Some Antipsychotics May Raise Risk Of Death In Dementia Patients

Some antipsychotic drugs may raise risk of death in elderly dementia patients, according to a new large study from Harvard Medical School published in BMJ on Thursday that looked at over 75,000 residents over the age of 65 living in US nursing homes. 

Although the study does not prove that specific antipsychotics cause the increased risk, and the researchers say they can't rule out all other possible factors, they conclude their findings suggest that risk of death with antipsychotics is "generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine".

The senior author of the study is Dr Sebastian Schneeweiss, associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics of Brigham and Women's Hospital and Harvard Medical School, in Boston in the US.

For their study, the largest of its kind ever undertaken in the US, Schneeweiss and colleagues looked at data on 75,445 older residents aged 65 and over living in nursing homes in 45 US states between 2001 and 2005.

Over a six-month period, during which 6,598 of the patients died from non-cancer related causes, the researchers assessed risks of death associated with individual antipsychotic drugs such as aripiprazole, haloperidol, olanzapine, quetiapine, risperidone and ziprasidone.

49% of deaths were reported as due to circulatory disorders, 10% to brain disorders and 15% to respiratory disorders.

The analysis shows that patients treated with haloperidol had double the risk of death compared to those taking risperidone, while patients taking quetiapine had a reduced risk.

The researchers also found that the link with haloperidol was strongest during the first 40 days of treatment which did not change after a dose adjustment.

They took into account a wide range of possible influencers, including gender, age, ethnicity, education, geographic location, as well as size, occupancy, staffing levels, ownership, resident characteristics and quality indicators of the nursing home, and whether it had special care units. They also corrected for the presence of any physical illnesses that might raise mortality risk.

While the study does not claim to deal with the trade off between effectiveness and safety that clinicians caring for dementia patients have to consider every day, in their conclusions, it suggests clinicians take into account the following points when they make their decisions:

"If the clinician faces a situation in which use of these drugs seems inevitable, our findings underscore the importance of always prescribing the lowest possible dose and of closely monitoring patients, especially shortly after the start of treatment," write the authors.

"The evidence accumulated so far implies that use of haloperidol in this vulnerable population cannot be justified because of the excess harm. Quetiapine might be somewhat safer than other atypical drugs, but these findings will require replication in other studies," they add.

In 2005, the US Food and Drug Administration (FDA) issued a public health advisory about "off-label" use of antipsychotic drugs approved for the treatment of schizophrenia and mania to treat other disorders. They had determined that "treatment of behavioral disorders in elderly patients with dementia with atypical (second generation) antipsychotic medications is associated with increased mortality". In 2008, the agency extended the warning to include conventional antipsychotics.

Schneeweiss and his fellow authors write that despite these warnings, doctors are likely to continue prescribing these drugs because there is a need for some type of intervention and the dementia population continues to grow.

Among their conclusions, they note:

"The evidence provided in our study reinforces the important risks associated with the use of these drugs and underscores the need to try alternative means of dealing with behavioural problems in older patients with dementia."

In an accompanying editorial, Dr McCleery of the Oxford NHS Foundation Trust, calls for future studies to focus more on how non-drug interventions might be made more effective and implemented more simply and efficiently.