Antipsychotic Agents, Suddent Death, the New England Journal and Implications for Research and Disease Management

There have been a flurry of mainstream media reports (here and here and here, for example) about a study published in the New England Journal of Medicine (NEJM) that showed there was an increased risk of ‘sudden death’ among persons who use antipsychotic agent drugs.

The Disease Management Care Blog at your service. Unlike many in the media who quote from other’s press releases, it looked at the original study for numbers behind the media facts.

Briefly, the authors pulled 15 years’ worth of insurance claims data from Tennessee’s Medicaid program for persons with an average age of about 45 years who were using thioridazine (Mellaril is one brand name), haloperidol (Haldol is one brand name), clozapine (Clozaril is one brand name), quetiapine (Seroquel is one brand name), olanzapine (Zyprexa is one brand name) and respirdone (Resperdal is one brand name). These persons' sudden death rates were compared to matched persons with a similar insurance-medical profile who were not taking these drugs. That’s possible because every insurance claim indicates a diagnosis or a treatment and can be linked to age and gender.

What’s sudden death? Just what it sounds like. It’s a death that occurs within an hour of the onset of symptoms, though it’s usually thought of as simply keeling over. It’s usually but not always caused by a heart problem/coronary artery disease. It happens, but it’s rare, compared to other types of death, especially in this age group.

Antipsychotic agents block the action of dopamine in the brain and are widely prescribed for serious mental illness including psychosis. Because they also commonly have a ‘calming’ effect on users without causing sedation, they are also used by physicians for other mental illness when it is complicated by agitation such as Alzheimer’s Disease.

These drugs have been known for a long time to have side effects. They include weight gain (up to approximately ten lbs), the development of diabetes (it may go as high as 10%), higher blood pressure (more than 10 points systolic or the top number) and alterations (acquired long QT) in how electrical impulses are routed through the heart (which accounts for the electrocardiogram or ECG) in the course of normal beating (up to 3%).

The increase in weight, blood sugar and blood pressure could lead to an increased death rate from heart attacks. The alteration in the ECG could also lead to electrical instability in otherwise normal hearts. Whatever the cause, physicians have been long aware that patients who take antipsychotic agents have a higher risk of cardiac related death and/or sudden death. This risk appears to be particularly high when the newer antipsychotic agents (clozapine, quetiapine, olanzapine and respirdone) are used in elderly persons with Alzheimers Disease: the death rate can go from a baseline of 2.6% (remember, these are elderly persons) to 4.5% (in other words, the risk is increased by 1.9%) over three to four months. That's like a whopping 18% a year.

Based on the old information that there are heart problems associated with these drugs, is the information in the NEJM all that momentous? Decide for yourself: the authors found there were 895 deaths among ‘624,591 person-years’ (perhaps mathematically best thought of as 624,591 persons followed for one year) or a risk of 895 divided by 624,591 or 0.14 percent (just over a tenth of a percent) per year in the group of persons NOT taking antipsychotic drugs. Persons taking the drugs, on the other hand, experienced 223 deaths among 79,589 person-years or 0.29% per year. This overall death rate changed slightly depending on the types of drugs used, but the excess rate held up across all categories.

For comparison’s sake, check out the causes of death and their frequency in this population here. Therefore, while the risk of sudden seems very low for any single individual (3 in a thousand over a year), it’s a significant number from a population perspective (hundreds of Tennessee's citizens).

What can students of population-based health learn from this little gem of a study?

1. Once again, we’re witnessing the rise of rigorous insurance claims-based population studies that have an adequate comparison (control group) without having to rely on stodgy, time consuming expensive randomized prospective controlled clinical trials (RCTs). In fact, studies like this are more powerful than RCTs because they can draw on thousands of patients over many years and find important and statistically significant differences in the range of tenths of a percent. Disease management organizations also preside over huge data bases in their information systems and should draw a lesson from this study. They can and should also be doing this kind of research.

2. Disease management organizations that offer mental health programs have an additional reason to be vigilant about the use of antipsychotic agents in their patients. Since antipsychotic agents can mean the difference in being able to function for persons with chronic psychosis, the low risk of sudden death, when these drugs are truly needed, is outweighed by their benefit. On the other hand, use of these drugs in children or the elderly for their calming effect is dangerous (and promotion on that basis by pharmaceutical companies is illegal and expensive), especially when other approaches work just as well and are safer. Disease management organizations have a role to play (or perhaps a market opportunity?) in keeping that to a minimum through patient coaching and provider feedback.