Atypical Antipsychotics and
Alzheimer's Disease
by Dr. Blaine S. Greenwald and Leslie Gonzalez

A recent study supportedby The National Institute of Mental Health (NIMH) reports that Risperdal,
Seroquel and Zyprexa, so-called "atypical" or "second-generation" antipsychotic drugs often
prescribed to Alzheimer's disease (AD) clients, offer only modest benefit These drugs are called
atypical or second-generation to distinguish them from older or so-called 'conventional' antipsychotic
agents like haloperidol (Haldol) and chlorpromazine (Thorazine) which have a different chemical
structure and somewhat different mechanism of action. The finding adds to a nationwide controversy
over the use of antipsychotics to treat AD clients, following a 2005 mandate by the U.S. Food and
Drug Administration (FDA) that manufacturers post special warnings citing risk of increased
mortality or serious side effects.
Results of the $17 million study led by AD experts Dr. Lon S. Schneider of the University of
Southern California and Dr. Constantine Lyketsos of Johns Hopkins were published in the New
England journal of Medicine.
The "Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE)Alzheimer's Disease" study tested second generation antipsychotics risperidone (Risperdal),
quetiapine (Seroquel), and olanzapine (Zyprexa) against a placebo in 421 AD clients at 45 sites from
2001 through 2005. Although these drugs showed some benefit for some patients, the researchers
concluded that adverse effects, such as uncontrolled muscle movements, excessive sedation, orsened
mental functioning and confusion, offset the advantages in the study group. Widely prescribed at an
annual cost of about $10 billion, the question is whether these newer, popular antipsychotics are
worth their higher cost.
An estimated 5.5 million Americans suffer from AD, which is regularly associated with changes in
personality and behavior. Delusions (false fixed beliefs), hallucinations (perceptions without a
stimulus) and aggressive behaviors can be extremely taxing on both clients and caregivers. Such
behavioral disturbances are often the key factor in a family's decision to place a loved one in
residential care. Antipsychotic drugs are widely used with AD and related dementia patients.
particularly in nursing homes, to help control serious · aggressive behaviors and psychiatric
symptoms. This is called "off-label" use of these medications, since none of these drugs are currently
FDA-approved for elderly clients with dementia. Janssen Pharmaceutica makes Risperdal;
AstraZeneca makes Seroquel; and Eli Lilly and Co. makes Zyprexa. Although the manufacturers say
they do not recommend their products for JUD, more than a quarter of all AD clients in nursing
homes are prescribed these drugs, which were initially developed for schizophrenia. Doctors who
prescribe them to their dementia clients are thus relying on their clinical judgment.
On the basis of the reports indicating increased mortality associated with second generation
antipsychotics, in April 2005, the FDA ordered "black box" warnings citing potential for increased
risk.of death in elderly dementia clients taking such antipsychotics including the
aforementioned Risperda). Seroquel. Zyprexia; plus aripiprazole (Abilify), clozapine
(Ciozaril), ziprasidone (Geodon) and olanzapine/fluoxetine (Symbyax). A black box or
blackbordered warning, is a type of eye-catching graphic that appears on prescription drug
information, wherein that drug may cause serious or even life-threatening adverse effects. It is the strongest warning that the FDA requires. In a number of trials of Ability, Risperdal. Seroquel and Zyprexa among approximately 5000 aggregate subjects, many reports showed statistical increases in mortality. The rate of death was about 4.5 percent, compared with a rate of 2.6 percent· in placebo clients. Causes of death included heart failure, sudden death, or infections, particularly pneumonia. Antipsychotics have also been shown to increase the risk of diabetes and stroke. These drugs fall into different classes based on chemical structure, and because the mortality risk was seen in all of them. the FDA required Clozaril. Geodon, and Symbyax, a combination product used to treat bipolar disorder, to also carry the same warning. late last year, another article appeared in the New Engla11d Journal of Medicine that reported that the older, conventional antipsychotic medication is at least as likely to increase the risk of dying among elderly patients as the second generation agents, and that conventional antipsychotics should not therefore be viewed as ready replacements for atypicals discontinued because of the FDA warning. As such, the increased risk may be an antipsychotic "class” effect and must be balanced against the perceived usefulness of these agents by treating clinicians. "I can't agree with it (the negative publicity) all think these drugs have an important. place in controlling agitation for some patients. Many doctors use them," said LIAF Medical Advisory Board member Dr. Arnold P. Levy of Long Island College Hospital who did note Zyprexa's particular notoriety for weight gain. "1'be concern is metabolic syndrome . but even with that, I had a family demand that I put their loved one back on this drug. These drugs work for some patients. You draw from your experience; you inform the patient and family about the risk/benefit ratio, and with their agreement you use clinical judgment. You need to use discretio . as to what works for what people." "I think they may have been dispensed too liberally," said Dr. Max. Rudansky of Huntington Hospital "1'bere is a 'gray zone' for first level behaviors. It still has a role, particularly at the point of hallucinations or delusions. I think the issue was indiscretion, especially with nursing homes that oversedate. So there was a pulling back." Dr. Rudansky recommended more discrimination in usage and discussion with caregivers to prescribe in a more judicious way. He compared keeping clients home using Seroquel or Zyprexa versus placement in a facility. "In my experience, they are still best to use when (the client) is very paranoid." All experts agree that extra care should be taken first to ensure that agitation is not related to environmental, medical or social factors that can be addressed non-pharmacologically. Staff in adult care and skilled nursing facilities may need additional training in behavioral techniques to calm residents without medication.


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