Association Between Risperidone Treatment and Cerebrovascular Adverse Events in Elderly Patients With Dementia

To the Editor: We have read with interest the review of treatment of elderly patients with antipsychotics drug published in the Journal of the American Geriatrics Society.1,2 One of the neuroleptic drugs most commonly used to treat some of the behavioral and psychological symptoms of dementia is risperidone.3–5 A potential association has been suggested between treatment with risperidone and increased incidence of cerebrovascular adverse events (CVAEs) such as stroke and transient ischemic attack (TIA),6 although such association was not supported by other studies.3,7 Three hundred twenty consecutive patients with dementia aged 65 and older from six centers were evaluated to assess the possibility of an association between use of risperidone and an increased risk of CVAEs. Patients were included in the group on neuroleptic treatment when they had taken a neuroleptic drug for at least 15 consecutive days, because it was a usual practice for patients included to take the neuroleptic as required in a flexible regimen. The main variable recorded was the occurrence of any type of CVAE during follow-up treatment since dementia was diagnosed. Two hundred fourteen women (67%) and 106 men were included. Mean age±standard deviation was 81.1± 6.8. Mean time since diagnosis of dementia was 31.1±24.0 months. Mean values in Reisberg's Global Deterioration Scale were 5.3±1.1. One hundred sixty-six patients (52%) were receiving treatment for hypertension, 69 (22%) for diabetes mellitus, and 43 (13%) for dyslipidemia. One hundred thirty-one patients (41%) were taking antiaggregant therapy, and 15 (5%) were taking oral anticoagulation therapy. A prior CVAE was found in 77 (24%) patients, of whom 75% were on antiaggregant therapy and 6% on anticoagulant therapy. Thirty-seven patients (12%) had atrial fibrillation, which was being treated with oral anticoagulants in 11 patients. One hundred ninety-one patients (60%) had received treatment with neuroleptic drugs: 168 risperidone (53%), 10 haloperidol, six levomepromazine, four olanzapine, two quetiapine, and one thioridazine. The daily dose of risperidone ranged from 0.5 mg to 3 mg, and the mean time since the start of risperidone was 10.1±12.0 months. Six patients experienced a new stroke during follow-up (mean 20 months): three of them in the risperidone group and three in the other group (two patients not taking neuroleptics and one on thioridazine); there were no significant differences (P=1.0). Four patients experienced a TIA during follow-up (mean 18.4 months): one in the risperidone group and three in the other group (two not taking neuroleptics and one taking levomepromazine) (P=.34). Overall, 10 patients experienced some CVAE during follow-up (mean 19 months): four in the risperidone group and six in the other group (four not taking neuroleptics and one each on thioridazine and levomepromazine) (P=.52). When data were analyzed depending on whether patients had taken neuroleptic treatment, no significant differences were found in stroke (4 vs 2; P=.90) or TIA (2 vs 2; P=.90), nor were they found when both events were analyzed together (6 vs 4; P=.90). Table 1 shows the characteristics of patients with a new CVAE. Data on a potential increase in the number of CVAEs in elderly patients with dementia taking risperidone come from an analysis of four placebo-controlled trials showing CVAEs in 4% of patients in the risperidone group, compared with 2% in the placebo group, although there were no mortality differences.6 The studies were not designed to test the hypothesis as to whether risperidone increased the risk of stroke. Moreover, in a recent study7 involving 1,130 cases and 3,658 controls, no association was found between risperidone and an increased risk of CVAEs. In an attempt to find an explanation for this possible association, a potential increase in orthostatic hypotension has been suggested, despite the fact that no postural changes in blood pressure have been noted in patients treated with risperidone.3,5 A further possibility would be an increased risk of thromboembolic disease, but neither risperidone nor its active metabolite caused changes in platelet shape or aggregation in in vitro studies.8–10 Other highly unlikely causes would be that an increased sedation resulted in a certain dehydration or that a possible increase in prolactin secretion triggered an accelerated atherosclerosis. When assessing the limitations of our study, it should be taken into account that any possible stroke that had caused the death of the patient was not included, although no mortality differences were reported in previous studies.6 It is also possible, although unlikely, that the patients or main caregivers did not report some TIAs. Although the limitations imposed by a retrospective study using flexible doses and a small sample size should not be disregarded, our conclusion is that there is no association between the use of risperidone and an increased incidence of CVAEs. Financial Disclosure: All authors have been occasionally on the speaker's bureau of Janssen. Author Contributions: The main author (Francesc Formiga) is solely responsible for the study concept, design, and data interpretation, and for preparation of the manuscript. Sponsor's Role: Janssen was not involved in the design, methods, subjects recruitment, data collection, analysis, or original preparation of this article.