What does the evidence say about the risks and benefits of the atypical antipsychotics in dementia?

College of Physicians and Surgeons of Alberta Messenger, Optimized Prescribing with Seniors Leave a Comment

Betty, an 84-year-old woman with moderate Alzheimer’s disease, lives at home with her husband. She had become quite agitated and aggressive at one time and was started on risperidone, which settled her aggression. She has been on it since and her husband wonders if she should remain on it.

Issue: What does the evidence say about the risks and benefits of the atypical antipsychotics in dementia?

Bottom Line: Atypical antipsychotics may have a role in the management of aggression +/- agitation and psychosis (delusions/hallucinations). Risks include a 1.6 fold increase in the risk for death and a 1-2% increase in the risk for cerebrovascular accident. Periodic attempts at withdrawal should be considered.

Betty has been on the drug for a while and — knowing that the behaviors may be transient — a tapering off of risperidone could be considered.

Evidence: The atypical antipsychotics were developed to be safer alternatives to the typical antipsychotics. There is a clear role for these agents in the treatment of psychiatric/psychotic disorders.

Health Canada indications fall into four categories[i]:

  • Schizophrenia & related disorders: aripiprazole; asenapine; clozapine; lurasidone; olanzapine; paliperidone; quetiapine; risperidone; ziprasidone
  • Bipolar Disorder (mania): aripiprazole; asenapine; olanzapine; quetiapine; risperidone; ziprasidone
  • Adjunctive treatment of major depressive disorder: aripiprazole; quetiapine XR
  • Behavior disturbance in severe dementia (short term): risperidone [“short term” is undefined but opinion suggests three to six months]

Efficacy of the atypical agents has been reviewed[ii] in the setting of aggression +/- agitation and psychosis (delusions/hallucinations) in Alzheimer’s disease. Trials with 5,574 participants studied aripiprazole, olanzapine, risperidone and quetiapine. Although the trials had limitations, only risperidone in a dose of up to 2 mg and olanzapine in a dose of up to 10 mg showed significant benefit for aggression. Risperidone in a dose of 1 mg showed significant benefit and aripiprazole in a dose of up to 5 mg showed benefit in psychosis. A significant increase in adverse events was seen versus placebo.

Lack of efficacy of atypical antipsychotics has been shown for numerous symptoms including:

  • Wandering.
  • Restless pacing.
  • Fidgeting/nervous twitching.
  • Repetitive vocalizations.
  • Hoarding.
  • Inappropriate voiding.
  • Lack of social behavior skills.
  • Poor self-care practices.
  • Indifference to surroundings.

Safety issues are similar between drugs, with incidence rates that vary between agents. Extrapyramidal symptoms including akathisia, Parkinsonism and tardive dyskinesia are well recognized, as are lipid and glucose disorders and weight gain.

Prolonged QT syndrome is a significant issue with most agents, with only aripiprazole showing minimal effect on QT, and lurasidone potentially having somewhat less impact than the other agents. While rare, neuroleptic malignant syndrome is fatal in up to 20% of individuals affected.

Floppy Iris Syndrome has been reported with risperidone, paliperidone and quetiapine. Other reported adverse effects include:

  • Postural hypotension
  • Somnolence
  • Falls
  • Body temperature dysregulation
  • Accelerated cognitive decline
  • Social withdrawal

In 2002, pooled trials demonstrated a 4% CVA/TIA rate amongst those on risperidone vs. a 2% rate for those on placebo.[iii] In 2004 similar data for olanzapine demonstrated a 1.3% CVA/TIA rate amongst those on olanzapine vs. 0.4% for those on placebo.[iv]

A 2005 review of 15 trials[v] with 5,110 participants in either community or nursing home settings using aripiprazole, olanzapine, quetiapine or risperidone reported a mortality rate of 3.5% amongst those on an antipsychotic vs. 2.3% on placebo [OR 1.54].

A Health Canada alert[vi] the same year based on 13 placebo controlled trials involving 3,965 participants with dementia using olanzapine, quetiapine, or risperidone demonstrated a mortality risk of 1.6 for those on antipsychotics vs. those on placebo. This led to the addition of a “black box” warning for all atypical antipsychotics related to increased mortality risk. In 2007, a similar risk was demonstrated with the typical antipsychotics.[vii]

Is it safe to withdraw an antipsychotic?

Consensus opinion suggests that behavioral disturbance in many dementia syndromes tends to be transient and to improve over time. Declerq et al[viii] looked at planned withdrawal across nine trials and found successful withdrawal reported in seven of them without re-emergence of neuropsychiatric symptoms. There was an increased risk of relapse for individuals who had had a good initial response to the treatment and for those with more severe behavioral disturbance at initiation of the therapy.

In Alberta, the Seniors Health and Addiction and Mental Health Strategic Clinical Networks’ Appropriate Use of Antipsychotics in long-term care initiative is showing significant successful reductions in use of these agents with benefits for residents.

In terms of alternative agents, there is limited evidence for benefit from sertraline and citalopram, though hyponatremia, falls and gastrointestinal bleeding are risks. Cholinesterase inhibitor trials have been mixed though there may be benefit in those who have never previously been on an agent. Trazodone and valproic acid have not been shown to be beneficial in RCTs, and carbamazepine has had mixed results.

When use of one of these agents is being contemplated for behavioral disturbance, it is important to:

  • Have ruled out any potentially reversible contributors.
  • Know that the behavior is potentially responsive to the drug.
  • Consider the risk/benefit ratio.
  • Discuss and document the discussion.
  • “Start low and go slow,” using the minimally effective dose that will manage the symptoms.

Whenever an atypical antipsychotic is being used, consideration should be given to periodic attempts at withdrawal using a tapering approach and watching for symptom re-emergence.


[i] Respective Canadian Product Monographs.

[ii] Ballard CG, Waite J, Birks J. Atypical antipsychotics for aggression and psychosis in Alzheimer`s disease. Cochrane Database of Systematic Reviews 2012, Issue 5.

[iii] Risperdal (risperidone) and cerebrovascular adverse events in placebo-controlled dementia trials [Dear Healthcare Professional Letter]. Toronto: Janssen–Ortho Inc.; 2002 Oct 11. Available: www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/advisory/industry/risperdal1_e.pdf.

[iv] Olanzapine (Zyprexa) and cerebrovascular adverse events in placebo-controlled elderly dementia trials [Dear Healthcare Professional Letter]. Toronto: Elli Lilly Inc.; 2004 Mar 10. Available: www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/zyprexa_hpc_e.pdf.

[v] Schneider LS, Dagerman K, Insel P. Risk of Death with Atypical Antipsychotic Drug Treatment for Dementia. JAMA 2005;294:1934-43.

[vii] Schneeweiss S, Setoguchi S, Brookhart A, Dormuth C, Wang PS. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ 2007; 176(5):627-32.

[viii] Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AIM, van Driel ML, Christiaens T. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database of Systematic Reviews 2013, Issue 3.

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