Subramoniam Madhusoodanan, MD

[[{"type":"media","view_mode":"media_crop","fid":"22010","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_669433247055","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"1598","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"margin: 3px; width: 175px; height: 131px; float: right;","title":" ","typeof":"foaf:Image"}}]]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.

 Although the etiology of AD psychosis is not clear, genetic association studies posit a link between psychosis and the absence of 

 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

In a meta-analysis, the median prevalence of psychotic symptoms (delusions or hallucinations) in patients with AD was 41.1%.

 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.

 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.

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.

 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.

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 (

). 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).

Symptoms can also be a source of frustration for caregivers, leading to burnout. Unmanageable behavioral symptoms in community-dwelling patients lead to nursing home placement. Hence, the severity of behavior symptoms seen in institutionalized patients is much higher than in community dwellers. This contributes to the increased use of antipsychotics in institutionalized patients.

Excluding underlying medical conditions that may cause behavioral or psychotic symptoms or delirium, such as infection, medications with anticholinergic effects, corticosteroid use, or neurological insults is the first step in the decision-making process for treatment. During the assessment, it is important to delineate the targeted symptoms and document the need for treatment. Justification for treatment is especially important for elderly patients because the risk for adverse effects is increased in this population.

In their meta-analysis, Brodaty and Arasaratnam6 found significant benefits of nonpharmacological interventions for behavioral and psychological symptoms of dementia. Their findings also revealed that caregiver interventions can decrease behavioral and psychological symptoms of dementia in addition to decreasing the caregiver’s negative reactions. Behaviors that are likely to improve with nonpharmacological interventions included agitation, aggression, disruption, shadowing, depression, and repetitive behaviors

A limitation of this study is that the diversity of multicomponent strategies from different studies prevented the identification of specific elements that were effective. In addition, the population reviewed appears to have had less severe behavioral disturbances compared with drug trial participants, and the analysis generally excluded psychotic patients. Moreover, control groups were not adequate in size and in duration of exposure to clinicians.

Identification of patients who are likely to respond to nonpharmacological interventions is important, as is identification of specific stressors or triggers for behavioral symptoms. The patient may be bothered by a roommate who sleeps with the lights on. Or he or she may have paranoid ideation directed at a specific person. Although the stressor may not always be easily identified, once it is, the intervention can be specific to the stressor. Interventions should also be directed toward the caregivers. Successful interventions consist of 9 to 12 sessions tailored to the needs of the patient and his caregivers.

In March 2013, the New York State Department of Health issued guidelines for dementia care management in nursing homes, which included nonpharmacological interventions recommended by the American Psychiatric Association 2007 practice guidelines.

 In general, none of the nonpharmacological interventions have been subject to rigorous clinical trials. However, they are in clinical use and are supported by small trials or case studies. Behavioral approaches attempt to alter the environment by studying the antecedents and consequences of behavior. Recreational therapy, art therapy, music therapy, and pet therapy help improve pleasurable activities for patients and are included under stimulation-oriented treatments. Other modalities, such as supportive psychotherapy and reminiscence therapy, may have moderate benefits, depending on the stage of dementia. Reality orientation and cognitive retraining may not have the expected benefits and may even cause frustration, agitation, or depression.

Pharmacological intervention becomes necessary when nondrug interventions are unsuccessful and delusions or hallucinations, or aggressive, assaultive, highly disruptive, or dangerous behavior continues. For patients with behavioral and psychological symptoms of AD, conventional antipsychotics were the mainstay of treatment until the advent of atypical antipsychotics.

Controlled trials of conventional antipsychotics show that they are 18% to 26% more effective than placebo.

 However, they come with a high burden of serious cardiovascular and anticholinergic adverse events, extrapyramidal symptoms, and tardive dyskinesia. Extrapyramidal symptoms decrease mobility and increase the risk of infections and falls, the need for personal care, nursing home admission, and mortality risk. There are no FDA-approved medications for the treatment of AD psychosis and/or behavioral and psychological symptoms of dementia.

Atypical antipsychotics are the most widely used class of psychotropic medications in the treatment of AD psychosis and/or behavioral and psychological symptoms of dementia. A meta-analysis of atypical antipsychotics for aggression and psychosis in AD suggests that both risperidone and olanzapine help reduce aggression and risperidone helps reduce psychosis.

 However, both medications were associated with serious cerebrovascular events and extrapyramidal symptoms.

The Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer Disease (CATIE-AD) study showed beneficial effects of risperidone and olanzapine on the NPI total score, but the rate of discontinuation because of adverse effects was high.

 Quetiapine had limited efficacy on symptoms, which may have been because of the low doses prescribed, although sedation that occurred in this group suggested some medication effect. The CATIE-AD study did not show improvement in functioning, care needs, or quality of life. This study also showed worsening of cognitive function among those treated with atypical antipsychotics compared with those who received placebo.

Risperidone is the best studied of the atypical antipsychotics for psychosis and behavioral disturbances associated with dementia. Its advantages include minimal sedation, less weight gain, and fewer metabolic and anticholinergic effects compared with olanzapine and clozapine.

 The main concerns include dose-related extrapyramidal symptoms, hyperprolactinemia, osteoporosis, orthostatic hypotension and associated falls, and metabolic adverse effects. A long-acting injectable formulation is available. A study on relapse risk by Devanand and colleagues

 showed that discontinuation of risperidone increased the risk of relapse among AD patients with psychosis or agitation.

Olanzapine was shown to decrease psychosis and overall behavioral disturbances; however, the dropout rate was high.

 The incidence of extrapyramidal symptoms is low with olanzapine.

 Both short- and long-acting intramuscular formulations are available. The main concerns for olanzapine include sedation, weight gain, metabolic adverse events, orthostatic hypotension, and anticholinergic effects, as well as postinjection delirium/sedation syndrome for the long-acting injectable preparation.

In a placebo-controlled study, quetiapine showed no efficacy for psychotic symptoms, although secondary measures of agitation improved.

 The advantages of quetiapine include negligible extrapy-ramidal symptom risk, minimal anticholinergic effects, and fewer metabolic adverse effects. The main concerns include sedation and orthostatic hypotension.

Aripiprazole showed modest efficacy in placebo-controlled clinical trials, with improvements in psychosis and agitation.

 Aripiprazole is generally well tolerated-mild somnolence was one of the most frequently reported adverse events, but it was not associated with falls or accidental injury. No clinically significant ECG abnormalities or weight changes were seen.

There are no controlled trials of clozapine for patients with AD. Clozapine has the advantages of low risk of extrapyramidal symptoms and tardive dyskinesia, and it may be effective for treatment-resistant symptoms. The main concerns include agranulocytosis, lowered seizure threshold, weight gain, metabolic adverse effects, anticholinergic effects, orthostatic hypotension, and myocarditis.

There are no controlled studies of newer atypical antipsychotics, including ziprasidone, paliperidone, iloperidone, asenapine, and lurasidone in patients with AD. These medications generally have a more favorable metabolic profile and individual advantages and areas of concerns. Further studies are needed to establish efficacy in behavioral and psychotic symptoms of AD.

Divalproex showed efficacy in treating aggressive behaviors associated with dementia, with a mean decrease of 3.1 points on the Brief Psychiatric Rating Scale Agitation Factor.

 However, a double-blind, placebo-controlled study of nursing home residents with AD showed no benefit of divalproex for treatment of agitation.

 And a more recent review corroborates that valproate is ineffective in treating agitation among patients with dementia and is associated with adverse effects.

A meta-analysis of antidepressants for agitation and psychosis in dementia showed that sertraline and citalopram were associated with a reduction in symptoms of agitation compared with placebo.

 There was no difference in the rates of withdrawal because of adverse events for SSRIs compared with placebo. A 17-day study showed significant improvement in agitation and lability subscales of hospitalized patients treated with citalopram.

 The withdrawal rate was 52% for citalopram and 57% for placebo, mostly because of lack of efficacy. The main concerns for these medications include risk of internal bleeding and vasospastic complications secondary to the blockade of platelet uptake and pulmonary endothelial metabolism of serotonin. Trazodone has had partial success in the management of agitation in dementia.

Benzodiazepines provide acute relief of agitation but are associated with sedation and an increased risk of falls. Patients who received cholinesterase inhibitors, such as donepezil, rivastigmine, and galantamine, have shown some behavioral improvements compared with those who received placebo.

 A recent study demonstrated that memantine did not significantly improve agitation in patients with moderate to severe AD. However, it was shown to be more efficacious than placebo for cognition.

In April 2005, the FDA issued a black box warning of increased cerebrovascular accidents and mortality risk in elderly patients treated with atypical antipsychotics for behavioral disturbances associated with dementia.

 The analysis showed a 1.6- to 1.7-fold increase in mortality for patients who received atypical antipsychotics compared with those who received placebo. Risk was related to increasing dose, but no difference in mortality risk was noted between drugs. The causes of death varied.

More recent studies have added new information regarding antipsychotics and mortality. Findings from a study on patients with AD in the outpatient setting suggest that the primary correlate of negative outcomes (likely to die, admitted to nursing homes) was due to psychiatric symptoms rather than the drugs used to treat the symptoms.

 This is especially important because the studies that reported the association between mortality and antipsychotic use were based on institutionalized patients-a clinically heterogeneous group with complex interactions of multiple factors.

 In a report of their 2-year prospective study, Raivio and colleagues

 concluded that neither conventional nor atypical antipsychotics increased mortality or hospital admission, whereas the use of restraints doubled the mortality risk.

Mortality risk associated with several antipsychotics was compared in an outpatient study by Kales and colleagues.

 In the first 30 days, the highest risk was seen with haloperidol. Risperidone, olanzapine, and valproic acid and its derivatives had similar risk, while quetiapine had lower risk. These 4 agents had the highest risk of mortality in the first 120 days.

In an initial analysis of a 10-week prospective study in 6000 patients, Arai and colleagues

 found no statistically significant difference in overall mortality between patients who received antipsychotics and those who did not. When final results of this study become available, we may have to change our current concepts about mortality risk with these medications.

In a long-term study of 957 patients with mild to moderate probable AD, Lopez and colleagues

 found that antipsychotic medications-both conventional and atypical-were not associated with time to nursing home admission or time to death after adjusting for covariates. The risks of nursing home placement and death were linked to psychiatric symptoms, including psychosis and agitation.

Some studies have shown an association between antipsychotic use and increased risk of mortality without establishing causality. Recent studies show that when antipsychotic use was adjusted for severity of illness and psychiatric symptoms, the latter were found to be more of an independent risk factor for mortality (

The decision to start treatment with medications is a balancing act. The severity and potential danger of the symptoms have to be weighed against potentially serious adverse effects and modest efficacy of medications. Thus, the first step is careful consideration of whether medications are really indicated. As stated, pharmacological interventions are recommended when nondrug interventions are unsuccessful or highly disruptive symptoms continue to be present. A discussion with patients and family about the risks and benefits, alternatives, and goals of treatment is important. Document any comments or apprehensions that arise during this discussion.

For patients with mild to moderate behavioral symptoms without psychosis and for patients with behaviors with specific triggers, we recommend nonpharmacological interventions, including psychosocial, environmental, and caregiver interventions. For patients with moderate to severe symptoms and psychosis and for those in whom nonpharmacological interventions have failed, medications are indicated. Atypical antipsychotics are the preferred initial choice. There is good evidence (as shown above) that risperidone is a good first choice option. For less severe agitation, a trial with citalopram, sertraline, trazodone, divalproex, or a cholinesterase inhibitor may be considered. The starting dose should be low and titration gradual.

The choice of agents should be guided by the patient profile and efficacy and safety of the drug. Drug-drug interactions should be considered. Chemistry panel, lipid profile, glycosylated hemoglobin, and weight should be assessed at baseline to address metabolic effects of atypical antipsychotics. A baseline ECG should also be obtained to measure QTc.

For severe symptoms or when the risk of adverse events is high, follow-up should take place within 1 week. Otherwise, typical follow-up should take place within 1 month after initiation of treatment with atypical antipsychotics. Neuropsychiatric symptoms of dementia typically wax and wane, and regular attempts to withdraw these medications are recommended. For severe symptoms that have responded to antipsychotics, careful consideration regarding withdrawal and tapering is important in the context of relapse risk.

Federal regulations-1987 Omnibus Budget Reconciliation Act-address residents’ rights and quality of care in nursing homes. Clear documentation is needed for the use of psychotropic drugs. Residents should be maintained on minimal effective doses and should be free from unnecessary drugs. This includes avoidance of excessive dosages and duration, inappropriate indications, and adverse consequences. Gradual dose reductions must be attempted unless contraindicated. These regulations have been revised and updated, and fiscal penalties enforced for nursing homes found to be noncompliant. Recent Centers for Medicare and Medicaid Services guidelines called for a 15% reduction in the use of antipsychotics in dementia patients for the current year. The national prevalence of antipsychotic use has already been reduced by 9.1% in nursing homes in the first quarter of 2013 compared with the last quarter of 2011.

AD psychosis appears to be a distinct clinical entity, with poorer outcomes associated with greater impairment and mortality. Management of the disorder is complex, and careful consideration regarding risks and benefits is critical. Atypical antipsychotics are preferred because of their efficacy; however, there is significant potential for adverse effects and increased mortality risk. Once medications are started, regular assessments should be continued for possible tapering and discontinuation.

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.

 Vilalta-Franch J, LÃ³pez-Pousa S, CalvÃ³-Perxas L, Garre-Olmo J. Psychosis of Alzheimer disease: prevalence, incidence, persistence, risk factors, and mortality. 

 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. 

 Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related dementias. Diagnostic criteria for a distinct syndrome. 

 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. 

 Madhusoodanan S, Shah P, Brenner R, Gupta S. Pharmacological treatment of the psychosis of Alzheimer’s disease: what is the best approach? 

 Brodaty H, Arasaratnam C. Meta-analysis of nonpharmacological interventions for neuropsychiatric symptoms of dementia [published correction appears in Am J Psychiatry. 2013;170:227]. 

Practice Guideline for the Treatment of Patients With Alzheimer’s Disease and Other Dementias

. 2nd ed. Arlington, VA: American Psychiatric Association; 2007.

 LanctÃ´t KL, Best TS, Mittmann N, et al. Efficacy and safety of neuroleptics in behavioral disorders assciated with dementia. 

 Ballard CG, Waite J, Birks J. Atypical antipsychotics for aggression and psychosis in Alzheimer’s disease. 

. 2012;5. doi10.1002/14651858.CD003476.pub2.

 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. 

 Vigen CL, Mack WJ, Keefe RS, et al. Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD. 

 Madhusoodanan S. Introduction: antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric patients. 

 Devanand DP, Mintzer J, Schultz SK, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s disease [published correction appears in 

 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. 

 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 

 De Deyn PP, Drenth AF, Kremer BP, et al. Aripiprazole in the treatment of Alzheimer’s disease.

 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 

 Porsteinsson AP, Tariot PN, Jakimovich LJ, et al. Valproate therapy for agitation in dementia: open-label extension of a double-blind trial.

 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. 

 Lonergan E, Luxenberg J. Valproate preparations for agitation in dementia. 

 Seitz DP, Adunuri N, Gill SS, et al. Antidepressants for agitation and psychosis in dementia. 

 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. 

 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. 

 Fox C, Crugel M, Maidment I, et al. Efficacy of memantine for agitation in Alzheimer’s dementia: a randomized double-blind placebo controlled trial. 

 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.

 Lopez OL, Becker JT, Chang YF, et al. The long-term effects of conventional and atypical antipsychotics in patients with probable Alzheimer’s disease. 

 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. 

 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. 

 Kales HC, Kim HM, Zivin K, et al. Risk of mortality among individual antipsychotics in patients with dementia. 

 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.

 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.

 Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. 

 Suh GH, Shah A. Effect of antipsychotics on mortality in elderly patients with dementia: a 1-year prospective study in a nursing home. 

 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. 

 Gisev N, Hartikainen S, Chen TF. Effect of comorbidity on the risk of death associated with antipsychotic use among community-dwelling older adults. 

 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. 

Articles

Alzheimer disease psychosis appears to be a distinct clinical entity. This article focuses on management strategies.

Subramoniam Madhusoodanan, MD

Articles

Managing Psychosis in Patients With Alzheimer Disease