2.5 Million US Children Prescribed Antipsychotics_ FDA ADHD--ADR Review

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2.5 Million US Children Prescribed Antipsychotics_ FDA ADHD--ADR

Review

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

http://www.ahrp.org/cms/

FYI

The Associated Press reports that a newly released study by Dr.

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

amphetamines, 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. "

The review was conducted in preparation for an upcoming FDA Pediatric

Advisory Committee meeting on Wednesday, March 22, 2006. [see details

below]

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

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

212-595-8974

veracare@...

~~~~~~~~~~~

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

Filed at 4:40 p.m. ET

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. , 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, 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.

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.

Safer, a psychiatrist affiliated with s 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. 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.

FAIR USE NOTICE: This may contain copyrighted (© ) material the use

of which has not always been specifically authorized by the copyright

owner. Such material is made available for educational purposes, to

advance understanding of human rights, democracy, scientific, moral,

ethical, and social justice issues, etc. It is believed that this

constitutes a 'fair use' of any such copyrighted material as provided

for in Title 17 U.S.C. section 107 of the US Copyright Law. This

material is distributed without profit.

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.

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

for 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)

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.

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