Alzheimer disease (AD) is one of the major causes of neurocognitive dysfunction. It has an insidious onset, with gradual progression of cognitive and behavioral symptoms, and is associated with behavioral and psychological symptoms of dementia. Symptoms of AD psychosis include delusions and hallucinations, agitation, aggression, and depression. Studies show that AD psychosis may be a distinct clinical entity with poor outcomes.1 Although the etiology of AD psychosis is not clear, genetic association studies posit a link between psychosis and the absence of APOE*4 alleles.2 Jeste and Finkel3 suggest diagnostic criteria for AD psychosis, including:
• Delusions and/or hallucinations (auditory or visual) that have been present for 1 month or longer
• Symptoms not continuously present before the onset of dementia
Prevalence
In a meta-analysis, the median prevalence of psychotic symptoms (delusions or hallucinations) in patients with AD was 41.1%.4 The median prevalence of delusions was 36%: delusions of theft were the most common. Visual hallucinations were more prevalent than auditory hallucinations (median, 18.7% and 9.2%, respectively). A higher prevalence of psychotic symptoms tended to occur in inpatient settings than in outpatient settings.
In a cross-sectional study, the prevalence of AD psychosis by specific criteria was 7.3%, with a cumulative incidence of 10.6% at 12 months.1 After 1 year, psychotic symptoms persisted in 68.7% of patients with an initial AD psychosis. Symptoms of agitation, aggression, and wandering have also been seen in at least 75% of patients with AD.5
AD psychosis defines a phenotype with greater severity; patients with AD psychosis scored lower in the Cambridge Cognitive Examination and Mini-Mental State Examination and higher on the Rapid Disability Rating Scale-2 and Zarit Burden Interview.1 Moreover, AD psychosis leads to faster functional impairment and increased mortality risk.
Various measures have been developed to assess psychosis and behavioral symptoms objectively. These include the Neuropsychiatric Inventory (NPI), the Consortium to Establish a Registry for Alzheimer Disease-Behavior Rating Scale for Dementia, and the Behavioral Pathology in Alzheimer Disease Scale. The Cornell Scale for Depression in Dementia and the Dementia Mood Assessment Scale are commonly used to measure depressive symptoms, and the Cohen-Mansfield Agitation Inventory assesses symptoms of agitation.
Management
Treatment of elderly patients with dementia and behavioral disturbances is complicated by a multitude of factors, including:
• Age-related pharmacokinetic and pharmacodynamic changes
• Comorbidities and concurrent use of medications
• Safety and efficacy issues of pharmacological treatments, such as FDA black box warnings and limited efficacy
• Cost factors and lack of studies with adequate control group and duration of exposure for nonpharmacological interventions
• Regulatory issues for institutionalized patients
Management of AD psychosis consists of both nonpharmacological and pharmacological interventions (Algorithm). Left untreated, symptoms may be significant enough to present a danger to self or others. This may be due to agitation: yelling, lashing out against others when feeling threatened, or general aggression. Patients may refuse care because of paranoia, wander into unsafe situations, or have agitation resulting in injury (eg, falls).
Dr Madhusoodanan is Clinical Professor of Psychiatry at SUNY Downstate Medical Center in Brooklyn, NY, and Associate Chair in the department of psychiatry at St John’s Episcopal Hospital in Far Rockaway, NY. Dr Ting is PGY-3 Resident in the department of psychiatry at St John’s Episcopal Hospital. The authors report no conflicts of interest concerning the subject matter of this article.
1. Vilalta-Franch J, López-Pousa S, Calvó-Perxas L, Garre-Olmo J. Psychosis of Alzheimer disease: prevalence, incidence, persistence, risk factors, and mortality. Am J Geriatr Psychiatry. 2013 Feb 6; [Epub ahead of print].
2. Christie D, Shofer J, Millard SP, et al. Genetic association between APOE*4 and neuropsychiatric symptoms in patients with probable Alzheimer’s disease is dependent on the psychosis phenotype. Behav Brain Funct. 2012;8:62.
3. Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related dementias. Diagnostic criteria for a distinct syndrome. Am J Geriatr Psychiatry. 2000;8:29-34.
4. Ropacki SA, Jeste DV. Epidemiology of and risk factors for psychosis of Alzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am J Psychiatry. 2005;162:2022-2030.
5. Madhusoodanan S, Shah P, Brenner R, Gupta S. Pharmacological treatment of the psychosis of Alzheimer’s disease: what is the best approach? CNS Drugs. 2007;21:101-115.
6. Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia [published correction appears in Am J Psychiatry. 2013;170:227]. Am J Psychiatry. 2012;169:946-953.
7. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Alzheimer’s Disease and Other Dementias. 2nd ed. Arlington, VA: American Psychiatric Association; 2007.
8. Lanctôt KL, Best TS, Mittmann N, et al. Efficacy and safety of neuroleptics in behavioral disorders assciated with dementia. J Clin Psychiatry. 1998;59:550-561.
9. Ballard CG, Waite J, Birks J. Atypical antipsychotics for aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev. 2012;5. doi10.1002/14651858.CD003476.pub2.
10. Sultzer DL, Davis SM, Tariot PN, et al; CATIE-AD Study Group. Clinical symptom responses to atypical antipsychotic medications in Alzheimer’s disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry. 2008;165:844-854.
11. Vigen CL, Mack WJ, Keefe RS, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD. Am J Psychiatry. 2011;168:831-839.
12. Madhusoodanan S. Introduction: antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric patients. Am J Geriatr Psychiatry. 2001;9:283-288.
13. Devanand DP, Mintzer J, Schultz SK, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s disease [published correction appears in N Engl J Med. 2012;367:2458]. N Engl J Med. 2012;367:1497-1507.
14. Verhey FR, Verkaaik M, Lousberg R; Olanzapine-Haloperidol in Dementia Study Group. Olanzapine versus haloperidol in the treatment of agitation in elderly patients with dementia: results of a randomized controlled double-blind trial. Dement Geriatr Cogn Disord. 2006;21:1-8.
15. Tariot PN, Schneider L, Katz IR, et al. Quetiapine treatment of psychosis associated with dementia: a double-blind, randomized, placebo-controlled clinical trial [published correction appears in Am J Geriatr Psychiatry. 2006;14:988]. Am J Geriatr Psychiatry. 2006;14:767-776.
16. De Deyn PP, Drenth AF, Kremer BP, et al. Aripiprazole in the treatment of Alzheimer’s disease. Expert Opin Pharmacother. 2013;14:459-474.
17. De Deyn P, Jeste DV, Swanink R, et al. Aripiprazole for the treatment of psychosis in patients with Alzheimer’s disease: a randomized, placebo-controlled study [published correction appears in J Clin Psychopharmacol. 2005;25:560]. J Clin Psychopharmacol. 2005;25:463-467.
18. Porsteinsson AP, Tariot PN, Jakimovich LJ, et al. Valproate therapy for agitation in dementia: open-label extension of a double-blind trial. Am J Geriatr Psychiatry. 2003;11:434-440.
19. Tariot PN, Raman R, Jakimovich L, et al; Alzheimer’s Disease Cooperative Study; Valproate Nursing Home Study Group. Divalproex sodium in nursing home residents with possible or probable Alzheimer disease complicated by agitation: a randomized, controlled trial. Am J Geriatr Psychiatry. 2005;13: 0942-949.
20. Lonergan E, Luxenberg J. Valproate preparations for agitation in dementia. Cochrane Database Syst Rev. 2009;(3):CD003945.
21. Seitz DP, Adunuri N, Gill SS, et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev. 2011;(2):CD008191.
22. Pollock BG, Mulsant BH, Rosen J, et al. Comparison of citalopram, perphenazine, and placebo for the acute treatment of psychosis and behavioral disturbances in hospitalized, demented patients. Am J Psychiatry. 2002;159:460-465.
23. Rodda J, Morgan S, Walker Z. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer’s disease? A systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr. 2009;21:813-824.
24. Fox C, Crugel M, Maidment I, et al. Efficacy of memantine for agitation in Alzheimer’s dementia: a randomized double-blind placebo controlled trial. PLoS One. 2012;7:e35185.
25. US Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. April 11, 2005. http://www.fda.gov/Drugs/DrugSafety/Postmarket DrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm053171.htm. Accessed October 28, 2013.
26. Lopez OL, Becker JT, Chang YF, et al. The long-term effects of conventional and atypical antipsychotics in patients with probable Alzheimer’s disease. Am J Psychiatry. 2013;170:1051-1058.
27. Huybrechts KF, Gerhard T, Crystal S, et al. Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study. BMJ. 2012;344:e977.
28. Raivio MM, Laurila JV, Strandberg TE, et al. Neither atypical nor conventional antipsychotics increase mortality or hospital admissions among elderly patients with dementia: a two-year prospective study. Am J Geriatr Psychiatry. 2007;15:416-424.
29. Kales HC, Kim HM, Zivin K, et al. Risk of mortality among individual antipsychotics in patients with dementia. Am J Psychiatry. 2012;169:71-79.
30. Arai H, Kobayashi H, Taguchi M, et al. Risk of mortality associated with antipsychotics in patients with dementia: a prospective cohort study. Presented at: 2013 Annual Meeting of the American Association for Geriatric Psychiatry; March 14-17, 2013; Los Angeles. Abstract NR51.
31. Gardette V, Lapeyre-Mestre M, Coley N, et al. Antipsychotic use and mortality risk in community-dwelling Alzheimer’s disease patients: evidence for a role in dementia severity. Curr Alzheimer Res. 2012;9:1106-1116.
32. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294:1934-1943.
33. Suh GH, Shah A. Effect of antipsychotics on mortality in elderly patients with dementia: a 1-year prospective study in a nursing home. Int Psychogeriatr. 2005;17:429-441.
34. Ballard C, Hanney ML, Theodoulou M, et al; DART-AD Investigators. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol. 2009;8:151-157.
35. Gisev N, Hartikainen S, Chen TF. Effect of comorbidity on the risk of death associated with antipsychotic use among community-dwelling older adults. Int Psychogeriatr. 2012;24:1058-1064.
36. Langballe EM, Engdahl B, Nordeng H, et al. Short- and long-term mortality risk associated with the use of antipsychotics among 26,940 dementia outpatients: a population-based study. Am J Geriatr Psychiatry. 2013 Sep 6; [Epub ahead of print].
