Special Article
Efficacy and Adverse Effects of Atypical Antipsychotics for Dementia: Meta-analysis of Randomized, Placebo-Controlled Trials

https://doi.org/10.1097/01.JGP.0000200589.01396.6dGet rights and content

Objective

Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease (AD) and other dementia. Several clinical trials have not shown efficacy, and there have been concerns about adverse events. The objective of this study was to assess the evidence for efficacy and adverse events of atypicals for people with dementia

Methods

MEDLINE, the Cochrane Register of Controlled Trials, meetings, presentations, and information obtained from sponsors were used in this study. Published and unpublished randomized, placebo-controlled, double-blind, parallel-group trials in patients with AD or dementia of atypical antipsychotics marketed in the United States were studied. Clinical and trials characteristics, outcomes, and adverse events were extracted. Data were checked by a second reviewer. Fifteen trials including 16 contrasts of atypical antipsychotics with placebo met selection criteria: aripiprazole (k = 3), olanzapine (k = 5), quetiapine (k = 3), and risperidone (k = 5). A total of 3,353 patients were randomized to drug and 1,757 to placebo. Standard meta-analysis methods were used to summarize outcomes.

Results

Quality of the reporting of trials varied. Efficacy on rating scales was observed by meta-analysis for aripiprazole and risperidone, but not for olanzapine. Response rates were frequently not reported. There were smaller effects for less severe dementia, outpatients, and patients selected for psychosis. Approximately one-third dropped out without overall differences between drug and placebo. Adverse events were mainly somnolence and urinary tract infection or incontinence across drugs, and extrapyramidal symptoms or abnormal gait with risperidone or olanzapine. Cognitive test scores worsened with drugs. There was no evidence for increased injury, falls, or syncope. There was a significant risk for cerebrovascular events, especially with risperidone; increased risk for death overall was reported elsewhere.

Conclusions

Small statistical effect sizes on symptom rating scales support the evidence for the efficacy of aripiprazole and risperidone. Incomplete reporting restricts estimates of response rates and clinical significance. Dropouts and adverse events further limit effectiveness. Atypicals should be considered within the context of medical need and the efficacy and safety of alternatives. Individual patient meta-analyses are needed to better assess clinical significance and effectiveness.

Section snippets

Search Strategy, Trials Selection, and Data Retrieval

The search strategy was described in detail previously.13 Briefly, MEDLINE (1966–April 2005) and the Cochrane Central Register of Controlled Trials (2005, Issue 1)15 were searched using the headings aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone (i.e., atypical antipsychotics marketed in the United States), dementia, “Alzheimer disease,” and “clinical trial.” This was supplemented by hand reviewing materials from conferences and web postings. Pharmaceutical

Search Flow

The retrieval results are detailed elsewhere13 and ultimately yielded five trials from MEDLINE and six from the Cochrane registry that included the five MEDLINE references. One placebo-controlled trial of olanzapine (N = 16 subjects)21 was not included because the only available documentation was an abstract with inadequate information; one was a review with information on an olanzapine trial not contained elsewhere.22

One recently published trial of quetiapine was included but was not

DISCUSSION

A considerable number of placebo-controlled trials of atypical antipsychotics for patients with dementia have been undertaken and not all have been published, involving over 5,000 patients treated for generally 8–12 weeks. Patients on average were advanced in age, in their 80s, most had AD, and a minority cerebrovascular dementia. After statistically combining the trials there was evidence for symptomatic efficacy of aripiprazole and risperidone. Olanzapine was not associated with efficacy

LIMITATIONS

Meta-analyses are observational studies and are subject to various biases, including the complete ascertainment of trials performed, assessing the trials' qualities, deciding on the analytic protocol, information to be abstracted, studies to be combined, statistics, and interpretation of the results. Trials varied somewhat in their inclusion criteria. Patients included may have been restricted to AD or not, or on the basis of agitation or aggression or delusions or hallucinations. There were

PRACTICE IMPLICATIONS

The modest efficacy and uncertain response rates combined with the risks detailed here suggest that antipsychotics should be used with more deliberate consideration. Medications should be prescribed and adjusted to maximize efficacy while minimizing adverse events; the adverse event evidence coupled with the efficacy evidence suggests that the use of lower doses might be prudent and effective.

Clinical improvement should be expected well within 10 or 12 weeks, the length of the trials. If

References (44)

  • PP De Deyn et al.

    Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer's disease

    Int J Geriatr Psychiatry

    (2004)
  • C Ballard et al.

    Quetiapine and rivastigmine and cognitive decline in Alzheimer's disease: randomised double blind placebo controlled trial

    BMJ

    (2005)
  • KM Sink et al.

    Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence

    JAMA

    (2005)
  • W Chan et al.

    A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients

    Int J Geriatr Psychiatry

    (2001)
  • PN Tariot et al.

    Quetiapine in nursing home residents with Alzheimer's dementia and psychosis. Poster presented at the 15th Annual Meeting of the American Association for Geriatric Psychiatry; Feb 24–27; Orlando, Fla

    Am J Geriatr Psychiatry

    (2002)
  • LS Schneider et al.

    Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials

    JAMA

    (2005)

  • Health Canada Therapeutic Products Directorate, Risperdal warning letter

  • The Cochrane Library, Issue 1, 2005

    (2005)
  • Racoosin JA: Evaluating a safety signal in the postmarking period: cerebrovascular adverse events associated with...
  • Bristol-Myers Squibb Medical Letter. Labeling Change for Abilify on Risk of CVA in Elderly. Feb 10,...
  • Schneider LS, Tariot PN, Mintzer J, et al: Cerebrovascular adverse events and quetiapine: a pooled analysis in elderly...

  • Review Manager (RevMan) [computer program]. Version 4.2

    (2004)

    • Cited by (743)

    • Pimavanserin for psychosis in Parkinson's disease dementia: Subgroup analysis of the HARMONY Trial

      2024, Parkinsonism and Related Disorders

    • Adverse Drug Event Prevention and Detection in Older Emergency Department Patients

      2023, Clinics in Geriatric Medicine

    • Visual Dysfunction is a Risk Factor of Postoperation Delirium in Parkinson Disease

      2023, World Neurosurgery

    • Vocally disruptive behaviour in nursing home residents in Ireland: A descriptive study

      2023, Irish Journal of Psychological Medicine

    • Safety Profile of Pimavanserin Therapy in Elderly Patients with Neurodegenerative Disease-Related Neuropsychiatric Symptoms: A Phase 3B Study

      2024, Journal of Alzheimer's Disease

    • A short staff training system for behavioural and psychological symptoms of dementia in care facilities, based on functional analysis and positive behaviour support: a single-arm pre- and post-comparative study

      2024, Psychogeriatrics
    View all citing articles on Scopus

    This article has online material available at http://www.AJGPonline.org.

    View full text
    Copyright © 2006 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.