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Schneider LS, et al. "Effectiveness of Atypical Antipsychotic Drugs in Patients with Alzheimer's Disease". The New England Journal of Medicine. 2006. 355(15):1525-38.
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Clinical Question

Among patients with Alzheimer disease, do atypical antipsychotics reduce the behavioral symptoms of psychosis, aggression, or agitation?

Bottom Line

Among patients wth Alzheimer disease and psychosis, aggression, or agitation, the atypical antipsychotics olanzapine, quetiapine, and risperidone failed to improve outcomes compared to placebo.

Major Points

Most patients with Alzheimer disease will develop psychosis, aggression, or agitation at some time during their care, and even despite a dearth of data, these behaviors had commonly been treated with antipsychotic agents. Mounting evidence that antipsychotics were associated with an increased risk of cerebrovascular events including stroke and death prompted a prospective, randomized, double-blind, placebo-controlled trial of antipsychotics for the treatment of psychosis, aggression, or agitation among patients with Alzheimer disease.

The Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer's Disease study (CATIE-AD) enrolled 421 patients with Alzheimer disease and psychosis, aggression, or agitation, and randomized them in a 2:2:2:3 fashion to olanzapine, quetiapine, risperidone, or placebo. Drug dosages were adjusted by the investigator to the desired effect, and responders continued treatment for up to 36 weeks. The primary outcome was time until discontinuation of treatment for any reason. The main secondary outcome was improvement on the Clinical Global Impression of Change (CGIC) scale at week 12. At the end of the study period, there were no between-group differences in the time to discontinuation (median time ranged from 5.3-8.1 weeks). Extrapyramidal symptoms were more common with olanzapine and risperidone (12% each) compared to quetiapine (2%) or placebo (1%). There were no between-group differences in cerebrovascular events or death, but the event rates were small for these outcomes.

CATIE-AD contributes to a body of literature recognizing the limited efficacy and significant toxicity of antipsychotics in the treatment of dementia-related psychosis and agitation. For example, a 2006 Cochrane systematic review of 5 placebo-controlled trials of risperidone and olanzapine in Alzheimer disease with psychosis demonstrated that the two agents modestly reduced aggressive and psychotic symptoms and behaviors, but also increased the risk of cerebrovascular events and extrapyramidal effects.[1] A paucity of published survival data precluded the Cochrane review authors from drawing conclusions about the relative risk of death with antipsychotics. Nevertheless, analysis of unpublished data by the FDA led to its issuance of a Public Health Advisory in 2005 reporting the 1.6-1.7–fold increased risk of death among patients with dementia and psychosis treated with antipsychotics.[2] Consequently, the FDA required manufacturers of antipsychotics to include a Boxed Warning in the prescribing information, noting the increased mortality seen among elderly patients with dementia-associated psychosis.[3] Expert statements and guidelines recommend against the routine use of antipsychotics for treating the behavioral symptoms of dementia.[4] Consequently, efforts have been made to limit the use of antipsychotics among patients with Alzheimer disease and psychosis, aggression, or agitation. Randomized data from DART-AD (2008) demonstrated that antipsychotic agents could be safely discontinued without untoward effects such as drug withdrawal.[5] In 2012, analysis of prescriptions indicated a modest decline in antipsychotic use for dementia-associated psychosis following the issuance of FDA Boxed Warnings.[6]


American Psychiatric Association (2007, summarized)[7]
The APA guidelines reiterate that the published efficacy of antipsychotics in dementia-associated psychosis, agitation, and aggression must be weighed against a growing body of adverse events.


  • Double-blind, placebo-controlled trial
  • N=421 outpatients with Alzheimer disease and psychosis, aggression, or agitation
    • Olanzapine (n=100)
    • Quetiapine (n=94)
    • Risperidone (n=85)
    • Placebo (n=142)
  • Setting: 45 US sites
  • Enrollment: 2001-2004
  • Follow-up: Up to 36 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Time until discontinuation of treatment
  • Secondary outcome: Improvement on CGIC scale at week 12


Inclusion Criteria

  • Alzheimer dementia according to DSM-IV, or probable Alzheimer disease
  • MMSE score 5-26
  • Ambulatory
  • Living at home or assisted living facility
  • Delusions, hallucinations, aggression, or agitation
    • Must have developed after onset of dementia
    • Must be present daily for 1 week or intermittently for 4 weeks
    • Must be sufficiently severe to disrupt functioning and justify treatment
  • BPRS rating of moderate

Exclusion Criteria

  • Primary psychotic disorder, delirium, or other dementia
  • Psychosis, aggression, or agitation due to medical condition, medication, or drug abuse
  • Requiring psychiatric admission
  • Suicidality
  • Planned treatment with cholinesterase inhibitor or antidepressant
  • Prior treatment with 2 of the study drugs
  • Contraindications to any study drug

Baseline Characteristics

  • Mean age 78 years, females 56%, white 79%
  • Reside at home 89%, assisted living facility 10%
  • Married 59%
  • MMSE score 15, ADAS 35, NPI 37, ADCS-ADL 39
  • Medications
    • Antidepressant or antipsychotic: 25%
    • Antidepressant: 15%
    • Conventional antipsychotic: 5%
    • Atypical antipsychotic: 10%
    • Cholinesterase inhibitor: 60%


  • Double-blind randomization in 2:2:2:3 fashion to:
    • Olanzapine
    • Quetiapine
    • Risperidone
    • Placebo
  • Dose adjustment permitted by study physicians
  • Additionally, investigators could prescribe benzodiazepine or haloperidol
  • Duration of study treatment determined by investigator
    • If inadequate response after 2 weeks, could discontinue
    • If adequate response, could continue up to 36 weeks
  • Patients who discontinued prior to 36 weeks could undergo double-blind randomization to one of the study drugs they did not receive, or they could receive citalopram. This NEJM publication did not report these results.


Primary Outcome

Time to discontinuation of treatment for any reason
Olanzapine Quetiapine Risperidone Placebo P value
8.1 weeks 5.3 weeks 7.4 weeks 8.0 weeks 0.52

Secondary Outcomes

Outcome measure Olanzapine Quetiapine Risperidone Placebo P value
Initial dose, mean (range), mg 3.2 (0-10) 34.1 (0-100) 0.7 (0.5-2.5) - -
Final dose, mean (range), mg 5.5 (0-17.5) 56.5 (0-200) 1.0 (0-2.0) - -
↑CGIC score at 12 weeks 32% 26% 29% 21% 0.22

Adverse Events

Adverse events
Variable Olanzapine Quetiapine Risperidone Placebo P value
Any SAE 14% 18% 11% 13% 0.35
Stroke/TIA 2% 1% 1% 1% 0.92
Death 1% 3% 1% 2% 0.68
Extrapyramidal signs 12% 2% 12% 1% <0.001
Sedation 24% 22% 15% 5% <0.001
Weight gain 11% 6% 11% 3% 0.10


Suboptimal therapy
The relatively low dosages achieved in this trial could have resulted in suboptimal or inadequate responses seen, which would bias results against these antipsychotic agents. For example, the mean daily dose of quetiapine achieved (56.5 mg) is significantly less than the 100 mg many agree is this agent's optimal dose.[8]
Choice of outcome
Time until discontinuation of treatment was selected as a pragmatic primary outcome, and therefore it is difficult to compare this study's results to those of other trials, which used improvement on various psychiatric scores.
Low event rates
This was an appropriately sized trial with adequate follow-up to study the primary outcome. But because the event rate was low for other important outcomes including cerebrovascular events and death, one must take care to not over-interpreting these data.
Generalizability is limited by this study's inclusion of only patients with Alzheimer disease (eg, excluding those with vascular dementia and dementia with Lewy bodies) and of outpatients only (rather than inpatients).


Funded by the National Institute of Mental Health.

Further Reading

  1. Ballard C, Waite J. The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD003476.
  2. Public Health Advisory: Deaths with Antipsychotics in Elderly Patients with Behavioral Disturbances. April 11, 2005.
  3. Information for Healthcare Professionals: Conventional Antipsychotics. June 16, 2008.
  4. Corbett A, et al. Don't use antipsychotics routinely to treat agitation and aggression in people with dementia. BMJ. 2014 Nov 3;349:g6420.
  5. Ballard C, et al. A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial). PLoS Med. 2008 Apr 1;5(4):e76.
  6. Desai VC, et al. Impact of the Food and Drug Administration's antipsychotic black box warning on psychotropic drug prescribing in elderly patients with dementia in outpatient and office-based settings. Alzheimers Dement. 2012 Sep;8(5):453-7.
  7. Practice Guideline for the Treatment of Patients With Alzheimer’s Disease and Other Dementias. Second Edition. October 2007.
  8. Scharre DW, Chang SI. "Cognitive and behavioral effects of quetiapine in Alzheimer disease patients." Alzheimer Dis Assoc Discord. 2002 Apr-Jun;16(2):128-30.