Antidepressant use doubles in U.S., study finds

Dropping “cold turkey” off any medication, most especially mind altering medications, can often be MORE DANGEROUS than staying on the drugs.

The most dangerous and most common mistake someone coming off the SSRI antidepressants makes is coming off these drugs too rapidly. Tapering off very, very, VERY SLOWLY–OVER MONTHS (and for long-term users—a year or more), NOT JUST WEEKS!—has proven the safest and most effective method of withdrawal from this type of medication. Thus the body is given the time it needs to readjust its own chemical levels. Patients must be warned to come very slowly off these drugs by shaving minuscule amounts off their pills each day, as opposed to cutting them in half or taking a pill every other day. This cannot be stressed strongly enough! This information on EXTREMELY gradual withdrawal is the most critical piece of information that someone facing withdrawal from these drugs needs to have. A REMINDER: IT IS EASIER TO GET DOWN OFF A MOUNTAINTOP ONE GUARDED STEP AT A TIME THAN TO JUMP FROM THE TOP TO THE BOTTOM.  Learn More   No matter how few or how many side effects you have had on these antidepressants, withdrawal is a whole new world. The worst part of rapid withdrawal does not hit for several months AFTER you quit. So even if you think you are doing okay you quickly find that it becomes much worse. If you do not come off correctly and rebuild your body as you do, you risk:

• Creating bouts of overwhelming depression
• Producing a MUCH longer withdrawal and recovery period than if you had come off slowly
• Overwhelming fatigue causing you to be unable to continue daily tasks or costing your job
• Having a psychotic break brought on by the terrible insomnia from the rapid withdrawal, and then being locked in a psychiatric ward
• Ending up going back on the drugs (each period on the drugs tends to be more dangerous and problematic than the previous time you were on the drugs) and having more drugs added to calm the withdrawal effects
• Seizures and other life threatening physical reactions
• Violent outbursts or rages

Although the book contains massive amounts of information you can find nowhere else on these drugs, it does not have the extensive amount of information contained in the tape on withdrawal. The tape contains newer and updated information on safe withdrawal from these drugs. The tape details over an hour and a half the safest ways found over the last ten years to withdraw from antidepressants. It also lists many alternative treatments that can assist you in getting though the withdrawal. And it contains information on how to rebuild your health after you have had it destroyed by the drugs so that you never end up on these drugs again. The tape is very inexpensive and will save you thousands in medical bills which you will spend trying to do it on your own. Many have lamented that they wished they would have had the information on this tape before attempting withdrawal.To order Dr. Tracy’s book or audio, “Help, I Can’t Get Off My Antidepressant,” click here.

This is a tape doctors can also benefit from when attempting to withdraw their patients from these drugs that the World Health Organization has now told us are addictive and produce withdrawal.

The Aftermath of Antidepressants

“In 2005 the FDA issued strong warnings about changes in dose for antidepressants. They warned that ANY abrupt change in dose of an antidepressant, whether increasing or decreasing the dose. So if you are switching antidepressants, starting or stopping antidepressants, forgetting to take a pill, skipping doses, taking a pill one day & not the next, etc., can cause suicide, hostility, and/or psychosis – generally a manic psychosis which is why so many are given a diagnosis for Bipolar Disorder after this reaction. Clearly coming down too rapidly can be very, very dangerous. We encourage you to arm yourself with knowledge by downloading our CD on safe withdrawal.”

click here. order a CD download.

http://www.himalmag.com/Bodies-for-hire;-The-outsourcing-of-clinical-trials_nw3213.html

Bodies for hire; The outsourcing of clinical trials August 2009
By: Sandhya Srinivasan

Medical testing by Western countries is having a staggering impact on India, if only we were to care to pay attention. And the government’s own policies are encouraging this.

Karen Haydock
In November 2008, the Hindustan Times’ LiveMint broke the story of an infant in Bangalore having died after being administered a vaccine in a drugs trial. The Drugs Controller-General of India (DCGI), Dr Surinder Singh, halted the testing, reportedly the first time that the office of the DCGI had taken such action. The trial, for a new pneumonia vaccine, was being conducted by a Hyderabad-based contracted research organisation, GVK Biotech, for the US-based multinational Wyeth Pharmaceuticals. The infant had been recruited from St. John’s Medical College, a reputed private medical institution in Bangalore.

GVK’s spokesperson claimed that the vaccine had nothing to do with the death, as the child had received an approved and widely used vaccine – not the experimental product. However, the DCGI’s investigation revealed that the infant had a heart condition, and that the trial had been meant to be conducted only on healthy babies. According to C M Gulhati, editor of the Monthly Index of Medical Specialities, India and a Delhi-based expert on clinical-trial regulations, the investigation revealed a number of other irregularities as well: the informed-consent document had not been signed before the child was recruited; and the St John’s ethics committee had not been properly constituted, as it was not chaired by an external member to ensure independent functioning.

Yet the infant’s death was not an aberration. In December 2008, 25-year-old K Surender, of Hyderabad, died in a ‘bioequivalence’ trial of a blood-pressure drug, felodipine. Bioequivalence trials test generic versions of drugs to ensure that they are as effective as the original, and involve administering the drug and then monitoring the individual through blood tests and other investigations. These tests are conducted on healthy people who are paid for their participation. The Hyderabad trial also happened to be run by GVK Biotech, which subsequently issued a statement that Surender had simultaneously been part of many bioequivalence studies, with GVK as well as other contracted research organisations. This multiple trial participation could have accounted for his death, argued the company.

Such an explanation is unconvincing. If Surender had taken part in many trials, it would only have been for the money, which would amount to an inducement according to national and international ethical guidelines for research – an inducement that might have made him overlook the risks of the trials. And, in any case, why did the company let him take part in the felodipine trial when it was aware that he had taken part in many others? The answer to this question lies in the compulsions of the global pharmaceutical industry. The GVK trials are among the increasing number of international clinical trials that are taking place in India – and the concerns that they raise will come up increasingly frequently in the future. The reports of various government and private bodies put the potential of the clinical-trial industry into billions of dollars, though the method of calculating these numbers is not available. One market-research company, Frost and Sullivan, reportedly estimates a USD two billion turnover by 2010.

Marcin Bondarowicz
The growth of the outsourced clinical-trial industry in India followed changes in the law in January 2005 that encourage clinical research in India. The most important of these was an amendment to the Drugs and Cosmetics Rules, permitting clinical trials in India to be carried out at the same time that they are done in other countries, rather than waiting until the results of drug trials in other countries were made public. Previously, this ‘phase lag’ had ensured that India was of no interest to big pharmaceutical companies to test their drugs. At that time, Phase II trials were permitted in India only after the results of a Phase III trial abroad were declared. And Phase I trials of foreign drugs were simply not permitted. (Phase I or safety trials are done on healthy ‘volunteers’, Phase II trials look at the drug’s safety and effectiveness on patients, and Phase III trials also look at safety and effectiveness, but in large numbers of patients.) It should be noted, though, that an exception was made for drugs deemed of importance to India. While the Drugs and Cosmetics Rules do not specify, such drugs would probably include the HIV vaccine.

This changed in January 2005, and India is now prominently on the radar screen of the international pharmaceutical industry in terms of clinical trials, given its vast population of potential trial subjects. As of today, the bulk of clinical trials are still located in rich countries. To illustrate, as of 19 July 2009, the US government clinical-trial database lists a total of 76,018 trials, of which 44,758 have sites in North America and 17,878 have sites in Europe – accounting for the bulk of trials. In contrast, only 1021 clinical trials have sites in India, in addition to 122 in Pakistan, 61 in Bangladesh and 12 each in Nepal and Sri Lanka.

However, the number of trials in India is growing fast. Figures given by the DCGI’s office show that the number of newly approved trials every year went from 100 in 2005, when the new rules kicked in, to about 500 in 2008. What is of concern here is that many of the trials that come to countries such as India are likely to be those rejected as unethical in Western countries. As trials shift to countries such as India, there has been an international debate on ethical concerns of the outsourcing boom. This debate has been partly responsible for amendments in the World Medical Association’s Declaration of Helsinki, “Ethical Principles for Medical Research Involving Human Subjects” in 1996, 2000 and in October 2008. Drug regulators in Europe and the US require that clinical trials submitted to them adhere to the Declaration.

Some of these changes have dealt with placebos or ‘sugar pills’. The October 2008 revision took a strong stance against the use of a placebo in a trial when a treatment exists. Clinical trials compare the effect of an experimental drug to an existing drug. If there is no drug for the condition, the experimental drug may be compared to a placebo. Using a placebo when a treatment exists deprives the trial participant of effective treatment. The ethical guidelines of the Indian Council of Medical Research and the World Medical Association’s Declaration of Helsinki both forbid the use of a placebo when an effective treatment exists, with certain specific exceptions. While both of these documents have been a bit ambiguous in the past, the 2008 revision of the Helsinki Declaration is clear: placebos can be used only when absolutely methodologically necessary, and when the risk to the participant is low. This revision was reportedly preceded by behind-the-scenes lobbying by the drug industry to permit greater use of placebo controls.

In the same month that the revised Declaration was announced, the US Food and Drug Administration (FDA) amended its own requirements for clinical trials. While placebos are rarely necessary, regulatory bodies such as the FDA require placebo-controlled trials to give marketing approval to new drugs. Yet as of October 2008, trials conducted for FDA approval no longer had to adhere to the Declaration of Helsinki – an internationally accepted document, but not binding unless incorporated into national regulations. The FDA would continue to require placebo controls, and no one was going to tell them otherwise.

Concerns about the ethics of clinical trials do not exist merely in the realm of speculation. The GVK exposés are not unusual. An increasing number of reports are coming to light of unethical and illegal practices that exploit people’s social and economic vulnerability, subject them to serious risks without their knowledge and consent, and do not even assure them of access to the drugs developed from the trials. Certain types of trials depend on paid volunteers who desperately need money. In Gujarat, unemployed diamond workers and migrants from Uttar Pradesh and Bihar get paid between INR 5000 and INR 20,000 to take part in bioequivalence trials – sums large enough for them to put money over personal safety. Indeed, trial participants may be both financially and socially vulnerable. It is reported that Surender, who died in the Hyderabad felodipine trial, was one of a number of Dalit students being recruited for clinical trials in that city. Likewise, some years ago, a 22-year-old Adivasi youth died in a bioequivalence trial of the antidepressant citalopram by the Sun Pharma Advanced Research Centre in Vadodara.

Certain types of trials are more likely to be conducted in India and other countries where regulatory and monitoring mechanisms are weak, or regulators are too willing to please drug companies. The use of placebos is a good example, as it is not difficult to conduct placebo trials in India. In 2005-06, Indian patients with schizophrenia were taken off their regular medication and given either a new, ‘extended-release’ formulation of an approved drug (quetiapine, marketed by AstraZeneca) or a placebo, to compare the time it took for people in each group to have a relapse attack of schizophrenia. The trial was conducted by a Contract Research Organisation (CRO) called Quintiles, in India as well as a number of countries in Eastern Europe. One patient (not in India) who was on the placebo committed suicide. Experts are unanimous in their view that a placebo was methodologically unnecessary in that trial, as the new formulation could have been compared to the existing ‘immediate-release’ drug. But the European regulators required a placebo-controlled trial, noted Irene Schipper and Francis Weyzig of the Dutch research organisation Centre for Research on Multinational Corporations, in a 2008 report. They also argued that placebo-controlled trials for severe conditions, which put the participants at greater risk, are more likely to be conducted in developing countries.

Trials in government hospitals in India can also be of special concern. In one trial, 290 people who had been hospitalised because they were having a severe attack of acute mania were given either a drug (risperidone, marketed by Johnson & Johnson) or a placebo. The idea, of course, was to examine how many people recovered with the drug, and how many with the placebo. This subjected seriously ill people to harm. The majority of patients in this India-only trial, also conducted by Quintiles, were recruited from government hospitals where, according to the principal investigator of the trial, the most seriously ill patients could be found. It is also where patients can be recruited easily, because trial participation ensures a hospital bed and free, quality treatment.

Another concern about trials in government hospitals is that they are conducted on poor people who may have no access to the drugs tested on them after the trial is over. In August 2008, the media reported that 49 children died in 42 clinical trials that were conducted over two and a half years in the Department of Paediatrics at the All India Institute of Medical Sciences (AIIMS) in Delhi. An investigation ordered by the National Human Rights Commission concluded that the trials were conducted properly: the children in the trials were seriously ill, and all the deaths occurred because of the serious illnesses, not the treatments. However, the committee’s report left many questions unanswered. What, for instance, was the purpose of these trials? Would they help other poor children in India?

One of these trials tested the blood-pressure drug valsartan, supplied by its manufacturer Novartis. Paediatric hypertension is indeed a serious condition, but companies conduct paediatric trials for various reasons, including to get information for the benefit of doctors who prescribe the drug to children. Another reason is because the US FDA extends a drug’s exclusive marketing rights when it is tested on children; this provision is meant to encourage research on children who are otherwise prescribed drugs based on the results of research on adults. However, companies also use this clause to maximise their profits. Another trial was linked to gene-activated human glucocerebrosidase, a treatment for Gaucher’s disease, a serious genetic condition in which a fatty substance (lipid) gets deposited in cells and specific organs. The drug for this trial was provided by the US-based Shire Human Genetic Therapies. Will the drug be made available in India once it is proved effective? Both the Helsinki Declaration and the ICMR’s guidelines emphasise that a community on which a drug is tested should have access to the drugs, if proven effective, once the trial is over. Unfortunately, this is rarely the case. Although all of the new drugs being tested in India will indeed be available in India, this will be at prices unaffordable to the very people who agree to have them tested on their bodies.

More generally, but of no less concern, AIIMS has stated that the trials did not “target” children from poor backgrounds. But there is no need to target poor people at AIIMS – they constitute the majority of patients at this government referral hospital. The simple fact is that the vast majority of people seeking care at the AIIMS centre would be there because they cannot afford treatment elsewhere.

Body market
The pharmaceutical industry depends on constantly getting new drugs into the market. New drugs include new uses for old drugs (a cancer drug that can also be used for infertility?) or ‘improved’ or ‘me-too’ versions of older drugs (all those antacids, blood-pressure and cholesterol-lowering drugs, anti-depressants or antibiotics). These drugs must be tested on human beings before they can go into the market. Permission has to be obtained, patients have to be recruited, trials carried out and the results filed – all at top speed, because time is money.

This is where the Contract Research Organisation – the CRO, such as GVK Biotech referred to earlier – steps in. The CRO undertakes all aspects of the process involved in getting regulatory clearance: getting the necessary permissions, tying up with doctors and hospitals to recruit patients on whom the drugs are to be tested, analysing the data that emerges from the trials, monitoring the trial to make sure that the information collected meets standards, putting together reports and even ghostwriting articles for publication in medical journals. Of course, the most important aspects of all this is the recruitment of patients. The best place to recruit patients for, say, a diabetes-drug trial, is a country with a large diabetic population. And diabetics who have not received treatment make better trial subjects, as the results of drugs tested on them will not be ‘contaminated’ with the results of drugs that they have already used.

Clinical trials in developing countries depend not only on physical infrastructure – hospitals and laboratories – and trained human power. They also depend on drug companies getting access to bodies on which they can test their drugs. So, CROs in India market Indian bodies. In a 2006 advertisement on their website (which has since been removed), a CRO named Igate advertised the ‘India advantage’ as “40 million asthmatics, about 34 million diabetics, 8-10 million people HIV positive, 8 million epileptic patients, 3 million cancer patients.”

CROs in India all claim to have ‘access’ to patients with various health problems for which drugs can be tested. For instance, a research group called Veeda claims to have “access to vast patient populations and has specific expertise in recruiting patients with cardiovascular disease, oncology, diabetes, renal disease”. The CRO Quintiles India once boasted that, for a paediatric-flu-vaccine trial, it recruited 201 one- to three-year-olds from three sites in India in just six days. What kind of network does Quintiles have, and what kind of influence does it have with the medical profession, that it can round up 200 children and convince their parents to let them get an experimental flu shot – all in just six days flat?

It seems that at least some of this is able to take place through wilful misinformation. Spectrum Clinical Research specialises in recruiting patients, collecting patients through networks of private clinics, hospitals, specialists and family physicians. It also runs ‘awareness campaigns’ – for instance, a “white ribbon initiative” on osteoporosis, co-organised with the women’s magazine Femina of the Times of India stable, collected data on 2000 patients with osteoporosis. Another campaign, this time to “defeat diabetes”, collected data on 1000 patients with diabetes. In these ways, people who think they are joining patient-support groups are actually being tracked so they can potentially be put on a trial.

Behind a veil
Other than the boasts of CROs, there is little information available on the hundreds of clinical trials being conducted in India. This is despite the evidence that many of these trials are conducted for the benefit of international drug companies, at unacceptable cost to the local population; that trial subjects could be put at risk; that subjects often have not given their informed consent to participate; that they might be provided care that is of lower quality than if they had been recruited for a trial in the West; that injuries during a trial might not be investigated thoroughly, and that those injured may not receive treatment of the highest standard, or even compensation; and that drugs that are tested are often too expensive for people who need them in India.

The only institution to have direct power over the conduct of a trial is the ethics committee (EC). Research institutions appoint their own institutional ethics committee to conduct an ethics review of all research proposals from within the institution. Independent or freelance ethics committees undertake ethics review for a fee, from anyone who applies – usually the CRO or drug company who coordinates the trial at a number of small nursing homes or private clinics, which don’t have their own ethics committee. The EC is a collection of specialists from various fields who review trial documents, including the trial design, the manner in which subjects are recruited, the patient information sheet and the informed-consent form, and approve or reject the application. These committees also have the authority to investigate a trial, and even to stop it if they feel that something is not right.

Ethicist Amar Jesani points out that ethics committees have a lot of power, as the DCGI requires that all trials be passed by such an appointed group. In fact, the DCGI only requires approval by an ethics committee, since it does not monitor the actual conduct of the trial – it does not check that informed consent is taken, that the investigators do their job correctly, that subjects are not harmed, and so on. Thus, says Jesani, it is the ethics committee, not the DCGI, that is the real regulator of clinical trials.

Yet the effectiveness of an ethics committee depends entirely on the setting in which it functions. Important factors, for instance, include the institution that funds the committee’s work or that determines its level of independence, the training of its members, and their competence in terms of doing a proper ethics review. Likewise ‘independent’ or freelance ethics committees are more accountable to the companies that pay for their services. Even the patient information sheet and informed-consent document are treated as confidential documents by the ethics committee – and, of course, the trial’s sponsor. These contain the information on the purpose of the trial, its risks and benefits, and an assurance that a patient’s treatment will not be jeopardised by refusal to participate, or withdrawal from a trial. There is nothing here of proprietary value – on the contrary, everything in these documents is of public interest, and they should be available to the public. Ethics committees are also often poorly educated in their responsibilities.

The reports of people dying in trials are likely to be merely the tip of the proverbial iceberg. And many more are likely to suffer an injury related to the trial drug, injuries that require treatment and that could result in temporary or permanent disability. Indian guidelines require that trial participants be compensated for injuries suffered during research. However, a study by Urmila Thatte and others in a 2009 issue of the UK-based Journal of Medical Ethics found that many trial investigators as well as ethics committee members are not even aware of this requirement. The guidelines of trial sponsors – such as drug companies – provide for medical treatment of any participant who suffers a trial-related injury, or reimbursement of their medical costs. However, Thatte and her colleagues found that none of the companies sponsoring trials, or ethics committees reviewing their trials, had a policy of compensation for trial-related disability or death. Yet for ethics committees to be a law unto themselves is hardly surprising, given the overall environment of lax regulation and monitoring.

Now, the FDA’s decision to do away with the Declaration of Helsinki will create a dilemma for the DCGI. If CROs in India are to follow the FDA requirements – such as using a placebo even when it is not absolutely necessary, and when it might put subjects at risk – they will be violating Indian regulations, which require that the Declaration of Helsinki be followed. The latest revision of the Declaration is quite clear that the placebo may be used in very few circumstances. At the moment, however, the DCGI’s record – permitting a number of unethical trials – suggests that his office places greater value on the potential financial returns of clinical trial outsourcing than on protecting the people who take part in drug trials in India.

Sandhya Srinivasan is a Bombay-based journalist specialising in public health and development issues. She is executive editor of the Indian Journal of Medical Ethics.

Paragraphs 11 though 14 read: “To combat attention disorders and other conditions, the teen took Ritalin, Zoloft, Prozac and Adero, among other drugs, Bryce said, toting the various prescriptions with him in a pill sorter.”

“The medicine sedated Adrian for hours. He was often unresponsive and seemingly unaware of people talking to him while on the medication, Bryce said.”

“The assortment of pills ‘took a toll on him,’ he said.”

“Other times Adrian displayed anger he seemed unable to control, Bryce said. Some of it was typical teen behavior, but sometimes Adrian “blacked out” and later forgot about the episodes, Bryce said.”

http://www.dailycomet.com/article/20090731/ARTICLES/907319905/-1/SPORTS12?Title=Dad-says-There-s-something-wrong-with-him -

Dad says, ‘There’s something wrong with him’

Father grieves for son suspected of shooting deputy.
By Matthew Pleasant
Staff Writer

Published: Friday, July 31, 2009 at 12:24 p.m.
Last Modified: Friday, July 31, 2009 at 12:24 p.m.

BOURG ­ To understand what happened, Bryce Broussard sifts through memories of his son.
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He cries as he remembers an 18-year-old boy who struggled to read, who needed help filling out job applications and had an unpredictable and explosive temper, he said.

The same young man earned money by cutting Hope Street yards, who welded his own workout bench in school and sometimes fell asleep wearing headphones.

The teen, Adrian Broussard, is now charged with attempted first-degree murder, accused of shooting Terrebonne deputy David Bourg three times Tuesday and leaving him in critical condition.

Still reeling over the arrest, Bryce, 36, said he and his wife, Amy, plan to support his son. He finds it hard to comprehend Adrian committing the crime, he said, but recognizes the behavior problems that may have contributed to the shooting.

“He was a good kid, but there’s something wrong with him,” said Bryce, an offshore worker. “He would blow up over nothing.”

Adrian Broussard’s last steady home was 128 Hope St. in Bourg, where his father said Adrian lived for two years before moving to live with a relative in Montegut.

He struggled through school at South Terrebonne High to earn a technical-skill degree, Bryce said. Rusting in the yard is a workout bench and frames for four-wheelers ­ all of it Adrian’s work.

Often unable to concentrate, Adrian took a slew of medications, his father said. But he never seemed more focused or content than when welding or dissembling a motor.

“He wanted to make different things that nobody else had,” Bryce said.

To combat attention disorders and other conditions, the teen took Ritalin, Zoloft, Prozac and Adero, among other drugs, Bryce said, toting the various prescriptions with him in a pill sorter.

The medicine sedated Adrian for hours. He was often unresponsive and seemingly unaware of people talking to him while on the medication, Bryce said.

The assortment of pills “took a toll on him,” he said.

Other times Adrian displayed anger he seemed unable to control, Bryce said. Some of it was typical teen behavior, but sometimes Adrian “blacked out” and later forgot about the episodes, Bryce said.

His unwieldy behavior and penchant for mechanic work followed the family to Disney World last summer, where the teen preferred to stay at the hotel rather than visit the parks, they said. When the family truck broke down, he worked on it without hesitation.

The father and son bought parts and repaired the truck in the hotel parking lot, he said.

“He helped me piece by piece, tearing it down,” he said.

Bryce said the family tried to help him find a job after graduation. The family ate at Golden Corral during one trip into Houma, and Adrian’s temper flared at servers who told him the restaurant wasn’t serving steak.

He berated the kitchen staff, telling them none knew how to cook, Bryce said. He also threw his cup in the dining room, sending drink all over surrounding tables.

“It was nothing nice,” he said.

Neighbors said the Broussard family seemed to have a troubled home life, citing fights and police visits to the trailer. Bryce and Amy Broussard said they were close despite the incidents.

“We’re not saying we’re perfect,” Amy Broussard said.

Adrian Broussard left the Hope Street trailer several months ago to stay with cousins in Montegut and only occasionally spent time with his father after that, Bryce said.

Just before midnight Tuesday, Adrian allegedly gunned down a deputy investigating reports of a suspicious person outside the Montegut Post Office.

By 1 a.m. Wednesday, deputies were at the Broussard’s trailer demanding to know where Adrian was, Bryce said. He said he spent much of the morning handcuffed inside a police cruiser that drove through Montegut in search of the teen.

The elder Broussard was charged that day with simple criminal damage to property and theft of goods over $500, according to jail records. Broussard said the arrest stemmed from outstanding warrants.

Adrian was arrested about 12 hours after the shooting when a resident found him inside an abandoned home, police have said. He is being held at the Terrebonne Parish jail in lieu of a $2 million bond on the attempted first-degree-murder charge. He is also charged with simple burglary, trespassing, possession of marijuana and illegal carrying a weapon, deputies said.

Deputies had searched for Adrian Broussard earlier Tuesday to arrest him on warrants for felony theft and criminal damage. His bond for the warrant charges is $20,000.

Deputy Bourg, a five-year veteran of the Sheriff’s Office who is married with children, remains in stable condition in the critical care unit at Terrebonne General Medical Center.

While Bryce is hoping for the best outcome for his son, he says he also hopes Bourg is able to heal.

“We are praying for a full recovery,” Bryce said. “We apologize to the family, and we’re very sorry for what happened.”

Staff Writer Matthew Pleasant can be reached at 857-2202 or matthew.pleasant@houmatoday.com.

“Get Off the Pharm”

Written & Performed by Phil Garrison of Five Branches University

(c) 2008
Two versions of a rap I did back in 2008 for my Pharmacology class at Five Branches University.

Lyrics (c) 2008 Philip G. Garrison
Produced by Philip G. Garrison

www.archive.org/details/GetOffThePharmLearn More

http://fbupharmacology.pbwiki.com/Get-Off-the-Pharm

Click on “Read more…”

lyrics: (c) 2008 Philip G. Garrison

Five Branches

http://www.fivebr
anches.edu/

my other musical projects

http://www.myspace.com/wavespan

http://www.myspace.com/creepingbanditos

1st Verse

I went to the Doc to see what’s wrong with me,

He turned out to be a pill-pusher MD,

As he reached for his pen with the drug name on it,

I said, “Stop right there, mon frer, I don’t want it!”

He said, “You must be crazy,” as I broke for the door,

Crashed into somebody, and landed on the floor,

With a slutty type of woman lookin’ down at me,

She had the names of different drugs displayed on her bikini.

She said, “Hey Doc, I was hopin’ you were free,

‘Cause I’m the new Rep’ from the drug company.”

I thought, “Damn…this has gone too far,”

As I raced out the door and hoped into my car.

Turned on the radio, tryin’ to catch the news,

But…all that did was just give me the blues.

With a story of a mom who killed her whole fami-ly,

(While) she was on the same drug the Doc had tried to give me.

An S-S-R-I that made her crazy in the head,

Like Eric Harris was takin’ when he shot those kids dead.

So before you take a drug that might mess up your dome,

Think about Columbine and Google serotonin syndrome,

The human brain is more than just a chemistry lab,

‘n’ drugs can cause hallucinations like an LSD tab.

But drugs are big business in the U-S-A,

So they try to push ‘em on you even if you’re okay.

2nd Verse

Before we get into hardcore pharmacology,

Let me break down some terminology…

An agonist is a drug with a response that may be

An increase or decrease in cellular activity,

(But) this all depends on the receptors it binds to,

Receptors all do different things: let me remind you.

Antagonists still bind, but their job is opposite,

Nothing can bind to the receptor where they sit

Efficacy is the degree of maximal effect,

Like…how hard a person tries to earn your respect.

Potency is similar but with a slightly different bent,

The amount of drug needed to produce a response of fifty-percent.

I went…to the pharmacology class,

Chillin’ out at school with my man Chris Ras.

The subject is vast–and requires concentration…

Like the Henderson-Hasselbalch equation,

Like Beta-2 receptors cause broncho-dilation,

If you give epinephrine to a member of the population.

And Beta-1 causes heart rate to get tachy,

‘Cause your body responds like you’re under attack, see?

And while we’re on the subject, one last thing I’d like to mention,

Beta blockers are the drugs often used for hypertension.

And if you’re unclear about how they work,

It’s like being stuck in line, while some big fat jerk,

Ties up the on-ly available cashier,

You don’t get the simile, let me make it more clear:

The cashier is the receptor and the jerk is the drug,

And my rhyme’s so tight, you might say it’s snug.

3rd Verse

I rock from A-to-Z: from Advair to Zocor,

Even though I pass on Flomax, I still flow more,

Than a river, non-toxic to your liver,

My delivery’s so cold it makes a polar bear shiver.

Don’t ingest Celebrex–I wrecks ill text,

You must hit the Prednisone, ’cause you look all vexed,

Whack cats sleep on this, like they’re dosed on Ambien,

Real heads peep on this, ’cause they know I came to win.

(If) MCs step I leave ‘em dead like IV’s of Levophed

My rhyme’s like Oxycontin, many fools addict-ed.

I come harder than a senior on a dose of Viagra,

Take on drug companies, watch ‘em fall like Niagra.

Just hit you with the facts, illest rapper on wax,

Val-i-um and Xa-nex try to help you relax,

But…trouble comes when it’s time for cessation,

Symptoms like anxiety, insomnia, and agitation.

You know how they roll, they say, “Take your medication,”

In every doctors office, in this medicated nation,

You’re probably better off just to take a vacation,

Or find another way to reach a state of elation.

Vaccination is a controversial topic we’ve discussed,

Many Doctors these days make you think they’re a must,

But your child’s life depends on in whom you place your trust,

That’s why I educate with the rhymes I bust.

Verse 4

Many people in our country have some type of chronic pain,

While it is their loss, it’s the drug companies gain,

They got: codeine, and morphine, and Vicodin too,

And depending on the pain, one of these drugs they’ll sell you.

Or…they might try an NSAID instead,

‘Till you pass black stools, ’cause you upper GI bled,

They inhibit prostaglandins, thus reducing inflammation,

But injure the GI and decrease platellete aggregation.

Cortio-steroids also work for many types inflammation,

Decrease of immunity is an important consideration,

A course of just 10 days, will suppress it for a year,

So if you have an infection, yell it in the doctor’s ear.

If you’re scheduled for surgery, you better tell them too,

‘Cause if you catch an infection, man, you might be through,

Inhibition of phagocytosis by neutrophils is serious

Cushing’s syndrome and psychosis: side-effects you might experience.

Heart disease is a cause of many deaths per year,

So drug companies try to use this fear,

If cholesterol is high, they want to put you on Statins,

But the ones who benefit are the ones who own the patents.

People need more education and nutrition advice,

Improper intake of food is a national vice,

So before you’re on a drug that makes you pay the price,

Change your life-style and diet, no need to think twice.

Digitoxin is a heart-drug from the foxglove plant,

For Congestive Heart Failure when you start pant,

Lasix helps water retention: another a goal of therapy,

As is improvement of cardiac contractility.

They work by inhibition of the Na-K pump,

But they still have side-effects so you still might crump,

‘Cause they mess with the way that your heart goes thump,

Better save yourself now and take that junk-food to the dump.

5th Verse

By now I hope you’ve learned just a little bit more,

About the nature of the game, I came to settle the score,

Anti-biotics that you’re on, create microbial war

You could become a casualty, without knowing what for.

Do your research, wake up, and make a choice for your health,

‘Cause the person you save — just might be yourself,

Don’t spend another dollar of your hard earned wealth,

For another empty vial on the medicine shelf.

You might think I’m a cynic for the rhymes I drop,

I’m just givin’ you the facts, and I just don’t stop,

Now you know who’s the master of medical hip-hop,

Rock mics skill-fully, when I flip I never flop.

You must be a sheep, if you’re still on the pharm,

I tried to liberate your mind, and reveal potential harm,

I guess maybe you’re just in a pharmaceutical haze,

Like the latest drug craze, I leave you all in a daze.

“This Adverse Event Report, from a study appearing in the New England Journal of Medicine, shows that of 133 children 17 & under on Zoloft there were 2 who reported “Homicidal Ideation”. There were no reports of “Homicidal Ideation” in the placebo group.

“According to the Physicians Desk Reference, a Frequent adverse reaction is one that occurs in 100 people or less. Homicidal Ideation occurred in 1 in 66 children on Zoloft aged 17 and under.

“This Adverse Event Report was the appendix for this study in the New England Journal of Medicine.”

And with this new information from the New England Journal of Medicine I want to include information out of Australia which is that Pfizer, the maker of Zoloft, along with the Therapeutic Goods Administration (TGA similar to our FDA), recommends that any SSRI antidepressant should not be prescribed to
Australians under the age of 24. Funny, but I missed that warning from Pfizer for Americans under 24, didn’t you?

Next I will send that article that just came out over the weekend because it ties in so closely with this new information on Zoloft. And because there is so much to read in this article alone I am going to cut my comments at this point and let the article speak for itself.

Ann Blake-Tracy, PhD, Executive Director,
International Coalition for Drug Awareness
_www.drugawareness.org_ (http://www.drugawareness.org/) &
_www.ssristories.org_ (http://www.ssristories.org/)
Author of Prozac: Panacea or Pandora? – Our
Serotonin Nightmare & the audio, Help! I Can’t
Get Off My Antidepressant!!! (800-280-0730)

E-mail: _atracyphd1@…_ (mailto:atracyphd1@…)

_http://content.nejm.org/cgi/content/full/NEJMoa0804633_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633)

Published at www.nejm.org October 30, 2008 (10.1056/NEJMoa0804633)
Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood
Anxiety

John T. Walkup, M.D., Anne Marie Albano, Ph.D., John Piacentini, Ph.D.,
Boris Birmaher, M.D., Scott N. Compton, Ph.D., Joel T. Sherrill, Ph.D., Golda
S. Ginsburg, Ph.D., Moira A. Rynn, M.D., James McCracken, M.D., Bruce Waslick,
M.D., Satish Iyengar, Ph.D., John S. March, M.D., M.P.H., and Philip C. Kendall, Ph.D.

ABSTRACT
Background Anxiety disorders are common psychiatric conditions affecting children and adolescents. Although cognitive behavioral therapy and selective serotonin-reuptake inhibitors have shown efficacy in treating these disorders, little is known about their relative or combined efficacy.

Methods In this randomized, controlled trial, we assigned 488 children between the ages of 7 and 17 years who had a primary diagnosis of separation anxiety disorder, generalized anxiety disorder, or social phobia to receive 14 sessions of cognitive behavioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of sertraline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 ratio. We administered categorical and dimensional ratings of anxiety severity and impairment at baseline and at
weeks 4, 8, and 12.

Results The percentages of children who were rated as very much or much improved on the Clinician Global Impression “Improvement scale were 80.7% for combination therapy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for sertraline (P<0.001); all therapies were superior to placebo
(23.7%). Combination therapy was superior to both monotherapies (P<0.001).

Results on the Pediatric Anxiety Rating Scale documented a similar magnitude and pattern of response; combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Adverse events, including suicidal and homicidal
ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline.

Conclusions
Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate.

(ClinicalTrials.gov number,
NCT00052078 _[ClinicalTrials.gov]_
(http://content.nejm.org/cgi/external_ref?access_num=NCT00052078&link_type=CLINT\
RIALGOV) .)

____________________________________
Anxiety disorders are common in children and cause substantial impairment in
school, in family relationships, and in social functioning._1_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R1) ,_2_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R2) Such disorders
also predict adult anxiety disorders and major depression._3_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R3) ,_4_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R4) ,_5_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R5) ,_6_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R6) Despite a high
prevalence (10 to 20%_3_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R3)
,_7_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R7) ,_8_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R8) ) and substantial
morbidity, anxiety disorders in childhood remain underrecognized and
undertreated._1_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R1)
,_9_

(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R9)

An improvement in outcomes for children with anxiety disorders would have important public health
implications.In clinical trials, separation and generalized anxiety disorders and social
phobia are often grouped together because of the high degree of overlap in
symptoms and the distinction from other anxiety disorders (e.g., obsessive compulsive disorder). Efficacious treatments for these disorders include cognitive behavioral therapy_10_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R10) ,_11_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R11) and
the use of selective serotonin-reuptake inhibitors (SSRIs)._12_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R12) ,_13_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R13)

However, randomized, controlled trials comparing cognitive behavioral therapy, the use of an SSRI, or the combination of both therapies with a control are lacking. The evaluation of combination therapy is particularly important because approximately 40 to 50% of children with these disorders do not have a response to short-term treatment with either monotherapy.
_14_(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R14) ,_15_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R15)

Our study, called the Child “Adolescent Anxiety Multimodal Study, was designed to address the current gaps in the treatment literature by evaluating the relative efficacy of cognitive behavioral therapy, sertraline, a combination of the two therapies, and a placebo drug. This article reports the results of short-term treatment.

Methods
Study Design and Implementation

This study was designed as a two-phase, multicenter, randomized, controlled trial for children and adolescents between the ages of 7 and 17 years who had separation or generalized anxiety disorder or social phobia. Phase 1 was a 12-week trial of short-term treatment comparing cognitive behavioral therapy, sertraline, and their combination with a placebo drug. Phase 2 is a 6-month open extension for patients who had a response in phase 1.

The authors designed the study, wrote the manuscript, and vouch for the data gathering and analysis. Pfizer provided sertraline and matching placebo free of charge but was not involved in the design or implementation of the study, the analysis or interpretation of data, the preparation or review of the manuscript, or the decision to publish the results of the study.

Study Subjects

Children between the ages of 7 and 17 years with a primary diagnosis of separation or generalized anxiety disorder or social phobia (according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision
[DSM-IV-TR]_16_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R16) ),
substantial impairment, and an IQ of 80 or more were eligible to participate. Children with coexisting psychiatric diagnoses of lesser severity than the three target disorders were also allowed to participate;
such diagnoses included attention deficit–hyperactivity disorder (ADHD) whilereceiving stable doses of stimulant and obsessive compulsive, post-traumatic stress, oppositional defiant, and conduct disorders. Children were excluded if they had an unstable medical condition, were refusing to attend school
because of anxiety, or had not had a response to two adequate trials of SSRIs or an adequate trial of cognitive behavioral therapy.

Girls who were pregnant or were sexually active and were not using an effective method of birth control
were also excluded. Children who were receiving psychoactive medications other than stable doses of stimulants and who had psychiatric diagnoses that made participation in the study clinically inappropriate (i.e., current majordepressive or substance-use disorder; type ADHD; or a lifetime history of bipolar, psychotic, or pervasive developmental disorders) or who presented an acute risk to themselves or others were also excluded.

Recruitment occurred from December 2002 through May 2007 at Duke University Medical Center, New York State Psychiatric Institute Columbia University Medical Center New York University, Johns Hopkins Medical Institutions, Temple University University of Pennsylvania, University of California, Los Angeles,and
Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center. The protocol was approved and monitored by institutional review boards at each center and by the data and safety monitoring board of the National Institute of Mental Health. Subjects and at least one parent provided written informed consent.

Interventions

Cognitive behavioral therapy involved fourteen 60-minute sessions, which included review and ratings of the severity of subjects’ anxiety, response to treatment, and adverse events. Therapy was based on the Coping Cat program,_17_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R17) ,_18_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R18) which was adapted for the
subjects’ age and the duration of the study._19_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R19)

Each subject who was assigned to receive cognitive behavioral therapy received training in anxiety-management skills, followed by behavioral exposure to anxiety-provoking situations. Parents
attended weekly check-ins and two parent-only sessions. Experienced psychotherapists, certified in the Coping Cat protocol, received regular site-level and cross-site supervision.

Pharmacotherapy involved eight sessions of 30 to 60 minutes each that included review and ratings of the severity of subjects’ anxiety, their response to treatment, and adverse events. Sertraline (Zoloft) and matching placebo were administered on a fixed flexible schedule beginning with 25 mg per day and adjusted up to 200 mg per day by week 8. Through week 8, subjects who were considered to be mildly ill or worse and who had minimal side effects were eligible for dose increases.

Psychiatrists and nurse clinicians with experience in medicating children with anxiety disorders were certified in the study pharmacotherapy protocol and received regular site-level and cross-site supervision.
Pill counts and medication diaries were used to facilitate and document adherence. Combination therapy consisted of the administration of sertraline and cognitive behavioral therapy. Whenever possible, therapy and medication sessions occurred on the same day for the convenience of subjects.

Objectives
Study objectives were, first, to compare the relative efficacy of the three active treatments with placebo; second, to compare combination therapy with either sertraline or cognitive behavioral therapy alone; and third, to assess the safety and tolerability of sertraline, as compared with placebo. We hypothesized that all three active treatments would be superior to placebo and that combination therapy would be superior to either sertraline or cognitive behavioral therapy alone.

Outcome Assessments
We obtained demographic information, information on symptoms of anxiety, and data on coexisting disorders and psychosocial functioning using reports from both the subjects and their parents and from interviews of subjects and parents at the time of screening, at baseline, and at weeks 4, 8, and 12.

The interviews were administered by independent evaluators who were unaware of study-group assignments.
We used the Anxiety Disorders Interview Schedule for DSM-IV-TR, Child Version,_20_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R20) to establish diagnostic eligibility. The categorical primary outcome was the treatment response at week 12, which was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression Improvement scale,_21_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R21) which ranges from 1 to 7, with lower scores indicating more improvement, as compared with baseline. A score of 1 or 2 reflects a substantial, clinically meaningful improvement in anxiety severity and normal functioning. The dimensional primary
outcome was anxiety severity as measured on the Pediatric Anxiety Rating Scale, computed by the summation of six items assessing anxiety severity, frequency, distress, avoidance, and interference during the previous week._22_(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R22)

Total scores on this scale range from 0 to 30, with scores above 13 indicating clinically meaningful anxiety. The Children’s Global Assessment Scale_23_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R23) was used to rate
overall impairment.

Scores on this scale range from 1 to 100; scores of 60 or lower are considered to indicate a need for treatment, and a score of 50 corresponds to moderate impairment that affects most life situations and is readily observable. Agreement among the raters was high for anxiety severity (r=0.85) and diagnostic
status (intraclass correlation coefficient= 0.82 to 0.88) on the basis of a videotaped review of 10% of assessments by independent evaluators that were performed at baseline and at week 12.

Adverse Events
Adverse events were defined as any unfavorable change in the subjects’ pretreatment condition, regardless of its relationship to a particular therapy. Serious adverse events were life-threatening events, hospitalization, or events leading to major incapacity. Harm-related adverse events were defined as thoughts of harm to self or others or related behaviors. All subjects were interviewed at the start of each visit by the study coordinator with the use of a standardized script. Identified adverse events and harm-related events were then evaluated and rated by each subject’s study clinician.

This report presents data on all serious adverse events, all harm-related adverse events, andmoderate and severe (i.e., functionally impairing) adverse events that occurred in 3% or more of subjects in any study group. The data and safety monitoring board of the National Institute of Mental Health performed a quarterly review
of reported adverse events. Given the greater number of study visits (and hence more reporting
opportunities) and the unblinded administration of sertraline in the combination-therapy group, the test of the adverse-event profile of sertraline focused on statistical comparisons between sertraline and placebo and sertraline and cognitive behavioral therapy.

Randomization and Masking
The randomization sequence in a 2:2:2:1 ratio was determined by a computer-generated algorithm and maintained by the central pharmacy, with stratification according to age, sex, and study center. Subjects were assigned to study groups after being deemed eligible and undergoing verbal reconsent with a study investigator. Subjects in the sertraline and placebo groups did not know whether they were receiving active therapy, nor did their clinicians. However, subjects who received combination therapy knew they were receiving active sertraline. The study protocol called for independent evaluators who completed assessments to be unaware of all treatment assignments.

Statistical Analysis
On the basis of previous studies,_10_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R10) ,_11_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R11) ,_12_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R12)
,_13_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R13) ,_14_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R14) ,_15_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R15)
we hypothesized that 80% of children in the combination-therapy group, 60% in either the sertraline group
or the cognitive-behavioral-therapy group, and 30% in the placebo group would be considered to have had a response to treatment at week 12. We determined that we needed to enroll 136 subjects in each active-treatment group and 70 subjects in the placebo group for the study to have a power of 80% to detect a minimum difference of 17% between any two study groups in the rate of response, assuming an alpha of 0.05 and a two-tailed test with no adjustment for multiple comparisons.

Analyses were performed with the use of SAS software, version 9.1.3 (SAS Institute). For categorical outcomes (including data regarding adverse events), treatments were compared with the use of Pearson’s chi-square test, Fisher’s exact test, or logistic regression, as appropriate. Logistic-regression models included the study center as a covariate. For dimensional outcomes, linear mixed-effects models (implemented with the use of PROC MIXED) were used to determine predicted mean values at each assessment point (weeks 4, 8, and 12)
and to test the study hypotheses with respect to between-group differences at week 12.

In each linear mixed-effects model, time and study group were included as fixed effects, with linear and quadratic time and time-by-treatment group interaction terms. Each model also began with a limited number of covariates (e.g., age, sex, and race), followed by backward stepping to identify thebest-fitting and most parsimonious model. In all models, random effects included intercept and linear slope terms, and an unstructured covariance was used to account for within-subject correlation over time. All comparisons were planned and tests were two-sided. A P value of less than 0.05 was considered to indicate statistical significance. The sequential Dunnett test was used to control the overall (familywise) error rate._24_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R24)

We analyzed data from all subjects according to study group. Sensitivity analyses were performed with the last observation carried forward (LOCF) and multiple imputation assuming missingness at random. Results were similar for the two missing-data methods. We report the results of the LOCF analysis because the
response rates were lower and hence provide a more conservative estimate of outcomes.

Results
Subjects
A total of 3066 potentially eligible subjects were screened by telephone
(_Figure 1_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#F1) ). Of these subjects, 761 signed consent forms and completed the inclusion and exclusion evaluation, 524 were deemed to be eligible and completed the baseline assessment, and 488 underwent randomization. Eleven subjects (2.3%) stopped
treatment but were included in the assessment (treatment withdrawals); 46 subjects (9.4%) stopped both treatment and assessment (study withdrawals).

On the basis of logistic-regression analyses, pairwise comparisons indicated that subjects in the cognitive-behavioral-therapy group were significantly less likely to withdraw from treatment than were those in the sertraline group (odds ratio, 0.33; 95% confidence interval [CI], 0.13 to 0.87; P=0.03) or the placebo
group (odds ratio, 0.24; 95% CI; 0.09 to 0.67; P=0.006). Of the 488 subjects who underwent randomization, 459 (94.1%) completed at least one postbaseline assessment, 396 (81.1%) completed all four assessments, and 440 (90.2%) completed the assessment at week 12. Subjects were recruited primarily through advertisements (52.2%) or clinical referrals (44.1%).
(http://content.nejm.org/cgi/content/full/NEJMoa0804633v2/F1)
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Figure 1. Enrollment and Outcomes.
Subjects who are shown as having withdrawn from treatment discontinued their assigned therapy but continued to undergo study assessment. Subjects who are shown as having withdrawn from the study discontinued both therapy and assessment. CBT denotes cognitive behavioral therapy.

Of 14 possible sessions of cognitive behavioral therapy, the mean (±SD) number of sessions completed was 12.7±2.8 in the combination-therapy group and 13.2±2.0 in the cognitive-behavioral-therapy group. The mean dose of sertraline at the final visit was 133.7±59.8 mg per day (range, 25 to 200) in the combination-therapy group, 146.0±60.8 mg per day (range, 25 to 200) in the sertraline group, and 175.8±43.7 mg per day (range, 50 to 200) in the placebo group.

Demographic and Clinical Characteristics
There were no significant differences among study groups with respect to baseline demographic and clinical characteristics (_Table 1_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#T1) ). The mean age of participants was 10.7±2.8 years, with 74.2% under the age of 13 years.

There were nearly equal numbers of male and female subjects. Most subjects were white (78.9%), with
other racial and ethnic groups represented. Subjects came from predominantly middle-class and upper-middle-class families (74.6%) and lived with both biologic parents (70.3%). Most subjects had received the diagnosis of two or more primary anxiety disorders (78.7%) and one or more secondary disorders
(55.3%). At baseline, subjects had moderate-to-severe anxiety and impairment (_Table
2_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#T2) ).

Given the geographic diversity among study centers, there were significant differences among sites on several baseline demographic variables (e.g., race and socioeconomic status). Overall, these variables were equally distributed among study groups within each center; however, three centers had one instance each of
unequal distribution for sex, race, or socioeconomic status.

View this table:
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Table 1. Baseline Characteristics of the Subjects and Recruitment According
to Study Center.

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Table 2. Key Outcomes at 12 Weeks.

Clinical Response
In the intention-to-treat analysis, the percentages of children who were rated as 1 (very much improved) or 2 (much improved) on the Clinical Global Impression–Improvement scale at 12 weeks were 80.7% (95% CI, 73.3 to 86.4) in the combination-therapy group, 59.7% (95% CI, 51.4 to 67.5) in the cognitive-behavioral-therapy group, 54.9% (95% CI, 46.4 to 63.1) in the sertraline group, and
23.7% (95% CI, 15.5 to 34.5) in the placebo group (_Table 2_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#T2) ).

With the study center as a covariate, planned pairwise comparisons from a logistic-regression model showed
that each active treatment was superior to placebo as follows: combination therapy versus placebo, P<0.001 (odds ratio, 13.6; 95% CI, 6.9 to 26.8); cognitive behavioral therapy versus placebo, P<0.001 (odds ratio, 4.8; 95% CI, 2.6 to 9.0); and sertraline versus placebo, P<0.001 (odds ratio, 3.9; 95% CI, 2.1 to 7.4). Similar pairwise comparisons revealed that combination therapy was superior to either sertraline alone (odds ratio, 3.4; 95% CI, 2.0 to 5.9; P<0.001) or cognitive behavioral therapy alone (odds ratio, 2.8; 95% CI, 1.6 to 4.8; P=0.001). However, there was no significant difference between sertraline and cognitive behavioral therapy (P=0.41).

There was no main effect for center (P=0.69); however, a comparison among centers according to study group revealed a significant difference in response to combination therapy but no differences with respect to the response to sertraline alone (P=0.15) or cognitive behavioral therapy alone (P=0.25).

Further evaluation of response rates revealed that the average response rate for combination therapy at one center was significantly lower than at the other centers (P=0.002). A sensitivity analysis of site response rates showed that when data from the one site were removed, the average response rate of the other sites was consistent with that of the full sample.

The mixed-effects model for the Pediatric Anxiety Rating Scale revealed a significant quadratic effect for time (P<0.001) and a significant quadratic time-by-treatment interaction for cognitive behavioral therapy versus placebo (P=0.01) but not for either combination therapy or sertraline versus placebo. In other words, as compared with placebo, cognitive behavioral therapy had a linear mean trajectory (_Figure 2_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#F2) ). Planned pairwise comparisons of the expected mean scores on the Pediatric Anxiety Rating Scale at week 12 revealed a similar ordering of
outcomes, with all active treatments superior to placebo, according to the following comparisons: combination therapy versus placebo, t=–5.94 (P<0.001); cognitive behavioral therapy versus placebo, t=–2.11 (P=0.04); and sertraline versus placebo, t=–3.15 (P=0.002). In addition, combination therapy was
superior to both sertraline alone (t=–3.26, P=0.001) and cognitive behavioral therapy alone (t=–4.73, P<0.001). No significant difference was found between sertraline and cognitive behavioral therapy (t=1.32, P=0.19). The same magnitude and pattern of outcome was found for the Clinical Global Impressio Severity
scale and the Children’s Global Assessment Scale.
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Figure 2. Scores on the Pediatric Anxiety Rating Scale during the 12-Week
Study.

Scores on the Pediatric Anxiety Rating Scale range from 0 to 30, with scores higher than 13 consistent with moderate levels of anxiety and a diagnosis of an anxiety disorder. The expected mean score is the mean of the sampling distribution of the mean.

Estimates of the effect size (Hedges’ g) and the number needed to treatbetween the active-treatment groups and the placebo group were calculated. Effect sizes are based on the expected mean scores on the Pediatric Anxiety
Rating Scale, derived from the mixed-effects model. The number needed to treat is based on the dichotomized, end-of-treatment scores on the Clinical Global Impression–Improvement scale with the use of LOCF. The effect size was 0.86 (95% CI, 0.56 to 1.15) for combination therapy, 0.45 (95% CI, 0.17 to 0.74) for
sertraline, and 0.31 (95% CI, 0.02 to 0.59) for cognitive behavioral treatment.

The number needed to treat was 1.7 (95% CI, 1.7 to 1.9) for combination therapy, 3.2 (95% CI, 3.2 to 3.5) for sertraline, and 2.8 (95% CI, 2.7 to 3.0) for cognitive behavioral therapy. Treatment and Study Withdrawals
Most treatment and study withdrawals were attributed to reasons other than adverse events (43 of 57, 75.4%) (_Table 3_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#T3) ).

Of the 14 withdrawals that were attributed to an adverse event, 11 (78.6%) were in the groups receiving either sertraline alone or placebo and consisted of 3 physical events (headache, stomach pains, and tremor) and 8 psychiatric adverse events (worsening of symptoms, 3 subjects; agitation or disinhibition, 3; hyperactivity, 1; and nonsuicidal self-harm and homicidal ideation, 1).
View this table:
_[in this window]_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633v2/T3)
_[in a new window]_
(http://content.nejm.org/cgi/content-nw/full/NEJMoa0804633v2/T3)
(http://content.nejm.org/cgi/powerpoint/NEJMoa0804633v2/T3)
Table 3. Subjects Who Withdrew from Treatment or the Study.

Serious Adverse Events
Three subjects had serious adverse events during the study period. One child in the sertraline group had a worsening of behavior that was attributed to the parents’ increased limit setting on avoidance behavior; the event was considered to be possibly related to sertraline. A child in the combination-therapy
group had a worsening of preexisting oppositional defiant behavior that resulted in psychiatric hospitalization; this event was considered to be unrelated to a study treatment. The third subject was hospitalized for a tonsillectomy, which was also considered to be unrelated to a study treatment
(_Table
4_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#T4) ).
View this table:
_[in this window]_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633v2/T4)
_[in a new window]_
(http://content.nejm.org/cgi/content-nw/full/NEJMoa0804633v2/T4)
(http://content.nejm.org/cgi/powerpoint/NEJMoa0804633v2/T4)
Table 4. Moderate-to-Severe Adverse Events at 12 Weeks.

Adverse Events
Subjects in the combination-therapy group had a greater number of study visits and therefore significantly more opportunities for elicitation of adverse events than did those in the other study groups, with a mean of 12.8±4.0 opportunities (range, 1 to 22) in the combination-therapy group, as compared with 9.9±3.6 (range, 1 to 14) in the sertraline group, 10.6±2.0 (range, 1 to 14) in the cognitive-behavioral-therapy group, and 9.7±4.2 (range, 1 to 14) in the placebo group (P<0.001 for all comparisons). Rates of adverse events,
including suicidal and homicidal ideation, were not significantly greater in the sertraline group than in the placebo group. No child in the study attempted suicide. Among children in the cognitive-behavioral-therapy group, there were fewer reports of insomnia, fatigue, sedation, and restlessness or fidgeting than in the sertraline group (P<0.05 for all comparisons). For a list of mild adverse events that were not associated with functional impairment, as well as moderate and severe events, see the _Supplementary Appendix_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633/DC1) ,

available with the full text of this article at www.nejm.org.

Discussion
Our study examined therapies that many clinicians consider to be the most promising treatments for childhood anxiety disorders. Our findings indicate that as compared with placebo, the three active therapies combination therapy with both cognitive behavioral therapy and sertraline, cognitive behavioral therapy alone, and sertraline alone — are effective short-term treatments for children with separation and generalized anxiety disorders and social phobia, with combination treatment having superior response rates. No physical,psychiatric, or harm-related adverse events were reported more frequently in the sertraline group than in the placebo group, a finding similar to that for SSRIs, as identified in previous studies of anxious children._12_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R12) ,_13_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R13) ,_25_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R25)

Few withdrawals from either treatment or the study were attributed to adverse events. Suicidal ideation and homicidal ideation were uncommon. No child attempted suicide during the study period. Since they were recruited at multiple centers and locations, the study subjects were racially and ethnically diverse. However, despite intense outreach, the sample did not include the most socioeconomically disadvantaged children.
Subjects were predominantly younger children and included those with ADHD and other anxiety disorders, factors that allow for generalization of the results to these populations.

Conversely, the exclusion of children and teens with major depression and pervasive developmental disorders may have limited the generalizability of the results to these populations.The observed advantage of combination therapy over either cognitive behavioral therapy or sertraline alone during short-term treatment (an improvement of 21 to 25%) suggests that among these effective therapies, combination therapy
provides the best chance for a positive outcome. The superiority of combination therapy might be due to additive or synergistic effects of the two therapies. However, additional contact time in the combination-therapy group, which was unblinded, and expectancy effects on the part of both subjects and
clinicians cannot be ruled out as alternative explanations.

Nonetheless, the magnitude of the treatment effect in the combination-therapy group (with two
subjects as the number needed to treat to prevent one additional event) suggests that children with anxiety disorders who receive quality combination therapy can consistently expect a substantial reduction in the severity of anxiety. An increased number of visits in the combination-therapy group resulted in increased opportunities for elicitation of adverse events. Consequently, the potential for expectancies among subjects, parents, and clinicians regarding the side effects of medications in the context of more visits may have increased the rate of some adverse events in the combination-therapy group and may limit conclusions that can be drawn regarding the rates of adverse events in combination therapy.

The positive benefit of cognitive behavioral therapy, as compared with placebo, adds new information to the existing literature._26_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R26)
The number needed to treat for cognitive behavioral therapy in this study (three subjects) is the same as that
identified in a meta-analysis of studies comparing subjects who were assigned to cognitive behavioral therapy with those assigned to a waiting list for therapy or to sessions without active therapy._14_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R14)

Our study’s test of cognitive behavioral therapy included children with moderate-to-severe anxiety and addresses criticism of previous trials that included children with only mild-to-moderate
anxiety._14_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R14)
Before our study, cognitive behavioral therapy for childhood anxiety was considered to be
“probably efficacious.”_26_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R26)

This evaluation of cognitive behavioral therapy and other recent studies_27_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R27)
,_28_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R28) suggests that
such therapy for childhood anxiety is a well-established, evidenced-based treatment._29_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R29)

Given that the risk of some adverse events was lower in the behavioral-therapy group than in the sertraline group, some parents and their children may consider choosing cognitive behavioral therapy as their initial treatment.

The results of our study confirm the short-term efficacy of sertraline for children with generalized anxiety disorder_25_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R25) and show that
sertraline is effective for children with separation anxiety disorder and social phobia. The number needed
to treat for sertraline in our study (three subjects) was the same as that previously identified in a meta-analysis_15_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R15) of six
randomized, placebo-controlled trials of SSRIs for childhood anxiety disorders._12_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R12) ,_13_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R13) ,_25_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R25)
,_30_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R30) ,_31_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R31)

These studies and others_27_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R27)
suggest that SSRIs, as a class, are the medication of choice for these conditions. The titration schedule that we used, which emphasized upward dose adjustment in the absence of response and adverse events, suggests that the average end-point dose of sertraline in this study is the highest dose consistent with good outcome and tolerability. No adverse events were observed more frequently in the sertraline group than in the placebo group. In contrast to the apparent risk of suicidal ideation and behavior in studies of depression in children and
adolescents,_15_ (http://content.nejm.org/cgi/content/full/NEJMoa0804633#R15) our study did not demonstrate any increased risk for suicidal behavior in the sertraline group. Given the benefit of sertraline alone or in combination with cognitive behavioral therapy and the limited risk of adverse events associated with the drug in our study, the well-monitored use of sertraline and other SSRIs in the treatment of childhood anxiety disorders is indicated.

Cognitive behavioral therapy and sertraline either in combination or as monotherapies appear to be effective treatments for these commonly occurring childhood anxiety disorders. Results confirm those of previous studies of SSRIs and cognitive behavioral therapy and, most important, show that combination
therapy offers children the best chance for a positive outcome. Our findings indicate that all three of the treatment options may be recommended, taking into consideration the family’s treatment preferences, treatment availability, cost, and time burden. To inform more prescriptive selection of patients for
treatment, further analysis of predictors and moderators of treatment response may identify who is most likely to respond to which_32_
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#R32) of these
effective alternatives.
Supported by grants (U01 MH064089, to Dr. Walkup; U01 MH64092, to Dr.
Albano; U01 MH64003, to Dr. Birmaher; U01 MH63747, to Dr. Kendall; U01 MH64107,
to Dr. March; U01 MH64088, to Dr. Piacentini; and U01 MH064003, to Dr. Compton)
from the National Institute of Mental Health (NIMH).

Sertraline and matching placebo were supplied free of charge by Pfizer. Dr. Walkup reports receiving consulting fees from Eli Lilly and Jazz Pharmaceuticals and fees for legal consultation to defense counsel and
submission of written reports in litigation involving GlaxoSmithKline, receiving lecture fees from CMP Media, Medical Education Reviews, McMahon Group, and DiMedix, and receiving support in the form of free medication and matching placebo from Eli Lilly and free medication from Abbott for clinical trials funded by the NIMH; Dr. Albano, receiving royalties from Oxford University Press for the Anxiety Disorders Interview Schedule for DSM-IV, Child and Parent Versions, but not for interviews used in this study, and royalties from the Guilford Press; Dr. Piacentini, receiving royalties from Oxford University Press for treatmentmanuals on childhood obsessive compulsive disorder and tic disorders and from the Guilford Press and APA Books for other books on child mental health and receiving lecture fees from Janssen-Cilag; Dr. Birmaher, receiving consulting fees from Jazz Pharmaceuticals, Solvay Pharmaceuticals, and Abcomm, lecture fees from Solvay, and royalties from Random House for a book on children with bipolar disorder; Dr. Rynn, receiving grant support from Neuropharm, BoehringerIngelheim Pharmaceuticals, and Wyeth Pharmaceuticals, consulting fees from Wyeth, and royalties from APPI for a book chapter on pediatric anxiety disorders; Dr. McCracken, receiving consulting fees from Sanofi-Aventis and Wyeth, lecture fees from Shire and UCB, and grant support from Aspect, Johnson & Johnson, Bristol-Myers Squibb, and Eli Lilly; Dr. Waslick, receiving grant support from Baystate Health, Somerset Pharmaceuticals, and GlaxoSmithKline; Dr. Iyengar, receiving consulting fees from Westinghouse for statistical consultation; Dr. March, receiving study medications from Eli Lilly for an NIMH-funded clinical trial and receiving royalties from Pearson for being the author of the Multidimensional Anxiety Scale for Children, receiving consulting fees from Eli Lilly, Pfizer, Wyeth, and GlaxoSmithKline, having an equity interest in MedAvante, and serving on an advisory board for AstraZeneca and Johnson & Johnson; and Dr. Kendall, receiving royalties from Workbook Publishing for anxiety-treatment materials.

No other potential conflict of interest relevant to this article was reported.

The views expressed in this article are those of the authors and do not necessarily represent the official views of the NIMH, the National Institutes of Health, or the Department of Health and Human Services.
We thank the children and their families who made this study possible; and J. Chisar, J. Fried, R. Klein, E. Menvielle, S. Olin, J. Severe, D. Almirall, and members of NIMH’s data and safety monitoring board.
* The study investigators are listed in the Appendix.
(http://content.nejm.org/cgi/content/full/NEJMoa0804633#RFN1)

Source Information
From the Johns Hopkins Medical Institutions, Baltimore (J.T.W., G.S.G.); New York State Psychiatric Institute–Columbia University Medical Center, New York (A.M.A., M.A.R.); the University of California at Los Angeles, Los Angeles (J.P., J.M.); Western Psychiatric Institute and Clinic University of Pittsburgh Medical Center, Pittsburgh (B.B., S.I.); Duke University Medical Center, Durham, NC (S.N.C., J.S.M.); the Division of Services and Intervention Research, National Institute of Mental Health, Bethesda, MD (J.T.S.); Baystate
Medical Center, Springfield, MA (B.W.); and Temple University, Philadelphia
(P.C.K.).

This article (10.1056/NEJMoa0804633) was published at www.nejm.org on
October 30, 2008. It will appear in the December 25 issue of the Journal.
Address reprint requests to Dr. Walkup at the Division of Child and
Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns
Hopkins Medical Institutions, 600 N. Wolfe St., Baltimore, MD 21287.
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Appendix
The following investigators participated in this study: Steering Committee:
J. Walkup (chair), A. Albano (cochair); Statistics–Experimental Design: S.
Compton, S. Iyengar, J. March; Cognitive Behavioral Therapy: P. Kendall, G.
Ginsburg; Pharmacotherapy: M. Rynn, J. McCracken; Assessment: J. Piacentini,
A. Albano; Study Coordinators: C. Keeton, H. Koo, S. Aschenbrand, L. Bardsley,
R. Beidas, J. Catena, K. Dever, K. Drake, R. Dublin, E. Fontaine, J. Furr, A.
Gonzalez, K. Hedtke, L. Hunt, M. Keller, J. Kingery, A. Krain, K. Miller, J.
Podell, P. Rentas, M. Rozenmann, C. Suveg, C. Weiner, M. Wilson, T. Zoulas;
Data Center: M. Fletcher, K. Sullivan; Cognitive Behavior Therapists: E.
Gosch, C. Alfano, A. Angelosante, S. Aschenbrand, A. Barmish, L. Bergman, S.
Best, J. Comer, S. Compton, W. Copeland, M. Cwik, M. Desari, K. Drake, E.
Fontaine, J. Furr, P. Gammon, C. Gaze, R. Grover, H. Harmon, A. Hughes, K.
Hutchinson, J. Jones, C. Keeton, H. Kepley, J. Kingery, A. Krain, A. Langley,
J. Lee, J. Levitt, J. Manetti-Cusa, E. Martin, C. Mauro, K. McKnight, T. Peris, K.
Poling, L. Preuss, A. Puliafico, J. Robin, T. Roblek, J. Samson, M.
Schlossberg, M. Sweeney, C. Suveg, O. Velting, T. Verduin; Pharmacotherapists:
M. Rynn, J. McCracken, A. Adegbola, P. Ambrosini, D. Axelson, S. Barnett, A. Baskina,
B. Birmaher, C. Cagande, A. Chrisman, B. Chung, H. Courvoisie, B. Dave, A.
Desai, K. Dever, M. Gazzola, E. Harris, G. Hirsh, V. Howells, L. Hsu, I.
Hypolite, F. Kampmeier, S. Khalid-Khan, B. Kim, D. Kondo, L. Kotler, M.
Krushelnycky, J. Larson, J. Lee, P. Lee, C. Lopez, L. Maayan, J. McCracken, R.
Means,L. Miller, A. Parr, C. Pataki, C. Peterson, P. Pilania, R. Pizarro, H. Ravi,
S. Reinblatt, M. Riddle, M. Rodowski, D. Sakolsky, A. Scharko, R. Suddath, C.
Suarez, J. Walkup, B. Waslick; Independent Evaluators: A. Albano, G.
Ginsburg, B. Asche, A. Barmish, M. Beaudry, S. Chang, M. Choudhury, B. Chu, S.
Crawley, J. Curry, G. Danner, N. Deily, R. Dingfelder, D. Fitzgerald, P.
Gammon, S. Hofflich, E. Kastelic, J. Keener, T. Lipani, K. Lukin, M. Masarik, T.
Peris, T. Piacentini, S. Pimentel, A. Puliafico, T. Roblek, M. Schlossberg, E.
Sood, S. Tiwari, J. Trachtenberg, P. van de Velde; Pharmacy: K. Truelove, H.
Kim; Research Assistants: S. Allard, S. Avny, D. Beckmann, C. Brice, B.
Buzzella, E. Capelli, A. Chiu, M. Coles, J. Freeman, M. Gringle, S. Hefton, D.
Hood, M. Jacoby, J. King, A. Kolos, B. Lourea-Wadell, L. Lu, J. Lusky, R. Maid, C.
Merolli, Y. Ojo, A. Pearlman, J. Regan, S. Rock, M. Rooney, N. Simone, S.
Tiwari, S. Yeager.

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Dr. Frederick K. Goodwin, senior author of the study and director of the psychopharmacology research center at George Washington University Medical Center

Journal of the American Medical Association

The new study, published today in The Journal of the American Medical Association, found that patients taking Depakote were 2.7 times as likely to kill themselves as those taking lithium. Earlier studies by others had also found that lithium could prevent suicide, but today’s report is the first to compare suicide and attempted suicide rates in lithium and Depakote users. The study was based on medical records of 20,638 patients aged 14 and older in Washington State and California who were treated from 1994 to 2001.

9/17/2003

Study Links Older Bipolar Drug to Fewer Suicides

http://www.nytimes.com/2003/09/17/health/17SUIC.html

Dr. Frederick K. Goodwin, senior author of the study and director of the psychopharmacology research center at George Washington University Medical Center

Journal of the American Medical Association

The new study, published today in The Journal of the American Medical Association, found that patients taking Depakote were 2.7 times as likely to kill themselves as those taking lithium. Earlier studies by others had also found that lithium could prevent suicide, but today’s report is the first to compare suicide and attempted suicide rates in lithium and Depakote users. The study was based on medical records of 20,638 patients aged 14 and older in Washington State and California who were treated from 1994 to 2001.

Lithium, an old and inexpensive drug that has fallen out of favor with many psychiatrists, is better than the most commonly prescribed drug, Depakote, at preventing suicide in people who have manic-depressive illness, researchers are reporting.

People with the illness, also called bipolar disorder, swing back and forth between bleak spells of depression and periods of high excitability that may run the gamut from euphoria to rage. From 1.3 percent to 1.5 percent of people in the United States suffer from bipolar disorder, and their risk of committing suicide is estimated to be 10 to 20 times that of the rest of the population.

Perhaps because patients are more likely to seek medical help when they are depressed than when they are manic, the disorder is often misdiagnosed at first as depression alone, but antidepressants are not the correct treatment for bipolar disorder and may in fact make it worse.

The new study, published today in The Journal of the American Medical Association, found that patients taking Depakote were 2.7 times as likely to kill themselves as those taking lithium. Earlier studies by others had also found that lithium could prevent suicide, but today’s report is the first to compare suicide and attempted suicide rates in lithium and Depakote users. The study was based on medical records of 20,638 patients aged 14 and older in Washington State and California who were treated from 1994 to 2001.

Solvay Pharmaceuticals, a maker of lithium, paid for the study, but did not influence the findings or the way they were reported, the authors said.

The study included 53 actual suicides and 383 attempted suicides that led to hospitalization. But the researchers, as well as Depakote’s manufacturer, cautioned that because this study was based only on patients’ records, it was not conclusive.

Precisely how lithium might prevent suicide is not known, although it is believed to help regulate levels of serotonin, a brain chemical that influences mood.

“Lithium is clearly being underutilized,” said Dr. Frederick K. Goodwin, the senior author of the study and director of the psychopharmacology research center at George Washington University Medical Center. The drug can save lives, he said, adding, “The real tragedy is that a lot of young psychiatrists have never learned to use lithium.”

Lithium, which can smooth out the highs and the lows of bipolar disorder, was first used in the 1950’s, and in the 1970’s was the first drug to be designated a “mood stabilizer” by the Food and Drug Administration. But the drug has been around for so long that its patent has expired and generic versions exist, meaning that lithium cannot generate substantial earnings for industry, Dr. Goodwin said. Drug companies promote newer, more profitable drugs like Depakote.

Some difficult cases referred to Dr. Goodwin turn out to be people who have never taken lithium because their psychiatrists, often under 40, never thought of prescribing it. But Dr. Goodwin also emphasized that lithium did not work for everyone and that other drugs like Depakote were also needed.

Dr. John Leonard, a spokesman for Abbott Laboratories, the maker of Depakote, questioned the findings. Dr. Leonard said that studies looking back at patients’ records were inherently flawed and not as reliable as studies in which patients were randomly assigned by researchers to take one drug or the other. He said conclusions could not be drawn from the data, and doctors should not base treatment decisions on it.

By Ross Grant
Health ScoutNews Reporter

Thomas Jefferson University
Philadelphia

Here is more evidence that there is significant brain alteration within brain cells in response to synthetic chemicals that change brain function in many unknown ways. Could these abnormal proteins that form in response to foreign chemicals that cross the blood brain barrier, be part of the mysterious amyloid deposits that are markers for Alzheimers Disease? An educated guess, from some observers who have noted a relationship between Alzheimer’s and people who have taken a lot of brain-altering drugs during their lifetimes, says yes. Has anybody else noticed such a connection? Until we have a long term study on that very question, the drug companies have to be up front and say that they don’t know if their particular synthetic chemical can cause Alzheimers or not. In the meantime, we should avoid taking their drugs until they can prove that they don’t have such long term adverse effects.

Adolescent Drug Use Creates Long-Term Imbalance
Even commonly prescribed amphetamines may lead to addictive behavior.

http://www.healthscout.com/template.asp?ap=43&page=newsDetail&id=510032

By Ross Grant
Health ScoutNews Reporter

Thomas Jefferson University
Philadelphia

Here is more evidence that there is significant brain alteration within brain cells in response to synthetic chemicals that change brain function in many unknown ways. Could these abnormal proteins that form in response to foreign chemicals that cross the blood brain barrier, be part of the mysterious amyloid deposits that are markers for Alzheimers Disease? An educated guess, from some observers who have noted a relationship between Alzheimer’s and people who have taken a lot of brain-altering drugs during their lifetimes, says yes. Has anybody else noticed such a connection? Until we have a long term study on that very question, the drug companies have to be up front and say that they don’t know if their particular synthetic chemical can cause Alzheimers or not. In the meantime, we should avoid taking their drugs until they can prove that they don’t have such long term adverse effects.

Drug use during adolescence, including such commonly prescribed drugs as Ritalin, may upset brain chemistry more than any other time in a person’s life, new research says.

The findings should help scientists better understand why addictions generally begin during adolescence, and what the long-term risks result.

“This is a major public health question,” says the lead researcher, Dr. Michelle Ehrlich, a neurology professor at Thomas Jefferson University in Philadelphia. “The adolescent brain appears to be more sensitive to certain effects of these psycho-stimulant drugs. We need to see whether this sensitivity leads to permanent brain changes and behavior changes.”

In the study, which just appeared in the Journal of Neuroscience, the researcher gave cocaine and amphetamine to groups of adult, adolescent and baby mice every day for a week. Then they compared the chemistry in two sections of the mice brains against that of a control group. Because mice have many of the same brain functions as humans, scientists believe the results should shed light on our brains, Ehrlich says. After taking the drugs, all the mice had elevated levels of an addiction-marking protein in the part of the brain that controls movement and hyperactivity. But adolescent mice also had high levels of the protein in the part of the brain that controls the “reward” mechanism.

Because of that chemical imbalance, adolescents may depend on drugs to stimulate their reward mechanism, leading to addictive behavior, Ehrlich says. Meanwhile, other studies have shown that the protein, called DeltaFosB, stimulates other chemical responses in the brain months after drug use has stopped, which may contribute to drug cravings.

“The implications are that there is an increased adaptation in the younger brain than in the older brain to these psycho-stimulants,” Ehrlich says. But Ehrlich isn’t worried only about the effects of illegal drugs. The same long-term changes in brain chemistry may also occur after adolescents take prescribed amphetamine.

“Amphetamine is one of the most commonly used drugs for attention deficit disorder. Ritalin is one of the most well-known ones,” Ehrlich says. “I prescribe these drugs. I work with children on these drugs. I’m not saying we shouldn’t use them, but we should know about their long-term effects.”

In some cases, the risks of prescribing amphetamine drugs are worthwhile, says Dr. Eric Nestler, chairman of the psychiatry department at the University of Texas Southwestern Medical Center. But Nestler, who was one of the first researchers to discover Delta FosB, says such drugs are prescribed too often, when the risks aren’t worthwhile.

“There has to be a concern,” he says. “Kids with attention deficit disorder are really impaired. A drug like Ritalin works well with those conditions, and to deny it to a kid who really need it is a disservice. The problem comes when the diagnosis of attention deficit disorder is made too frequently.”

So far, though, no one has studied whether Ritalin and other prescribed drugs raise the level of Delta FosB like cocaine and amphetamine, Nestler says. “That would be an interesting study,” he says.

Nestler says he is surprised that Erlich’s team didn’t see higher Delta FosB levels in both parts of the adult mouse brain. In his research, he found that both adolescent and adult mice have elevated levels, although he thinks he used a more sensitive method of detecting Delta FosB.

Still, if Ehrlich’s research shows that adolescents have a higher level of Delta FosB than do adults, it reveals key evidence about the addiction process, he says.

“This is the first finding to suggest that the adolescent brain is more sensitive. That is very interesting,” Nestler says. What To Do

To learn more about these drugs, visit this site at the California State University at San Marcos. Or for more information about how amphetamine is prescribed to treat attention deficit/hyperactivity disorder, try the National Center for Birth Defects and Developmental Disabilities. Copyright © 2002 ScoutNews, LLC. All rights reserved. Last updated 11/5/2002

Funny, I thought true sorrow included stopping the thing you are doing that
is wrong. Obviously it has never stopped. Only the names of the drugs have
changed. The standard practice remains the same: deny the truth, then hide
the evidence, then deny you knew what the outcome would be when you did know,
then fight the victims in court to avoid having to pay for what you did to
them and badger them enough so that they will drop their suit against you.

This is also a wake up call to the dangers of mad cow disease in this
country. Any blood product, which human growth hormone is, can carry this
disease. (Of course now that it is synthetically produced we are to believe
it is now safe.) The last mad cow (CJD) death in Utah was a young man who got
it from eating Elk that he had hunted. The CDC came into Utah to investigate
as they have thought the wild animals did not yet have the disease. There was
great alarm generated by the fact that this young father had given blood over
the years. As CJD lies dormant for many years before manifesting the
symptoms, they were afraid that several years down the road we would see many
more cases of mad cow due to the blood transfusions that came from this man’s
blood. Blood products of any kind are suspect.

Dr. Ann Blake Tracy, Executive Director,
International Coalition For Drug Awareness
www.drugawareness.org
______________________________

Sunday, May 21, 2000 | L A Times

A Wonder Drug That Carried the Seeds of Death

Human growth hormone held promise for thousands, but contamination of early
samples has been linked to a fatal disease. A purification method was known
but not used.

By EMILY GREEN, Times Staff Writer

In 1958, an American scientist managed to do what nature had failed to.
He made a dwarf grow. For the first time, man had harnessed human growth
hormone.

By 1963, while technically still an experimental drug, the hormone was
being supplied free of charge by the National Institutes of Health to
pediatricians across America. For the next 22 years, the drug was
administered to more than 8,000 stunted children.

It worked. The children grew–collectively, more than a mile. They went
on to become soldiers, doctors, journalists and secretaries. They married and
had children. But then, decades after taking the hormone, a small but steady
succession of recipients began to develop strange symptoms.

First they lost their balance. In the case of a 32-year-old foot surgeon
from Brooklyn, N.Y., Dr. Stacey Crair, she suddenly started toppling over. As
a child, Crair had received growth hormone treatment for 12 years.

Nearby on Long Island, a water safety engineer named Mike Nofi remembers
that his 30-year-old wife, Wendy, suddenly started feeling like “she was on a
boat.” She had received growth hormone for six years.

Soon they began to stagger and drool. Their personalities changed.
Within months they were in comas. Their brains were turning to sponge.

They had Creutzfeldt-Jakob disease, or CJD, a human variant of the
so-called mad cow disease. CJD is incurable. The agent that causes it is
unknown. How they got it, however, was clear. They had been infected by
contaminated hormone. Twenty other hormone recipients in the United States
have also died from CJD, and the toll continues to rise.

But the NIH has not apologized, or even helped with the care of victims.
Having investigated the debacle, the NIH has insisted for the last 15 years
that the deaths were unforeseeable.

“It was an experimental treatment, and people signed informed consents,”
NIH spokeswoman Jane Demouy said recently.

However, The Times has unearthed British court documents showing that
the deaths were not only foreseeable, they were foreseen. The NIH lab called
in to investigate the deaths in 1985 had been warned of the danger of
contamination seven years earlier.

Moreover, a body of research shows that a safer method for processing
the drug had been available from the inception of the program. But scientists
under contract to the NIH chose a cheaper, less labor-intensive method.

Shown the documents, Demouy said the NIH involvement was limited to
funding the program:

“Physicians around the country administered the hormone. Decisions
regarding the program were made more than 35 years ago, and the people
involved are deceased or retired. In 1985, when it was learned that three
patients who had received human growth hormone had contracted CJD,
distribution of human growth hormone [from cadavers] was ended.”

Plundering the Pituitary Gland

Today human growth hormone is synthetic, and safe. So it is easy to
forget how crude its early forms were–or that it was an important medicine.
A sign of how fast its development has been is that, at the turn of the 20th
century, the word “hormone” did not even exist. Endocrinology–the study of
the network of glands that produce hormones responsible for growth, sexual
maturation, reproduction and digestion–was a new science.

Early research was brutal but effective. Experimenting on animals,
mainly dogs, scientists in Europe and North America deduced what endocrine
glands did by surgically removing the organs and seeing what happened.
Usually the dogs died.

In 1921, a University of Toronto team found not only that removal of a
dog’s pancreas caused diabetes but also that injecting the dog with
pancreatic extract appeared to cure the disease. The extract contained the
lifesaving hormone insulin. Within a year, insulin from the pancreases of
cows was being injected into diabetic children. The first American recipient
went on to live to the age of 74
and came to describe the hormone as “unspeakably wonderful.”

Plundering the pituitary gland proved a good deal trickier. Located
behind the bridge of the nose, the bean-size organ was difficult to remove
without killing the test animal. By the 1950s, however, not only had
scientists managed this, but it had also become clear that the pituitary was
home to a complex cache of hormones governing growth, maturation and
reproduction.

The first pituitary hormone to receive the insulin-style extraction
treatment was human growth hormone. But unlike insulin from cattle, bovine
growth hormone had no effect on people. Scientists needed human pituitary
glands to make people grow. They would have to look to morgues.

In 1958, a Boston-based researcher named Maurice Raben at the Tufts
University School of Medicine produced another first. A 17-year-old boy, whom
Raben had experimentally injected with human growth hormone, grew 2.1 inches
in 10 months.

For parents of stunted children, this offered precious hope: Their
children might be spared lives as dwarfs.

But then they were asked to wait. Dwarfism wasn’t diabetes. It wasn’t
life-threatening. Unlike insulin, human growth hormone was not seen by drug
companies as commercially viable.

Almost immediately, the most enterprising parents enrolled their
children in small trials, very like the first Raben experiment. Even then
there were not enough pituitaries for steady production of the growth
hormone. Some parents turned organ scavengers, personally petitioning
hospitals and morgues for pituitary glands from cadavers.

By 1963, pressure from parents, pediatricians and endocrinologists had
become so intense that the NIH stepped in. It formed the National Pituitary
Agency out of Baltimore’s Johns Hopkins University. The agency would organize
collection and redistribution of the glands to three universities for
processing into growth hormone: Emory in Atlanta, Tufts in Boston and Cornell
in Ithaca, N.Y.

Soon, the NIH was guardian of a sweeping experimental drug trial. For 22
years, from 1963 to 1985, it supplied the hormone to 8,157 children
nationwide and to about 50 foreign-born children who came to America for
treatment.

For the first 14 of these years, the largest seat of hormone production
was at Emory, supervised by Alfred E. Wilhelmi. A former Rhodes scholar, he
was at the peak of a charmed career. He had received a doctorate from Oxford
University in England and taught at Yale before moving to Emory. Soon to
become president of the Endocrine Society, he was the NIH expert of choice.

But more advanced work was going on in Sweden, at the University of
Uppsala, where chemists had observed problems with the human growth hormone
being extracted using Wilhelmi’s method; it caused immune responses and was
far from pure.

The Swedes, by contrast, had developed a method to produce hormone that
was 95% pure. It did not spark immune response and appeared to be more potent
in inducing growth. The difference was part effort–the Swedes took a much
more labor-intensive approach to gland collection and storage–and part
technology–they filtered their drug using a process called Sephadex gel
filtration.

Wilhelmi chose not to use the filter.

“Wilhelmi’s philosophy was that the material was human protein, and
human protein cannot harm human beings,” said Albert Parlow, a
Harvard-educated biochemist who was at Emory at the time.

The result was that the NIH supplied thousands of American children with
a drug that could have been pure, but wasn’t. In 1969, Wilhelmi unveiled what
he described as an “improved method” for hormone extraction. But the
improvement was in yield, not purity. The resulting hormone was, Wilhelmi
wrote in the Journal for Clinical Endocrinology, “clinically useful and . . .
may be purified further for chemical use and immunochemical studies.”

Put more simply, this meant that Wilhelmi regarded the hormone as safe
for children but in need of further refinement for use in experiments.

Another believer in the acceptability of clinical grade hormone was Anne
Stockell Hartree, an American-born biochemist then on staff at Cambridge
University in England. She co-wrote the 1969 Wilhelmi paper announcing the
“improved” hormone and was using the method to process the hormone being
employed in an almost identical program in Britain.

By 1973, both Wilhelmi and Hartree were facing questions. A member of
the British hormone program’s steering committee raised concerns about the
safety of the drug.

Wilhelmi replied: “We have been preparing hGH since 1958 in increasing
quantities, and in all that time there has never been a complaint of that
kind of contamination. . . . We are presently going to modify our procedure
to include a step of filtration on Sephadex G-100, and this, I think, will
provide further assurance of removing virus from the system.”

The Times could find no record that Wilhelmi or Hartree ever used the
Swedish-style Sephadex filtering.

The method wasn’t officially adopted until after Wilhelmi’s retirement
in 1977. That year, the NIH put hormone production out to bid. The winner was
Parlow, by then a research professor of obstetrics and gynecology at the UCLA
School of Medicine. Written into his proposal was strict incorporation of
Swedish-style protocols.

The same year, British purification was moved from Hartree’s lab to one
that also began filtering the drug.

Even so, for the next seven years, Wilhelmi’s confidence in his method
seemed justified. As he had once observed to those questioning his methods,
nobody seemed to “have caught anything.”

Woman’s Death Sparks a Crisis

But in March 1984, in the English cathedral town of Winchester, that
changed. What began as an off day for a 22-year-old woman quickly escalated
into an international public health crisis.

Alison Lay, a secretary at a local Barclay’s bank, noticed that her
balance was unsteady. “She progressed from not being able to go to work,”
recalls her mother, Mavis Lay, “to not being able to feed herself and not
being able to walk without help.”

On Feb. 12, 1985, eight days short of her 23rd birthday, Alison Lay died
from CJD.

When she was 2, surgery to remove a brain tumor had also taken out her
pituitary gland. To compensate, between the ages of 10 and 14, she had
received more than 550 injections of human growth hormone.

Unbeknown to the Lays, CJD cases were also being recognized in young
people in the U.S.: a 22-year-old in Buffalo, a 34-year-old in Dallas, a
21-year-old in San Francisco. All had received human growth hormone.

CJD is among the rarest of diseases, striking about one in a million
people per year. It is rarer yet in the young. Of more than 3,000 cases
recorded in international literature, before 1985 only nine were in patients
younger than 30. The typical age was between 55 and 65.

But when autopsy results from the first four hormone recipients came in,
the average age was 25.

Alarms blared. After an urgent meeting on April 20, 1985, the NIH
suspended the National Pituitary Program. The anguished reaction of
University of Virginia pediatrician Robert Blizzard was typical. He wrote
British colleagues: “Just an hour ago I left a meeting at NIH and I am very
depressed. . . . I realize full well the implications of this worldwide–both
for investigators and for patients. The implications are tragic.”

By June, programs had been stopped in Belgium, Finland, Greece, the
Netherlands, Sweden, Britain and Australia. An estimated 27,000 children
worldwide had been given the drug. In the U.S., the Centers for Disease
Control and Prevention in Atlanta was brought in to track down the 8,157
American recipients.

Meanwhile, the NIH switched hats from overseer of the program to its own
accident investigator. Sponsor of the hormone program had been the National
Institute of Diabetes and Digestive and Kidney Diseases. Assessing the
disaster fell to a sister institute, the National Institute of Neurological
and Communicative Disorders.

A pediatrician there, Dr. Daniel Carleton Gajdusek, had received the
Nobel Prize for physiology or medicine in 1976 for his work on CJD. In 1968,
he had published in Science magazine an article showing that CJD was
transmissible through exposure to infected brain tissue.

However, the man who would lead the institute’s investigation was
Gajdusek’s colleague, Dr. Paul Brown, then establishing himself as a
world-class epidemiologist on the spread of CJD.

When the first CJD case appeared in a growth hormone recipient, Brown
thought it was a coincidence. Then, as other cases rolled in, he became
convinced that the hormone was the culprit. He began systematically testing
remaining stocks of the drug.

“One of the lots that was inoculated did in fact transmit disease to an
animal,” he told The Times.

It took Brown six years to publish an estimate of how many glands
infected with CJD might have entered the system. By 1991, the official
estimate was 140.

As shocking as this seems in retrospect, Brown takes pains to stress
that, at the time, too little was known about CJD. “Before 1985, nobody had
any idea it [the hormones] would be contaminated,” he said.

Veterinary Geneticist Raises the Alarm

That is where American knowledge stood for the next 15 years. It was
regrettable, but unavoidable. Nobody could have known.

Except, it emerges, someone did.

In reviewing the documents generated during the 1996 British human
growth hormone trial, The Times found a paper trail between the British
government and the NIH. Its existence had remained unknown in America and its
significance unrecognized in Britain.

The man who raised the alarm was not a Nobel laureate, not a
neurologist, but a specialist in an obscure disease of sheep: veterinary
geneticist Alan Dickinson, founder of the Neuropathogenesis Unit at the
University of Edinburgh in Scotland.

Dickinson specialized in the sheep form of CJD, called scrapie. In
decades of experimentally infecting mice with scrapie, he had observed that
the pituitary glands became both infected and infectious.

On Oct. 5, 1976, nine years before the first cases of CJD appeared,
Dickinson called to warn the British Medical Research Council of the danger
posed by its growth hormone program.

“My intrusion came after the sudden realization that they were using
human pituitaries,” he said.

But it was only four months later, after Gajdusek reported that CJD
could be spread by surgical instruments, that curiosity among the British
officials was roused. Even so, a member of the British pituitary program took
more than a year to write Gajdusek, seeking his opinion about Dickinson’s
warning. By then Gajdusek was traveling abroad.

On May 8, 1978, a visiting Australian pathologist named Colin Masters
answered on his behalf. Masters echoed Dickinson’s warning: “It would be
reasonable to expect that the pituitary gland and/or surrounding tissue taken
from a case of CJD disease would be contaminated with the virus.”

At Masters’ invitation, the British then forwarded the purification
protocols to the NIH for review. But there is no record that Masters ever
made good on his offer to evaluate either the Swedish or Wilhelmi methods for
their ability to remove CJD contamination.

And in spite of the now-acknowledged danger, neither the British nor the
Americans moved to exclude the use of glands from organ donors who had died
of CJD. Nor did Masters warn the NIH’s National Pituitary Program.

Masters subsequently returned to Australia, where he is now head of the
Australian National CJD Surveillance Unit at Melbourne University. Asked why
he did not relay the warning, he responded, “Presumably the people who were
running the pituitary programs should have been aware of the warnings that
were being sounded in the medical press.”

Both Brown and Masters were in Gajdusek’s lab at the NIH. But, while
Brown insists that the danger of CJD contamination was unforeseeable before
1985, to the mind of Masters, it was too obvious to mention.

By 1979, the British were worried enough to give Dickinson money to test
the Swedish protocol for its ability to eliminate CJD. Pituitaries were
deliberately infected, then purified and injected into test mice. The
Wilhelmi-Hartree method, however, was not tested. In 1982, Dickinson had his
answer: The Swedish method appeared to be safe.

The results were not published for three years. Both Dickinson and the
British hormone program sponsors were sensitive to the potential for a scare.
But in the wake of Alison Lay’s death in 1985, the results showing the
Swedish method’s safety were seen to have a calming effect. They were
published in the same issue of the Lancet as her case history.

The drug appeared safe for children, including 4,000 Americans, who had
received the drug after 1977, the year Parlow took over production and
insisted on the filtration.

The other roughly 4,000 American children treated before 1977 with
hormone from Emory, Tufts and Cornell no longer needed Dickinson to test the
drug on mice. They were the mice, and it was official: The drug was
potentially deadly.

After the Lancet report, in September 1985, Brown reported on the three
American deaths in the New England Journal of Medicine. America faced, Brown
wrote, the “ominous possibility of a burgeoning epidemic” of CJD.

Survivors Mired in Legal Battles

Public displays of concern about a potential epidemic of CJD were one
thing. Doing something to help the victims proved to be another. When Wendy
Nofi first descended into madness between July and November 1995, her
husband, Mike, sought assistance from the NIH. “I was in contact with the NIH
when she first got sick,” he said. “I told them I wanted to keep apprised. I
haven’t received one thing.”

The Crairs say they too were rebuffed. “We called the NIH to seek help,
but we received no counseling, no support whatsoever,” said Stacey’s sister,
Lisa Crair. “At first we couldn’t even get a doctor who would take Stacey
on.”

By 1996, Gajdusek’s lab was in turmoil. In March, as the laureate
addressed a scientific meeting in Europe, the mad cow crisis erupted in the
Britain. The next month, Gajdusek was arrested in Maryland on charges of
child molestation. Found guilty in April 1997, he served a year of an
18-month sentence and then left for France.

Mike Nofi had his wife placed on a feeding tube in a rest home. It took
her 2 1/2 years to die. The Crairs nursed Stacey at home for four years.

Both Lisa Crair and Mike Nofi are now lost in legal battles that they
say they neither relish nor understand. Crair’s lawsuit has been thrown out
of court over legal technicalities in three states where the hormone was
processed. Nofi has been given leave in New York state courts to sue numerous
doctors, technicians and every university that handled the hormone–even
Parlow’s UCLA lab, the very place that in 1977 cleaned up the hormone.

But Nofi is not suing the NIH. According to Pamela Liapakis, former
president of the Assn. of Trial Lawyers of America, the agency enjoys what
the legal profession calls “sovereign privilege” and is exceedingly difficult
to sue under federal tort law.

In Britain, however, outraged families did sue the government. In 1990,
an English lawyer named David Body tracked Dickinson down in a drafty stone
house outside Edinburgh, where he had been living in retirement for three
years. Body then represented three of what are now 34 families of British
hormone victims. He was going to try something nobody had ever done
successfully in Britain: sue the Department of Health in a personal injury
case.

He needed an expert witness. After interviewing Dickinson, Body realized
that he could “never put him on the stand.”

The scientist was frail and prone to severe migraines. But he typed out
a statement that both outlined the state of knowledge about CJD 25 years ago
and recounted his 1976 warning about the risk of contamination. In July 1996,
the court decided against the British government to the tune of more than
$7.5 million. Anyone treated with the potentially contaminated hormone after
Dickinson’s warning was issued would be compensated. Damages are now even
going to the “worried well.”

Although Alison Lay’s death sparked the 1985 crisis in Britain, her
parents were excluded from the settlement, because their daughter was treated
before Dickinson sounded the warning.

“At least in this country we did have the trial,” said Mavis Lay. “And
the government admitted that it was at fault and caused the deaths.’

By the time of the trial, Hartree had returned home to Nashville. She
refuses all contacts with the media, lawyers and hormone recipients. In her
absence, the British judge concluded that Hartree’s failure to use Sephadex
was, by analogy, “a commercial decision: quantity before quality.”

The court stopped short of finding the government negligent in the
preparation of the hormone. “In the English claims, the issue of purification
became secondary to the policy failures,” said Body. “I’d like to see
purification explored further in the United States.”

The more time that passes, the more difficult this will be. In 1994, at
the age of 84, Wilhelmi died at his home in Atlanta.

However, Parlow, his former colleague who upgraded the purity of the NIH
hormone, said clear “warning bells” were ignored. Describing the early
hormone, he said, “It was painful on injection. This signaled impurities.”

That was confirmed by a second side effect. “Ten to 15% of the kids
treated developed antibody formation,” said Parlow. “Though this is not
life-threatening, it is not a good thing, and it means that there is
something wrong with the product.”

In addition to the 22 Americans who have died from Wilhelmi-era hormone,
CJD has killed five New Zealanders and one Brazilian who received pre-1977
American hormone. In Britain, 34 people have died, and the global toll stands
at more than 125. The Centers for Disease Control says the rate of CJD cases
among hormone recipients worldwide is increasing.

Tracing the Growth Hormone

* * *
1901-05: The word “hormone” coined

* * *
1921: Creutzfeldt-Jakob disease (CJD) discovered in Germany.

* * *
1925-45: Growth and reproductive hormones found in the pituitary glands
in the brains of animals

* * *
1958: Maurice Raben at Tufts University School of Medicine in Boston
spurs 2.1 inches of growth in a dwarf by injecting him with human growth
hormone extracted from pituitary glands taken from the brains of cadavers

* * *
1963: The National Institutes of Health takes up sponsorship of the
National Pituitary Program.

The largest seat of production is the lab of Alfred E. Wilhelmi, head of
the biochemistry department at Emory University in Atlanta. Swedish
scientists notice that American growth hormone causes immune reactions and
publish an alternative method for making the drug.

* * *
1968: NIH doctor Daniel C. Gajdusek writes in Science magazine that CJD
is transmissible via infected brain tissue. *

* * *
1976: Edinburgh-based veterinary geneticist Alan Dickinson warns the
British government that its pituitary program might spread CJD.

* * *
1977: Wilhelmi retires. The NIH moves production of human growth hormone
to the UCLA lab of Albert Parlow, who begins filtering the drug. The British
hormone program also switches from the Wilhelmi protocol to the Swedish
extraction method.

* * *
1978: Dickinson’s fears of CJD contamination in the hormone are passed
to Gajdusek’s lab at the NIH. In May, a visiting Australian pathologist
replies on NIH letterhead that pituitary glands could be contaminated with
CJD. But he does not pass the warning to the NIH’s own pituitary program. *

* * *
1985: Alison Lay, a hormone recipient, dies in Britain. Three
unidentified American recipients also die. The NIH suspends the human growth
hormone program. Paul Brown of Gajdusek’s lab is called in to investigate. He
warns of a potential “epidemic” of CJD.

* * *
1991: Brown and others report in the Journal of the American Medical
Assn. that 8,157 American children received the drug and that as many as 140
glands infected with CJD may have entered the system.

* * *
1996: A class-action lawsuit on behalf of hormone recipients is brought
against the British government. A London high court awards the plaintiffs
$7.5 million.

* * *
2000: The CJD death toll among American recipients of pre-1977
unfiltered hormone stands at 22. The Centers for Disease Control and
Prevention in Atlanta reports that the incidence of CJD in hormone recipients
is rising from one case a year to two.

* * *

Failed Warnings

NIH epidemiologist Paul Brown was called in by the human growth hormone
program to investigate CJD contamination in 1985. Since then, he has
insisted,”Before 1985, nobody had any idea it [the hormone] would be
contaminated.” But newly discovered letters show that in 1978, a colleague in
Brown’s own lab acknowledged the danger and failed to alert the hormone
program.

* * *
Letter to British government acknowledging danger in 1978.

* * *
Robin Mayper in the Times library contributed to this story.

Search the archives of the Los Angeles Times for similar stories about:
National Institutes Of Health, Medical Research, Experiments, Drugs, Medical
Treatments, Human Growth Hormone, Creutzfeldt Jakob Disease, Health Hazards.
You will not be charged to look for stories, only to retrieve one.

Please note that I have highlighted the statement about Dr. Angell leaving
the New England Journal of Medicine as a doctor with very close ties to the
pharmaceutical companies comes in to replace her as the journal’s editor. So
much for any honesty coming from the New England Journal of Medicine now. As
Dr. Angell leaves her prestigious post she is basically airing the industry’s
dirty laundry. The subject of her article that follows this e-mail is Dr.
Bodenheimer’s journal article mentioned below – a long needed followup to Dr.
Seymour Fisher’s classic article, “Hanky Panky in the Pharmaceutical
Industry.” (Dr. Fisher’s article has been posted at www.pssg.org if you would
like to read it.)

Free speech? Protection from conflicts of interest that could cost consumers
their lives? You will not fine either in this industry! Clearly patients need
to understand that medicine in America has become just another very big
business.

Dr. Ann Blake Tracy, Executive Director,
International Coalition for Drug Awareness
www.drugawareness.org
________________________________

http://www.drkoop.com/news/stories/may/r/trials_money.html

Profit Motive Creates Conflicts in Drug Trials

May 21, 2000

Reuters Health Information

NEW YORK — Pharmaceutical companies that pay researchers to design and
interpret drug trials sometimes spin or suppress unfavorable findings, The
New England Journal of Medicine reported on Wednesday.

The scathing new report discusses tactics used to mask negative results and
warns that the profit motive of commercial research outfits threatens to
further corrupt the high-stakes process of translating science into
marketable drugs.

The report, “Uneasy Alliance — Clinical Investigators and the
Pharmaceutical Industry,” was written by Dr. Thomas Bodenheimer of the
University of California at San Francisco (UCSF) School of Medicine.

Bodenheimer’s interviews with people involved in the drug trial process
highlight the conflicts that arise in the process of
testing new drugs and publishing those results.

An accompanying editorial by Dr. Marcia Angell, the journal’s editor,
picks apart the cozy relationship that has developed between clinical
researchers and industry.

“Academic institutions and their clinical faculty members must take care
not to be open to the charge that they are for sale,” she writes.

The articles come a week after the peer-reviewed journal’s publisher,
the Massachusetts Medical Society, announced that it had named Dr. Jeffrey M.
Drazen, a prominent asthma researcher with strong ties to the drug industry,
as its new editor. He replaces Angell, who will be retiring.

Jeffrey Trewhitt, a spokesperson for the drug industry’s lobbying
group, the Pharmaceutical Research and Manufacturers of America, told
Reuters that “the articles overlook many safeguards in the system, including
the fact that the FDA (US Food and Drug Administration) reviews all the study
data.”

Trewhitt said that the FDA issued financial disclosure rules 18 months
ago “and they help to avoid conflicts of interest.” But six investigators
interviewed by Bodenheimer cited cases in which a sponsor actually halted
publication or altered a report’s content.In one instance, Dr. Steven
Cummings, professor of medicine and epidemiology at University of California,
San Francisco, said that a company held up the prepublication review process
for more than 6 months, secretly penning a competing article that favored the
company’s point of view.

Another investigator who found adverse reactions while studying a drug
was told by the sponsor that it would never fund his research again. It
published a competing article that barely mentioned the adverse reactions.

Critics have long questioned the integrity of drug research funded by
the pharmaceutical industry. But Bodenheimer warns of a deepening conflict as
more and more of those studies are farmed out to commercial research outfits.

When academia conducts drug studies, there is at least the potential
that researchers’ scientific goals will offset the pharmaceutical industry’s
commercial interests, he notes. “In contrast, trials conducted in the
commercial sector are heavily tipped toward industry interests, since
for-profit CROs (contract-research organizations) and SMOs (site-management
organizations), contracting with industry in a competitive market, will fail
if they offend their funding sources,” he argues.

Bodenheimer’s article recalls the time Dr. Curt Furberg, a professor of
public health sciences at Wake Forest University School of Medicine, refused
to place his name on published results of a study because the sponsor was
“attempting to wield undue influence on the nature of the paper.” Furberg
describes the effort as “so oppressive that we felt it inhibited academic
freedom.”

Furberg noted, “Companies can play hardball, and many investigators
can’t play hardball back. You send the paper to the company for comments, and
that’s the danger. Can you handle the changes the company wants? Will you
give in a little, a little more, then capitulate? It’s tricky for those who
need money for more studies.”

SOURCE: The New England Journal of Medicine 2000;342:1539-1544, 1516-1518.

A BOSTON GLOBE EDITORIAL

Better drug reporting deal with a wide range of conditions, from depression
to osteoporosis, doctors are reaching increasingly for their prescription
pads. Patients who consume these drugs have faith that any side effects other
patients have had are carefully reported by physicians and monitored by
officials so that, if need be, warnings can be issued.

That faith is misplaced.

While the drug companies and the US Food and Drug Administration have a
system for maintaining an adverse-event database, doctors are not required to
report the serious problems patients have with a drug. As a result, there are
distinct limitations in the system to track bad reactions and then add new
warnings on the drug’s label or withdraw it altogether. Public Citizen, a
watchdog group in Washington, D.C., reports that actual surveys of medical
records turn up 10 times as many drug reactions as are reported voluntarily
by doctors.

Under current practices, drug companies are required to alert the FDA within
15 days of any severe reactions to drugs and within a year of less serious
reactions, but without more mandatory reporting by practitioners (hospitals
and nursing homes are required to make such reports), companies’ own
awareness of problems will be stalled.

If reporting by doctors of bad reactions were mandatory, both the FDA and Eli
Lilly and Co. would know more than they do about some of the problems
connected with Lilly’s popular antidepressant, Prozac. While Prozac and
similarly acting drugs have been hailed by both doctors and patients for
relieving symptoms that can often presage suicide, there have long been
reports of extreme agitation and anxiety among a small percentage of users.

One argument against mandated reporting of adverse reactions from doctors is
the extra paperwork this would entail. But, for the past several years, the
FDA has maintained a Web site that permits doctors – and patients – to make
online reports with little fuss. Closer monitoring could give both health
professionals and the public a greater awareness of what to be alert for as
they make use of the drugs that are changing American medicine.

By Jessie Seyfer
The Associated Press

S A N F R A N C I S C O, May 5 — Pharmaceutical maker
Genentech Inc. has warned doctors that the breast cancer drug
Herceptin is linked to 15 deaths and 47 other adverse reactions
in patients.

In a letter to doctors sent Thursday, the company said the
adverse effects included allergic shock and extreme respiratory
distress.

“We sent the letter to oncologists to heighten their awareness
and educate them about infrequent adverse events that can
occur in certain patients,” Genentech spokesman Neil Cohen
said.

An estimated 23,000 patients have been treated with Herceptin.

Severe Reactions
Severe reactions to Herceptin had not occurred in clinical trials
before the drug gained Food and Drug Administration approval
in 1998, Cohen said.

But sometimes reactions can’t be foreseen in trials, he said.

“A lot of times you might see some safety issues once the drug
gets put into a larger patient population,” Cohen said.

Cohen said he didn’t know when the company first heard of the
deaths and reactions, but analysis had confirmed the link to
Herceptin.

Symptoms Seen Within 24 Hours
In nine of the 15 deaths, symptoms arose within 24 hours of the
time Herceptin was administered, according to the letter.

Genentech is working with the FDA to have the drug’s label
amended to reflect the new risks, Cohen said.

Herceptin is used to treat breast cancer patients that have too
many copies of the HER2 gene. A healthy version of this gene
produces a protein that signals cells to grow and multiply
normally. But in women with too much HER2, the breast cells
reproduce out of control and spread throughout the body.
Herceptin, an antibody, blocks excess HER2, shrinking and
eliminating tumors.

Copyright 2000 The Associated Press. All rights reserved. This
material may not be published, broadcast, rewritten or
redistributed.

http://www.abcnews.go.com/sections/living/DailyNews/breastca

ncer_drug0505.html