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Conventional antipsychotic drugs such as haloperidol have been supplanted by newer, atypical antipsychotics (risperidone [Risperdal], olanzapine [Zyprexa], quetiapine [Seroquel], ziprasidone [Geodon], aripiprazole [Abilify]), although no medication has an FDA indication for the treatment of behavioral symptoms in patients with dementia
Antipsychotic drugs have been the primarypsychopharmacological mainstay of treatmentfor psychosis, agitation, and aggression inAlzheimer Disease (AD) and other dementias.
Conventional antipsychotic drugs such as haloperidol have been supplanted by newer, atypical antipsychotics (risperidone [Risperdal], olanzapine [Zyprexa], quetiapine [Seroquel], ziprasidone [Geodon], aripiprazole [Abilify]), although no medication has an FDA indication for the treatment of behavioral symptoms in patients with dementia.1-5
During the past 3 years, a number of placebo-controlled clinical trials of atypical antipsychotics for behavioral symptoms have reported small treatment effect sizes coupled with adverse effects at rates that exceed those observed in placebo-treated patients.6,7 Results from some prospective randomized controlled trials of dementia and subsequent meta-analyses suggest that atypical antipsychotic pharmacotherapy is associated with an increased risk of mortal-ity and cerebrovascular adverse events (CVAEs).8,9 These developments have fueled an ongoing debate over the appropriate prescribing of antipsychotics.9-11
Widespread acceptance of atypical antipsychotics for psychosis and behavioral symptoms preceded the availability of a supportive evidence base. In light of ongoing controversies and recently published data, it is essential that clinicians understand the most current information about the use of atypical antipsychotics in patients with dementia.
Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) was the first head-to-head, prospective, randomized, double-blind, placebo-controlled effectiveness study of atypical antipsychotic therapy in AD.7 The unique design measured outcomes associated with real-world prescribing of these medications to treat behavioral symptoms. The goal of the study was to determine the effectiveness and tolerability of 3 atypical antipsychotics (compared with placebo) in the treatment of dementia-related behavioral symptoms in patients residing in community settings. The multicenter trial was funded by the National Institute of Mental Health.
In the initial, 36-week phase of the study, outpatients with mild to severe AD and behavioral symptoms (delusions, hallucinations, aggression, agitation) of at least moderate severity were randomly selected to receive flexible dosing with olanzapine (n = 100), risperidone (n = 85), quetiapine (n = 94), or placebo (n = 142). (Aripiprazole and ziprasidone were not included in the study because they were not available in the United States at the time the trial was designed.)
The study population was moderately cognitively impaired (Mini-Mental State Examination score, 15 ± 5.8). The mean age was 77.9 ± 7.5 years. Baseline behavioral symptoms were of moderate severity (Neuropsychiatric Inventory score, 36.9 ± 18.3), and 60% of the study participants received adjunctive acetylcholinesterase inhibitor therapy at study entry.
Participants who responded adequately to therapy could continue the trial up to 36 weeks. If the physician determined that response was inadequate for any reason after the initial 2 weeks of therapy, treatment was discontinued. Patients whose therapy was discontinued could enter phase 2 of the trial wherein they would be randomly selected to receive one of the other antipsychotics or citalopram under double-blind conditions. Only phase 1 data have been published at this time.
The primary outcome was time to discontinuation of treatment for any reason in phase 1 of the study. In this study design, "time to discontinuation" was a composite outcome that incorporated the combined effects of efficacy, tolerability, and caregiver burden for each treatment condition.
Time to discontinuation for lack of efficacy was significantly longer for participants receiving risperidone (26.7 weeks) or olanzapine (22.1 weeks) than for those receiving placebo (9.0 weeks). Notably, overall effectiveness (as measured by time to treatment discontinuation for any reason) was not significantly different between any of the active-treatment groups or the placebo group. Except for quetiapine (at a 56.5-mg dose), the mean daily dose of olanzapine (5.5 mg) and risperidone (1.0 mg) at the study's end point was within the usual accepted range for treatment of neuropsychiatric symptoms.
The lowest rate (5%) of intolerable adverse effects or death was seen in placebo-treated patients. Significantly higher rates of discontinuation for adverse effects were reported in all active-treatment groups: 24% in the group that received olanzapine, 18% in the group that received risperidone, and 16% in the group that received quetiapine.
Sedation occurred more frequently with active treatment than with placebo for all antipsychotics, while confusion and psychotic symptoms were observed at significantly higher rates with olanzapine than with placebo or the other atypical antipsychotic drugs. Treatment-emergent parkinsonism occurred more commonly in patients assigned to receive either olanzapine or risperidone. Although higher rates of parkinsonism and sedation were observed in the active-treatment groups, no differences in the incidence of falls, fractures, or injuries across all treatment groups were observed.
CATIE-AD was the first prospective head-to-head study to explore whether an association existed between atypical antipsychotic treatment and development of metabolic adverse effects in older adults with AD. The mean changes in weight and in blood glucose, total cholesterol, and triglyceride levels for risperidone, olanzapine, and quetiapine treatment groups were not significantly different from the observed changes in the placebo group. A small but significant increase in body mass index (BMI) and monthly weight gain was reported for participants receiving olanzapine (1.0 lb), quetiapine (0.7 lb), or risperidone (0.4 lb) during the study compared with a weight loss of less than 1 lb and 20.2 BMI units per month for those receiving placebo.
Although significant changes in serum glucose and lipid levels have not been reported in earlier short-term (6- to 12-week) placebo-controlled trials of atypical agents for dementia, the association of atypical antipsychotics with weight gain and metabolic abnormalities in younger patients has been a long-standing concern for clinicians treating older patients.12-14 Analyses of post-marketing reports of treatment-emergent hyperglycemia and diabetes in patients with schizophrenia or bipolar illness have identified the mean age at onset as between the third and fifth decades of life.15
The risk of significant metabolic effects appears to differ between atypicals. In younger patients, clozapine and olanzapine appear to be most commonly associated with hyperlipidemia and hyperglycemia, whereas aripiprazole and ziprasidone are least implicated.15 Risperidone and quetiapine have intermediate effects on weight gain and metabolic parameters. It remains unclear whether antipsychotic-induced metabolic effects are a class effect or a consequence of the interaction of antipsychotics with the complex diathesis of psychiatric illness, ge- netics, and dietary factors.16,17
GUIDELINES ON OFF-LABEL USE
Efficacy and Comparative Effectiveness of Off-Label Use of Atypical Antipsychotics, a publication of the Agency for HealthCare Research and Quality, retrospectively reviewed efficacy and safety of clinical trial data related to the most common off-label uses for the atypical antipsychotics: treatment of agitation in dementia, depression, obsessive-compulsive disorder, posttraumatic stress disorder, personality disorders, and Tourette syndrome.18 It was published online in January 2007 (http://effectivehealthcare.ahrq.gov/reports/topic.cfm?topic=8&sid=34&rType=3).
Data for the agitation in dementia analysis were drawn from randomized controlled trials in dementia, including the CATIE-AD study. Conclusions about the relative effectiveness of risperidone, olanzapine, quetiapine, and aripiprazole were in general agreement with results of a recently published meta-analysis of 15 placebo-controlled atypical antipsychotic trials that reported small but significant benefits on agitation and psychosis for risperidone and aripiprazole.19 A trend favoring the effectiveness of olanzapine for psychosis in dementia that did not reach statistical significance also was noted.
No conclusions were reached about quetiapine or ziprasidone use in dementia. Design and outcome measures of the 3 available trials of quetiapine for dementia were too different to be included in the analysis, and no randomized controlled trials have been conducted for ziprasidone in dementia.
DOCUMENTED ADVERSE EFFECTS
Analysis of CVAE risk: prospective trials. The current FDA-approved product labeling for olanzapine, risperidone, and aripiprazole includes cautionary language about increased rates of CVAE observed in some dementia trials. Although previous analyses of pooled clinical trial data linked atypical antipsychotic treatment of behavioral symptoms in patients with dementia to an increased risk of CVAE, there were no differences in the rates of stroke noted between the groups receiving atypical antipsychotic treatment and placebo-treated patients in CATIE-AD.7
In a post hoc analysis of pooled data from 6 dementia trials that compared olanzapine with placebo, risperidone, or haloperidol, Kryzhanovskaya and colleagues analyzed the CVAE data and reported that the incidence of CVAE was nearly 3 times higher in olanzapine-treated patients (1.3%) than in placebo-treated patients (0.4%).11 However, exposure-adjusted CVAE rates were not significantly different for olanzapine versus risperidone or olanzapine versus haloperidol.
Analysis of mortality risk: prospective trials. The discovery of the increased risk of death in pooled data from risperidone, olanzapine, quetiapine, and aripiprazole placebo-controlled dementia trials led the FDA to add a black box warning to the product labeling for all atypical antipsychotics in April 2005. The warning was added for all atypicals, despite that one of these medications (ziprasidone) had never been studied in dementia trials.20
Schneider and colleagues19 published a meta-analysis of 15 short-term placebo-controlled trials of risperidone, olanzapine, quetiapine, and aripiprazole for dementia-related behavioral symptoms. Risk of death was increased relative to placebo (odds ratio, 1.54; 95% confidence interval [CI], 1.06 to 2.23) for patients randomly selected to receive 1 of the 4 antipsychotics. This report confirmed the FDA analysis that found a similarly increased risk of death among dementia patients treated with risperidone, olanzapine, or quetiapine in placebo-controlled trials.
In contrast to the previous analyses, CATIE-AD failed to demonstrate increased risk of mortality associated with treatment compared with placebo or between treatment groups assigned to risperidone, olanzapine, or quetiapine.7 The lack of significance for incidence of stroke or increased rate of death during the trial is not surprising considering some important differences between the AD population studied in CATIE-AD and the heterogeneity of some of the populations under study in the short-term (6- to 12-week) antipsychotic dementia trials, which included both patients with AD and those with mixed dementia.8,12
A number of trials of atypical antipsychotic agents included patients with dementia and significant cardiovascular risk factors; others studied the effects of treatment in frail nursing home patients who may be at higher risk for adverse medication-related outcomes and all-cause mortality.8,12,13
Analysis of mortality risk: retrospective claims data. Examination of the mortality rates for 2 of the studies with a haloperidol comparator included in the FDA analysis revealed that although the risk of death in patients treated with haloperidol was increased compared with the placebo group, the differences were not significant after adjustment for exposure (relative risk [RR], 2.07; 95% CI, 0.78 to 5.51; P = .15).9
Wang and colleagues21 used US claims data to investigate death rates in a large cohort of older adults receiving either conventional or atypical antipsychotic therapy and found that compared with users of atypical antipsychotics, a significantly greater risk of death in patients for whom older antipsychotics were prescribed was seen. Rates of fatal events were greatest (conventional agents, 17.9%; atypical agents, 14.6%) in the first 40 days after starting therapy and remained significant even after adjusting for diagnosis of dementia or nursing home residence.
Using Canadian claims data and a similar study design, Schneeweiss and colleagues22 also demonstrated an increased risk of death associated with conventional antipsychotics that significantly exceeded event rates in patients receiving newer agents. Choice of conventional antipsychotic had an impact on the risk of mortality in patients with dementia.22 Compared with risperidone, haloperidol was associated with the greatest increase in mortality (RR, 2.14; 95% CI, 1.86 to 2.45) and loxapine with the lowest (RR, 1.29; 95% CI, 1.19 to 1.40).
Despite high background mortality rates, use of either a conventional or atypical antipsychotic was associated with greater risk of dying for patients residing in either community or nursing home settings in the most recently published case-control study according to US claims data.23 Within 30 days of starting an atypical antipsychotic, nursing home residents with a dementia diagnosis were more likely to die (hazard rate [HR], 1.55; 95% CI, 1.15 to 2.07) than untreated patients with dementia still residing in the community (HR, 1.31; 95% CI, 1.02 to 1.70).
UNDERSTANDING THE RISKS
To improve individual patient outcomes, clinicians must identify modifiable factors that facilitate or amplify antipsychotic-related adverse effects and understand what (if any) patient-specific characteristics decrease the risk of serious events.
CVAE. Kryzhanovskaya and colleagues11 analyzed possible associations between CVAE and patient demographics, dementia diagnosis, and treatment-emergent adverse effects. A diagnosis of mixed or vascular dementia was significantly associated with CVAE in patients 80 years or older who were receiving either olanzapine or placebo. Orthostatic hypotension and gender were not significant risk factors in this analysis.
Antipsychotic agents and mortality risk. The impact of select characteristics (baseline sedation, malnutrition, dehydration, change in weight, BMI, extrapyramidal adverse effects, number of concurrent medications, and dysphagia) on risk of dying during olanzapine dementia trials also was investigated.11 Conditions identified as additive risk factors for death in olanzapine-treated patients included age 80 years or older, treatment-emergent sedation, benzodiazepine use, and treatment- emergent pulmonary conditions. Presence of multiple risk factors, in addition to treatment assignment to olanzapine, significantly amplified the risk of dying during the studies (0.7% if no risk factors; 1.5% with 1 risk factor; 3.8% with 2 risk factors; 18.7% with 3 risk factors; and 30% with 4 risk factors).
Atypical antipsychotic agents will continue to be prescribed for the behavioral symptoms of dementia in the absence of more effective, better-tolerated, and safer alternatives. The current evidence, although incomplete, suggests that modest treatment effect sizes are offset by the risk of considerable adverse effects.
In CATIE-AD, it was reported that the sum total of the risk/benefit equation of atypical antipsychotic therapy was no greater than that achieved by placebo. However, CATIE-AD was designed to study the efficacy of atypical antipsychotic treatment in community-dwelling patients with AD. It is uncertain whether the results can be generalized to the populations of dementia patients residing in nursing homes who have more severe cognitive impairment and significant behavioral symptoms.
Nursing home patients with dementia complicated by severe behavioral symptoms-particularly agitation and aggression without accompanying psychosis-may achieve more symptomatic benefit from atypical antipsychot-ic treatment than patients with milder behavioral symptoms. Subgroup analyses across atypical antipsychotic trials showed that larger effect sizes were associated with greater cognitive impairment, residence in nursing home versus community settings, and the presence of severe agitation without psychosis.19
Nevertheless, patients who reside in extended-care settings, are 80 years or older, have pulmonary conditions such as chronic obstructive pulmonary disease or asthma, and are receiving benzodiazepines probably represent a highly vulnerable subgroup.11 Indeed, benzodiazepine-associated sedation exacerbates preexisting cognitive impairment and increases the risk of complications such as aspiration pneumonia. The report by Kryzhanovskaya and colleagues11 suggests the need for caution in antipsychotic dose titration and in the monitoring of patients who have multiple risk factors.
Aggressive monitoring of signs of adverse effects in the first 1 to 2 months of antipsychotic therapy may be especially important. In 2 studies, the risk of death was greatest up to 40 days after an antipsychotic agent was initiated.17,19 Factors such as titration-related sedation, gait instability, and increased risk of injury when symptoms are not initially responsive to treatment may be contributive.
PRESCRIBING ATYPICAL AGENTS AND RISK MANAGEMENT
According to Recupero and Rainey,20 who recently developed a framework for managing medicolegal risks when prescribing atypical antipsychotics for dementia-related psychiatric and behavioral problems, symptom severity and frequency, as well as assessment of the risk of self-harm or endangerment of others, should be carefully considered in assessing whether a patient requires antipsychotic therapy.
If nonpharmacological methods fail, the risk of adverse effects must be weighed against the potential benefit of antipsychotic treatment,20 particularly in the patient with comorbidities such as cardiac disease, diabetes, obesity, and movement disorders.
The treatment plan should include ongoing assessment and documentation of potential adverse effects of antipsychotic therapy, such as weight gain, hyperlipidemia, and hyperglycemia, which may exacerbate comorbidities.
When unsatisfactory outcomes occur, malpractice lawsuits are more likely to be initiated if patients and caregivers feel excluded from the treatment planning process. If the patient's decision-making ability is impaired, it is recommended that consent for treatment with antipsychotic therapy is obtained from the patient's designated proxy.20
Education on the adverse effects associated with the atypical antipsychotics and other pharmacological interventions allows the caregiver to share in the decision-making process. Use of written materials such as Treatment of Dementia and Agitation: A Guide for Families and Caregivers can inform and facilitate discussions with caregivers.24
Current evidence suggests that the potential cost of adverse effects associated with antipsychotic treatment of behavioral and psychiatric symptoms may offset marginal therapeutic benefits for many patients with dementia. In the absence of better alternatives, off- label prescribing of antipsychotic agents for dementia-related neuropsychiatric symptoms will continue. Documentation of the risk-benefit assessment and a monitoring plan are important risk management strategies.
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Franco KN, Messinger-Rapport B. Pharmacologicaltreatment of neuropsychiatric symptomsof dementia: a review of the evidence. J Am MedDir Assoc. 2006;7:201-202.
Lane HY, Chang YC, Su MH, et al. Shiftingfrom haloperidol to risperidone for behavioraldisturbances in dementia: safety, response predictors,and mood effects. J Clin Psychopharmacol.2002;22:4-10.
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Wang PS, Brookhart MA, Setoguchi S, et al.Psychotropic medication use for behavioralsymptoms of dementia. Curr Neurol Neurosci Rep.2006;6:490-495.
Ballard C, Waite J. The effectiveness of atypicalantipsychotics for the treatment of aggression andpsychosis in Alzheimer’s disease. Cochrane DatabaseSyst Rev. 2006(1):CD003476.
Schneider LS, Tariot PN, Dagerman KS, et al.Effectiveness of atypical antipsychotic drugs inpatients with Alzheimer’s disease. N Engl J Med.2006;355:1525-1538.
Brodaty H, Ames D, Snowdon J, et al. A randomizedplacebo-controlled trial of risperidonefor the treatment of aggression, agitation, andpsychosis of dementia. J Clin Psychiatry. 2003;64:134-143.
Schneider LS, Dagerman KS, Insel P. Risk ofdeath with atypical antipsychotic drug treatmentfor dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294:1934-1943.
Brodaty H, Ames D, Snowdon J, et al.Risperidone for psychosis of Alzheimer’s diseaseand mixed dementia: results of a double-blind,placebo-controlled trial. Int J Geriatr Psychiatry.2005;20:1153-1157.
Kryzhanovskaya LA, Jeste DV, Young CA, etal. A review of treatment-emergent adverseevents during olanzapine clinical trials in elderlypatients with dementia. J Clin Psychiatry. 2006;67:933-945.
Katz IR, Jeste DV, Mintzer JE, et al. Comparisonof risperidone and placebo for psychosis andbehavioral disturbances associated with dementia:a randomized, double-blind trial. RisperidoneStudy Group. J Clin Psychiatry. 1999;60:107-115.
Street JS, Clark WS, Gannon KS, et al. Olanzapinetreatment of psychotic and behavioralsymptoms in patients with Alzheimer disease innursing care facilities: a double-blind, randomized,placebo-controlled trial. The HGEU StudyGroup. Arch Gen Psychiatry. 2000;57:968-976.
Zhong KX, Tariot PN, Mintzer J, et al. Quetiapineto treat agitation in dementia: a randomized,double-blind, placebo-controlled study. CurrAlzheimer Res. 2007;4:81-93.
Newcomer JW. Metabolic considerations inthe use of antipsychotic medications: a review ofrecent evidence. J Clin Psychiatry. 2007;68(suppl1):20-27.
Lieberman JA, Stroup TS, McEvoy JP, et al.Effectiveness of antipsychotic drugs in patientswith chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.
Nasrallah HA. Metabolic findings from theCATIE trial and their relation to tolerability. CNSSpectr. 2006;11(7, suppl 7):32-39.
18. Shekelle P, Manglione M, Bagley S, et al.Comparative Effectiveness of Off-Label Use ofAtypical Antipsychotics. Available at:
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Schneider LS, Dagerman K, Insel PS. Efficacyand adverse effects of atypical antipsychotics fordementia: meta-analysis of randomized, placebocontrolledtrials. Am J Geriatr Psychiatry. 2006;14:191-210.
Recupero PR, Rainey SE. Managing riskwhen considering the use of atypical antipsychoticsfor elderly patients with dementia-relatedpsychosis. J Psychiatr Pract. 2007;13:143-152.
Wang PS, Schneeweiss S, Avorn J, et al. Riskof death in elderly users of conventional vs atypicalantipsychotic medications. N Engl J Med.2005;353:2335-2341.
Schneeweiss S, Setoguchi S, Brookhart A, etal. Risk of death associated with the use of conventionalversus atypical antipsychotic drugsamong elderly patients. CMAJ. 2007;176:627-632.
Gill SS, Bronskill SE, Normand SL, et al. Antipsychoticdrug use and mortality in older adultswith dementia. Ann Intern Med. 2007;146:775-786.
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