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.     

Animal Models of Psychosis in Alzheimer Disease

Psychosis in Alzheimer Disease (AD) represents a distinct clinicopathologic variant associated with increased cognitive and functional morbidity and an accelerated disease course. To date, extant treatments offer modest benefits with significant risks. The development of new pharmacologic treatments for psychosis in AD would be facilitated by validated preclinical models with which to test candidate interventions. The current review provides a brief summary of the process of validating animal models of human disease together with a critical analysis of the challenges posed in attempting to apply those standards to AD-related behavioral models. An overview of phenotypic analogues of human cognitive and behavioral impairments, with an emphasis on those relevant to psychosis, in AD-related mouse models is provided, followed by an update on recent progress in efforts to translate findings in the pathophysiology of psychotic AD into novel models. Finally, some future directions are suggested to expand the catalogue of psychosis-relevant phenotypes that may provide a sturdier framework for model development and targets for preclinical treatment outcomes.     

Functional Ability in Executive Variant Alzheimer's Disease and Typical Alzheimer's Disease

A frontal, or executive, variant of Alzheimer's disease (EAD) has been described in the literature in which frontal dysfunction accompanies temporal and parietal changes in the early stages of the illness. However, no study has empirically investigated associated aspects, such as neuropsychiatric symptoms, instrumental activities of daily living, or caregiver burden in this EAD subgroup. We compared the performance of two subgroups of mild Alzheimer's disease patients (e.g., EAD and typical Alzheimer's disease; TAD) on neuropsychological and associated measures. Results revealed that the EAD group, selected based on poor executive scores, did not significantly differ from the TAD group on nonexecutive neuropsychological tests of intelligence, language, verbal and nonverbal memory, or visual-spatial abilities. However, the EAD group evidenced more severe neuropsychiatric symptoms, impaired activities of daily living, and greater caregiver distress than the TAD group. Thus, the EAD subgroup is characterized by executive dysfunction, neuropsychiatric symptoms, and functional disability in excess of that seen in TAD. Whether our EAD subgroup represents an actual frontal variant of Alzheimer's disease awaits replication in a larger sample including neuroimaging and pathological confirmation, as well as longitudinal assessment of cognition and neuropsychiatric symptoms.     

The Art of PrescribingPharmacological Management of Psychosis in Alzheimer's Disease: Clinical Challenges Associated With Second-Generation Antipsychotic Medications

QUESTION.  There is growing concern about the use of second-generation or atypical antipsychotic medications in the management of psychosis in patients with Alzheimer's disease (AD). As a practicing advanced practice psychiatric nurse in a local nursing home, this issue is a frequent clinical challenge. Please discuss the most recent clinical findings concerning the pharmacological management of psychosis in patients with AD, specifically the second-generation antipsychotic medications and the implications for prescribing psychiatric nurses .
DEBORAH ANTAI-OTONG REPLIES.  You are correct about the growing concerns involving the use of second-generation antipsychotic medication in patients with AD. In fact, although these agents are widely used to treat neuropsychiatric disorders in older adults, many questions linger about the efficacy and safety, further complicating clinical decision-making. As our society ages, the number of individuals with psychosis increases. The rise in AD in the U.S. population makes this discussion especially timely and relevant to the safe and quality management of psychosis in persons with AD.     

Current Understanding of Psychosis in Parkinson’s Disease

Psychosis in Parkinson’s disease (PD) is one of the greatest determinants of nursing home placement and caregiver stress. Traditionally associated with medications with dopaminergic effect, it has now been linked to other medications and other stressors e.g. systemic illnesses. The development of hallucinations in a PD patient can herald the onset of dementia and usually predicts increased mortality risk. Medication reduction in PD psychosis usually reduces the symptoms; however, this comes at the cost of worsening motor function. If gradually decreasing the patient’s medications does not resolve the psychosis, the treatment of choice is an atypical antipychotic. Though only clozapine has level A recommendation for this indication, other atypicals like quetiapine continue to get used for this purpose on account of the logistics involved with clozapine use. Cholinesterase inhibitors are also increasingly being used for PD psychosis on account of the association with dementia. The treatment of PD psychosis is an unmet need in PD management and search for suitable agents constitutes an active area of research in PD.     

ECT in the Treatment of Organic Psychosis in Huntington's Disease

Huntington's disease (HD) is a progressive neurological disorder characterized by choreiform movements, dementia, and psychiatric symptoms. The psychiatric symptoms often lead to long-term psychiatric hospitalization. We report the case of a 49-year-old woman with HD of 1 year's duration who presented with an organic psychotic syndrome with voices telling her to kill herself or her children. The psychosis was refractory to neuroleptic treatment (up to 1,250 mg chlorpromazine equivalents per day). Depressive symptoms emerged but were neither of a magnitude nor of a duration to suggest a major affective disorder. Nonetheless, we treated the patient empirically with antidepressants, which had to be discontinued because of symptomatic orthostatic hypotension. Based on the persistent psychosis with suicidal and homicidal ideation and possible long-term state psychiatric hospitalization, we recommended electroconvulsive therapy (ECT). ECT was successful in treating the psychosis as well as the depressive symptoms. There was no worsening of the patient's dementia and only a slight progression in her choreiform movements. The authors question whether ECT may be of benefit in treating the psychosis of HD in the presence or absence of depressive symptoms and call for further research to determine if the use of ECT in HD patients with psychosis could prevent, or at least delay, placement in a long-term psychiatric hospital.     

Brainstem Pathologies Correlate With Depression and Psychosis in Parkinson's Disease

BackgroundThe pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus.MethodsThe brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants’ history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation.ResultsOf the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ² = 7.1, p = 0.008, df = 1) and depression (χ² = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5–6.4, χ² = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3–5.0, χ² = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra.ConclusionThese results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.     

The Alzheimer's Disease Exposome

IntroductionEnvironmental factors are poorly understood in the etiology of Alzheimer's disease (AD) and related dementias. The importance of environmental factors in gene environment interactions (GxE) is suggested by wide individual differences in cognitive loss, even for carriers of AD-risk genetic variants.Results and DiscussionWe propose the “AD exposome” to comprehensively assess the modifiable environmental factors relevant to genetic underpinnings of cognitive aging and AD. Analysis of endogenous and exogenous environmental factors requires multi-generational consideration of these interactions over age and time (GxExT). New computational approaches to the multi-level complexities may identify accessible interventions for individual brain aging. International collaborations on diverse populations are needed to identify the most relevant exposures over the life course for GxE interactions.     

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.