Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging

OBJECTIVE: The authors report findings from a study of 5,092 community residents who constituted 90% of the elderly resident population of Cache County, Utah. METHOD: The 5,092 participants, who were 65 years old or older, were screened for dementia. Based on the results of this screen, 1,002 participants (329 with dementia and 673 without dementia) underwent comprehensive neuropsychiatric examinations and were rated on the Neuropsychiatric Inventory, a widely used method for ascertainment and classification of dementia-associated mental and behavioral disturbances. RESULTS: Of the 329 participants with dementia, 214 (65%) had Alzheimer's disease, 62 (19%) had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or behavioral disturbances in the past month. Apathy (27%), depression (24%), and agitation/aggression (24%) were the most common in participants with dementia. These disturbances were almost four times more common in participants with dementia than in those without. Only modest differences were observed in the prevalence of mental or behavioral disturbances in different types of dementia or at different stages of illness: participants with Alzheimer's disease were more likely to have delusions and less likely to have depression. Agitation/aggression and aberrant motor behavior were more common in participants with advanced dementia. CONCLUSIONS: On the basis of their findings in this large community population of elderly people, the authors conclude that a wide range of dementia-associated mental and behavioral disturbances afflict the majority of individuals with dementia. Because of their frequency and their adverse effects on patients and their caregivers, these disturbances should be ascertained and treated in all cases of dementia.     

Neuropsychiatric symptoms in dementia-frequency, relationship to dementia severity and comparison in Alzheimer's disease, vascular dementia and frontotemporal dementia

Noncognitive behavioral and psychiatric disturbances are common in dementia and help in the clinical differentiation of the various subtypes. We studied the frequency of neuropsychiatric disturbances, their relationship to dementia severity and compared these disturbances in Alzheimer's disease (AD), vascular dementia (VaD) and frontotemporal dementia (FTD) using the 12-item Neuropsychiatric Inventory (NPI). A total of 98 patients (AD-44, VaD-31, FTD-23) were evaluated. All subjects were community dwelling at the time of evaluation. The three groups were comparable on global dementia severity and functional ability. All patients had clinically significant scores on the NPI with apathy, irritability and agitation being very common (>90% of patients). AD and VaD patients in Clinical Dementia Rating (CDR) stage 2 had significantly higher scores on the total NPI, agitation and disinhibition subscales compared to those in CDR stage 1. Mean scores in the domains of aberrant motor behavior, disinhibition and appetite/eating behavior differentiated FTD from AD and VaD. Neuropsychiatric disturbances in dementia appear to be universal with agitation, disinhibition and irritability being more frequent in the later stages. In this cohort disinhibition, aberrant motor behavior and appetite/eating disturbances could reliably differentiate AD and VaD from FTD. There were no significant differences between the neuropsychiatric profiles of AD and VaD.     

Drug-induced alzheimerism

A 74-year-old man with parkinsonism developed progressive cognitive and behavioral dysfunction suggesting coexistent Alzheimer's disease. The intellectual and behavioral disturbances were reversed following withdrawal of his anticholinergic antiparkinsonian medication. This case demonstrates that anticholinergic drugs used to treat parkinsonism may mimic or exacerbate the clinical signs of Alzheimer's disease and suggests that these medications should be withdrawn for all parkinsonian patients who develop significant impairments of cognition or behavior.     

The use of benzodiazepines in the management of behavioral symptoms in demented patients.

Hard data on the efficacy of benzodiazepines in the treatment of behavioral disturbances in Alzheimer's disease are not available. Short-acting benzodiazepines, such as oxazepam, appear safer than long-acting benzodiazepines and more efficient than placebo in the short-term (4-8 weeks) treatment of behavioral disturbances in geriatric, psychogeriatric, and demented patients. It is unknown whether oxazepam is superior to neuroleptic drugs or other commonly prescribed sedatives in this context. To some extent these findings may apply to patients with Alzheimer's disease as well, but there are several arguments against an uncritical extrapolation of conclusions drawn from other geriatric populations to patients with Alzheimer's disease. When, despite the lack of well-founded knowledge in this field, such a treatment modality is chosen, short-acting benzodiazepines should be preferred over long-acting agents. Drug interactions and pharmacokinetic aspects of the specific agent in the individual patient should always be considered carefully. Future studies on the treatment of behavioral disturbances in Alzheimer's disease need to clarify which specific behavioral symptoms should be treated pharmacologically, which therapeutic agents have the most advantageous risk-benefit ratio in this context, and what is the optimal treatment duration.     

Role of Cholinesterase Inhibitors in Managing Behavioral Problems in Alzheimer's Disease

Alzheimer's disease is characterized by progressive cognitive and functional decline and the emergence of behavioral disturbances. Behavioral symptoms, in particular, cause great distress to caregivers, creating an emotional and financial burden that often prompts the caregiver to place the patient in a nursing facility. The clinical deterioration in Alzheimer's disease is, in part, a result of deficits involving several neurochemical pathways. The cholinergic system, which is the most consistently and dramatically affected neurotransmitter system in Alzheimer's disease, has been strongly implicated in the emergence of neuropsychiatric symptoms. This article reviews evidence suggesting that, in addition to effects on cognition and function, the cholinesterase inhibitors benefit the behavioral symptoms of Alzheimer's disease. Pharmacologic and nonpharmacologic treatment strategies for the management of behavioral symptoms are discussed.     

Neuropsychiatric symptoms in the dementias

PURPOSE OF REVIEW: Neuropsychiatric, or non-cognitive symptoms are increasingly recognized as manifestations of dementias. RECENT FINDINGS: In Alzheimer's disease, recent advances have included the identification of behavioral profiles, differentiation of apathy and depression, characterization of risk factors for psychosis and its links to agitation and aggression, and an analysis of depressive symptoms in the absence of major depression. Functional neuroimaging data mainly supported the role of the anterior cingulate in apathy. The orbitofrontal and anterior cingulate tangle burden were associated with agitation, and increased orbitofrontal and mid-temporal muscarinic M2 receptors with psychosis and hallucinations. Selected genetic polymorphisms of dopamine and serotonin receptors or transporters were linked with aggression, hallucinations or psychosis. When compared with other dementias, individuals with frontotemporal dementia disclosed, as expected, different behaviors and particularly aberrant social behavior. The frequency of delusions and visual hallucinations was increased in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies, suggesting common mechanisms such as Lewy body pathology and cholinergic deficiency. The latter was supported by an improvement of these symptoms by cholinesterase inhibitors. SUMMARY: Future research directions include both clinical and basic neuroscience investigations. The detection of early neuropsychiatric symptoms might be a marker for dementia, and the possible existence of a mild neuropsychiatric impairment syndrome should be explored. More longitudinal studies with pathological confirmation will facilitate correlations with neuropsychiatric symptoms. Functional neuroimaging and behavioral neurogenetics will permit in-vivo correlations and consequently help patient management and care.     

Platelet tritiated imipramine binding and MAO activity in Alzheimer's disease patients with agitation and delusions

Decreased platelet 3H-imipramine binding density and decreased monoamine oxidase (MAO) activity have been considered as biological characteristics of several neuropsychiatric disorders, and may be related to central serotonin defects. Since serotonin system defects occur in Alzheimer's disease (AD), and decreased brain 3H-imipramine binding density, and increased brain and platelet MAO activity are reported also, we studied platelet 3H-imipramine binding density (Bmax) and platelet MAO activity in AD outpatients without antecedent psychiatric disorder. AD subjects with significant symptomatic behavioral disorder, predominantly agitation and delusions, and AD subjects without symptomatic behaviors were compared with controls. Age, sex, mini-mental state examination score, and illness duration did not distinguish the two AD groups. The agitated/delusional group showed significantly lower Bmax values than uncomplicated AD subjects or controls. MAO activity was significantly increased among female AD subjects without symptomatic behaviors compared to those who were agitated or to controls. These results indicate that 3H-imipramine binding and MAO activity may distinguish AD subjects with agitation or delusions from those without symptomatic behaviors, and suggest the existence of a biologically based Alzheimer's behavioral subtype.     

Non-pharmacological and pharmacological treatment of the cognitive and behavioral symptoms of Alzheimer disease

This paper discusses the various pharmacological and behavioral treatments for the cognitive, emotional, and behavioral symptoms of Alzheimer disease (AD). The medications that are currently FDA-approved for the treatment of the cognitive/functional deficits of AD will first be discussed. Next, neuropsychiatric behavioral disturbances, including hallucinations and delusions, agitation and aggression, activity disturbances, depression, and anxiety will be described along with treatment interventions. Sleep disturbance and its treatment in AD and the issue of fitness to drive a motor vehicle are also reviewed. Principles of behavioral management, tips for communication, and recommendations for caregivers are discussed. Lastly, risk and protective factors and their relevance to delaying the expression of dementia are also examined.     

Agitation and other noncognitive abnormalities in Alzheimer's disease.

Agitation and other noncognitive abnormalities in patients with Alzheimer's disease are present in at least 50% of patients and are a serious problem for caregivers. Agitation can be divided into aggressive agitation, physically nonaggressive agitation, and verbal agitation. Persecutory delusions of suspiciousness and stealing are the most common psychotic symptoms. Auditory and visual hallucinations are also associated with delusions. Similar to delusions are misidentifications, which are false beliefs probably secondary to agnosia. They occur in one third of patients with dementia of the Alzheimer type in the form of the belief that strangers are living in the home and misidentification of the patient's home and reflection in the mirror. Passive personality changes are present early in the disease, whereas agitation and psychotic symptoms occur with disease progression and predict a more rapid rate of cognitive decline. Agitation and wandering are related to more severe cognitive impairment and psychosocial variables, and neurochemical variables that may be related to behavior disturbance require further study. There are few systematic studies of behavioral or environmental interventions for behavioral symptoms in patients with Alzheimer's disease. Current treatment emphasizes education of families, the formation of Alzheimer units in the nursing home, and adjunctive psychotropic agents to treat well-defined target symptoms.     

Quantifying behavioral disturbance in Alzheimer's disease patients

In the course of a four-month study of interventions for behavioral disturbances in Alzheimer's disease (AD) patients, the following assessment instruments were examined for validity: the clinical global impression of change (CGIC), Cohen-Mansfield agitation inventory (CMAI); CERAD behavioral rating scale for dementia (BRSD), revised memory and behavioral problems checklist (RMBPC) and the agitated behavior in dementia scale (ABID). The four specific behavioral/agitation scales had excellent cross-sectional and longitudinal correlations with each other, suggesting high validity, but changes as indicated by CGIC scores did not correlate well with change scores on the other instruments. We conclude that specific behavioral instruments are preferable to the more general CGIC for detecting and quantifying behavioral disturbances in AD patients.     

Risperidone, olanzapine and quetiapine in the treatment of behavioral and psychological symptoms in patients with Alzheimer's disease: preliminary findings from a naturalistic, retrospective study

The objectives of this retrospective, naturalistic study were to provide preliminary data on the effects of 6 months treatment with risperidone, olanzapine and quetiapine on behavioral disturbances, within a sample of outpatients with mild to moderate Alzheimer's disease, and on predictors of response. Between July 2005 and December 2005, data were collected from 58 consecutive outpatients with a DSM-IV-TR diagnosis of Alzheimer's disease with behavioral disturbances, who received a 6-month treatment with risperidone, olanzapine or quetiapine. Primary outcome measures were Neuropsychiatric Inventory (NPI) total score and its items forming the basic core of behavioral disturbances in Alzheimer's disease: delusions, hallucinations and agitation/aggressiveness. Secondary outcome measures were Mini-Mental State Examination (MMSE), Activities of Daily Living, Instrumental Activities of Daily Living and Clinical Insight Rating scale. Correlations between baseline MMSE score and improvements in behavioral disturbances were investigated. At 6 months mean NPI total score had fallen 43.5% in the risperidone group, 45.6% in the olanzapine group and 33.3% in the quetiapine group, with no significant between-group differences. Global cognitive function showed no significant change from baseline to end-point. Incidence of adverse events was low. A significant correlation was found between MMSE score and NPI total score and NPI item agitation decreases. Risperidone, olanzapine and quetiapine produced significant improvements in behavioral disturbances and were well tolerated. No significant differences emerged among treatments. The preliminary results also suggest that baseline cognitive function might influence treatment response.     

Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease.

OBJECTIVE: The authors tested the hypothesis that evening bright light pulses would improve sleep-wake patterns and reduce agitation in patients with Alzheimer's disease who have severe sundowning (a syndrome of recurring confusion and increased agitation in the late afternoon or early evening) and sleep disorders. METHOD: Ten inpatients with Alzheimer's disease on a research ward of a veterans' hospital were studied in an open clinical trial. All patients had sundowning behavior and sleep disturbances. After a week of baseline measurements, patients received 2 hours/day of exposure to bright light between 7:00 p.m. and 9:00 p.m. for 1 week. During the baseline week, the treatment week, and a posttreatment week, patients were rated by nurses for agitation, sleep-wake patterns, use of restraints, and use of prescribed-as-needed medication. On the last 2 days of each week, patients wore activity monitors. Activity counts were analyzed for circadian rhythmicity. RESULTS: Clinical ratings of sleep-wakefulness on the evening nursing shift improved with light treatment in eight of the 10 patients. The proportion of total daily activity occurring during the nighttime decreased during the light-treatment week. The relative amplitude of the circadian locomotor activity rhythm, a measure of its stability, increased during the light-treatment week. More severe sundowning at baseline predicted greater clinical improvement. CONCLUSIONS: Evening bright light pulses may ameliorate sleep-wake cycle disturbances in some patients with Alzheimer's disease. This effect may be mediated through a chronobiological mechanism.     

Regression to the mean: implications for clinical trials of psychotropic agents in dementia

Effective drug development depends on understanding and optimizing results from controlled clinical trials. A recent double-blind, randomized, controlled trial of the treatment of agitation in patients with Alzheimer's disease (AD) found no difference among the four arms of the study: haloperidol, trazodone, behavioral therapy, placebo. The current analysis was undertaken to further investigate the issues bearing on this outcome and to identify better means of detecting psychotropic effects in trials involving patients with AD. This was post hoc analysis of a clinical trial data set. Patients in the placebo group were divided into responders (25% reduction in symptoms), worseners (25% worsening in baseline agitation scores), and those without a change in symptoms. Analysis of the trial outcomes demonstrated that the reduction observed in the placebo group was of the same magnitude as predicted by regression to the mean. Patients exhibiting greater improvement had more severe baseline behavioral disturbances. The relatively modest severity of agitation and the low medication doses achieved in the study may have further contributed to the failure to distinguish among treatment groups. Research design adjustments such as collection of both screening and baseline measures to determine eligibility may limit the effects of regression to the mean on trial outcomes and reduce this challenge to clinical trials.     

Treatment of the agitation of late-life psychosis and Alzheimer’s disease

In older as well as younger people, antipsychotic medication is commonly used to treat psychoses. In clinical practice, antipsychotic medication is also used to control severe behavioral disturbances such as agitation, wandering, self-mutilation, as well as assaultiveness. Neuroleptic and non-neuroleptic drug treatments are used to control severe agitation and disruptive behavior.Among typical neuroleptics, very low doses (e.g., 0.25 mg of haloperidol 1–4 times per day) may be effective and limit the development of severe extrapyramidal reactions.Recent experience suggests that the atypical neuroleptics, olanzaine, risperidone, and quetiapine, are also useful for controlling severe agitation in elderly demented nursing home residents.The benzamides are also known for the treatment of behavioral disturbances in Europe, but there is little experience in the U.S.A.Although research studies in this area are virtually nonexistent, growing clinical experience sugests that the following may be quite useful: 1) trazodone; 2) buspirone (Buspar®); 3) anticonvulsants (e.g., valproate); and 4) β-blockers.     

Atypical antipsychotics: sedation versus efficacy

Many patients with schizophrenia or bipolar disorder experience disturbances in their sleep-wake cycle, which may be a result of the disorder itself, of pharmacotherapy, or of a comorbid sleep disorder. These sleep disruptions can seriously impair patients' functioning as well as their quality of life. Therefore, accurate assessment of sleep problems is essential to appropriately treat patients and promote symptomatic remission. Sedating antipsychotics may ameliorate sleep disturbances, as well as agitation or other behavioral emergencies; however, these agents may also sedate patients to the point of dissatisfaction with the medication and/or impaired functioning, which may, in turn, increase treatment noncompliance and nonadherence. Using short-term adjunctive medications, such as benzo-diazepines or hypnotic agents, with a nonsedating antipsychotic to alleviate sleep disturbances is a reasonable treatment option for patients with schizophrenia or bipolar disorder. Overall, the pharma-cokinetics and pharmacodynamics of atypical antipsychotics are important factors to consider in the risk-benefit analysis, as are dosing strategies and individual patient factors, and clinicians must decide which agents are most appropriate for which patients.     

Agitation in Alzheimer's disease is a manifestation of frontal lobe dysfunction

OBJECTIVES: (1) To investigate the prevalence and characteristics of agitation in patients with Alzheimer's disease (AD) and other forms of dementia; (2) to explore the association between agitation and other clinical variables, including disease severity, functional impairment and other neuropsychiatric symptoms, and (3) to determine the predictors of agitation. METHODS: Data for 427 men and women with dementia from outpatient clinics of the University of California, Los Angeles Alzheimer's Disease Center were analyzed. There were 277 patients with AD, 43 with vascular dementia, 47 with mixed dementia, 45 with frontotemporal dementia and 15 with dementia with Lewy bodies. Patients were evaluated with the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Functional Activities Questionnaire (FAQ), neuropsychological tests and the Caregiver Appraisal instrument. SPSS10 was utilized for statistical analysis. RESULTS: There was no difference in agitation subscale scores among patients with dementia of various etiologies. In patients with AD, there was increased prevalence of agitation with increasing dementia severity. Agitation contributed substantially to caregiver burden and impact. There was a significant correlation between the FAQ and the NPI agitation subscale score after adjusting for MMSE scores. Delusion, disinhibition and irritability subscale scores in AD patients were correlated with agitation across disease severity. Subscale scores of frontally mediated behaviors including irritability, delusions and disinhibition predicted most of the variance in agitation levels. CONCLUSION: Agitation is common in AD and other dementias and has a marked impact on caregivers. It is related to dementia severity and to specific types of associated psychopathology implicating frontal lobe dysfunction. The present study is the largest and most comprehensive assessment of agitation reported. The data suggest that agitation in AD is a frontal lobe syndrome. Frontal lobe dysfunction may predispose AD patients to agitation by exaggerating behavioral responses to many types of coexisting psychopathology or environmental provocations.     

Psychosis and antipsychotic medications in Alzheimer's disease: clinical management and research perspectives

Psychosis is common in patients with Alzheimer's disease (AD) and contributes substantially to patient morbidity and caregiver distress. Antipsychotic medications are used to treat psychosis and other psychiatric or behavioral symptoms in AD, although optimal treatment guidelines have been elusive. Choosing the most advantageous medication for an individual patient is challenging. This article provides an overview of clinical management principles and medication treatment strategies for patients with AD and psychosis. Effects of individual medications are also described. Medications in the conventional neuroleptic, atypical antipsychotic, cholinesterase inhibitor, and serotonergic classes have been shown to ameliorate psychosis and behavioral symptoms in patients with AD, although the evidence is not conclusive for many medications. Side effects vary substantially across medication classes and modestly among individual patients. Improvement in agitation, aggression, or other behaviors with antipsychotic medication treatment may not depend on distinct antipsychotic effects. In contrast, there is preliminary evidence that delusions and hallucinations may respond to treatment with medications outside the antipsychotic class. Many important clinical questions warrant further research study. In particular, studies to compare how individual symptoms respond to different medications, and to examine how to best manage overlapping symptoms or incomplete treatment response are needed.     

A clinical overview of cholinesterase inhibitors in Alzheimer's disease

This review provides an overview of the three most widely used cholinesterase (ChE) inhibitors: donepezil, rivastigmine, and galantamine. Differences in pharmacologic profiles will be discussed, and consideration will be given to how such differences may relate to and influence the clinical efficacy and tolerability of the various agents. In addition to providing cognitive benefits in patients with Alzheimer's disease (AD), growing clinical evidence also suggests that ChE inhibitors can produce favorable and clinically relevant effects on neuropsychiatric/behavioral disturbances and activities of daily living. Furthermore, recent data indicate that these agents may be effective at all levels of disease severity and for all rates of disease progression. The clinical utility of ChE inhibitors in a wider spectrum of dementias which share a common cholinergic deficit, such as Lewy body dementia, Parkinson's disease dementia, and vascular dementia, is currently under investigation. Beyond symptomatic relief, data suggest that ChE inhibitors may also slow the underlying disease process. As clinical and research experience with these agents continues to accumulate, the differences in their effects will become more apparent and will help physicians tailor ChE inhibition treatment to the needs of the individual patient.