The interrelations between psychosis, behavioral disturbance, and depression in Alzheimer disease

Behavioral changes are common in Alzheimer disease (AD), and heterogeneous in their presentation. Subtle personality changes tend to occur early; these include apathy, irritability and inability to pay attention. Later agitation, aggression and disinhibited behaviors may appear. We have utilized the Columbia University Scale for Psychopathology in Alzheimer's Disease to monitor a number of behavioral symptoms in 235 patients with early probable AD. Markov analyses were used to predict the probability of developing or retaining a given symptom at 6-month follow-up. The results show that the symptoms of psychopathology in AD fluctuate with time. Agitation was both the most frequent and persistent symptom, while paranoid delusions and hallucinations were less persistent. Most behavioral disturbances, except paranoid delusions, were associated with greater cognitive impairment. There was no association between depressive features and either cognitive or functional impairment. These results have important implications for the optimal treatment of the psychopathological symptoms of AD.     

Presentation and stability of cognitive and noncognitive symptom patterns in patients with Alzheimer's disease. Disease course over a two-year period under constant treatment conditions with rivastigmine

The course of behavioural and psychotic features of patients with Alzheimer's disease treated with an inhibitor of the acetylcholinesterase (rivastigmine), and their association to cognitive impairment is presented in the study. Standardized examination of global functional deterioration (GDS), cognitive impairment (MMSE) and behavioural or psychotic symptoms (Behave-AD) were performed over two years. We could analyse the complete data from 44 of initially 91 patients with mild to moderate Alzheimer's disease. The cognitive component (measured by MMSE, ADAS-cog) and the functional assessment (GDS) showed a continuous decline after a one year period of stabilization, in contrast with behavioural and psychotic symptoms, especially delusions, which still improved after treatment of two years. While cognitive items in correlation with functional aspects formed a homogeneous factor over the two-year period, psychotic features displayed more variability over time evaluated by factor analysis. Nevertheless mood and anxiety disorder in combination with aggressive behaviour as well as hallucinations formed an independent factor in the course of Alzheimer's disease. In addition to other studies of the course of Alzheimer's disease we could demonstrate that distinct behavioural and psychotic symptoms may also present as independent factors in Alzheimer patients under constant treatment conditions with an inhibitor of the acetylcholinesterase (rivastigmine).     

Overview of depression and psychosis in Alzheimer's disease

The authors reviewed 30 studies on Alzheimer's disease to determine the prevalence and phenomenology of affective and psychotic symptoms in patients with this disorder. Depressive and psychotic symptoms occurred in 30%-40% of the Alzheimer's disease patients. Isolated symptoms were two to three times as frequent as diagnosable affective or psychotic disorders. Paranoid delusions were the most common psychotic symptoms reported. Implications of the relationship of psychiatric symptoms to the clinical presentation of Alzheimer's disease, patterns of cognitive dysfunction, clinical management, and areas for future research are discussed.     

Depression and Alzheimer's disease

In his classic case, Alzheimer described cognitive symptoms such as amnesia, aphasia, and apraxia and noncognitive symptoms such as delusions and agitation. Recent studies have suggested that depression also occurs in Alzheimer's disease. In this study, 144 patients who met criteria for Alzheimer's disease were examined for depression on a modified version of the Present State Examination. The prevalence rate of major depression was 17%. The depressed Alzheimer's disease patients were more cognitively impaired and more disabled than the nondepressed patients. Studies are needed to clarify the etiology and treatment of depression in Alzheimer's disease.     

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 physical aggression in probable Alzheimer's disease

OBJECTIVE: The purpose of this study was to determine the frequency and type of psychotic symptoms in patients with probable Alzheimer's disease and to test whether there is a relationship between specific psychotic symptoms and episodes of physical aggression. METHOD: From 209 patients with possible or probable Alzheimer's disease who had been assessed in a research clinic every 6 months for up to 4.5 years, 181 subjects with probable Alzheimer's disease were selected for study. On the basis of the summary note for each visit in the patients' charts, the presence of delusions, hallucinations, misidentifications, and episodes of physical aggression was determined. Data regarding psychotic symptoms and aggression were available for 170 and 169 subjects, respectively. RESULTS: Delusions had been reported for 74 (43.5%) of the patients and were the most frequent psychotic symptom; persecutory delusions were the most common type. Physical aggression had been noted for 50 (29.6%) of the patients. Delusions and misidentifications frequently preceded and were significantly associated with episodes of physical aggression. The presence of delusions was a significant predictor of physical aggression but accounted for only 3.5% of the variance. CONCLUSIONS: This study suggests that delusions are a risk factor for physical aggression in patients with probable Alzheimer's disease who have moderate to severe cognitive impairment. As delusions accounted for only a small percentage of the variance, further research is needed to identify other variables that may be significant predictors of physical aggression in this population.     

A double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia.

OBJECTIVE: To compare citalopram and risperidone for the treatment of psychotic symptoms and agitation associated with dementia, with a priori hypotheses that risperidone would be more efficacious for psychosis and citalopram for agitation. METHODS: A 12-week randomized, controlled trial in nondepressed patients with dementia hospitalized because of behavioral symptoms (N = 103) was conducted at the University of Pittsburgh Medical Center. Participants were consecutively recruited on an inpatient unit if they had at least one moderate to severe target symptom (aggression, agitation, hostility, suspiciousness, hallucinations, or delusions). Once they improved sufficiently, they were discharged to nursing homes, personal care homes, or residential homes for continued treatment. Planned pre-post and mixed model analyses of the main outcome measures of Neurobehavioral Rating Scale and Side Effect Rating Scale at baseline and at weekly/biweekly intervals were conducted. RESULTS: Completion rates did not differ for citalopram and risperidone (overall completion rate: 44%). Agitation symptoms (aggression, agitation, or hostility) and psychotic symptoms (suspiciousness, hallucinations, or delusions) decreased in both treatment groups but the improvement did not differ significantly between the two groups. There was a significant increase in side effect burden with risperidone but not with citalopram such that the two groups differed significantly. CONCLUSION: No statistical difference was found in the efficacy of citalopram and risperidone for the treatment of either agitation or psychotic symptoms in patients with dementia. These findings need to be replicated before citalopram or other serotonergic antidepressants can be recommended as alternatives to antipsychotics for the treatment of agitation or psychotic symptoms associated with dementia.     

The effects of olanzapine in reducing the emergence of psychosis among nursing home patients with Alzheimer's disease

BACKGROUND: Elderly patients with Alzheimer's disease (AD) commonly exhibit psychotic symptoms, prompting clinicians to administer antipsychotics. This article compares the effects of olanzapine and placebo in the emergence of hallucinations or delusions in AD patients with symptoms of agitation/aggression but little or no psychotic symptomatology at baseline. METHOD: A multicenter, double-blind, placebo-controlled study was conducted in nursing home patients with AD according to DSM-IV criteria and symptoms of agitation/aggression and/or psychosis. Patients (N = 206) were randomly assigned to receive either placebo or fixed-dose olanzapine (5, 10, or 15 mg/day) for up to 6 weeks. This article analyzes data from a subgroup of patients (N = 165) with no or minimal delusions and/or hallucinations at baseline as measured by the Neuropsychiatric Inventory-Nursing Home Version (NPI/NH). Three subsets of patients were identified on the basis of their symptoms at baseline: those with no clinically significant hallucinations, those with no clinically significant delusions, and those with no clinically significant delusions or hallucinations. RESULTS: Of the patients without hallucinations or delusions at baseline (N = 75), the placebo-treated patients showed significantly greater development of these symptoms compared with olanzapine-treated patients overall (NPI/NH hallucinations + delusions mean change score, +2.73 vs. +0.27, p = .006). Similarly, of the patients without baseline hallucinations (N = 153), the placebo-treated patients showed greater hallucinations score increases than did olanzapine-treated patients overall (+1.25 vs. +0.33, p = .026), whereas patients without baseline delusions (N = 87) showed no significant treatment effects. Olanzapine had a favorable safety profile in each patient subset. CONCLUSION: These results suggest that, overall, olanzapine effectively attenuated emergence of psychosis in a short-term trial of patients with Alzheimer's disease.     

Sleep-disordered breathing and agitation in institutionalized adults with Alzheimer disease.

OBJECTIVE: The authors examined the relationship between sleep-disordered breathing (SDB) and agitation in patients with Alzheimer disease (AD). METHODS: Thirty-eight AD patients (29 women, 9 men) in nursing homes in San Diego, CA participated. The mean age was 82.3 years, with a range of 61 to 95 years. Mean Mini-Mental State Exam score was 6.5 (range: 0-16). Sleep was recorded for one night, and agitation was measured with behavioral observations and ratings by nursing staff. RESULTS: SDB was very prevalent in this sample and was related to some types of agitation during the day but not in the evening or night. Aggressive Agitation on the Cohen-Mansfield Agitation Inventory and Manual Manipulation on the Agitated Behavior Rating Scale were greater with more severe SDB. Searching and wandering agitation decreased with more severe SDB. CONCLUSION: This study supports the hypothesis that SDB is related to agitation in AD, although the results are specific to certain types of agitation. Treatment of SDB may decrease agitation, easing the burden of caregiving and prolonging the time that patients are able to remain at home.     

Cognitive deficits of patients with Alzheimer's disease with and without delusions.

OBJECTIVE: The goal of this investigation was to study the prevalence of delusions in Alzheimer's disease and to compare the performance of the delusional and nondelusional groups on a neuropsychological test battery. METHOD: The authors studied 107 patients with Alzheimer's disease and 51 age- and education-comparable normal subjects using a standardized psychiatric interview and a neuropsychological test battery. RESULTS: Thirty-seven patients with Alzheimer's disease had delusions with or without hallucinations. Patients with delusions were significantly more impaired than those without delusions (and the normal comparison group) on the Mini-Mental State examination; Blessed Information-Memory-Concentration Test; Dementia Rating Scale, especially its conceptualization and memory subtests; and a test of verbal fluency. The delusional group also tended to be somewhat more impaired than the nondelusional group on the modified Wisconsin Card Sorting Test and the similarities subtest of the Wechsler Adult Intelligence Scale-revised. CONCLUSIONS: Approximately one-third of patients with Alzheimer's disease had developed psychotic symptoms sometime after the onset of dementia. The presence of psychotic symptoms in Alzheimer's disease was associated with greater cognitive impairment, especially frontal/temporal dysfunction, and possibly with a more rapidly progressive dementia.     

Impact of psychiatric hospitalization on behavioral complications of Alzheimer's disease.

OBJECTIVE: The authors conducted a prospective study of the clinical utility of the four DSM-III-R subtypes of primary degenerative dementia of the Alzheimer type (with delirium, with delusions, with depression, or uncomplicated) and acute psychiatric hospitalization for treatment of these subtypes. METHOD: The subjects were 120 consecutive inpatients with Alzheimer's disease, most of whom had behavioral abnormalities. Each subject received detailed physical, neurological, psychiatric, and mental status examinations. The presence or absence of specific behavioral problems was also documented. Patients were treated with medication, psychotherapy, and behavioral techniques. RESULTS: While all patients could be assigned to one of the four DSM-III-R behavioral subtypes, the uncomplicated subtype did not accurately reflect the burden of behavioral symptoms in the patients who did not have delirium, delusions, or depression. Each behavioral subtype responded in a characteristic way to inpatient treatment, as reflected by changes in scores on four psychometric scales used to assess cognitive impairment, psychiatric symptoms severity, and level of functioning at admission and at discharge, as well as by changes in residential setting following hospitalization. Half of all patients admitted from their homes and two-thirds of those with depression were able to go home following discharge. CONCLUSIONS: Behavioral syndromes in Alzheimer's disease should not be overlooked, because they have both clinical and prognostic significance. Short-term psychiatric hospitalization is effective and efficient for achieving the goal of returning patients to their homes and for safely implementing specific treatments in this frail population, and it may reduce the need for institutionalization.     

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.     

Apolipoprotein E genotype influences presence and severity of delusions and aggressive behavior in Alzheimer disease

AIM: We investigated differences in the prevalence and severity of 10 neuropsychiatric and behavioral symptoms according to apolipoprotein E (APOE) genotype and dementia severity in Alzheimer disease (AD). METHODS: Neuropsychiatric and behavioral symptoms of 110 AD patients were assessed using the Neuropsychatric Inventory. Dementia severity was assessed using the Mini Mental State Examination (MMSE). RESULTS: There were 27 APOE-epsilon4-negative patients, 65 heterozygous patients and 18 homozygous patients. There was a significant association between the number of APOE epsilon4 alleles and prevalence and severity of neuropsychiatric and behavioral symptoms that was mainly attributable to delusions and agitation/aggression, which were more common and severer among homozygous APOE epsilon4 carriers. In addition, the presence of hallucinations, anxiety, apathy and aberrant motor behavior increased with deteriorating MMSE score, independently of APOE epsilon4 status. CONCLUSIONS: The present study showed that the APOE epsilon4 genotype modifies neuropsychiatric and behavioral phenotype in AD. In particular, it was shown that delusions and agitation/aggression were more common and severer among homozygous APOE epsilon4 carriers than among heterozygous or APOE-epsilon4-negative patients.     

Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype

Though efforts to identify the genetic etiology of Alzheimer disease (AD) have made substantial progress, to date only some of the genes contributing to AD risk have been identified. Utilization of more etiologically homogeneous subphenotypes represents one strategy to facilitate the identification of novel risk genes in complex disorders. In this review, we evaluate the hypothesis that psychotic symptoms, such as delusions and hallucinations, define a suitable subphenotype in AD patients for gene-mapping efforts. Psychotic symptoms occur in 40-60% of patients with AD and are associated with more severe cognitive deficits and a more rapidly deteriorating course. The presence of psychotic symptoms in AD confers increased risk of similar symptoms to affected siblings. Candidate gene association analyses and initial linkage analysis have yielded significant results. We discuss possible genetic models of psychotic symptoms in AD, and suggest strategies for further investigation. Identification of such genetic factors may facilitate gene-mapping studies for both AD and idiopathic psychoses.     

Neuropsychiatric Symptoms and Global Functional Impairment along the Alzheimer's Continuum

Background/Aims: Neuropsychiatric symptoms in Alzheimer's disease (AD) are highly prevalent. We sought to determine whether neuropsychiatric symptoms were related to global functional impairment at baseline and over a 3-year period in older normal control (NC), mild cognitive impairment (MCI) and mild AD dementia subjects. Methods: Eight hundred and twelve subjects (229 NC, 395 MCI, 188 AD) from the Alzheimer's Disease Neuroimaging Initiative study underwent cognitive and behavioral assessments over 3 years. Results: Greater hallucinations, anxiety and apathy were associated with greater global functional impairment at baseline, while the presence of hallucinations and apathy at baseline was associated with greater global functional impairment over time across all subjects. The following neuropsychiatric symptoms were not significantly associated with global functioning: delusions, agitation, depression, euphoria, disinhibition, irritability, aberrant motor behaviors, sleep and appetite. Conclusions: These results suggest that increased baseline hallucinations, apathy and anxiety are associated with current and future disease progression in AD.     

Variables linked to psychotic symptoms in Alzheimer's disease

This study is aimed at assessing the prevalence and feature sof psychotic symptoms in a sample of 180 patients with Alzheimer's disease (AD). Sixty-four patients (35.5% of the sample) showed one or more psychotic symptoms. The presence of these symptoms correlated with the severity of the patients' cognitive impairment, as well as the patients' age at first assessement. Sex, duration of illness, education and familiar history for dementia were not significantly correlated with the psychotic symptoms. Hallucination was the most common symptom (24.4% of the whole sample), followed by delusion (18.3%) and misperceptin (11.1%). Visual hallucinations were more frequent than auditory, and, among delusions, persecutory and theft thems were largely prevailing. Misperceptions included television related phenomena and phantom boarder illusions. A follow-up study of 37 patients demonstreated the association between the presence of psychotic symptoms and a steeper slop of cognitive deterioration.     

Noncognitive symptoms in Alzheimer's disease. A study of 150 community-dwelling patients using a questionnaire completed by the caregiver

We studied the noncognitive symptoms in 150 community-dwelling Alzheimer's patients using a questionnaire completed by the caregiver, the Echelle Psychopathologique de la Démence de Type Alzheimer, EPDTA (Psychopathologic Scale of Dementia of Alzheimer Type). EPDTA is a 44-item questionnaire derived from the BEHAVE-AD and the Depressive Mood Scale, covering many aspects of the behavior, affective and psychiatric disturbances. Each item is rated from 0 (never observed) to 6 (most of the time). Frequency (percentage of symptom present) and severity (mean score when the symptom was present) were assessed for each item. The cognitive status and severity of the disease were assessed by the MMSE and two scales completed by the caregiver assessing the Activities of Daily Living scale (ADL) and the Cognitive Difficulties Scale (CDS). Noncognitive symptoms were present in all patients but remained moderate in severity. A principal component analysis of the 33 items exploring the affective disturbances showed seven clinically relevant factors: apathy, anxiety, anosognosia-irritability, euphoria, dysphoria, emotional incontinence and agitation. The most frequent noncognitive symptoms were the affective disturbances, especially apathy, and the sexual behavioural disturbances. No correlation were found between the overall severity of behavioural disturbances and cognitive status, duration of the disease nor demographic variables. However, a slight negative correlation was found between scores on apathy and on the MMSE. A second evaluation was performed in 59 patients after a mean follow-up of 18,2 months. The patients showed a progression of the disease evidenced by the scores on the MMSE, ADL and CDS scales. However, the frequency and severity of the noncognitive symptoms remained identical except for eating disorders, psychotic symptoms and agitation which were more frequent at the second examination and negatively correlated with the MMSE score. Most patients showed affective disturbances and scored high for apathy and anxiety-emotional incontinence dimensions. Like in a previous study, we found a double dissociation between these two dimensions in some patients, suggesting that they depend from different mechanisms. Agressivity, mostly verbal, was found in three quarters of the patients and was correlated to apathy, anosognosia and psychotic symptoms. Conclusion: The relationship between noncognitive manifestations and cognitive deficits in AD is not clear, suggesting that they depend from different biological and psychological mechanisms. Various dimensions may be described in the behavioural disturbances but their relationship with hypothetical biological mechanisms remains difficult. Our study stresses the importance of apathy, which was corelated with various noncognitive psychobehavioral manifestations in AD patients.     

Impact of behavioral subsyndromes on cognitive decline in Alzheimer’s disease: data from the ICTUS study

Behavioral and psychological symptoms of dementia (BPSD) represent common manifestations among patients affected by Alzheimer’s disease (AD). Some reports have recently classified BPSD into specific clusters/subsyndromes exploring the internal structure of the Neuropsychiatric Inventory (NPI). We evaluated whether specific behavioral subsyndromes are associated with worsening cognitive function. Mild to moderate AD patients were recruited from the cohort of the Impact of Cholinergic Treatment USe (ICTUS) study. Neuropsychiatric symptoms were classified in three subsyndromes, identified at baseline, grouping different combinations of NPI items: (1) “psychotic” (“delusions” and/or “hallucinations”); (2) “affective” (“agitation” and/or “depression” and/or “anxiety” and/or “irritability”); and (3) “behavioral” (“euphoria” and/or “apathy” and/or “disinhibition” and/or “aberrant motor behavior”). Mixed model analyses were performed to measure six-monthly changes in the ADAS-Cog score over a follow-up of 2 years, according to these subsyndromes. All analyses were stratified according to AD severity as defined by the Clinical Dementia Rating (CDR). A total of 1,375 AD subjects were recruited. No NPI cluster was found to significantly (p < 0.05) affect the rate of cognitive decline across the 3 CDR classes. Our results suggest that the cognitive course of AD is not substantially influenced by the presence of specific neuropsychiatric phenotypes. Further studies are needed to extend the present findings and identify possible biological and clinical bases for behavioral subsyndromes.