Atypical antipsychotic drugs and risk of ischaemic stroke: population
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《英国医生杂志》
1 Institute for Clinical Evaluative Sciences, 2075 Bayview Avenue, Toronto, ON, Canada, 2 Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care, Toronto, 3 Division of Geriatric Psychiatry, Department of Psychiatry, Sunnybrook and Women's College Health Sciences Centre, Toronto, 4 Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, Toronto, 5 Toronto Rehabilitation Institute, Toronto, 6 Division of Geriatric Medicine, University of British Columbia, Vancouver, BC, Canada, 7 Department of Health Care Policy, Harvard Medical School and Harvard School of Public Health, Boston, MA, USA, 8 Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester, MA
Correspondence to: S S Gill, Room 1-152, Chapel Wing, St Mary's of the Lake Hospital, 340 Union Street, Kingston, ON, Canada K7L 5A2 gills@pccchealth.org
Abstract
A variety of behavioural disturbances such as physical aggression, agitation, hallucinations, and wandering commonly accompany dementia. The term behavioural and psychological symptoms of dementia—BPSD—describes this spectrum of non-cognitive manifestations of dementia.1 The presence of BPSD can decrease quality of life for patients and caregivers, and increases the likelihood of the patient being placed in an institution.2
Treatment of BPSD is challenging. A variety of non-pharmacological and pharmacological approaches have been assessed.3 4 Atypical antipsychotics are often prescribed to manage BPSD. Although such prescriptions represent off-label prescribing, this practise is widely endorsed because atypical antipsychotics are among the best studied treatments for BPSD and there is a perception that they have fewer adverse effects than typical antipsychotics.5 6 Recently, however, concerns have been raised that atypical antipsychotics may increase the risk of cerebrovascular adverse events, including stroke, among older adults with BPSD.
In October 2002, Health Canada and Janssen-Ortho (a manufacturer of atypical antipsychotics) issued a warning to Canadian clinicians of a possible link between risperidone use and cerebrovascular adverse events.7 This concern emerged from a clinical trial evaluating risperidone in the management of BPSD,8 and a subsequent meta-analysis of the risperidone trials for this indication also showed more cerebrovascular adverse events among participants receiving risperidone (4%) than among participants receiving placebo (2%).9 The US Food and Drug Administration issued a similar warning in April 2003.10 More recently, pooled data from clinical trials evaluating olanzapine for BPSD have shown that it may also be associated with an increased risk of cerebrovascular adverse events.11 12 These data suggest around a threefold increase in the relative risk of cerebrovascular events among people taking risperidone or olanzapine. Based on these data, the UK Committee on Safety of Medicines issued a warning in March 2004 advising that risperidone and olanzapine should no longer be used to manage BPSD, and that patients already receiving these drugs for BPSD should be switched to other treatments.12 These warnings have led to controversy among clinicians.13 14 To date, the warnings only extend to older adults receiving atypical antipsychotics for BPSD and not to patients receiving these drugs for schizophrenia or other indications. No warnings have been issued on the use of other atypical agents, such as quetiapine or aripiprazole, as few studies have been published on their use to manage BPSD. Recent data from a clinical trial of quetiapine to treat BPSD show no increased risk of cerebrovascular adverse events compared with placebo.15
The potential link between atypical antipsychotics and cerebrovascular adverse events in patients with BPSD is important, given the common use of these drugs in this patient population. If atypical antipsychotics are thought unsafe, clinicians may consider using typical antipsychotics to treat BPSD. We compared the incidence of admissions to hospitals for stroke among older adults with dementia who received atypical or typical antipsychotics.
Methods
We identified 32 710 older adults with dementia (17 845 dispensed atypical antipsychotics and 14 865 dispensed typical antipsychotics). The atypical antipsychotic cohort included 13 503 (75.7%) patients receiving risperidone, 3459 (19.4%) receiving olanzapine, and 883 (4.9%) receiving quetiapine. Table 1 lists the personal characteristics and comorbidities of patients in both cohorts. In general, the cohorts had similar personal details (standardised differences for most comparisons were < 10%). Baseline characteristics were also similar for the subcohorts taking high potency typical antipsychotics (57.1%) and low potency typical antipsychotics (42.9%; data not shown). Between 1997 and 2002 a major shift took place towards increased prescribing of atypical antipsychotics. Traditional risk factors for ischaemic stroke, such as atrial fibrillation, hypertension, diabetes, and prior stroke, were common among older adults with dementia (table 1).
Table 1 Personal characteristics and details of comorbidity in cohorts of older adults (65 years) with dementia who received atypical antipsychotics or typical antipsychotics. Values are numbers (percentages) unless stated otherwise
In the unadjusted and multivariate analyses, we found that the risk of ischaemic stroke in older adults with dementia receiving atypical antipsychotics was not significantly different from those receiving typical antipsychotics (unadjusted hazard ratio 1.06, 95% confidence interval 0.89 to 1.27; adjusted hazard ratio 1.01, 0.81 to 1.26; table 2).
Table 2 Event rates and hazard ratios for older adults with dementia receiving atypical or typical antipsychotics
The subgroup analyses were all consistent with the main analysis as they showed no significant differences in the development of stroke between the cohorts receiving atypical antipsychotics and those receiving typical antipsychotics (table 3). The risk of stroke for patients receiving risperidone (adjusted hazard ratio 1.04, 0.82 to 1.31), olanzapine (0.91, 0.62 to 1.32), and quetiapine (0.78, 0.38 to 1.57) was not significantly different from that of patients receiving typical antipsychotics. Patients dispensed two or more consecutive prescriptions (chronic users) of atypical antipsychotics were not at increased risk of stroke compared with chronic users of typical antipsychotics. Finally, the risk of stroke in the subgroup of patients enrolled between 1 April 2000 and 31 March 2002 was not significantly different between those receiving atypical antipsychotics and those receiving typical antipsychotics (adjusted hazard ratio 0.98, 95% confidence interval 0.65 to 1.47).
Table 3 Event rates and hazard ratios for subgroup analyses of older adults with dementia receiving atypical or typical antipsychotics
Discussion
Cohen-Mansfield J, Billig N. Agitated behaviours in the elderly. I: a conceptual review. J Am Geriatr Soc 1998;36: 7-12.
Cohen CA, Gold DP, Shulman KI, Wortley JT, McDonald G, Wargon M. Factors determining the decision to institutionalize dementing individuals: a prospective study. Gerontologist 1993;33: 714-20.
Teri L, Logsdon RG, McCurry SM. Nonpharmacologic treatment of behavioral disturbance in dementia. Med Clin North Am 2002;86: 641-56.
Tariot PN, Ryan JM, Porsteinsson AP, Loy R, Schneider LS. Pharmacologic therapy for behavioral symptoms of Alzheimer's disease. Clin Geriatr Med 2001;17: 359-76.
Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56: 1154-66.
Liperoti R, Mor V, Lapane KL, Pedone C, Gambassi G, Bernabei R. The use of atypical antipsychotics in nursing homes. J Clin Psychiatry 2003;64: 1106-12.
Health Canada, important drug safety information: RISPERDAL* (risperidone) and cerebrovascular adverse events in placebo-controlled dementia trials—Janssen-Ortho. www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/risperdal1_e.html (accessed 15 Nov 2004).
Brodaty H, Ames D, Snowden J, Woodward M, Kirwan J, Clarnette R, et al. A randomized placebo controlled trial of risperidone for the treatment of aggression, agitation, and psychosis in dementia. J Clin Psychiatry 2003;64: 134-43.
Wooltorton E. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ 2002;167: 1269-70. 10
2003 Safety alert: RISPERDAL (risperidone). Washington, DC: US Food and Drug Administration; 1 Mar 2004. www.fda.gov/medwatch/SAFETY/2003/risperdal.htm (accessed 15 Nov 2004).
Wooltorton E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ 2004;170: 1395.
Atypical antipsychotic drugs and stroke: message from Professor Gordon Duff, Chairman, Committee on Safety of Medicines (CEM/CMO/2004/1). www.mca.gov.uk/ourwork/monitorsafequalmed/safetymessages/antipsystroke_9304.htm (accessed 15 Nov 2004).
Mowat D, Fowlie D, MacEwan T. CSM warning on atypical psychotics and stroke may be detrimental for dementia. BMJ 2004;328: 1262-b.
Smith DA, Beier MT. Association between risperidone treatment and cerebrovascular adverse events: examining the evidence and postulating hypotheses for an underlying mechanism. J Am Med Dir Assoc 2004;5: 129-32.
Quetiapine evaluated for agitation in people with Alzheimer's. www.alz.org/internationalconference/Pressreleases/072204_hottopics.doc (accessed 15 Nov 2004).
Mayo NE, Chockalingam A, Reeder BA, Phillips S. Surveillance for stroke in Canada. Health Rep 1994;6: 62-72.
Gladstone DJ, Kapral MK, Fang J, Laupacis A, Tu JV. Management and outcomes of transient ischemic attacks in Ontario. CMAJ 2004;170: 1099-104.
Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000;284: 2901-6.
Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004;328: 326-8.
Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW, Schopflocher DP. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology 2004;62: 2015-20.
Levy AR, O'Brien BJ, Sellors C, Grootendorst P, Willison D. Coding accuracy of administrative drug claims in the Ontario drug benefit database. Can J Clin Pharmacol 2003;10: 67-71.
Straus SE, Majumdar SR, McAlister FA. New evidence for stroke prevention: scientific review. JAMA 2002;288: 1388-95.
Schneeweiss S, Seeger JD, Maclure M, Wang PS, Avorn J, Glynn RJ. Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data. Am J Epidemiol 2001;154: 854-64.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40: 373-83.
Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP, Rochon PA. Atypical antipsychotic therapy in the treatment of behavioural and psychological symptoms of dementia: systematic review. BMJ 2004;329: 75-8.
Hollander M, Koudstaal PJ, Bots ML, Grobbee DE, Hofman A, Breteler MM. Incidence, risk, and case fatality of first ever stroke in the elderly population: the Rotterdam study. J Neurol Neurosurg Psychiatry 2003;74: 317-21.
Herrmann N, Mamdani M, Lanct?t KL. Atypical antipsychotics and risk of cerebrovascular accidents. Am J Psychiatry 2004;161: 1113-5.
Liperoti R. Cerebrovascular events among elderly patients treated with conventional or atypical antipsychotics. 2004 Annual meeting of the American Geriatrics Society. www.americangeriatrics.org/news/meeting/schedule_events.pdf (accessed 15 Nov 2004).
Kozma CM, Engelhart LM, Long S, Greenspan A, Mahmoud R, Baser O. Absence of increased relative stroke risk in elderly dementia patients treated with risperidone versus other antipsychotics. 2003 meeting of the International College of Geriatric Psychoneuropharmacology. www.icgp.org/ICGP_2003_program_Book.pdf (accessed 15 Nov 2004).
Wallaschofski H, Donne M, Eigenthaler M, Hentschel B, Faber R, Stepan H, et al. PRL as a novel potent cofactor for platelet aggregation. J Clin Endocrinol Metab 2001;86: 5912-9.
Harrison-Woolrych M, Clark DWJ. Nose bleeds associated with use of risperidone. BMJ 2004;328: 1416.
Zornberg GL, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study. Lancet 2000;356: 1219-23.
Brown TM, Boyle MF. Delirium. BMJ 2002;325: 644-7.
Guidance for the management of behavioural and psychiatric symptoms in dementia and the treatment of psychosis in people with history of stroke/TIA. Working group for the Faculty of Old Age Psychiatry RCPsych, RCGP, BGS, and Alzheimer's Society, following CSM restriction on risperidone and olanzapine. www.bgs.org.uk/publications/CSM%20anouncement%2009%2003%202004.pdf (accessed 15 Nov 2004).
Schneider LS, Tariot PN, Lyketsos CG, Dagerman KS, Davis KL, Davis S. National Institute of Mental Health clinical antipsychotic trials of intervention effectiveness (CATIE): Alzheimer's disease trial methodology. Am J Geriatr Psychiatry 2001;9: 346-60.
The CALM-AD trial—a randomised clinical trial of a cholinesterase inhibitor and atypical antipsychotic in the management of agitation in dementia. www.ihs.ox.ac.uk/csm/rep%20RCT.html#_Toc21853935 (accessed 15 Nov 2004).(Sudeep S Gill, adjunct scientist1, Paula)
Correspondence to: S S Gill, Room 1-152, Chapel Wing, St Mary's of the Lake Hospital, 340 Union Street, Kingston, ON, Canada K7L 5A2 gills@pccchealth.org
Abstract
A variety of behavioural disturbances such as physical aggression, agitation, hallucinations, and wandering commonly accompany dementia. The term behavioural and psychological symptoms of dementia—BPSD—describes this spectrum of non-cognitive manifestations of dementia.1 The presence of BPSD can decrease quality of life for patients and caregivers, and increases the likelihood of the patient being placed in an institution.2
Treatment of BPSD is challenging. A variety of non-pharmacological and pharmacological approaches have been assessed.3 4 Atypical antipsychotics are often prescribed to manage BPSD. Although such prescriptions represent off-label prescribing, this practise is widely endorsed because atypical antipsychotics are among the best studied treatments for BPSD and there is a perception that they have fewer adverse effects than typical antipsychotics.5 6 Recently, however, concerns have been raised that atypical antipsychotics may increase the risk of cerebrovascular adverse events, including stroke, among older adults with BPSD.
In October 2002, Health Canada and Janssen-Ortho (a manufacturer of atypical antipsychotics) issued a warning to Canadian clinicians of a possible link between risperidone use and cerebrovascular adverse events.7 This concern emerged from a clinical trial evaluating risperidone in the management of BPSD,8 and a subsequent meta-analysis of the risperidone trials for this indication also showed more cerebrovascular adverse events among participants receiving risperidone (4%) than among participants receiving placebo (2%).9 The US Food and Drug Administration issued a similar warning in April 2003.10 More recently, pooled data from clinical trials evaluating olanzapine for BPSD have shown that it may also be associated with an increased risk of cerebrovascular adverse events.11 12 These data suggest around a threefold increase in the relative risk of cerebrovascular events among people taking risperidone or olanzapine. Based on these data, the UK Committee on Safety of Medicines issued a warning in March 2004 advising that risperidone and olanzapine should no longer be used to manage BPSD, and that patients already receiving these drugs for BPSD should be switched to other treatments.12 These warnings have led to controversy among clinicians.13 14 To date, the warnings only extend to older adults receiving atypical antipsychotics for BPSD and not to patients receiving these drugs for schizophrenia or other indications. No warnings have been issued on the use of other atypical agents, such as quetiapine or aripiprazole, as few studies have been published on their use to manage BPSD. Recent data from a clinical trial of quetiapine to treat BPSD show no increased risk of cerebrovascular adverse events compared with placebo.15
The potential link between atypical antipsychotics and cerebrovascular adverse events in patients with BPSD is important, given the common use of these drugs in this patient population. If atypical antipsychotics are thought unsafe, clinicians may consider using typical antipsychotics to treat BPSD. We compared the incidence of admissions to hospitals for stroke among older adults with dementia who received atypical or typical antipsychotics.
Methods
We identified 32 710 older adults with dementia (17 845 dispensed atypical antipsychotics and 14 865 dispensed typical antipsychotics). The atypical antipsychotic cohort included 13 503 (75.7%) patients receiving risperidone, 3459 (19.4%) receiving olanzapine, and 883 (4.9%) receiving quetiapine. Table 1 lists the personal characteristics and comorbidities of patients in both cohorts. In general, the cohorts had similar personal details (standardised differences for most comparisons were < 10%). Baseline characteristics were also similar for the subcohorts taking high potency typical antipsychotics (57.1%) and low potency typical antipsychotics (42.9%; data not shown). Between 1997 and 2002 a major shift took place towards increased prescribing of atypical antipsychotics. Traditional risk factors for ischaemic stroke, such as atrial fibrillation, hypertension, diabetes, and prior stroke, were common among older adults with dementia (table 1).
Table 1 Personal characteristics and details of comorbidity in cohorts of older adults (65 years) with dementia who received atypical antipsychotics or typical antipsychotics. Values are numbers (percentages) unless stated otherwise
In the unadjusted and multivariate analyses, we found that the risk of ischaemic stroke in older adults with dementia receiving atypical antipsychotics was not significantly different from those receiving typical antipsychotics (unadjusted hazard ratio 1.06, 95% confidence interval 0.89 to 1.27; adjusted hazard ratio 1.01, 0.81 to 1.26; table 2).
Table 2 Event rates and hazard ratios for older adults with dementia receiving atypical or typical antipsychotics
The subgroup analyses were all consistent with the main analysis as they showed no significant differences in the development of stroke between the cohorts receiving atypical antipsychotics and those receiving typical antipsychotics (table 3). The risk of stroke for patients receiving risperidone (adjusted hazard ratio 1.04, 0.82 to 1.31), olanzapine (0.91, 0.62 to 1.32), and quetiapine (0.78, 0.38 to 1.57) was not significantly different from that of patients receiving typical antipsychotics. Patients dispensed two or more consecutive prescriptions (chronic users) of atypical antipsychotics were not at increased risk of stroke compared with chronic users of typical antipsychotics. Finally, the risk of stroke in the subgroup of patients enrolled between 1 April 2000 and 31 March 2002 was not significantly different between those receiving atypical antipsychotics and those receiving typical antipsychotics (adjusted hazard ratio 0.98, 95% confidence interval 0.65 to 1.47).
Table 3 Event rates and hazard ratios for subgroup analyses of older adults with dementia receiving atypical or typical antipsychotics
Discussion
Cohen-Mansfield J, Billig N. Agitated behaviours in the elderly. I: a conceptual review. J Am Geriatr Soc 1998;36: 7-12.
Cohen CA, Gold DP, Shulman KI, Wortley JT, McDonald G, Wargon M. Factors determining the decision to institutionalize dementing individuals: a prospective study. Gerontologist 1993;33: 714-20.
Teri L, Logsdon RG, McCurry SM. Nonpharmacologic treatment of behavioral disturbance in dementia. Med Clin North Am 2002;86: 641-56.
Tariot PN, Ryan JM, Porsteinsson AP, Loy R, Schneider LS. Pharmacologic therapy for behavioral symptoms of Alzheimer's disease. Clin Geriatr Med 2001;17: 359-76.
Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, et al. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001;56: 1154-66.
Liperoti R, Mor V, Lapane KL, Pedone C, Gambassi G, Bernabei R. The use of atypical antipsychotics in nursing homes. J Clin Psychiatry 2003;64: 1106-12.
Health Canada, important drug safety information: RISPERDAL* (risperidone) and cerebrovascular adverse events in placebo-controlled dementia trials—Janssen-Ortho. www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/risperdal1_e.html (accessed 15 Nov 2004).
Brodaty H, Ames D, Snowden J, Woodward M, Kirwan J, Clarnette R, et al. A randomized placebo controlled trial of risperidone for the treatment of aggression, agitation, and psychosis in dementia. J Clin Psychiatry 2003;64: 134-43.
Wooltorton E. Risperidone (Risperdal): increased rate of cerebrovascular events in dementia trials. CMAJ 2002;167: 1269-70. 10
2003 Safety alert: RISPERDAL (risperidone). Washington, DC: US Food and Drug Administration; 1 Mar 2004. www.fda.gov/medwatch/SAFETY/2003/risperdal.htm (accessed 15 Nov 2004).
Wooltorton E. Olanzapine (Zyprexa): increased incidence of cerebrovascular events in dementia trials. CMAJ 2004;170: 1395.
Atypical antipsychotic drugs and stroke: message from Professor Gordon Duff, Chairman, Committee on Safety of Medicines (CEM/CMO/2004/1). www.mca.gov.uk/ourwork/monitorsafequalmed/safetymessages/antipsystroke_9304.htm (accessed 15 Nov 2004).
Mowat D, Fowlie D, MacEwan T. CSM warning on atypical psychotics and stroke may be detrimental for dementia. BMJ 2004;328: 1262-b.
Smith DA, Beier MT. Association between risperidone treatment and cerebrovascular adverse events: examining the evidence and postulating hypotheses for an underlying mechanism. J Am Med Dir Assoc 2004;5: 129-32.
Quetiapine evaluated for agitation in people with Alzheimer's. www.alz.org/internationalconference/Pressreleases/072204_hottopics.doc (accessed 15 Nov 2004).
Mayo NE, Chockalingam A, Reeder BA, Phillips S. Surveillance for stroke in Canada. Health Rep 1994;6: 62-72.
Gladstone DJ, Kapral MK, Fang J, Laupacis A, Tu JV. Management and outcomes of transient ischemic attacks in Ontario. CMAJ 2004;170: 1099-104.
Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000;284: 2901-6.
Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004;328: 326-8.
Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW, Schopflocher DP. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology 2004;62: 2015-20.
Levy AR, O'Brien BJ, Sellors C, Grootendorst P, Willison D. Coding accuracy of administrative drug claims in the Ontario drug benefit database. Can J Clin Pharmacol 2003;10: 67-71.
Straus SE, Majumdar SR, McAlister FA. New evidence for stroke prevention: scientific review. JAMA 2002;288: 1388-95.
Schneeweiss S, Seeger JD, Maclure M, Wang PS, Avorn J, Glynn RJ. Performance of comorbidity scores to control for confounding in epidemiologic studies using claims data. Am J Epidemiol 2001;154: 854-64.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40: 373-83.
Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP, Rochon PA. Atypical antipsychotic therapy in the treatment of behavioural and psychological symptoms of dementia: systematic review. BMJ 2004;329: 75-8.
Hollander M, Koudstaal PJ, Bots ML, Grobbee DE, Hofman A, Breteler MM. Incidence, risk, and case fatality of first ever stroke in the elderly population: the Rotterdam study. J Neurol Neurosurg Psychiatry 2003;74: 317-21.
Herrmann N, Mamdani M, Lanct?t KL. Atypical antipsychotics and risk of cerebrovascular accidents. Am J Psychiatry 2004;161: 1113-5.
Liperoti R. Cerebrovascular events among elderly patients treated with conventional or atypical antipsychotics. 2004 Annual meeting of the American Geriatrics Society. www.americangeriatrics.org/news/meeting/schedule_events.pdf (accessed 15 Nov 2004).
Kozma CM, Engelhart LM, Long S, Greenspan A, Mahmoud R, Baser O. Absence of increased relative stroke risk in elderly dementia patients treated with risperidone versus other antipsychotics. 2003 meeting of the International College of Geriatric Psychoneuropharmacology. www.icgp.org/ICGP_2003_program_Book.pdf (accessed 15 Nov 2004).
Wallaschofski H, Donne M, Eigenthaler M, Hentschel B, Faber R, Stepan H, et al. PRL as a novel potent cofactor for platelet aggregation. J Clin Endocrinol Metab 2001;86: 5912-9.
Harrison-Woolrych M, Clark DWJ. Nose bleeds associated with use of risperidone. BMJ 2004;328: 1416.
Zornberg GL, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study. Lancet 2000;356: 1219-23.
Brown TM, Boyle MF. Delirium. BMJ 2002;325: 644-7.
Guidance for the management of behavioural and psychiatric symptoms in dementia and the treatment of psychosis in people with history of stroke/TIA. Working group for the Faculty of Old Age Psychiatry RCPsych, RCGP, BGS, and Alzheimer's Society, following CSM restriction on risperidone and olanzapine. www.bgs.org.uk/publications/CSM%20anouncement%2009%2003%202004.pdf (accessed 15 Nov 2004).
Schneider LS, Tariot PN, Lyketsos CG, Dagerman KS, Davis KL, Davis S. National Institute of Mental Health clinical antipsychotic trials of intervention effectiveness (CATIE): Alzheimer's disease trial methodology. Am J Geriatr Psychiatry 2001;9: 346-60.
The CALM-AD trial—a randomised clinical trial of a cholinesterase inhibitor and atypical antipsychotic in the management of agitation in dementia. www.ihs.ox.ac.uk/csm/rep%20RCT.html#_Toc21853935 (accessed 15 Nov 2004).(Sudeep S Gill, adjunct scientist1, Paula)