Science Refutes Claims of Drug Benefit: Antipsychotics Found Harmful_NEJM

"The sky is falling" as science blows away psychiatry’s house of cards. The scientific evidence refutes psychiatry’s claims about the "safety and efficacy" of the new generation neuroleptics (a.k.a. atypical antipsychotics). Those claims are not based on scientific evidence, but rather on drug manufacturers’ marketing hype. The wide dissemination of that hype–both in the lay press and the scientific journals–succeeded in deceiving physicians, mental health providers, insurance companies, and the public alike.

The latest scientific analysis reported in The New England Journal of Medicine (abstract below) from a government sponsored comparison study involving 421 Alzheimer patients who were randomly prescribed either one of three popular atypicals or placebo, shows that after 12 weeks the drugs-Eli Lilly’s Zyprexa (olanzapine), Johnson & Johnson’s Risperdal (risperidone), AstraZeneca’s  Seroquel (quetiapine)-were ineffective in controlling agitation and aggression. However, the drugs produced toxic adverse effects.

The front page article in The New York Times states:
"The drugs most commonly used to soothe agitation and aggression in people with Alzheimer’s disease are no more effective than placebos for most patients, and put them at risk of serious side effects, including confusion, sleepiness and Parkinson’s disease-like symptoms, researchers are reporting today."

Benedict Carey correctly notes that this is not the only group of patients who are exposed to these drugs’ hazard without demonstrating any of the benefits that psychiatry’s leading spokespeople had claimed. Readers are reminded that: "The report is the third large study in the last year to conclude that atypical antipsychotics are not as effective or as safe as initially portrayed. Last year, government researchers found that three of four drugs tested were no more effective than an older, far less expensive drug in treating schizophrenia – the disorder for which the medications were originally approved.  And last week, English researchers published a study that found that schizophrenia patients did as well on older medications – or better – than on newer, atypical drugs."

Indeed, the incontrovertible evidence from controlled clinical trials has proven that these widely prescribed drugs-recommended as first line treatments-present a very unfavorable risk / benefit ratio for patients.Inasmuch as its professional prescribing practices and treatment recommendations are contraindicated by evidence of harm without benefit, the credibility of psychiatry as a medical profession collapses.

To appreciate the success of this multi-billion dollar profit making deception one must examine the intricate web of interconnections among the financially invested stakeholders. First and foremost, is the inordinate control wielded by the manufacturers of these drugs whose money buys influence. The drug industry exerts inordinate influence on FDA’s drug approval process which is designed to err on the side of industry. Did FDA reviewers miss the fact that the new neuroleptic drugs failed to demonstrate efficacy? In point of fact they did not. FDA’s letter of approval to Janssen, signed by Dr. Robert Temple, deputy director of the Center for Drug Evaluation (CDER) underscores the drug’s failure to demonstrate either superior safety or effectiveness:
"We would consider any advertisement or promotion labeling for Risperdal false, misleading.under section 502(a) and 502 (n) of the ACT if there is presentation of data that conveys the impression that Risperdal is superior to haloperidol or any marketed antipsychotic drug product with regard to
safety or effectiveness."

Safety, however, appears not have been a concern for the FDA. Absent any evidence of efficacy, how could FDA officials disregard the documented
signals of severe adverse effects that were present in the data submitted tothe FDA from company controlled premarketing trials? In his book, Mad in
America, Robert Whitaker, warned that those early signals of toxicity represent major health hazards. Those hazards cannot be justified in the absence of a demonstrable clinical benefit.

Through their immense financial support of  psychiatry’s professional associations (American Psychiatric Association, the American College of Neuropsychopharmacology, American Academy of Child and Adolescent Psychiatry, etc.); its key opinion leaders (KOLs) in academia, and state and
federal government agencies that set public policy and budget allocations, industry has been able to orchestrate and control the entire process.

Dr. Thomas R. Insel, director of the National Institute of Mental Health, which financed the research, said, "What this study shows is that these drugs are clearly not the answer; they may be helpful for a minority of patients but we need to come up with better medications."

The authors of the NEJM study caution:
"Clinicians and caregivers would do well to deal with such potential triggers of agitation before considering antipsychotic medication."

The FDA whose mission is to protect the public health from hazardous drugs demonstrates once again, its utter disregard for drug safety when it approved Risperdal for the treatment of aggression in autistic children. This label change was made without so much as an advisory panel hearing. It
will open the floodgates for increased exposure of children to the lethal hazards of antipsychotic drugs.
 
Below is a letter describing one child’s experience when prescribed Risperdal for autism.

Contact: Vera Hassner Sharav
veracare@ahrp.org
~~~~~~~~~~~~~~~~~~~~~~~~

http://content.nejm.org/cgi/content/short/355/15/1525
NEW ENGLAND JOURNAL OF MEDICINE
Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer’s Disease
Lon S. Schneider, M.D., Pierre N. Tariot, M.D., Karen S. Dagerman, M.S., Sonia M. Davis, Dr.P.H., John K. Hsiao, M.D., M. Saleem Ismail, M.D., Barry D. Lebowitz, Ph.D., Constantine G. Lyketsos, M.D., M.H.S., J. Michael Ryan, M.D., T. Scott Stroup, M.D., David L. Sultzer, M.D., Daniel Weintraub, M.D., Jeffrey A. Lieberman, M.D., for the CATIE-AD Study Group

ABSTRACT
Background Second-generation (atypical) antipsychotic drugs are widely used
to treat psychosis, aggression, and agitation in patients with Alzheimer’s
disease, but their benefits are uncertain and concerns about safety have
emerged. We assessed the effectiveness of atypical antipsychotic drugs in
outpatients with Alzheimer’s disease.
Methods In this 42-site, double-blind, placebo-controlled trial, 421
outpatients with Alzheimer’s disease and psychosis, aggression, or agitation
were randomly assigned to receive olanzapine (mean dose, 5.5 mg per day),
quetiapine (mean dose, 56.5 mg per day), risperidone (mean dose, 1.0 mg per
day), or placebo. Doses were adjusted as needed, and patients were followed
for up to 36 weeks. The main outcomes were the time from initial treatment
to the discontinuation of treatment for any reason and the number of
patients with at least minimal improvement on the Clinical Global Impression
of Change (CGIC) scale at 12 weeks.

Results There were no significant differences among treatments with regard
to the time to the discontinuation of treatment for any reason: olanzapine
(median, 8.1 weeks), quetiapine (median, 5.3 weeks), risperidone (median,
7.4 weeks), and placebo (median, 8.0 weeks) (P=0.52). The median time to the
discontinuation of treatment due to a lack of efficacy favored olanzapine
(22.1 weeks) and risperidone (26.7 weeks) as compared with quetiapine (9.1
weeks) and placebo (9.0 weeks) (P=0.002). The time to the discontinuation of
treatment due to adverse events or intolerability favored placebo. Overall,
24% of patients who received olanzapine, 16% of patients who received
quetiapine, 18% of patients who received risperidone, and 5% of patients who
received placebo discontinued their assigned treatment owing to
intolerability (P=0.009). No significant differences were noted among the
groups with regard to improvement on the CGIC scale. Improvement was
observed in 32% of patients assigned to olanzapine, 26% of patients assigned
to quetiapine, 29% of patients assigned to risperidone, and 21% of patients
assigned to placebo (P=0.22).
Conclusions Adverse effects offset advantages in the efficacy of atypical
antipsychotic drugs for the treatment of psychosis, aggression, or agitation
in patients with Alzheimer’s disease. (ClinicalTrials.gov number,
NCT00015548 [ClinicalTrials.gov] .)

Source Information
>From the Keck School of Medicine, University of Southern California, Los
Angeles (L.S.S., K.S.D.); the Banner Alzheimer’s Institute, Phoenix, AZ
(P.N.T.); Quintiles, Research Triangle Park, NC (S.M.D.); the National
Institute of Mental Health, National Institutes of Health, Bethesda, MD
(J.K.H.); the University of Rochester Medical Center, Rochester, NY (M.S.I.,
J.M.R.); the School of Medicine, University of California, San Diego, La
Jolla (B.D.L.); the Department of Psychiatry, Johns Hopkins Bayview, Johns
Hopkins University, Baltimore (C.G.L.); the School of Medicine, University
of North Carolina at Chapel Hill, Chapel Hill (T.S.S.); Veterans Affairs
Greater Los Angeles Healthcare System, University of California, Los
Angeles, Los Angeles (D.L.S.); the School of Medicine, University of
Pennsylvania, Philadelphia (D.W.); and the College of Physicians and
Surgeons, New York (J.A.L.).

Address reprint requests to Dr. Schneider at the Keck School of Medicine,
University of Southern California, 1510 San Pablo St., HCC 600, Los Angeles,
CA 90033, or at lschneid@usc.edu
—————————————————————

From: GloriaBer@aol.com [mailto:GloriaBer@aol.com]
Sent: Tuesday, October 10, 2006 6:05 AM

In summer of 2000, about to enter the second grade, my son Adam was
prescribed Risperdal. (At that time we knew something was going on, but his
Autism was not diagnosed until 2004.) His psychiatrist told me there was a
chance he might get Tardive Dyskinesia, but that if I noticed any tics, we
would just take him off the Risperdal and they would go away.

For the first few months, it worked wonders, though there was a tremendous
weight gain. He was docile, which was a welcome change.  Within a few months
though,  I noticed an increase in agitation and aggression, beyond the
levels which he displayed pre-Risperdal. I also noticed that he constantly
jerked his head up and down, violently and incessantly. In addition his body
would jerk at times.

At our next meeting, his psychiatrist informed me that this was a
manifestation of Tardive Dyskinesia, and she informed me at that time that
it was permanent, and might lessen, but would never go away entirely. Her
attitude was something along the lines of "well that’s the price you have to
pay".

Naturally I was devastated. I immediately weaned him off the Risperdal. At
once his behavior calmed, and though the tics continued full blown for the
next year or so, I was relieved to see that they lessened considerably as
time went on. It terrifies me to think of what would have happened had I not
stopped the Risperdal right away. Children with Autism have enough
differences from other people without tics being added to their problems.

It is now October of 2006. I am happy to say that my son never went back on
any medication after 2000. Instead I focused on behavior modification and
other non-drug treatments. He is a polite, intelligent boy, able to function
in any setting. He occasionally gets frustrated but now handles it without
flying off the handle. His tics are barely noticeable now.

I am writing this today because I just found out that the FDA approved
Risperdal, (also known as  Risperidone, Belivon, Rispen) for use on children
with Autism. Nowhere do I see mentioned the risks involved. Nowhere do I see
mentioned the risk of damage to the kidneys if not carefully monitored.
This is a neuroleptic, an anti-psychotic drug. In many cases it causes TD,
which is defined as: "A chronic disorder of the nervous system characterized
by involuntary jerky movements of the face, tongue, jaws, trunk, and limbs,
usually developing as a late side effect of prolonged treatment with
antipsychotic drugs."

A study in the June 2006 edition of the journal Pharmacotherapy has
highlighted a possible link between risperidone and pituitary tumors. The
study examined the FDA’s Adverse Event Reporting System database and found
77 pituitary tumors associated with antipsychotics. Of these, risperidone
was associated with 54 (70%).
Many children balloon up, and never lose the weight. My son still has a lot
extra weight. This drug should not be used on children with Autism, ever.

Christina Ouillette
~~~~~~~~~~~~~~

http://www.nytimes.com/2006/10/12/health/12dementia.html
THE NEW YORK TIMES
October 12, 2006
Alzheimer’s Drugs Offer No Help, Study Finds
By BENEDICT CAREY

The drugs most commonly used to soothe agitation and aggression in people
with Alzheimer’s disease are no more effective than placebos for most
patients, and put them at risk of serious side effects, including confusion,
sleepiness and Parkinson’s disease-like symptoms, researchers are reporting
today.

The report, based on a large government comparison of the drugs’
effectiveness, challenges current practice so sharply that it could quickly
alter prescribing habits, some experts said. About 4.5 million Americans
suffer from the progressive dementia of Alzheimer’s disease, and most
patients with the advanced disease exhibit agitation or delusions at some
point.
The drugs tested in the study – Zyprexa from Eli Lilly; Seroquel from
AstraZeneca; and Risperdal from Janssen Pharmaceutical – belong to a class
of medications known as atypical antipsychotics. The drugs are used to treat
schizophrenia and other psychoses, and are commonly prescribed for elderly
patients in long-term care facilities.

About a third of the estimated 2.5 million Medicare beneficiaries in nursing
homes in the United States have taken the medications, researchers found.
And the use of atypical antipsychotics in the elderly accounts for an
estimated $2 billion in the annual sales of the drugs, much of the cost paid
by Medicare and Medicaid.

Spokesmen for Lilly, AstraZeneca and Johnson & Johnson, which owns Janssen,
noted that the drugs were not approved by the Food and Drug Administration
for use in Alzheimer’s patients, and that the companies did not market them
for that purpose.

The results of the study, published today in The New England Journal of
Medicine, simply reflected the need for more research into the treatment of
behavioral problems in Alzheimer’s patients, the spokesmen said.

Prescribing information for the drugs warns that patients with
Alzheimer’s-related psychosis "are at increased risk of death compared to
placebo."
But the medications are commonly prescribed for Alzheimer’s patients "off
label" by doctors because families are desperate, because these drugs
sometimes seem to help, and because company-sponsored doctors promoted them.

"The question is whether these drugs have a place in the treatment of
Alzheimer’s patients at all," said Dr. Jason Karlawish, an associate
professor of medicine at the University of Pennsylvania who wrote an
editorial accompanying the study. "I think the answer is yes, but only for a
subgroup of patients who can tolerate them, and in facilities that have the
expertise to manage the side effects."
In the study, researchers followed 421 Alzheimer’s patients with disabling
agitation, delusions or hallucinations who were randomly assigned to receive
either dummy pills or one of the three antipsychotic drugs. Doctors adjusted
the doses as needed, tracked how long they stayed on the drugs, and noted
their improvement, if any.

Experts say that the amount of time a patient spends on a medication is an
important measure of its usefulness, because patients often stop taking a
drug if it is not doing any good or if the side effects are intolerable.
After 12 weeks, "there were no significant differences between the groups
with regard to improvement" on a scale that measured symptom relief, said
Dr. Lon S. Schneider, professor of psychiatry, neurology and gerontology at
the University of Southern California School of Medicine, and the lead
author of the study.
The researchers also found no significant difference in the amount of time
the patients stayed on the drugs or the placebos; about 80 percent stopped
taking the drugs and the placebos alike before the end of the study. But
those on the drugs were far more likely to quit because of side effects.

The side effects included sedation in 15 percent to 24 percent of the
patients, and confusion in 6 percent to 18 percent; both symptoms can
increase the risk of falls. And 12 percent of the patients on either Zyprexa
or Risperdal experienced Parkinson’s-like symptoms, including tremors.
"What the study does indicate is that this is a very sensitive population
and that any treatment needs to be done with a lot of forethought and
constant reevaluation" said Dr. Bruce J. Kinon, a Lilly psychiatrist.

Dr. Thomas R. Insel, director of the National Institute of Mental Health,
which financed the research, said, "What this study shows is that these
drugs are clearly not the answer; they may be helpful for a minority of
patients but we need to come up with better medications."

Dr. Gary Kennedy, director of geriatric psychiatry at Montefiore Medical
Center in the Bronx, said that the results gave psychiatrists the first
clear picture of what many had observed in their practices: that improvement
on the drugs is usually modest at best, and that behavior and environment
are often more important in managing combative behaviors.
"Oftentimes the family is unwittingly provoking the agitation," Dr. Kennedy
said.

A demented, confused person, he noted, can become suddenly aggressive over
seemingly trivial things, like a change in daily routine or feeling crowded
or rushed. "Working on these kinds of behavioral factors should always be
the first line of treatment," Dr. Kennedy said.

The report is the third large study in the last year to conclude that
atypical antipsychotics are not as effective or as safe as initially
portrayed. Last year, government researchers found that three of four drugs
tested were no more effective than an older, far less expensive drug in
treating schizophrenia – the disorder for which the medications were
originally approved.
And last week, English researchers published a study that found that
schizophrenia patients did as well on older medications – or better – than
on newer, atypical drugs.

Copyright 2006 The New York Times Company

http://www.washingtonpost.com/wp-dyn/content/article/2006/10/11/AR2006101101595_pf.html
Washington Post 
Little Benefit Seen in Antipsychotics Used in Alzheimer’s
By Shankar Vedantam
Thursday, October 12, 2006; A09

Antipsychotic drugs that are widely used to calm agitated patients with
Alzheimer’s disease help very few of them, and those modest benefits are
canceled out by the frequent side effects, a comprehensive government-funded
study has found.

The surprising finding is expected to trigger a broad reevaluation of the
widespread use of the drugs in patients with Alzheimer’s and other forms of
dementia. As many as a quarter of the Alzheimer’s patients in nursing homes
are prescribed the powerful drugs, even though they have never been formally
approved for this purpose.
"I wish I could say the odds are better," said Thomas R. Insel, director of
the National Institute of Mental Health, which funded the $17 million study.
"This paper says most people are not going to be any different on these
drugs than they would on placebo."

The researchers did not conclude that the drugs should never be used, and a
minority of patients do benefit. But the study suggests that doctors would
be well advised to prescribe the drugs sparingly and as a last resort,
experts said.

The study is the latest to produce sobering data on the newer, expensive
antipsychotics such as Zyprexa, Risperdal and Seroquel, which are among the
most widely prescribed drugs in the United States at an annual cost of about
$10 billion. Another government-funded study recently showed that the drugs
were no better than an older and much cheaper drug called perphenazine in
the treatment of schizophrenia.

Taken together, the government-sponsored clinical trials have highlighted
two troublesome issues in the regulation and use of psychiatric medications
in the United States.
The schizophrenia study showed that the short-term trials that
pharmaceutical companies sponsor to gain Food and Drug Administration
approval have limited value in telling doctors how patients will fare
overall, or whether newer drugs are worth their higher cost.

The Alzheimer’s study has revealed a different problem — the extent to
which physicians are prescribing and using medications in the absence of
empirical data to guide them. None of the antipsychotic drugs is currently
approved for Alzheimer’s disease, and several short-term industry-sponsored
clinical trials have failed to show a benefit. The FDA has required
prominent "black box" warnings on the drugs’ labels about side effects in
elderly people following cases where the drugs were associated with strokes
and death.

"Clearly the drugs cannot be cost-effective, because there is nothing to
choose between drugs and placebo," said Lon Schneider, the lead author of
the new study published today in the New England Journal of Medicine. "Most
patients are not benefiting."

Insel, Schneider and Jason H.T. Karlawish, an Alzheimer’s expert at the
University of Pennsylvania who wrote a commentary about the new study, said
it also underscores the desperate need to develop better treatments for
Alzheimer’s patients who are agitated or psychotic.

About 5 million Americans suffer from dementias, including Alzheimer’s, and
large numbers of them experience periods of agitation and psychotic symptoms
that are extremely debilitating for them, their caregivers and medical
facilities.
"You can’t respond to agitation by saying ‘Here is some olanzapine,’ " said
Karlawish, referring to the drug sold under the brand name Zyprexa. "The
question is, why is there agitation?" Such symptoms could be the result of
overstimulation, sleep deprivation, untreated pain, moving to a new
environment or dehydration, the experts said.

Like young children, patients with dementia can also be set off by a
conversation that normal adults brush off or find routine. Karlawish
suggested that this could be because dementias affect the frontal lobe of
the brain, which plays an important role in judgment and self-control.

"Any good parent knows there are effective and ineffective ways to respond
to their 4-year-old," Karlawish said. Similarly, he said, "there are
effective and non-effective ways to respond to someone with frontal-lobe
damage."

Clinicians and caregivers would do well to deal with such potential triggers
of agitation before considering antipsychotic medication, Schneider agreed.
The drugs might be useful in patients who continue to have agitation and
breaks with reality despite such efforts, but Schneider cautioned that the
drugs ought to be prescribed for limited periods and stopped if side effects
emerge. Those effects include uncontrolled muscle movements, excessive
sedation, worsened mental functioning and confusion.

The manufacturers of the three drugs used in the study all said they do not
recommend their products for Alzheimer’s patients. Eli Lilly and Co. makes
Zyprexa, AstraZeneca makes Seroquel, and Janssen Pharmaceutica makes
Risperdal.

The new study found that Risperdal and Zyprexa seemed to help Alzheimer’s
patients more than Seroquel, but those two medications also had more serious
side effects.
C 2006 The Washington Post Company

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