September 5, 2008 — Patients taking antipsychotic drugs are at an increased risk for stroke, a new study shows. This risk may be even higher in patients taking atypical antipsychotics or in patients with dementia, the researchers advise.

Reporting in the August 28 Online First issue of the BMJ, research fellow Ian Douglas and Liam Smeeth, a professor of clinical epidemiology at the London School of Hygiene and Tropical Medicine in the United Kingdom, suggest that the risk for stroke cannot be attributed to differences in baseline cardiovascular factors.

"All antipsychotics are associated with an increased risk of stroke, and the risk might be higher in patients receiving atypical antipsychotics than those receiving typical antipsychotics," the study authors explain.

"People with dementia seem to be at a higher risk of an associated stroke than people without dementia, and use of antipsychotics should, when possible, be avoided in these patients," they note.

Concerns About Stroke Risk

Concerns about antipsychotic drugs began in 2002 when results from limited trial data suggested an increased stroke risk. On the basis of these results, Health Canada and Janssen-Ortho, the maker of risperidone, issued a warning to prescribers.

In 2004, the United Kingdom's Committee on Safety of Medicines recommended against the use of atypical antipsychotic drugs in patients with dementia.

However, more recently, the European Pharmacovigilance working party concluded that the evidence that antipsychotic drugs increase the risk for stroke was weak.

The report suggested that uncontrolled confounding might have affected the findings to date. For example, the underlying cardiovascular risk in people prescribed and not prescribed antipsychotic drugs differs in ways that are difficult to quantify and control for.

To address this difficulty, the investigators of the present analysis conducted a within-person case series in an effort to eliminate confounding between individuals.

The investigators used UK–based electronic primary care records. They looked at 6790 patients in the general practice research database who had a stroke and at least 1 prescription for any antipsychotic drug before the end of 2002.

"We chose to censor follow-up for all patients at the end of 2002 as this was when concerns about the effects of antipsychotic drugs in patients with dementia first emerged," the study authors explain. "This should avoid possible biases arising from altered prescribing habits in the light of these findings."

Table. Association Between Antipsychotic Drug Use and Stroke*

*Figures are rate ratios (95% confidence interval).

The median duration of total observation included in the analysis was at least 4 years for each subgroup. The researchers observed that the risk for stroke is higher with atypical antipsychotic drugs.

In patients with dementia receiving any antipsychotic drug, the rate ratio was 3.50 (95% confidence interval, 2.97 - 4.12) and for patients without dementia, 1.41 (95% confidence interval, 1.29 - 1.55).

The magnitude of the increased risk for stroke associated with antipsychotic drug use is more than twice as great in patients with dementia vs those without dementia, the researchers point out.

One of the main strengths of the study was that it was large and statistically powerful, note the researchers. "Our study was based on routine clinical data from the general practice research database, which is largely representative of the population of the UK and so the results are likely to be highly generalizable."

Mechanism Unknown

A potential weakness of the study could be the quality of the clinical data, the researchers suggest. Another possible limitation of the study design is that time varying confounders can be difficult to take into account.

"We were unable to investigate possible mechanisms by which antipsychotics might cause stroke or why the risk seems to be greater with atypical antipsychotics," the investigators point out. "It is unclear if the effect represents a direct vascular toxicity or whether stroke might be a consequence of other well-established side effects such as weight gain."

They conclude, "We have established that all types of antipsychotics carry an increased risk, although the risk might be somewhat higher with the atypical drugs."

Dr. Smeeth is supported by a Wellcome Trust senior research fellowship in clinical science. Data from the general practice research database were made available through the access for UK academics via Medical Research Council agreement.

BMJ. Published online August 28, 2008.

Clinical Context

Study Highlights

• Study data were drawn from the UK general practice research database, which includes information on more than 600 million patients in more than 400 general practice sites.
• Study subjects were those with a first-ever diagnosis of stroke after being listed in the database for at least 12 months.
• Researchers compared when the patients with stroke were taking and not taking antipsychotic medications. Data were censured to include only strokes before December 2002, as this is when data regarding the stroke risk associated with antipsychotics may have begun to affect prescribing habits.
• 6790 subjects in the database had at least 1 prescription for antipsychotic medications as well as an incident stroke. The median ages at first exposure to the antipsychotic and the incident stroke were 80 and 81 years, respectively.
• 64% of subjects were women.
• 87% of participants received typical antipsychotics, of which phenothiazines were the most common. In the 905 subjects receiving atypical antipsychotics, 81% received risperidone.
• The median total observation period exceeded 4 years for all patient subgroups.
• Compared with periods in which subjects were not exposed to antipsychotic medications, the rate ratio of stroke during exposed periods was significant at 1.73.
• Atypical antipsychotics were more associated with the risk for stroke (rate ratio, 2.32) vs typical antipsychotics (rate ratio, 1.69).
• Patients with dementia were at a particularly high risk for stroke during treatment with antipsychotics (rate ratio, 3.50). Again, atypical antipsychotic medications increased the risk for stroke to a greater degree than typical antipsychotics in this patient subgroup.
• The risk for stroke decreased towards unity in the period after treatment with antipsychotics.
• Most strokes in this series were not classified as ischemic or hemorrhagic, but in the 233 patients with these data available, antipsychotic treatment appeared to increase only the risk for ischemic stroke.
• The increased risk for stroke associated with antipsychotic treatment was evident within the first 3 months of exposure, suggesting that factors other than weight gain might account for the increased risk for stroke associated with antipsychotics.

Pearls for Practice

• A previous study found that severe mental illness can increase the risk for mortality from coronary heart disease and stroke but not mortality from cancer.
• The current study finds that antipsychotic medications can increase the risk for stroke in older adults. This effect might be more pronounced with atypical antipsychotics vs typical antipsychotics and is most notable in patients with dementia.

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