he Food and Drug Administration (FDA) issued a public health advisory in April 2005 to alert the public and health professionals
that the family of drugs known as the atypical antipsychotics are associated with an increased risk of death when used to
treat dementia in elderly patients (see Worst Pills, Best Pills News July 2005). Since September 2005, all the atypical antipsychotics now carry a black box warning in their professional product labels.
A black box warning is the strongest type of alert that the FDA can request of a drug manufacturer.
The April advisory did not apply to the older conventional antipsychotic drugs. The risk of death with
these older agents in comparison to the newer atypical drugs is not known. A major concern is that prescribers are switching
their elderly patients from the atypical drugs to the older drugs without knowing whether the older drugs are actually safer.
Researchers from the Harvard Medical School addressed this question and published their results in the Dec. 1, 2005 New England Journal of Medicine.
The table above lists the atypical antipsychotic drugs and the typical antipsychotics included in the Harvard Medical School study.
The combination of olanzapine with the antidepressant fluoxetine (PROZAC) is approved by the FDA for
the treatment of depressive episodes associated with bipolar disorder. None of the drugs listed as atypical antipsychotics
are approved for the treatment of behavioral disorders in patients as a result of dementia.
The Harvard researchers studied 22,890 patients in Pennsylvania who were age 65 years or older, were
confined to nursing homes, and had drug insurance benefits. This group had begun taking a typical or atypical antipsychotic
drug between 1994 and 2003. The researchers analyzed death rates at various times after the patients began treatment with
either an atypical or typical antipsychotic drug.
The older antipsychotic drugs were found to have a statistically higher association with an increased
risk of death at all time intervals studied. The largest increases in the risk of death occurred soon after the drugs were
started and with higher dosages of the older antipsychotic medications.
The Harvard researchers concluded by saying:
If confirmed, these results suggest that conventional antipsychotic medications are at least as likely
as atypical agents to increase the risk of death among elderly persons and that conventional drugs should not be used to replace
atypical agents discontinued in response to the FDA warning.
The researchers were correctly cautious with their conclusion when they noted if their results were
“confirmed.” This is because the research methodology used in their study, called a retrospective cohort study,
is a type of observational or epidemiological research. This means that the researchers looked back in time, or retrospectively,
at two large groups (cohorts) of patients — those taking atypical or typical antipsychotic drugs. This type of research
does not conclusively establish a cause and effect relationship between the use of a drug and death.
Contrast the Harvard study with the evidence that was used by the FDA in their April 2005 warning about
the atypical antipsychotics and the risk of death. The FDA warning was based upon the results of 17 controlled clinical trials,
the scientific “gold standard” for establishing a cause and effect relationship. In the hierarchy of scientific
evidence, controlled clinical trials rank above retrospective cohort studies.
The Harvard results are not conclusive, but they do strike a cautionary note that must be taken seriously.
Further study is certainly required.
The use of either the atypical and typical antipsychotics in patients who are not psychotic to control
dementia is an off-label use for these drugs. Off-label drug uses have not been shown to be safe and effective and are not
approved by the FDA. Too often, when finally studied, off-label use has been revealed to result in more harm than good.
The misuse of drugs on elderly nursing home residents remains a concern. In December 2001, the Health
Care Financing Administration released draft guidelines on the use of chemical restraints. The guidelines are based on the
Omnibus Budget Reconciliation Act of 1987, which stated that nursing home residents have the right to be free from chemical
or physical restraints that are used for disciplinary purposes or staff convenience and that are not required to treat a resident’s
medical condition. Clearly, the concern here is that the use of atypical and typical antipsychotic drugs to control the behavior
of elderly nursing home residents who are not psychotic could be considered an unlawful chemical restraint.
What You Can Do
If you are a family member or the caregiver of an elderly person who has not been diagnosed as psychotic
but is nonetheless receiving an antipsychotic drug, talk to the prescribing physician about other options, such as increased