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.     

Nonpharmacological and pharmacological interventions for symptoms in Alzheimer's disease

Patients with Alzheimer's disease may suffer from noncognitive symptoms as well as cognitive symptoms, which the condition is better known for. Behavioral and psychiatric symptoms are common in patients with Alzheimer's disease and may cause great distress to them and their carers. Symptoms include agitation, aggression, wandering, shouting, depression, apathy and sleep disturbance. The safe and effective management of behavioral and psychiatric symptoms of Alzheimer's disease is one of the greatest challenges clinicians face. Traditionally, pharmacological interventions have been the mainstay of treatment but there is growing evidence for the effectiveness of a wide range of nonpharmacological measures. In this review, the evidence and appropriateness of both types of intervention for behavioral and psychiatric symptoms in Alzheimer's disease are discussed.     

Behavioral disturbances in geropsychiatric inpatients across dementia types

The objective of this study was to compare differences in behavioral, psychiatric, and cognitive status among geropsychiatric inpatients with Alzheimer's, vascular, alcohol-induced, and mixed dementia. Participants included 150 patients with dementia consecutively admitted to an acute geropsychiatric inpatient unit. Measures included the Mini-Mental State Examination, Cohen-Mansfield Agitation Inventory, Cumulative Illness Rating Scale, Basic and Independent Activities of Daily Living, Positive and Negative Syndrome Scale for Schizophrenia, and the Initiation/Perseveration subscale of the Dementia Rating Scale. No significant differences existed in the character or severity of agitation among patients with Alzheimer's, vascular, alcohol-related and mixed dementia. Interestingly, patients with vascular dementia compared to patients with other dementias admitted for behavioral disturbances were less cognitively impaired and more medically burdened.     

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.     

Validating the diagnosis of delirium and evaluating its association with deterioration over a one-year period.

The authors probed the associations between clinical diagnoses and independent research measures of cognitive, behavioral, and electroencephalographic (EEG) changes in hospitalized older patients and investigated the contribution of medical illness to deterioration. Patients (N=96; 47 of whom were hospitalized during the course of 1 year; 12 diagnosed with delirium) received tests of cognitive and physical functioning and the Cumulative Illness Rating Scale, specific neuropsychological tests, and a two-channel EEG. Delirium was associated with independent measures of cognitive decline and EEG slowing. Hospitalization was associated with deterioration in functional status during the year, whether or not patients showed delirium. Results suggest that medical illness leading to hospitalization can contribute significantly to deterioration in self-care, and, when it is associated with delirium, to deterioration in cognitive performance and cerebral activity over a period of 1 year.     

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.     

Relationship of behavioral and psychological symptoms to cognitive impairment and functional status in Alzheimer's disease

OBJECTIVE: This cross-sectional study examined the relationship of behavioral and psychological symptoms to cognitive and functional impairment in Alzheimer's disease (AD). DESIGN: One hundred and fourteen patients were evaluated consecutively at a university-affiliated outpatient memory disorders clinic and diagnosed with possible or probable Alzheimer's disease (AD) according to NINCDS-ADRDA criteria. Subjects were assessed with the Behavioral Pathology in Alzheimer's Disease Scale (BEHAVE-AD), Revised Memory and Behavior Problem Checklist (RMBPC), Blessed Dementia Scale (BDS), and Mini-Mental State Examination (MMSE). RESULTS: Several symptoms of behavioral pathology showed associations with MMSE scores, including activity disturbances, delusions, and hallucinations. After controlling for the variance associated with the MMSE, activity disturbances, diurnal disturbances, delusions, and hallucinations were linked with BDS scores. CONCLUSIONS: The results suggest that some non-cognitive symptoms may be related to the neurobiologic mechanisms underlying the increased cognitive dysfunction in AD. Specific symptoms of behavioral pathology may also impact a patient's ability to perform important self-maintenance behaviors.     

Behavioral and psychological symptoms assessed with the BEHAVE-AD-FW are differentially associated with cognitive dysfunction in Alzheimer's disease.

To assess the possible neurological basis of behavioral and psychological symptoms of dementia (BPSD), the relationships between BPSD and cognitive function were evaluated in 40 patients with Alzheimer's disease (AD). BPSD was assessed using the Behavioral Pathology in Alzheimer's Disease Frequency Weighted Severity Scale (BEHAVE-AD-FW) for behavioral symptoms and psychological symptoms separately, and cognitive function was also assessed using the Cognitive Abilities Screening Instrument (CASI). We found that only behavioral symptoms were associated with cognitive function based on the CASI total score and the score for the CASI attention domain. Administration of risperidone, an atypical anti-psychotic drug, for one month, improved the behavioral symptoms and the scores for the CASI attention and orientation domains. Our data suggest that BPSD in AD may reflect two largely independent pathophysiological processes: one associated with behavioral symptoms partly overlapping with attention, and the other associated with psychological symptoms predominantly unrelated to cognitive function.     

EEG correlates in the spectrum of cognitive decline.

OBJECTIVE: To investigate relations between EEG measures and performance on tests of global cognition, memory, language and executive functioning. METHODS: Twenty-two controls, 18 patients with mild cognitive impairment (MCI) and 16 with probable Alzheimer's disease (AD) underwent neuropsychological and EEG investigations. We used the following EEG measures: theta relative power during eyes closed, alpha reactivity during memory activation (i.e. the percentual decrease in alpha power as compared to eyes closed) and alpha coherence during eyes closed and memory activation. RESULTS: Theta relative power was increased in AD patients as compared with controls (p<0.001) and MCI patients (p<0.01) and related to decreased performance in all cognitive domains. Alpha reactivity was decreased in AD patients as compared with controls (p<0.005) and related to decreased performance on tests of global cognition, memory and executive functioning. Alpha coherence did not differ between groups and was unrelated to cognition. CONCLUSIONS: EEG power measures were associated with decreased performance on tests of global cognition, memory, language and executive functioning, while coherence measures were not. SIGNIFICANCE: The EEG yielded several power measures related to cognitive functions. These EEG power measures might prove useful in prospective studies aimed at predicting longitudinal cognitive decline and dementia.     

Rivastigmine in Alzheimer's disease and Parkinson's disease dementia: an ADAS-cog factor analysis

Rivastigmine treatment is associated with significant improvements on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) in patients with mild-to-moderate Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Both AD and PDD are purported to have different profiles of cognitive impairment, which may respond differentially to rivastigmine treatment. This was a retrospective analysis of 3 randomized, double-blind, rivastigmine trial databases (Investigation of transDermal Exelon in ALzheimer's disease [IDEAL; AD], EXelon in PaRkinson's disEaSe dementia Study [EXPRESS; PDD], and Alzheimer's Disease with ENA 713 [ADENA; AD]). Factor analyses of the 11 baseline ADAS-cog items derived the same factors in the 2 diseases, that is, "memory" and "language". Rivastigmine-treated AD and PDD patients showed significant improvements (P < .0001 versus placebo) on both factors. For both AD and PDD, rivastigmine had a numerically greater effect on memory than language. Treatment effect sizes were numerically greater in PDD compared with AD. Rivastigmine treatment is associated with improvement in memory and language in AD and PDD. The numerically greater response in PDD is consistent with greater cholinergic deficits in this disease state.     

Pharmacologic management of agitation in Alzheimer's disease

A large body of evidence has accrued that neuropsychiatric disturbances, such as agitation, are extremely common in Alzheimer's disease. These disturbances are associated with considerable morbidity including earlier nursing home admission, more rapid progression, exacerbation of functional and cognitive deficits, and increased caregiver distress. When attention to social or environmental causes, medical conditions, or other triggers of the behavioral disturbance fails to yield improvement, a role for medication may be indicated, whereby the most dominant behavioral target symptoms are matched to the most relevant medication class. Evidence is reviewed for various medication classes in treating agitation in the patient with Alzheimer's disease, and future treatment strategies may be aimed at delaying or preventing such neuropsychiatric disturbances.     

Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders.

OBJECTIVE: The objective of this study was to conduct exploratory analyses of data pertaining to the efficacy of donepezil treatment of patients with severe behavioral disturbances. Preliminary studies suggest that cholinesterase inhibitors, including donepezil, may reduce behavioral disturbances in patients with Alzheimer disease (AD). Most patients included in clinical trials have had low levels of psychopathology at baseline, and the effect of cholinesterase inhibitors on patients with more severe behavioral disturbances is unknown. The authors report the effects of donepezil on behavioral disturbances in patients with relatively severe psychopathology at baseline. METHODS: This is a hypothesis-driven secondary analysis of a three-phase study involving donepezil and sertraline. In phase 1, psychotropic agents were withdrawn; in phase 2, patients were treated in an open-label fashion with donepezil for 8 weeks; and in phase 3, patients on donepezil were randomized to receive placebo or sertraline for an additional 12 weeks. The data set analyzed is comprised of the patient population treated with donepezil (without sertraline) for 20 weeks. One hundred twenty patients were included in the analyses. Mean age was 76 years, average Mini-Mental State Examination Score was 18, and mean Neuropsychiatric Inventory (NPI) total score was 30. Primary efficacy assessments were the NPI, the Clinical Global Impression-Improvement, and the Clinical Global Impression-Severity scales. Secondary measures included the Behavioral Pathology in Alzheimer's Disease Rating Scale, The Hamilton Depression Rating Scale, and the Alzheimer's Disease Functional Assessment and Change Scale. RESULTS: Excellent concurrent validity was noted between the NPI and the Behavioral Pathology in Alzheimer's Disease Rating Scale. The total score of the NPI was significantly reduced over the 20 weeks of therapy with donepezil. Sixty-two percent of patients had at least a 30% reduction in the total NPI score (significantly greater than the number with no meaningful response). Likewise, more patients had total or partial resolution of depression and delusions than those who had no meaningful change. Factor analysis of baseline NPI data revealed five factors, including a psychosis factor, an agitation factor, mood factor, frontal lobe function factor, and appetite and eating disorders factor. Clinically meaningful treatment effect sizes were notable for the delusion factor (0.340) and the mood factor (0.39). There were significant correlations between the Clinical Global Impression-Improvement and reductions in mood and agitation scores. CONCLUSION: The results of these analyses suggest that donepezil reduces behavioral symptoms, particularly mood disturbances and delusions, in patients with AD with relatively severe psychopathology.     

Emergent psychopathology in Alzheimer's disease patients over 12 months associated with functional,not cognitive,changes

In a large, well-characterized population of community-dwelling persons with Alzheimer's disease (AD), we investigated the emergence of behavioral symptomatology and its association with changes in cognitive, global-clinical, and functional status. Behavioral Rating Scale for Dementia (BRSD) item responses from 235 AD patients with varying levels of dementia severity and without significant behavioral disturbance were taken from the baseline and 12-month visits in a study of cognitive and behavioral instruments. Item-level analysis revealed new symptoms at every dementia severity level. The symptoms that emerged in the greatest proportion of patients were change in weight, change in appetite, diurnal confusion, uncooperativeness, restlessness, clingy behavior, loss of initiative, and change in sleeping pattern. Changes in cognitive status over the 12 months were associated with changes in functional status and not with the emergence of behavioral symptomatology; however, change in the latter two domains tended to be associated. The findings support the hypothesis that increasing behavioral disturbance is not strongly associated with decreasing cognitive status and that, except for psychotic symptoms, a previously observed association between dementia severity and behavioral status may have been mediated partly by changes in functional abilities.     

Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results

BACKGROUND: Laboratory evidence of cholesterol-induced production of amyloid beta as a putative neurotoxin precipitating Alzheimer disease, along with epidemiological evidence, suggests that cholesterol-lowering statin drugs may favorably influence the progression of the disorder. OBJECTIVE: To determine if treatment with atorvastatin calcium affects the cognitive and/or behavioral decline in patients with mild to moderate Alzheimer disease. DESIGN: Pilot intention-to-treat, proof-of-concept, double-blind, placebo-controlled, randomized (1:1) trial with a 1-year exposure to once-daily atorvastatin calcium (80 mg; two 40-mg tablets) or placebo using last observation carried forward analysis of covariance as the primary method of statistical assessment. PARTICIPANTS: Individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination score of 12-28) were recruited. Of the 98 participants providing informed consent, 71 were eligible for randomization, 67 were randomized, and 63 subjects completed the 3-month visit and were considered evaluable. MAIN OUTCOME MEASURES: The primary outcome measures were change in Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Global Impression of Change Scale scores. The secondary outcome measures included scores on the Mini-Mental State Examination, Geriatric Depression Scale, the Neuropsychiatric Inventory Scale, and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. The tertiary outcome measures included total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol levels. RESULTS: Atorvastatin reduced circulating cholesterol levels and produced a positive signal on each of the clinical outcome measures compared with placebo. This beneficial effect reached significance for the Geriatric Depression Scale and the Alzheimer's Disease Assessment Scale-cognitive subscale at 6 months and was significant at the level of a trend for the Alzheimer's Disease Assessment Scale-cognitive subscale, Clinical Global Impression of Change Scale, and Neuropsychiatric Inventory Scale at 12 months assessed by analysis of covariance with last observation carried forward. CONCLUSION: Atorvastatin treatment may be of some clinical benefit and could be established as an effective therapy for Alzheimer disease if the current findings are substantiated by a much larger multicenter trial.     

Carbamazepine treatment of agitation in Alzheimer's outpatients refractory to neuroleptics

Nine outpatients who met well-defined criteria for probable Alzheimer's disease (AD) and who had significant behavioral agitation failed to improve with neuroleptic therapy and were subsequently treated with carbamazepine. Five patients showed a clear improvement, and one patient an equivocal response according to clinical evaluation and Brief Psychiatric Rating Scale scores; those results suggests that carbamazepine may be useful to treat agitated AD patients who have not previously responded to neuroleptics and patients with other organic mental syndromes.     

Effects of a newly developed cognitive intervention in amnestic mild cognitive impairment and mild Alzheimer's disease: a pilot study

Recent studies have shown that patients with Alzheimer's disease (AD) and its possible prodromal stage mild cognitive impairment benefit from cognitive interventions. Few studies so far have used an active control condition and determined effects in different stages of disease. We evaluated a newly developed 6-month group-based multicomponent cognitive intervention in a randomized controlled pilot study on subjects with amnestic mild cognitive impairment (aMCI) and mild AD patients. Forty-three subjects with aMCI and mild AD were recruited. Primary outcome measures were change in global cognitive function as determined by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini Mental Status Examination (MMSE). Secondary outcomes were specific cognitive and psychopathological ratings. Thirty-nine patients were randomized to intervention groups (IGs: 12 aMCI, 8 AD) and active control groups (CGs: 12 aMCI, 7 AD). At the end of the study, we found significant improvements in the IG(MCI) compared to the CG(MCI) in the ADAS-cog (p = 0.02) and for the secondary endpoint Montgomery Asberg Depression Rating Scale (MADRS) (p < 0.01) Effects on the MMSE score showed a non-significant trend (p = 0.07). In AD patients, we found no significant effect of intervention on the primary outcome measures. In conclusion, these results suggest that participation in a 6-month cognitive intervention can improve cognitive and non-cognitive functions in aMCI subjects. In contrast, AD patients showed no significant benefit from intervention. The findings in this small sample support the use of the intervention in larger scales studies with an extended follow-up period to determine long-term effects.     

Melissa officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease: a double blind,randomised, placebo controlled trial

OBJECTIVE: To assess the efficacy and safety of Melissa officinalis extract using a fixed dose (60 drops/day) in patients with mild to moderate Alzheimer's disease. DESIGN: A four month, parallel group, placebo controlled trial undertaken in three centres in Tehran, Iran. METHODS: Patients with mild to moderate Alzheimer's disease aged between 65 and 80 years (n = 42; 18 women, 24 men) with a score of >or= 12 on the cognitive subscale of Alzheimer's disease assessment scale (ADAS-cog) and 相似文献   

Use of electroencephalography to detect Alzheimer's disease in Down's syndrome

We studied the role of electroencephalography (EEG) in the diagnosis of Alzheimer-type dementia in patients with Down's syndrome. 197 patients with Down's syndrome were monitored for 5 to 8 years. Aspects of cognitive functioning were assessed twice yearly. EEGs were scored in a blind fashion, and changes in the EEG were compared to changes in cognitive functioning. When possible, a neuropathological post-mortem examination was performed. Cognitive functioning was drastically reduced in 29 patients. The dominant occipital rhythm became slower at the onset of the cognitive deterioration, and eventually disappeared. In 11 of these patients neuropathological examination showed a severe form of Alzheimer's disease. Changes in the frequency of the dominant occipital rhythm could distinguish between Alzheimer's disease or other causes as underlying the cognitive decline. Slowing of the dominant occipital rhythm seems to be related to Alzheimer's disease in patients with Down's syndrome, and the frequency of the dominant occipital activity decreases at the onset of cognitive deterioration. The EEG is thus an important tool in the clinical diagnosis of Alzheimer-type dementia in patients with Down's syndrome.     

Personality changes in Alzheimer's disease.

We profiled personality changes that were measured cross-sectionally on the Blessed Dementia Scale in 80 patients with Alzheimer's disease who were examined at a dementia clinic. The most common personality changes were diminished initiative/growing apathy (61.3%), relinquishment of hobbies (55.0%), and increased rigidity (41.3%). The least frequent personality change was sexual misdemeanor (3.8%). Discriminant function analysis showed that the Global Deterioration Scale, the Clinical Rating Scale for Symptoms of Psychosis in Alzheimer's Disease, and the duration of dementia symptoms were the best predictors to classify personality change in an overall score of personality. However, cognitive impairment, as measured by the Blessed Memory-Information-Concentration Test and Mini-Mental State Examination, was not a good predictor of overall personality change. Personality and behavioral changes are common in Alzheimer's disease and may not be attributed entirely to intellectual impairment.     

Behavioral and psychological symptoms in Taiwanese patients with Alzheimer's disease

OBJECTIVE: To investigate the prevalence of and risk factors for behavioral and psychological symptoms in Taiwanese Alzheimer's disease (AD) patients. METHOD: Consecutive AD patients from the Memory Clinic of the Taipei Veterans General Hospital were studied. Cognitive function was evaluated using the Chinese version of the Cognitive Abilities Screening Instrument. Primary caregivers were interviewed for the Clinical Dementia Rating scale, the Barthel Index, and the Alzheimer's Deficit Scale. Behavioral and psychological symptoms were assessed using the Behavioral Pathology in Alzheimer's Disease Rating Scale. RESULTS: Of the 142 participants, 73 (50.7%) had at least one delusion. The most frequent delusion was delusion of theft (N=43, 30.3%). Thirty-five patients (24.6%) experienced hallucination. Fifty-seven patients (40.1%) had activity disturbances and 39 (27.5%) had aggression. Patients were divided into two subgroups according to the presence or absence of each cluster of symptoms, namely, delusions, hallucinations, activity disturbance, aggression, diurnal rhythm change, affective symptoms, and anxiety. There was no significant correlation between age, age at onset of dementia, number of years of education, and duration of illness and each cluster of symptoms. Correlation between severity of behavioral and psychological symptoms of dementia and cognitive decline was noted. CONCLUSIONS: This study revealed a high prevalence of behavioral and psychological symptoms of dementia in Taiwanese patients with AD and suggests that these symptoms are associated with cognitive deficit.