Atypicals vs. typicals. Are atypicals worse than typicals in their effect on stroke risk?
Herrmann et al8,9 reviewed a health care database of 11,400 older persons and found no statistically significant increase in stroke rate with risperidone or olanzapine compared with typical antipsychotics. This study did not assess whether patients had dementia or primary psychotic disorders.
In a larger retrospective study of 32,710 older persons with dementia, Herrmann’s group10 found no greater stroke risk in those who took atypicals than in those who took typical antipsychotics.
So the evidence for the risk of stroke in older patients who take antipsychotics is based on a few reports and no definitive studies.
Risk of early death
What about the risk of early death? After reviewing 17 clinical trials of atypical antipsychotics in older patients with dementia, the FDA issued its warning in April 2005 about increased mortality risk (see Related resources). Fifteen of the trials showed an increased mortality risk, resulting in an estimated 1.6- to 1.7-fold increase in risk of death, mostly by cardiac or infectious causes.
A year earlier, Straus et al11 reported on risk of sudden cardiac death with antipsychotic use in a population-based, case-control study in the Netherlands. In this longitudinal, observational database of 250,000 patients, 75% were age >65 and <1% had dementia. Current use of antipsychotics was associated with a threefold increase in risk of sudden cardiac death (554 cases), after other predictors of sudden death were factored in. This risk increased with higher antipsychotic dosages and was similarly elevated for patients with and without schizophrenia-related disorders.
Mechanisms unknown
By what mechanisms could antipsychotics precipitate stroke, sudden cardiac death, or pneumonia? A clear biological mechanism has not been proposed, much less proven. The risks seen in clinical trials—usually lasting 12 weeks or less—suggest an acute effect rather than the more-gradual consequences of weight gain, altered lipid metabolism, or diabetes.
Speculations range widely. Possibilities awaiting study include postural hypotension, altered platelet aggregation, increased venous thromboembolism, peripheral vasodilation leading to cardiovascular collapse, acute dystonia, acute cardiomyopathy, arrhythmias related to QT prolongation, and other forms of cardiac toxicity.10,11
Remaining questions
The few studies plus two FDA advisories force clinicians to make complex treatment decisions on insufficient evidence. Here’s what we don’t know:
- The magnitude of stroke or sudden death risk in older patients who take antipsychotics for any diagnosis. (All studies have limitations, and public health policy should not rely on one or two studies, no matter how good they may be.)
- Who is at higher or lower risk with antipsychotic use—men vs women? blacks vs whites?etc.
- Biological mechanisms of an association between antipsychotics and risks of stroke and premature death.
Strategies for reducing risk
We can minimize patients’ clinical risk and our legal risk only by using the limited evidence, expert consensus, and sound clinical judgment. Suggested strategies are listed in Table 2.
Table 2
Strategies to minimize antipsychotic risk in patients age 65 and older
| Review and document risk factors for cardiovascular disease—including stroke—with physical examination, laboratory tests (lipid profile, fasting glucose), and ECG in consultation with a primary care physician or specialist |
| Try nonpharmacologic approaches first whenever possible to manage behavioral disturbances in patients with dementia; document results before trying an antipsychotic |
| Review antipsychotics’ risks and benefits with patient and family |
| Use low dosages and increase gradually, as sudden death risk is dose-related |
| Monitor antipsychotic effectiveness, and discontinue trials of questionable benefit |
| Monitor cardiovascular symptoms, heart rate, blood pressure and body mass index of patients with cardiovascular risk |
| Avoid using sedating antipsychotics for insomnia in patients without psychiatric disorders |
Dr. Wulsin treats psychiatric outpatients and has published reviews on depression and heart disease. He is training director, University of Cincinnati family medicine-psychiatry residency program.
- Food and Drug Administration. Advisory on increased risk of mortality with use of atypical antipsychotics to treat behavioral disturbances in older patients with dementia. www.fda.gov/cder/drug/advisory/antipsychotics.htm.
Drug brand names
- Olanzapine • Zyprexa
- Perphenazine • Trilafon
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Ziprasidone • Geodon
Disclosures
The author reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.