D., M.P.H., Medical Epidemiologist
Kate Phelan, R.Ph., Safety Evaluator

The DDRE ADHD Psychiatric Review Team
Division of Drug Risk Evaluation (DDRE)
Office of Drug Safety (ODS)

1 EXECUTIVE SUMMARY / INTRODUCTION

A BPCA (Best Pharmaceuticals for Children Act) review of methylphenidate products, prompted by Concerta pediatric exclusivity requirements, identified psychiatric adverse events as a possible concern. The review found some psychiatric adverse events mentioned in labeling, but a need for improved clarity was identified. The Pediatric Advisory Committee1 agreed at the June 2005 meeting at which the methylphenidate reviews were discussed, that the issue of psychiatric adverse events with all drugs indicated to treat ADHD should be examined with the goal of better characterizing these events so that drug labeling could be updated and made consistent between products. Thus, DDRE embarked on reviews of postmarketing and clinical trial reports of psychiatric adverse events associated with drugs used to treat ADHD. This document presents the results of the review of postmarketing reports. A companion document2, from Dr. Andrew Mosholder, presents the results of the review of clinical trial reports.

Information pertaining to selected psychiatric adverse event reports received since January 1, 2000 was requested from the manufacturers of products approved or with pending applications for the treatment of ADHD. Sponsors were asked to provide information regarding four broad categories of psychiatric adverse events: 1) signs and/or symptoms of psychosis or mania; 2) suicidal ideation and behavior; 3) aggression and violent behavior; and, 4) miscellaneous serious adverse psychiatric events. In addition, searches of the FDA AERS safety database were conducted covering the same time period, and the identified cases were assessed by a DDRE Review Team. Duplicates, and reports which were considered to be of poor quality or highly unlikely to be related to the drug of interest were excluded from this analysis.

Cases received from Sponsors, as well as those identified from the FDA AERS safety
database, were systematically reviewed and analyzed to assess the probability of adverse drug reactions and to describe characteristics or risk factors observed in these reports. This review focuses on postmarketing safety data from the first three search categories. The miscellaneous category was considered to be beyond the scope of this current analysis due to the large volume of data for review.

The most important finding of this review is that signs and symptoms of psychosis or mania, particularly hallucinations, can occur in some patients with no identifiable risk factors, at usual doses of any of the drugs currently used to treat ADHD. Current approved labeling for drug treatments of ADHD does not clearly address the risk of drug induced signs or symptoms of psychosis or mania (such as hallucinations) in patients without identifiable risk factors, and occurring at usual dosages. In addition, current labeling does not clearly state the importance of stopping drug therapy in any patient who develops hallucinations, or other signs or symptoms of psychosis or mania, during drug treatment of ADHD. We recommend that these issues be addressed.

A substantial proportion of psychosis-related cases were reported to occur in children age ten years or less, a population in which hallucinations are not common. The occurrence of such symptoms in young children may be particularly traumatic and undesirable, both to the child and the parents. The predominance in young children of hallucinations, both visual and tactile, involving insects, snakes and worms is striking, and deserves further evaluation. Positive rechallenge (i.e., recurrence of symptoms when drug is re-introduced) is considered a hallmark for causality assessment of adverse events. Cases of psychosis related events which included a positive rechallenge were identified in this review for each of the drugs included in this analysis.

In many patients, the events resolved after stopping the drug. In the FDA AERS review, resolution of the events after stopping the drug was reported in 58% of amphetamine /dextroamphetamine cases, 60% of modafinil cases, 33% of atomoxetine cases, and 48% of methylphenidate cases. (Note: Outcome of the psychiatric adverse events was not reported in 21% of amphetamine / dextroamphetamine cases, 9% of modafinil cases, 41% of atomoxetine cases, and 30% of methylphenidate cases.) For drugs currently approved for ADHD treatment, no risk factors were identified which could account for the majority of reports of psychosis-related events. For instance, drug abuse was reported in fewer than 3% of overall cases from the FDA AERS analysis of psychosis-related events. Also of note, in the overwhelming majority of cases (roughly 90% overall), the patient had no prior history of a similar condition.

Numerous postmarketing reports of aggression or violent behavior during drug therapy of ADHD have been received, most of which were classified as non-serious, although approximately 20% of cases overall were considered life-threatening or required hospital admission. In addition, a few cases resulted in incarceration of juveniles. The majority of the reports of aggression for drugs currently approved for the treatment of ADHD were in children and adolescents, with a striking male predominance. No specific risk factors for aggression or violent behavior were identified in this analysis. For instance, drug abuse was reported in fewer than 5% of overall cases identified from the FDA AERS search. Also of note, a striking majority (80 to 90% overall) of patients identified in this review had no prior history of similar events. Several cases describing positive rechallenge were reported or each of the drugs included in this analysis. Consideration should be given to stopping the medication in patients who develop aggressive or violent behavior during drug therapy of ADHD.

Suicidality has been identified as a safety issue for STRATTERA (atomoxetine), and this information is clearly conveyed in current labeling. A causal association between other drug therapies of ADHD and suicidality cannot be ruled out on the basis of this review.  Further evaluation of this issue is recommended. For instance, clinical case review of data obtained for this analysis may yield additional insights regarding possible co-occurrence of undesired psychiatric effects in some vulnerable patients that could contribute to suicidal ideation or behaviors.

1 Pediatric Advisory Committee Meeting, June 29 and 30, 2005;
http://www.fda.gov/oc/advisory/accalendar/2005/fda12604dd06293005.html

2 Mosholder. Psychiatric Adverse Events in Clinical Trials of Drugs for Attention Deficit Hyperactivity Disorder (ADHD). March 3, 2006. PID# D050243.

http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210b_10_01_Mosholder.pdf
Psychiatric Adverse Events in Clinical Trials of Drugs for
Attention Deficit Hyperactivity Disorder (ADHD)
Andrew Mosholder, MD
March 3, 2006

1 EXECUTIVE SUMMARY

In follow-up to the June 2005 Pediatric Advisory Committee meeting discussion of
adverse events with Concerta, it was decided to conduct a review of psychiatric adverse
events with drugs for attention deficit hyperactivity disorder (ADHD). Results of the
analysis of postmarketing reports will be presented separately. This consult summarizes
the data from approximately 90 clinical trials that was submitted in response to the
agency’s request. Sponsors of marketed products for ADHD and drugs under review for
that indication were asked to search their clinical trial databases for adverse psychiatric
events in three primary categories: psychosis and mania, suicidal events, and aggression.
This search was conducted electronically using selected, prespecified adverse event
terms. They were also asked to search their databases for additional miscellaneous
psychiatric events if the outcome was serious. Data on the duration of exposure to
treatment in the trials and subject characteristics were also requested, as were clinical
descriptions of the events and descriptions of the clinical trials in the ADHD
development programs. Data were pooled within development programs to estimate the
rates of the events of interest. The findings are subject to the usual limitations of such
safety analyses, which include potential lack of consistency of ascertainment of adverse
events across the various trials, the possibility of misclassification of cases, and statistical
power limitations imposed by the sample sizes.

With these limitations in mind, specific observations about these clinical trial data are as
follows. With respect to the clinical trial design, a large number of the controlled trials
required subjects who were known to respond to stimulants, or who had no history
of intolerance to stimulants. Also, many of the controlled trials were of very short duration.
These factors limit the utility and external generalizability of the safety datasets obtained from the trials.
With respect to specific findings, suicidal events were more frequent with atomoxetine and modafinil treatment
than with placebo. It should be noted that there were no completed suicides in ADHD trials with these drugs
(one completed suicide was reported in a placebo patient in an atomoxetine trial for another indication).
Aggressive events were more frequent with the methylphenidate transdermal patch, and to a lesser degree
with atomoxetine, than with placebo. None of these imbalances in rates reached customary levels of statistical
significance in this analysis, although Lilly’s previous analysis of suicidal events with atomoxetine did show a
statistically significant association. For aggression events, there was little evidence in these trials that drug
treatment reduced their frequency relative to placebo; only for modafinil was the event rate numerically lower
than for placebo and this was not statistically significant.

With respect to psychosis and mania events, although the numbers of such events with drug treatment were
small, the complete absence of such events with placebo treatment was notable. For 4028 pediatric ADHD
patients in these trials, there were no such events in 425 person-years of aggregated placebo treatment.
Similarly, there were no psychosis or mania events in these trials among adult ADHD patients receiving placebo.
Psychosis/mania events occurred during double-blind treatment with every compound
except Adderall XR (although there were psychosis/mania events with open label
Adderall XR treatment). Furthermore, as noted above, some subjects in Phase I studies of
these drugs experienced this type of event.

Patients and physicians should be aware of the possibility that these events, when they
arise in the course of drug treatment of ADHD, may represent adverse reactions to drugs.
In terms of future clinical trial designs, it should be borne in mind that short-duration
trials and trials which exclude subjects who are naïve to this class of drug, while they
may be efficient for determining efficacy, have limitations for defining the safety profile
of the drug.