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Antipsychotics and stroke: the story to date (Adverse drug reactions)

Both “conventional” antipsychotics and the newer “atypical” antipsychotics aredopamine receptor antagonists. However, the atypical antipsychotics areassociated with fewer neurological (and some other) side effects

by Deborah Layton and Anthony Cox

Both “conventional” antipsychotics and the newer “atypical” antipsychotics are dopamine receptor antagonists. However, the atypical antipsychotics are associated with fewer neurological (and some other) side effects.

In the UK and the US, the principle approved prescribing indication for antipsychotics is for schizophrenia, but these drugs are commonly prescribed to elderly and demented patients.1

Initial concerns

Initial concern focused on a possible association between risperidone and olanzapine and an increased risk of cerebrovascular adverse events, such as stroke and transient ischaemic attacks.2

A number of fatalities in randomised clinical trials (RCTs) of elderly patients prescribed these drugs for dementia were also of concern. These led to warnings being issued by the manufacturers and drug regulatory authorities for the two drugs.

In 2004, further data from clinical trials suggested the increased risk applied to patients with no pre-existing cardiovascular problems.3

The UK Committee on Safety of Medicines stated that the risk was sufficient to outweigh the benefit in the treatments of such patients and prescribing information was amended accordingly. Additional actions from drug regulators in the EU, US and Canada ensued.

At that time, other atypical or conventional antipsychotics were not subject to the same actions. However in 2005, the European Pharmacovigilance Working Party assessed the additional evidence from three observational studies (two of which have been published4,5) and concluded that the likelihood of cerebrovascular events associated with conventional antipsychotics was not significantly different from that with risperidone and olanzapine.

It was recommended that a possible risk of cerebrovascular adverse events associated with antipsychotics should be considered for all antipsychotics.6

Other observational pharmacoepidemiological studies also found significant increases in risk of approximately 50 per cent for conventional compared with atypical antipsychotics, particularly within the first months of starting treatment.7,8

Current knowledge

In June 2008, under new powers the US Food and Drug Administration (FDA) ordered manufacturers of older conventional antipsychotics to strengthen the warning about increased risk of death when the drugs are used for the unlicensed indication of dementia.9

The overall weight of evidence, including two observational epidemiological studies of methodological limitations,5,8 indicated to the FDA that conventional antipsychotics share the increased risk of death in elderly patients with dementia-related psychosis that has been observed for atypical antipsychotics.

As this increase in mortality was seen regardless of chemical structure, the FDA concluded that a class effect existed, and the prescribing information was revised for all antipsychotic drugs.

In August 2008, another observational study based on 6,700 patients from a GP database, with an average age of 80 years, reported that the risk of stroke in the overall patient population was increased by 1.69-fold for typical antipsychotics and 2.3-fold for atypical drugs. With any class of antipsychotic drug, risk was increased 3.5-fold in dementia.

The authors said their findings clarified the risks of stroke associated with antipsychotics, and highlighted the fact that a risk exists for older as well as newer drugs.10

Assessing the evidence

The individual RCTs are (and were at the time that this safety signal was generated) neither of large sample size or long enough duration to detect important adverse effects of interest. In this example, the original safety signal was not generated through spontaneous reporting schemes but resulted from pooling data from clinical trials.

However, publication bias can distort the results of meta-analysis. Retrospective observational studies, despite limitations such as confounding factors, made a substantial contribution to the assessment of the risks of antipsychotics. Post-marketing observational research supporting the association between all antipsychotics and an increase in risk of stroke has informed regulatory action worldwide, although the risk appears to be smaller than the original signal.

Discussion Solutions are required to produce more timely assessment of hypotheses of safety risks. Convergence in observational and RCT methods has been proposed. So-called “large simple trials” that focus on safety and attempt to recruit “real-world patients” are one possible solution. Better linkage of pharmacological and pharmacoepidemiological evidence would facilitate our understanding of risk.

Regulatory activities have summarised the limited evidence from all sources confusion about the use of antipsychotics for treating behavioural problems remains. While evidence-based guidelines are produced, an important limitation is that they quickly go out of date.11

Although unlicensed use of medicines is necessary in situations where clinicians have to make prescribing decisions without the support of robust clinical studies, the story of antipsychotics and stroke shows how sometimes unknown harms can be a consequence.


Deborah Layton, Drug Safety Research Unit, Southampton, and Anthony Cox, Aston Pharmacy School, Birmingham.



1. Haw C, Stubbs J. Off-label use of antipsychotics: are we mad? Expert Opinion Drug Safety 2007;6:533–45.

2. Wooltorton E, Practice Health and Drug Alerts. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ 2002;167:1269–70.

3. Duff G. CSM Urgent Message Ref CEM/CMO/2004/1. Atypical antipsychotic drugs and stroke
(PDF 60K)

4. Herrmann N, Mamdani M, Lanctot KL. Atypical antipsychotics and risk of cerebrovascular accidents. American Journal of Psychiatry 2004;161:1113–5.

5. Gill SS, Rochon PA, Herrmann N, Lee PE, Sykora K, Gunraj N et al. Atypical antipsychotic drugs and risk of ischaemic stroke: population based retrospective cohort study. BMJ 2005;330:445.

6. European Medicines Agency. European Pharmacovigilance Working Party, 2005. Antipsychotics and cerebrovascular accident. Available at: (accessed on 15 September 2008).

7. Wang PS, Schneeweiss S, Avorn J, Fischer MA, Mogun H, Solomon DH et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. New England Journal of Medicine 2005;353:2335–41.

8. Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 2007;176:627–32.

9. Food and Drug Administration. FDA Requests Boxed Warnings on Older Class of Antipsychotic Drugs

10. Douglas IJ, Smeeth L. Exposure to antipsychotics and risk of stroke: self controlled case series study. BMJ 2008;337:a1227.

11. Faculty of the Psychiatry of Old Age. Prescribing update for old age psychiatrists
(PDF 80K)

Citation: The Pharmaceutical Journal URI: 10045210

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