Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review
http://www.100md.com
《英国医生杂志》
1 Rotman Research Institute, Baycrest Centre for Geriatric Care, 3560 Bathurst Street, Toronto, ON, Canada M6A 2E1, 2 Institute for Clinical Evaluative Sciences (ICES), 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5, 3 Department of Medicine (Neurology), University of Toronto, 190 Elizabeth Street, Toronto, ON, Canada M5G 2C4, 4 Kunin-Lunenfeld Applied Research Unit (KLARU), Baycrest Centre for Geriatric Care
Correspondence to: P Lee pelee@providencehealth.bc.ca
Abstract
The term "behavioural and psychological symptoms of dementia" (BPSD) has been proposed to describe the spectrum of non-cognitive manifestations of dementia that include verbal and physical aggression, agitation, psychotic symptoms (hallucinations and delusions), sleep disturbances, and wandering.1 BPSD can decrease quality of life for patients and caregivers and increase the likelihood of admission to an institution.2
Management of BPSD has not been standardised and currently entails various non-pharmacological and pharmacological approaches. For many years, typical antipsychotic (neuroleptic) drugs were the most common treatment. Although there has been extensive experience with their use, typical anti-psychotics are only modestly effective and have potentially serious adverse effects that limit their usefulness in older adults.3
In the United States, concerns about overuse of antipsychotics led to the introduction of legislation (Omnibus Reconciliation Act 1987) that attempted to restrict prescribing of antipsychotics to residents of nursing homes.4 Before the introduction of the act, up to 55% of nursing home residents were treated with antipsychotic drugs.5 This legislation had a considerable impact on the use of such drugs in nursing homes.4 6 Several trials have shown that antipsychotics can often be safely discontinued in people in long term care.7 8 The experience in the United States has led some authors to examine how similar policies could be adopted in the United Kingdom.9
More recently, atypical antipsychotics have become available. These drugs have been widely adopted to treat psychotic disorders because they are perceived to have superior efficacy and safety compared with typical agents. Like typical antipsychotics, atypical antipsychotics block D2 receptors but they also antagonise serotonergic receptors such as 5-HT2. Depending on the specific drug, there may be effects on muscarinic, adrenergic, or histaminic receptors. The results of blocking these receptors include anticholinergic effects, orthostatic hypotension, and sedation.
Compared with typical antipsychotic agents, atypical antipsychotics are thought to be less likely to cause extrapyramidal symptoms such as parkinsonism and tardive dyskinesia.10-12 Data supporting the efficacy and safety of atypical antipsychotics need to be examined, especially in light of their high costs and newly identified adverse events. These drugs may be associated with serious adverse events, especially among patients with risk factors such as metabolic disease.13
While the use of atypical antipsychotic drugs has been well studied in younger adults with psychotic symptoms, less information is available regarding their use in older adults. In practice, however, atypical antipsychotics are increasingly used to treat older patients with BPSD, and there have been striking increases in expenditures for antipsychotic drugs with their introduction. A Canadian study using data from 1998-2000 found that 24% of nursing home residents with no previous exposure to antipsychotics were newly started on an antipsychotic drug during their first year after admission, and atypical antipsychotics accounted for 40% of these prescriptions.14 Despite their frequent use in Canada, only risperidone has been indicated for the treatment of behavioural disturbance in patients with severe dementia.15 In the United Kingdom and United States, the treatment of BPSD is not listed as an indication for the use of any atypical antipsychotic drug.16 17
To assess the benefits and risks of atypical antipsychotic drugs for BPSD, we performed a systematic review of the randomised trials in this field.
Methods
From the 77 abstracts reviewed, we identified five randomised trials (1570 patients).22-26 Of the remaining abstracts, 66 described articles that did not meet our inclusion criteria (for example, letters, review articles, observational studies), one study was an open label extension of a previously published trial, and four studies involved post hoc analyses of trial data. We also excluded a trial that evaluated intramuscular olanzapine21 because of the route of administration and short length of follow up (24 hours).
Four trials evaluated risperidone, and one evaluated olanzapine. All trials were sponsored by the pharmaceutical industry. Table 1 details the assessments of trial quality. In general, trials were of good quality, but only two adequately reported efforts to maintain concealment of allocation.20 Table 1 also gives characteristics of the participants. Most participants were in an institution (> 96%). The Chan trial also enrolled some people who were living in the community.23 The weighted mean age of participants was 82.3 years, and most had severe dementia (mean score on mini-mental state examination27 was 6.8 out of 30).
Table 1 Characteristics and methodological quality of randomised trials in review
Table 2 outlines the main efficacy results. Several factors made interpretation of the efficacy outcomes in the trials complex. Firstly, several different measurement scales were used to assess the benefits of atypical antipsychotics in managing BPSD. For example, the behavioural pathology in Alzheimer's disease rating scale (BEHAVE-AD) is a 25 item scale that measures behavioural symptoms in seven clusters (paranoid and delusional ideation; hallucinations; activity symptoms; aggressiveness; diurnal rhythm symptoms; affective symptoms; and anxieties and phobias) scored on 4 point scales of increasing severity.24 28 Other scales included the Cohen-Mansfield agitation inventory (CMAI),1 29 the neuropsychiatric inventory-nursing home version (NPI-NH),30 the brief psychiatric rating scale (BPRS),31 and the clinical global impressions (CGI) scale.32 33 A second element of complexity arose from the fact that trials measured "clinical response" to treatment in different ways. For example, De Deyn et al measured both the proportion of participants achieving > 30% reduction in total BEHAVE-AD scores and the change in mean BEHAVE-AD scores from baseline.24 In contrast, Katz et al defined clinical response as 50% reduction in BEHAVE-AD scores.25 Thirdly, the trials often reported changes on both total scores and several subscale scores (for example, the aggressiveness subscale of BEHAVE-AD). Finally, the use of multiple comparisons can inflate the type I error rate. Only three trials described statistical methods to compensate for making multiple comparisons.22 25 26
Table 2 Efficacy and safety results from included trials
Efficacy of atypical antipsychotics v placebo
Katz et al compared three fixed doses of risperidone (0.5, 1, and 2 mg/day) with placebo.25 The BEHAVE-AD, CMAI, and CGI were used to measure efficacy. Patients who received 1 or 2 mg/day of risperidone showed significant improvements compared with the placebo group on several outcome measures.
De Deyn et al compared risperidone (mean dose at end point 1.1 mg/day) with haloperidol (1.2 mg/day) and placebo.24 The primary outcome was the proportion of participants achieving 30% reduction from baseline to end point in BEHAVE-AD total scores. For this outcome, risperidone was not found to be superior to haloperidol or placebo (the proportions achieving this outcome in the risperidone, haloperidol, and placebo groups were 54%, 63%, and 47%, respectively). The authors, however, reported significant differences between risperidone and placebo on multiple secondary end points.
Brodaty et al compared flexible doses of risperidone (mean dose at end point 0.95 mg/day) with placebo.22 The least squares mean (mean adjusted for the effect of baseline score and investigator) of the CMAI total aggression scores were significantly better with risperidone than with placebo. BEHAVE-AD total and subscale scores and CMAI scores were also better with risperidone.
The only published trial evaluating oral olanzapine was reported by Street et al.26 This trial randomised participants to placebo or one of three fixed doses of olanzapine (5, 10, or 15 mg/day). The primary end point was the NPI-NH30 core total score, which was used to classify patients as responders ( 50% reduction from baseline) or non-responders. On this measure, olanzapine 5 and 10 mg/day were superior to placebo.
Efficacy of atypical v typical antipsychotic therapy
Two trials compared risperidone with haloperidol. A post hoc analysis by De Deyn et al failed to show greater improvements with risperidone than with haloperidol on the BEHAVE-AD total scores but did show significant improvements with risperidone over haloperidol on aggressiveness subscales of BEHAVE-AD and CMAI.24 Chan et al randomly assigned 58 participants to flexible doses of 0.5-2 mg/day of either risperidone or haloperidol.23 The primary outcome measure for this study was not specified. Both CMAI total scores and BEHAVE-AD subscores were reported, and no significant differences were found. However, the small sample size of this trial limits the conclusions that can be drawn from these results.
Adverse events and withdrawals
Investigators used various scales to specifically assess for extrapyramidal symptoms, a common adverse effect of antipsychotics. Symptom scales included the extrapyramidal symptom rating scale34 and the Simpson-Angus scale.35 Most symptoms examined were presumably due to parkinsonism because tardive dyskinesia would be unlikely to develop during these short trials (6-12 weeks). The trials of De Deyn et al24 and Brodaty et al22 (both of which used mean doses of about 1 mg/day of risperidone) did not document significant differences in extrapyramidal symptoms associated with treatment than with placebo. Katz et al found a dose dependent increase in extrapyramidal symptoms with risperidone that was significant for participants receiving 2 mg/day.25 Street et al reported no differences with olanzapine compared with placebo.26 The two trials that compared risperidone and haloperidol both found that extrapyramidal symptoms were more common with haloperidol.23 25
Other adverse events were often documented in the trials but were similar with treatment and placebo. De Deyn et al reported that somnolence was more common with risperidone than placebo.24 Street et al documented more somnolence and abnormal gait among participants receiving olanzapine than among those receiving placebo.26
Brodaty et al reported serious adverse events in 9% of participants receiving placebo and in 17% of those taking risperidone.22 In the risperidone group, six cerebrovascular adverse events were noted while none occurred in the placebo group.
Despite their short duration, most trials reported high withdrawal rates in the treatment and placebo groups. In two trials half of the withdrawals were due to adverse events.24 25 Katz et al found that withdrawals related to adverse events were dose dependent (12% of placebo subjects v 8%, 16%, and 24% of participants received 0.5, 1, and 2 mg/day of risperidone, respectively).25 A similar dose dependent withdrawal rate was found with olanzapine in the trial of Street et al.24 In the trial by Chan et al only three patients withdrew; one patient receiving risperidone withdrew because of a hip fracture.23
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.
Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc 1990;38: 553-63.
Shorr RI, Fought RL, Ray WA. Changes in antipsychotic drug use in nursing homes during implementation of the OBRA-87 regulations. JAMA 1994;271: 358-62.
Avorn J, Dreyer P, Connelly K, Soumerai SB. Use of psychoactive medication and the quality of care in rest homes. N Engl J Med 1989;320: 227-32.
Semla TP, Palla K, Poddig B, Brauner DJ. Effect of the Omnibus Reconciliation Act 1987 on antipsychotic prescribing in nursing home residents. J Am Geriatr Soc 1994;42: 648-52.
Avorn J, Soumerai SB, Everitt DE, Ross-Degnan D, Beers MH, Sherman D, et al. A randomized trial of a program to reduce the use of psychoactive drugs in nursing homes. N Engl J Med 1992;327: 168-73.
Van Reekum R, Clarke D, Conn D, Herrmann N, Eryavec G, Cohen T, et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Int Psychogeriatr 2002;14: 197-210.
Hughes CM, Lapane KL, Mor V, Turrell A, Castleden CM. Impact of legislation on nursing home care in the United States lessons for the United Kingdom. BMJ 1999;319: 1060-3.
Fabbrini G, Barbanti P, Aurilia C. Tardive dyskinesias in the elderly. Int J Geriatr Psychiatry 2001;16: S19-23.
Jeste DV, Lacro JP, Bailey A, Rockwell E, Harris MJ, Caligiuri MP. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 1999;47: 716-9.
Wirshing WC. Movement disorders associated with neuroleptic treatment. J Clin Psychiaty 2001;62: 15-8.
Buse JB. Metabolic side effects of antipsychotics: focus on hyperglycemia and diabetes. J Clin Psychiatry 2002;63: 37-41.
Bronskill SE, Anderson GM, Sykora K, Wodchis WP, Gill S, Shulman KI, et al. Neuroleptic drug therapy in older adults newly admitted to nursing homes: incidence, dose and specialist contact. J Am Geriatr Soc 2004 (in press).
Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association, 2003: 1505.
British Medical Association, Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMA, RPS, 2004: 179-183. (No 47.)
Physicians desk reference. 58th ed. Montvale, NJ: Thomson, 2004.
Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical handbook of psychotropic drugs. 12th ed. Toronto: Hogrefe & Huber, 2002.
Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17: 1-12.
Jüni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001;323: 42-6.
Meehan KM, Wang H, David SR, Nisivoccia JR, Jones B, Beasley CM Jr, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002;26: 494-504.
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.
Chan W, Lam LC, Choy CN, Leung VP, Li S, Chiu HF. A double-blind randomized comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 2001;16: 1156-62.
De Deyn PP, Rabheru K, Rasmussen A, Bocksberger JP, Dautzenberg PLJ, Eriksson S, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53: 946-55.
Katz I, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M, et al. Comparison of risperidone and placebo for psychosis and behavioural disturbances associated with dementia: a randomized, double blind trial. J Clin Psychiatry 1999;60: 107-15.
Street JS, Clark WS, Gannon KS, Cummings JL, Bymaster FP, Tamura RN, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU study group. Arch Gen Psychiatry 2000;57: 968-76.
Folstein MF, Folstein S, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12: 189-98.
Reisberg B, Borenstein J, Salob SP, Ferris SH, Franssen E, Georgotas A. Behavioral symptoms in Alzheimer's disease: phenomenology and treatment. J Clin Psychiatry 1987;48: 9-15.
Koss E, Weiner M, Ernesto C, Cohen-Mansfield J, Ferris SH, Grundman M, et al. Assessing patterns of agitation in Alzheimer's disease patients with the Cohen-Mansfield agitation inventory. Alzheimer Dis Assoc Disord 1997;11: S45-50.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44, 2308-14.
Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep 1962;10: 799-812.
Guy W. Clinical Global Impressions (CGI). In: ECDEU assessment manual for psychopharmacology. Bethesda, MD: NIMH Psychopharmacology Research Branch, 1976.
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. Validity and reliability of the Alzheimer's disease cooperative study-clinical global impression of change. Alzheimer Dis Assoc Disord 1997;11: S22-32.
Chouinard D, Ross-Canard A, Annable L, Jones BD. The extrapyramidal symptom rating scale. Can J Neurol Sci 1980;7: 233.
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 1970;212: 11-9.
Pwee KH, Shukla VK, Herrmann N, Skidmore B. Novel antipsychotics for agitation in dementia: a systematic review. Ottawa: Canadian Coordinating Office for Health Technology Assessment, 2003. (Technology report No 36.)
De Deyn PP, Wirshing WC. Scales to assess efficacy and safety of pharmacologic agents in the treatment of behavioral and psychological symptoms of dementia. J Clin Psychiatry 2001;62: 19-22.
Ballard CG, Margallo-Lana M, Fossey J, Reichelt K, Myint P, Potkins D, et al. A 1-year follow-up study of behavioral and psychological symptoms in dementia among people in care environments. J Clin Psychiatry 2001;62: 631-6.
Street JS, Clark WS, Kadam DL, Mitan SJ, Juliar BE, Feldman PD, et al. Long-term efficacy of olanzapine in the control of psychotic and behavioral symptoms in nursing home patients with Alzheimer's dementia. Int J Geriatr Psychiatry 2001;16: S62-70.
Davidson M. Long-term safety of risperidone. J Clin Psychiatry 2003;62: 26-8.
Lindenmeyer JP, Czobor P, Volavka J. Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am J Psychiatry 2003;160: 290-6.
Health Canada. www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/risperdal1_e.html (accessed 10 Feb 2004).
Food and Drug Administration. 2003 safety alert—Risperdal (risperidone). www.fda.gov/medwatch/SAFETY/2003/risperdal.htm (accessed 15 Mar 2004).
Professor Gordon Duff, chairman—Committee on Safety of Medicines. Atypical antipsychotics drugs and stroke. http://medicines.mhra.gov.uk/ (accessed 15 Mar 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.(Philip E Lee, behavioural)
Correspondence to: P Lee pelee@providencehealth.bc.ca
Abstract
The term "behavioural and psychological symptoms of dementia" (BPSD) has been proposed to describe the spectrum of non-cognitive manifestations of dementia that include verbal and physical aggression, agitation, psychotic symptoms (hallucinations and delusions), sleep disturbances, and wandering.1 BPSD can decrease quality of life for patients and caregivers and increase the likelihood of admission to an institution.2
Management of BPSD has not been standardised and currently entails various non-pharmacological and pharmacological approaches. For many years, typical antipsychotic (neuroleptic) drugs were the most common treatment. Although there has been extensive experience with their use, typical anti-psychotics are only modestly effective and have potentially serious adverse effects that limit their usefulness in older adults.3
In the United States, concerns about overuse of antipsychotics led to the introduction of legislation (Omnibus Reconciliation Act 1987) that attempted to restrict prescribing of antipsychotics to residents of nursing homes.4 Before the introduction of the act, up to 55% of nursing home residents were treated with antipsychotic drugs.5 This legislation had a considerable impact on the use of such drugs in nursing homes.4 6 Several trials have shown that antipsychotics can often be safely discontinued in people in long term care.7 8 The experience in the United States has led some authors to examine how similar policies could be adopted in the United Kingdom.9
More recently, atypical antipsychotics have become available. These drugs have been widely adopted to treat psychotic disorders because they are perceived to have superior efficacy and safety compared with typical agents. Like typical antipsychotics, atypical antipsychotics block D2 receptors but they also antagonise serotonergic receptors such as 5-HT2. Depending on the specific drug, there may be effects on muscarinic, adrenergic, or histaminic receptors. The results of blocking these receptors include anticholinergic effects, orthostatic hypotension, and sedation.
Compared with typical antipsychotic agents, atypical antipsychotics are thought to be less likely to cause extrapyramidal symptoms such as parkinsonism and tardive dyskinesia.10-12 Data supporting the efficacy and safety of atypical antipsychotics need to be examined, especially in light of their high costs and newly identified adverse events. These drugs may be associated with serious adverse events, especially among patients with risk factors such as metabolic disease.13
While the use of atypical antipsychotic drugs has been well studied in younger adults with psychotic symptoms, less information is available regarding their use in older adults. In practice, however, atypical antipsychotics are increasingly used to treat older patients with BPSD, and there have been striking increases in expenditures for antipsychotic drugs with their introduction. A Canadian study using data from 1998-2000 found that 24% of nursing home residents with no previous exposure to antipsychotics were newly started on an antipsychotic drug during their first year after admission, and atypical antipsychotics accounted for 40% of these prescriptions.14 Despite their frequent use in Canada, only risperidone has been indicated for the treatment of behavioural disturbance in patients with severe dementia.15 In the United Kingdom and United States, the treatment of BPSD is not listed as an indication for the use of any atypical antipsychotic drug.16 17
To assess the benefits and risks of atypical antipsychotic drugs for BPSD, we performed a systematic review of the randomised trials in this field.
Methods
From the 77 abstracts reviewed, we identified five randomised trials (1570 patients).22-26 Of the remaining abstracts, 66 described articles that did not meet our inclusion criteria (for example, letters, review articles, observational studies), one study was an open label extension of a previously published trial, and four studies involved post hoc analyses of trial data. We also excluded a trial that evaluated intramuscular olanzapine21 because of the route of administration and short length of follow up (24 hours).
Four trials evaluated risperidone, and one evaluated olanzapine. All trials were sponsored by the pharmaceutical industry. Table 1 details the assessments of trial quality. In general, trials were of good quality, but only two adequately reported efforts to maintain concealment of allocation.20 Table 1 also gives characteristics of the participants. Most participants were in an institution (> 96%). The Chan trial also enrolled some people who were living in the community.23 The weighted mean age of participants was 82.3 years, and most had severe dementia (mean score on mini-mental state examination27 was 6.8 out of 30).
Table 1 Characteristics and methodological quality of randomised trials in review
Table 2 outlines the main efficacy results. Several factors made interpretation of the efficacy outcomes in the trials complex. Firstly, several different measurement scales were used to assess the benefits of atypical antipsychotics in managing BPSD. For example, the behavioural pathology in Alzheimer's disease rating scale (BEHAVE-AD) is a 25 item scale that measures behavioural symptoms in seven clusters (paranoid and delusional ideation; hallucinations; activity symptoms; aggressiveness; diurnal rhythm symptoms; affective symptoms; and anxieties and phobias) scored on 4 point scales of increasing severity.24 28 Other scales included the Cohen-Mansfield agitation inventory (CMAI),1 29 the neuropsychiatric inventory-nursing home version (NPI-NH),30 the brief psychiatric rating scale (BPRS),31 and the clinical global impressions (CGI) scale.32 33 A second element of complexity arose from the fact that trials measured "clinical response" to treatment in different ways. For example, De Deyn et al measured both the proportion of participants achieving > 30% reduction in total BEHAVE-AD scores and the change in mean BEHAVE-AD scores from baseline.24 In contrast, Katz et al defined clinical response as 50% reduction in BEHAVE-AD scores.25 Thirdly, the trials often reported changes on both total scores and several subscale scores (for example, the aggressiveness subscale of BEHAVE-AD). Finally, the use of multiple comparisons can inflate the type I error rate. Only three trials described statistical methods to compensate for making multiple comparisons.22 25 26
Table 2 Efficacy and safety results from included trials
Efficacy of atypical antipsychotics v placebo
Katz et al compared three fixed doses of risperidone (0.5, 1, and 2 mg/day) with placebo.25 The BEHAVE-AD, CMAI, and CGI were used to measure efficacy. Patients who received 1 or 2 mg/day of risperidone showed significant improvements compared with the placebo group on several outcome measures.
De Deyn et al compared risperidone (mean dose at end point 1.1 mg/day) with haloperidol (1.2 mg/day) and placebo.24 The primary outcome was the proportion of participants achieving 30% reduction from baseline to end point in BEHAVE-AD total scores. For this outcome, risperidone was not found to be superior to haloperidol or placebo (the proportions achieving this outcome in the risperidone, haloperidol, and placebo groups were 54%, 63%, and 47%, respectively). The authors, however, reported significant differences between risperidone and placebo on multiple secondary end points.
Brodaty et al compared flexible doses of risperidone (mean dose at end point 0.95 mg/day) with placebo.22 The least squares mean (mean adjusted for the effect of baseline score and investigator) of the CMAI total aggression scores were significantly better with risperidone than with placebo. BEHAVE-AD total and subscale scores and CMAI scores were also better with risperidone.
The only published trial evaluating oral olanzapine was reported by Street et al.26 This trial randomised participants to placebo or one of three fixed doses of olanzapine (5, 10, or 15 mg/day). The primary end point was the NPI-NH30 core total score, which was used to classify patients as responders ( 50% reduction from baseline) or non-responders. On this measure, olanzapine 5 and 10 mg/day were superior to placebo.
Efficacy of atypical v typical antipsychotic therapy
Two trials compared risperidone with haloperidol. A post hoc analysis by De Deyn et al failed to show greater improvements with risperidone than with haloperidol on the BEHAVE-AD total scores but did show significant improvements with risperidone over haloperidol on aggressiveness subscales of BEHAVE-AD and CMAI.24 Chan et al randomly assigned 58 participants to flexible doses of 0.5-2 mg/day of either risperidone or haloperidol.23 The primary outcome measure for this study was not specified. Both CMAI total scores and BEHAVE-AD subscores were reported, and no significant differences were found. However, the small sample size of this trial limits the conclusions that can be drawn from these results.
Adverse events and withdrawals
Investigators used various scales to specifically assess for extrapyramidal symptoms, a common adverse effect of antipsychotics. Symptom scales included the extrapyramidal symptom rating scale34 and the Simpson-Angus scale.35 Most symptoms examined were presumably due to parkinsonism because tardive dyskinesia would be unlikely to develop during these short trials (6-12 weeks). The trials of De Deyn et al24 and Brodaty et al22 (both of which used mean doses of about 1 mg/day of risperidone) did not document significant differences in extrapyramidal symptoms associated with treatment than with placebo. Katz et al found a dose dependent increase in extrapyramidal symptoms with risperidone that was significant for participants receiving 2 mg/day.25 Street et al reported no differences with olanzapine compared with placebo.26 The two trials that compared risperidone and haloperidol both found that extrapyramidal symptoms were more common with haloperidol.23 25
Other adverse events were often documented in the trials but were similar with treatment and placebo. De Deyn et al reported that somnolence was more common with risperidone than placebo.24 Street et al documented more somnolence and abnormal gait among participants receiving olanzapine than among those receiving placebo.26
Brodaty et al reported serious adverse events in 9% of participants receiving placebo and in 17% of those taking risperidone.22 In the risperidone group, six cerebrovascular adverse events were noted while none occurred in the placebo group.
Despite their short duration, most trials reported high withdrawal rates in the treatment and placebo groups. In two trials half of the withdrawals were due to adverse events.24 25 Katz et al found that withdrawals related to adverse events were dose dependent (12% of placebo subjects v 8%, 16%, and 24% of participants received 0.5, 1, and 2 mg/day of risperidone, respectively).25 A similar dose dependent withdrawal rate was found with olanzapine in the trial of Street et al.24 In the trial by Chan et al only three patients withdrew; one patient receiving risperidone withdrew because of a hip fracture.23
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.
Schneider LS, Pollock VE, Lyness SA. A metaanalysis of controlled trials of neuroleptic treatment in dementia. J Am Geriatr Soc 1990;38: 553-63.
Shorr RI, Fought RL, Ray WA. Changes in antipsychotic drug use in nursing homes during implementation of the OBRA-87 regulations. JAMA 1994;271: 358-62.
Avorn J, Dreyer P, Connelly K, Soumerai SB. Use of psychoactive medication and the quality of care in rest homes. N Engl J Med 1989;320: 227-32.
Semla TP, Palla K, Poddig B, Brauner DJ. Effect of the Omnibus Reconciliation Act 1987 on antipsychotic prescribing in nursing home residents. J Am Geriatr Soc 1994;42: 648-52.
Avorn J, Soumerai SB, Everitt DE, Ross-Degnan D, Beers MH, Sherman D, et al. A randomized trial of a program to reduce the use of psychoactive drugs in nursing homes. N Engl J Med 1992;327: 168-73.
Van Reekum R, Clarke D, Conn D, Herrmann N, Eryavec G, Cohen T, et al. A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia. Int Psychogeriatr 2002;14: 197-210.
Hughes CM, Lapane KL, Mor V, Turrell A, Castleden CM. Impact of legislation on nursing home care in the United States lessons for the United Kingdom. BMJ 1999;319: 1060-3.
Fabbrini G, Barbanti P, Aurilia C. Tardive dyskinesias in the elderly. Int J Geriatr Psychiatry 2001;16: S19-23.
Jeste DV, Lacro JP, Bailey A, Rockwell E, Harris MJ, Caligiuri MP. Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients. J Am Geriatr Soc 1999;47: 716-9.
Wirshing WC. Movement disorders associated with neuroleptic treatment. J Clin Psychiaty 2001;62: 15-8.
Buse JB. Metabolic side effects of antipsychotics: focus on hyperglycemia and diabetes. J Clin Psychiatry 2002;63: 37-41.
Bronskill SE, Anderson GM, Sykora K, Wodchis WP, Gill S, Shulman KI, et al. Neuroleptic drug therapy in older adults newly admitted to nursing homes: incidence, dose and specialist contact. J Am Geriatr Soc 2004 (in press).
Compendium of Pharmaceuticals and Specialties. Ottawa: Canadian Pharmacists Association, 2003: 1505.
British Medical Association, Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMA, RPS, 2004: 179-183. (No 47.)
Physicians desk reference. 58th ed. Montvale, NJ: Thomson, 2004.
Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical handbook of psychotropic drugs. 12th ed. Toronto: Hogrefe & Huber, 2002.
Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17: 1-12.
Jüni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001;323: 42-6.
Meehan KM, Wang H, David SR, Nisivoccia JR, Jones B, Beasley CM Jr, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 2002;26: 494-504.
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.
Chan W, Lam LC, Choy CN, Leung VP, Li S, Chiu HF. A double-blind randomized comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 2001;16: 1156-62.
De Deyn PP, Rabheru K, Rasmussen A, Bocksberger JP, Dautzenberg PLJ, Eriksson S, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 1999;53: 946-55.
Katz I, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M, et al. Comparison of risperidone and placebo for psychosis and behavioural disturbances associated with dementia: a randomized, double blind trial. J Clin Psychiatry 1999;60: 107-15.
Street JS, Clark WS, Gannon KS, Cummings JL, Bymaster FP, Tamura RN, et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU study group. Arch Gen Psychiatry 2000;57: 968-76.
Folstein MF, Folstein S, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12: 189-98.
Reisberg B, Borenstein J, Salob SP, Ferris SH, Franssen E, Georgotas A. Behavioral symptoms in Alzheimer's disease: phenomenology and treatment. J Clin Psychiatry 1987;48: 9-15.
Koss E, Weiner M, Ernesto C, Cohen-Mansfield J, Ferris SH, Grundman M, et al. Assessing patterns of agitation in Alzheimer's disease patients with the Cohen-Mansfield agitation inventory. Alzheimer Dis Assoc Disord 1997;11: S45-50.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44, 2308-14.
Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep 1962;10: 799-812.
Guy W. Clinical Global Impressions (CGI). In: ECDEU assessment manual for psychopharmacology. Bethesda, MD: NIMH Psychopharmacology Research Branch, 1976.
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. Validity and reliability of the Alzheimer's disease cooperative study-clinical global impression of change. Alzheimer Dis Assoc Disord 1997;11: S22-32.
Chouinard D, Ross-Canard A, Annable L, Jones BD. The extrapyramidal symptom rating scale. Can J Neurol Sci 1980;7: 233.
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 1970;212: 11-9.
Pwee KH, Shukla VK, Herrmann N, Skidmore B. Novel antipsychotics for agitation in dementia: a systematic review. Ottawa: Canadian Coordinating Office for Health Technology Assessment, 2003. (Technology report No 36.)
De Deyn PP, Wirshing WC. Scales to assess efficacy and safety of pharmacologic agents in the treatment of behavioral and psychological symptoms of dementia. J Clin Psychiatry 2001;62: 19-22.
Ballard CG, Margallo-Lana M, Fossey J, Reichelt K, Myint P, Potkins D, et al. A 1-year follow-up study of behavioral and psychological symptoms in dementia among people in care environments. J Clin Psychiatry 2001;62: 631-6.
Street JS, Clark WS, Kadam DL, Mitan SJ, Juliar BE, Feldman PD, et al. Long-term efficacy of olanzapine in the control of psychotic and behavioral symptoms in nursing home patients with Alzheimer's dementia. Int J Geriatr Psychiatry 2001;16: S62-70.
Davidson M. Long-term safety of risperidone. J Clin Psychiatry 2003;62: 26-8.
Lindenmeyer JP, Czobor P, Volavka J. Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics. Am J Psychiatry 2003;160: 290-6.
Health Canada. www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/risperdal1_e.html (accessed 10 Feb 2004).
Food and Drug Administration. 2003 safety alert—Risperdal (risperidone). www.fda.gov/medwatch/SAFETY/2003/risperdal.htm (accessed 15 Mar 2004).
Professor Gordon Duff, chairman—Committee on Safety of Medicines. Atypical antipsychotics drugs and stroke. http://medicines.mhra.gov.uk/ (accessed 15 Mar 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.(Philip E Lee, behavioural)