Psychosis In Alzheimer Research Articles

Genetic associations with psychosis and affective disturbance in Alzheimer's disease.

Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated.Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms.Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not.Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.

Psychosis in Alzheimer’s disease is associated with specific changes in brain MRI volume, cognition and neuropathology

Psychosis in Alzheimer’s Disease (AD) is prevalent and indicates poor prognosis. However, the neuropathological, cognitive and brain atrophy patterns underlying these symptoms have not been fully elucidated. In this study, we evaluated 178 patients with AD neuropathological change (ADNC) and ante-mortem volumetric brain magnetic resonance imaging (MRI). Presence of psychosis was determined using the Neuropsychiatric Inventory Questionnaire. Clinical Dementia Rating Sum-of-boxes (CDR-SB) was longitudinally compared between groups with a follow-up of 3000 days using mixed-effects multiple linear regression. Neuropsychological tests closest to the time of MRI and brain regional volumes were cross-sectionally compared. Psychosis was associated with lower age of death, higher longitudinal CDR-SB scores, multi-domain cognitive deficits, higher neuritic plaque severity, Braak stage, Lewy Body pathology (LB) and right temporal lobe regional atrophy. Division according to the presence of LB showed differential patterns of AD-typical pathology, cognitive deficits and regional atrophy. In conclusion, psychosis in ADNC with and without LB has clinical value and associates with subgroup patterns of neuropathology, cognition and regional atrophy.

A multi‐omic approach to elucidate novel disease mechanisms and biomarkers for psychosis in Alzheimer’s disease

AbstractBackgroundPsychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD is associated with a distinct profile of microbiological changes, but little is known about the molecular processes driving etiology.MethodGenome‐wide DNA methylation, small non‐coding (nc) RNAs (microRNA, transfer RNA, piwiRNA) and long coding and ncRNAs (mRNA, lincRNA, cicular RNAs) were quantified from 248 whole blood samples obtained from the Norwegian registry of persons assessed for cognitive symptoms (NorCog) cohort. Multi‐omics profiles of AD patients with psychosis (AD+P) were compared to the patients without psychosis (AD‐P).ResultThere were significant differences in DNA methylation, small ncRNAs, and long coding and ncRNAs between AD+P and AD‐P patients. Further analysis revealed specific genomic regions and molecular pathways that were differentially methylated or expressed in AD+P patients compared to AD‐P patients.ConclusionOur findings suggest that there may be distinct molecular signatures associated with AD psychosis, and that these differences may potentially be used as biomarkers for the early detection and diagnosis of AD psychosis.

What Has Changed in 20 Years of Treating Agitation and Psychosis in Alzheimer's Disease?

What Has Changed in 20 Years of Treating Agitation and Psychosis in Alzheimer's Disease?

Clinical Trial Studies of Antipsychotics during Symptomatic Presentations of Agitation and/or Psychosis in Alzheimer’s Dementia: A Systematic Review

Aggressive behaviors of people with dementia pose a significant challenge to employees in nursing homes and aged care facilities. Aggressive behavior is a result of psychomotor agitation in dementia (BPSD). Globally, psychotropic interventions are the preferred treatment for BPSD. However, it is still unclear which psychotropic should be prescribed. The purpose of this systematic review is to compare pharmacological interventions for psychomotor agitation and psychosis symptoms. Method: The studies were extracted from databases, such as PubMed, OVID, and Cochrane, with a date restriction from 2000 to present, and in English. PRISMA steps were used to refine the extracted data. The RCTs extracted for this systematic review compared active ingredient medications to one another or to a placebo. Results: PRISMA was used to assess all selected trials comprehensively. Four trials are being conducted on quetiapine, two on haloperidol, one on olanzapine, three on risperidone, one on brexpiprazole, one on pimavanserin, and two on aripiprazole. Compared to typical antipsychotics, quetiapine showed tolerable adverse effects and did not worsen parkinsonism. Psychosis symptoms and behavioral improvements can be improved with haloperidol. Among elderly patients with psychosis, risperidone reduces angriness, paranoia, and aggression, as well as improves global functioning. As compared with other antipsychotics, aripiprazole provides a lower risk of adverse effects and demonstrated improvement in agitation, anxiety, and depression associated with psychosis. While olanzapine improves hostile suspiciousness, hallucinations, aggression, mistrust, and uncooperativeness, it worsens depression symptoms. Psychosis was treated effectively with pimavanserin without adverse effects on motor functions. Psychosis symptoms are well tolerated by brexpiprazole, but insomnia, headache, and urinary tract infections are common side effects. Conclusions: In this systematic review, we provide an overview of how to choose the correct antipsychotics and dosages for the management of BPSD and emphasize the importance of safe and conservative use of these drugs.

A systematic review of the neuroanatomical correlates and predictors of psychosis in Alzheimer’s disease

AbstractBackgroundPsychotic symptoms (delusions or hallucinations) are a particularly prevalent form of neuropsychiatric symptom in people with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). Notably, their presence has been associated with an aggravation of the clinical picture of AD, with features including more rapid cognitive and functional decline, increased distress for the individuals and their caregivers (resulting in a higher rate of hospitalisation), and increased mortality. A growing number of studies detailing the relationship between neuroanatomy and these symptoms have been published in the last three decades in an attempt to clarify the underlying mechanisms. The aim of this systematic review is to capture all of the studies on AD that report links between psychotic symptoms and neuroanatomy, and to synthesise and evaluate these. Differences in the neuroimaging techniques employed, psychosis assessment tools, and brain areas investigated, as well as the sample size of the studies and disease stage of the patients, are likely to produce heterogeneous results, and these factors will be investigated during the review process.MethodThe protocol for this systematic review has been pre‐registered using the Open Science Foundation (DOI 10.17605/OSF.IO/TG8XP). Searches were performed using the databases PubMed, Web of Science and PsycInfo. These were followed by screening titles and abstracts and then full texts. These steps were performed by two independent reviewers, and recorded in a PRISMA flowchart. Inclusion of the studies was determined according to the following eligibility criteria: studies were either cross‐sectional or longitudinal to investigate the brain regions/networks that predict the future manifestation of psychotic symptoms; they contained samples of people with AD and/or MCI; they had a focus on delusions and/or hallucinations; they were limited to publications in English and peer‐reviewed publications; they had no restriction on publication date.ResultData extraction on full texts is currently underway. Once extraction is complete, data will be synthesised through summary tables and narrative descriptions.ConclusionThis systematic review intends to provide a comprehensive summary and synthesis of the brain regions and networks that are associated with psychosis and will capture key elements of the studies that are likely to impact their findings.

Combination of antidepressants and antipsychotics as a novel treatment option for psychosis in Alzheimer's disease.

Psychotic symptoms are reported as one of the most common complications of Alzheimer's disease (AD), in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second-generation antipsychotics, confer modest efficacy in patients with AD and with psychosis (AD+P) and themselves increase mortality. Recent studies suggested the use and beneficial effects of antidepressants among patients with AD+P. This motivates our rationale for exploring their potential as a novel combination therapy option among these patients. We included electronic medical records of 10,260 patients with AD in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. A protein-protein interaction network representing AD+P was built, and network analysis methods were used to quantify the efficacy of these drugs on AD+P. A combined score was developed to measure the potential synergetic effect against AD+P. Our survival analyses showed that the co-administration of antidepressants with antipsychotics have a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well-separated, and antipsychotics and antidepressants have similar Signed Jaccard Index (SJI) scores to AD+P. Eight drug pairs, including some popular recommendations like aripiprazole/sertraline, showed higher than average scores which suggest their potential in treating AD+P via strong synergetic effects. Our proposed combinations of antipsychotic and antidepressant therapy showed a strong superiority over current antipsychotics treatment for AD+P. The observed beneficial effects can be further strengthened by optimizing drug-pair selection based on our systems pharmacology analysis.

An Epigenome‐wide association study of psychosis in Alzheimer's disease dorsolateral prefrontal cortex

AbstractBackgroundPsychosis is a debilitating syndrome occurring in 40‐60% of people with Alzheimer’s disease (AD) and corresponds with a more severe disease course. Evidence suggests that psychosis in AD (AD+P) is associated with a distinct profile of neurobiological changes, but little is known about the molecular processes driving etiology. In this study we performed an epigenome‐wide association study (EWAS) to investigate DNA methylation associated with AD+P in the dorsolateral prefrontal cortex of 192 post‐mortem brain samples.MethodBrain samples with corresponding in life neuropsychiatric assessments were obtained from the University of Pittsburgh Alzheimer’s disease Research Center (PITT‐ADRC). AD pathology was assessed and classified using CERAD neuritic plaque density score, Braak neurofibrillary tangle stages and NIA‐RI criteria. The presence or absence of delusions and hallucinations was scored on the CERAD Behavioral Rating Scale. DNA was extracted, bisulfite treated and then profiled on the Illumina Methylation EPIC Array.ResultAfter data processing and quality control we used linear regression models to compare 152 AD+P samples to 40 AD samples without psychosis (AD‐P). A regional analysis of spatially correlated p‐values highlighted four differentially methylated regions (DMRs) associated with psychosis, which are being replicated in other data sets and validated for cell specificity using fluorescence activated nuclei sorting (FANS).ConclusionThe development of effective therapies for AD+P is an urgent priority. To address this we have collated a well powered study cohort to interrogate the epigenetic basis of AD+P, finding significant methylomic variation. This variation provides an insight into potential mechanisms and biomarkers which will help to identify drug targets and enable better treatment with existing medications.

Psychosis in Alzheimer's Disease Is Associated With Increased Excitatory Neuron Vulnerability and Post-transcriptional Mechanisms Altering Synaptic Protein Levels.

Alzheimer's disease with psychosis (AD+P) is a heritable phenotypic variant of the disease which is associated with more rapid cognitive deterioration compared to Alzheimer's disease without psychosis (AD–P). Cognitive decline in AD correlates with synapse loss, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD–P. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD–P [Mean (SD) AD+P 0.295 (0.061); AD–P 0.324 (0.052), p = 0.026]. mRNA levels contributed only modestly to altered synaptic proteins in AD+P relative to AD–P. Instead, network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. We previously found that neuropathologies account for ~18% of the variance in the occurrence of psychosis in AD. Further inclusion of cell type proportions and differentially expressed modules increased the percent of the variance in psychosis occurrence accounted for in our AD cohort to 67.5%.

Increased retention of tau PET ligand [18F]-AV1451 in Alzheimer\u2019s Disease Psychosis

Psychosis in Alzheimer’s disease (AD) represents a distinct disease subtype with a more rapid progression of illness evidenced by an increased velocity of cognitive decline and a hastened mortality. Previous biomarker and post-mortem studies have implicated tau neuropathology as a possible mediator of the accelerated decline in AD psychosis. Tau positron emission tomography (PET) neuroimaging provides the opportunity to evaluate tau pathology in-vivo, so that clinical symptomatology can be correlated with disease pathology. [18F]-AV1451 (Flortaucipir) is a PET ligand with high affinity for insoluble paired-helical filaments (PHFs) of hyperphosphorylated tau. In order to determine whether the development of psychosis and worsened prognosis in AD is associated with an increased burden of tau pathology that can be identified with tau imaging, we identified subjects within the Alzheimer’s disease neuroimaging initiative (ADNI) who had [18F]-AV1451 imaging at baseline and became psychotic over the course of the study (N = 17) and matched them 1:3 for gender, age, and education to subjects who had [18F]-AV1451 imaging at baseline and did not become psychotic (N = 50). We compared baseline [18F]-AV1451 retention, in addition to cognitive and functional baseline and longitudinal change, in those who became psychotic over the course of participation in ADNI with those who did not. Results suggest that increases in tau pathology in frontal, medial temporal, and occipital cortices, visualized with [18F]-AV1451 binding, are associated with psychosis and a more rapid cognitive and functional decline.

Fingolimod mitigates synaptic deficits and psychosis-like behavior in APP/PSEN1 mice.

IntroductionCurrent treatments for psychosis in Alzheimer's disease (AD), a syndrome characterized by more rapid deterioration and reduced synaptic protein abundance relative to non‐psychotic AD, are inadequate. Fingolimod, a currently US Food and Drug Administration (FDA)–approved pharmacotherapy for multiple sclerosis, alters synaptic protein expression and warrants preclinical appraisal as a candidate pharmacotherapy for psychosis in AD.MethodsPresenilin and amyloid precursor protein transgenic mice (APPswe/PSEN1dE9) and wild‐type mice were randomized to fingolimod or saline for 7 days. Psychosis‐associated behaviors were quantified by open field testing, pre‐pulse inhibition of the acoustic startle response testing, and habituation of the acoustic startle response testing. Synaptic proteins were quantified by liquid chromatography/mass spectrometry in homogenate and postsynaptic density fractions.ResultsFingolimod treatment increased the synaptic protein abundance in cortical homogenates and normalized psychosis‐associated behaviors in APPswe/PSEN1dE9 mice relative to saline. Mitochondrial‐related proteins were preferentially altered by fingolimod treatment and correlated with improvements in psychosis‐associated behaviors.DiscussionPreclinical studies employing complementary psychosis‐associated behavioral assessments and proteomic evaluations across multiple AD‐related models are warranted to replicate the current study and further investigate fingolimod as a candidate treatment for psychosis in AD.

Pimavanserin and dementia-related psychosis: can HARMONY prevail?

Delusions and hallucinations are common in people with dementia,1 and although risperidone and olanzapine show efficacy for the treatment of psychosis in Alzheimer's disease, their use has been linked to cardiovascular adverse events and increased risk of death.2 Safe and effective treatments are needed when non-pharmacological interventions have been unsuccessful and symptoms continue to distress or place the patient and others at risk.

A narrative review of the pharmacological management of psychosis in Alzheimer's disease

AimsDementia is estimated to affect 50 million people worldwide, with around 60% of these cases attributable to Alzheimer's disease (AD). One of the common behavioural and psychological symptoms associated with AD is psychosis. Psychosis, experiencing delusions or hallucinations, can be one of the most distressing ordeals for patients with AD, as well as those around them. Effectively managing these symptoms can lead to a vast improvement in life quality. Currently, there are no medications specifically licensed in the UK for the treatment of psychosis in AD. To help guide clinical practice, we reviewed the evidence underpinning the pharmacological treatment of psychosis in AD. The aim of the study was to positively influence clinical practice and thereby improve the life quality of this patient group.MethodAn advanced PubMed search was used to identify studies which investigated the pharmacological treatments for acute psychosis in people with AD. Papers included were double blind, placebo controlled, randomised controlled trials specifically for AD dementia. Papers must have reported their findings using a specific psychosis subscale (PS); examples being “Behavioural Pathology in AD” (BEHAVE-AD-PS), “Brief Psychiatric Rating Scale” (BPRS-PS), and “Neuropsychiatric Inventory - Nursing Home Version” (NPI-NH-PS). Populations of both outpatients and residential patients were accepted. 14 papers, comprising some 3237 patients, were included and critically analysed in the final review.ResultRisperidone (BEHAVE-AD-PS: -1.3 [p = 0.004] & -1.9 [p = 0.039]; BPRS-PS: -0.5 [p = 0.08]) and aripiprazole (NPI-NH-PS: -1.0 [p = 0.169] & -1.8 [p = 0.013]) successfully reduced psychosis symptoms in patient populations. However, these medications were associated with a statistical increase in severe adverse events including strokes and cognitive decline. Pimavanserin (NPI-NH-PS: -1.9 [p = 0.045]) also offered a notable reduction in psychosis symptoms, but was associated with increased agitation/aggression. Whilst commonly used in clinical practice, quetiapine, olanzapine, and haloperidol showed negligible therapeutic changes compared to placebo using multiple psychosis subscales. Olanzapine and haloperidol were associated with increased rates of severe adverse events including extrapyramidal symptoms. Quetiapine showed limited side effects.ConclusionRisperidone and aripiprazole offer effective means to help AD patients cope with psychosis, but these medications also come with an increased risk of developing life-threatening complications. They should, therefore, be administered judiciously. Pimavanserin shows early promise in treating this group of patients, with no life-threatening adverse effects associated with its use. Further research is required before endorsing the use of pimavanserin. There is little evidence to support the therapeutic use of quetiapine, olanzapine, and haloperidol in this patient population. No financial sponsorship declared.

Clinical Cohort Validation of Sex-Specific Effect of Apolipoprotein E Status on Psychosis in Alzheimer's Disease

<h3>Introduction</h3> Psychosis is one of the most typical and persistent neuropsychiatric manifestations of AD where nearly half of AD patients experiences psychotic symptoms such as hallucinations and/or delusions (Ropacki & Jeste., 2005). Psychotic AD patients tend to have poorer overall health (Bassiony et al., 2000) and experience greater cognitive and functional impairments (Chui et al., 1994; Fischer et al., 2012). These qualities contribute to a reduced quality of life for patients and their caregivers. Researchers from our group found that psychosis risk in neuropathologically-diagnosed AD patients is significantly higher in females who are homozygous positive for <i>APOE</i> ε4 with the presence of Lewy body pathology (Kim et al., 2017). These results point to a sexual dimorphism in AD psychosis where the ε4 allele may play a larger role in influencing psychosis development in females. We hypothesize that AD patients with this high-risk profile (female and homozygous positive for <i>APOE</i> ε4) are more susceptible to psychosis, potentially leading to more severe symptoms as well as earlier disease onset respectively. As such, this exploratory study aims to validate the sex-specific effect of <i>APOE</i> ε4 status (i.e. high-risk profile) on psychosis in a clinical cohort. <h3>Methods</h3> We first obtained all required Research Ethics Board approval from St. Michael's Hospital and the National Alzheimer's Coordinating Centre (NACC). A series of parallel analyses were conducted via SPSS (Version 27.0.0.0). For each analysis, we first conducted a descriptive analysis of our sample including age, sex, cognitive status, psychosis status, and presence of the relevant alleles. Patients with CNS neoplasm, non-AD-induced dementia, and significant psychiatric co-morbidity were excluded as per the inclusion/exclusion criteria for NACC. Participants Selected participants from the NACC database had a presumptive etiological diagnosis of AD from a clinician. They also had available <i>APOE</i> ε4 status and Neuropsychiatric Inventory Questionnaire (NPI-Q) data. Subjects were categorized by high-risk profile. Subjects with either hallucinations or delusions as defined by the NPI-Q were considered psychotic (Figure 1). Procedure & Analyses We investigated the effect of having a high-risk profile (female and homozygous positive for <i>APOE</i> ε4) on age and neuropsychiatric test scores at initial visit, as well as presence and severity of psychotic symptoms (delusions or hallucinations). <h3>Results</h3> To investigate the effect of the high-risk profile on age, we conducted a one-way between-subjects analysis of variance in the high-risk vs. non-high-risk conditions. Subjects with the high-risk profile (M = 70.43, SD = 7.75) were significantly younger than those without the profile (M = 74.69, SD = 9.76) at the time of their initial visit [F(1, 16202) = 139.05, <i>p</i> < .001] (Figure 2). To investigate the effect of the high-risk profile on the presence of delusions and hallucinations, we conducted a binary logistical regression for each psychotic symptom. We found that the high-risk profile significantly predicted the presence of delusions, <i>b</i> = 0.302, df = 1, <i>p</i> = .004. There was no significance for hallucinations. Lastly, to study the effect of the high-risk profile on the severity of delusions and hallucinations, we conducted an ordinal logistical regression for each psychotic symptom. Subjects with the high-risk profile had a predicted increase of 0.388 in the log-odds of being in a more severe category for delusions, <i>p</i> = .041. Similarly, high-risk individuals had a predicted increase of 0.638 in the log-odds of being in a more severe category for hallucinations, <i>p</i> = .046. <h3>Conclusions</h3> From our results, the high-risk profile of being female and homozygous positive for <i>APOE</i> ε4 seems to be associated with an earlier age of initial visit, an increased presence of delusions and more severe psychotic symptoms. In terms of psychosis in AD, our findings are in line with our prior work suggesting <i>APOE</i> ε4 may play a modulatory role in the development of psychosis in female patients with AD, leading to earlier onset of symptoms, increased prevalence of delusions and more severe psychotic symptoms (Kim et al., 2017). Taken together, we believe that this high-risk profile may be a significant step towards understanding the mechanisms that underly AD and psychosis in AD. Future directions include elucidating the sex-specific cellular mechanisms on <i>APOE</i> ε4 status. <h3>Funding</h3> We wish to acknowledge the generosity of the St. Michael's Hospital Foundation and the Heather and Eric Donnelly endowment.

Pimavanserin for the Treatment of Psychosis in Alzheimer's Disease: A Literature Review

<h3>Introduction</h3> Alzheimer's disease (AD) is among the most prevalent forms of dementia in the world. Approximately 25%-50% of individuals with AD develop psychotic symptoms sometime during their illness. The presence of psychosis in AD worsens outcomes. Currently, there are no FDA-approved medications for the treatment of psychosis in AD. Pimavanserin, a novel atypical antipsychotic medication, was approved by the FDA for the treatment of hallucinations and delusions associated with psychosis in Parkinson disease. Pimavanserin is also currently in clinical trials for the treatment of psychosis in AD. The purpose of this literature review is to evaluate the existing literature regarding the use of pimavanserin for treating psychosis in individuals with AD. <h3>Methods</h3> A literature review of clinical studies of pimavanserin treatment for psychosis in individuals with AD was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Trials were identified by systematically searching PubMed, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2019. The 5-point JADAD scoring system was used to assess the methodologic quality of randomized placebo-controlled trials (RCT). <h3>Results</h3> A total of 499 citations were retrieved and pooled. After de-duplication, two separate screeners evaluated the titles, abstracts, and full text of the remaining 258 citations. Two publications from 1 RCT were included in the final analysis. The quality of evidence was assessed to be of good methodologic quality, scoring 4 out of 5 using the 5-point JADAD questionnaire with the JADAD Scoring calculation. This systematic review found only one RCT that evaluated the use of pimavanserin for the treatment of psychosis among individuals with AD. This phase 2 trial resulted in two publications, the second of which was a subgroup analysis from the original study. The evidence from these two publications indicated that pimavanserin improves psychotic symptoms among individuals with AD when compared to placebo at the week 6 checkpoint. <h3>Conclusions</h3> Pimavanserin may be a pharmacologic consideration for the treatment for psychosis in AD. Additional RCTs are needed to assess the evidence of effectiveness before pimavanserin is considered a standard treatment. <h3>Funding</h3> This research received no funding agency in the public, commercial, or not-for-profit sectors.

Pimavanserin responders in Alzheimer's psychosis also see benefit in agitation, aggression

Patients with Alzheimer's disease whose psychotic symptoms improved with use of pimavanserin also showed improvement in agitation and aggression compared with nonresponders to the treatment, a study has found. These differences on agitation and aggression also were apparent in patients with higher baseline levels of these symptoms, the researchers reported.

110 - Investigations of Risk, Resilience and Novel Therapeutics of Late Life Neuropsychiatric Disease

Converging data from multiple domains of preclinical and human studies has underscored the importance of focusing on genetic, synaptic and neural circuity as critical neurobiological mechanisms of late life neuropsychiatric disease. These complementary research approaches have been applied to identify novel molecular mechanisms that may represent early intervention targets, as well as promising new treatments. The symposium will include four speakers who span the range of studies in animal models, post-mortem brain tissue, molecular imaging and clinical trials combined with biomarkers. Dr Etienne Sibille will present his research on the procognitive, neurotrophic and neurogenic effects of novel compounds augmenting dendritic inhibition and restoring neuronal connectivity, which is affected in aging and in neurodegenerative disorders, such as Alzheimer’s disease. Dr. Robert Sweet will present new GWAS and human postmortem findings regarding risk/resilience to psychosis in Alzheimer's Disease, with an emphasis on synaptic mechanisms of resilience. Dr Helen Lavretsky will present a study of the neuroimaging, genetic and epigenetic effects of memantine and escitalopram treatment in late life depression. The strategy of incorporating biological measures into a clinical trial is an important opportunity to understanding the neurobiological mechanisms. Dr Gwenn Smith will present multi-modality molecular imaging data to understand the synaptic changes associated with Alzheimer’s Disease pathology in late life depression and mild cognitive impairment. Consideration of interdisciplinary research approaches and applications to different neuropsychiatric conditions may have particular relevance to understanding the neurobiological mechanisms underlying neuropsychiatric symptoms as risk factors or complications of neurodegenerative disease.Molecular imaging methods to visualize the neuropathology of Alzheimer’s disease (AD) in vivo provide an unprecedented opportunity to understand the neuropsychiatric (NPS) and cognitive symptoms observed in early stage AD by testing hypotheses informed by human neuropathology and animal models. A fuller understanding of the neurobiology of early AD and its clinical progression is essential to identify individuals at risk and to identify targets for prevention and treatment. Numerous neuroimaging studies have shown that beta-amyloid and tau is necessary but not sufficient to explain cognitive decline and that models to explain cognitive decline must also include measures associated with synaptic dysfunction (eg cerebral glucose metabolism or brain volumes). Human data and animal models support the further investigation of serotonin (5-HT) degeneration. Relative to other molecular targets, there is stronger evidence for 5-HT loss in both cognitive deficits and neuropsychiatric symptoms (NPS) in Alzheimer’s Disease. 5-HT compounds are the only agents with preclinical evidence of multiple therapeutic mechanisms relevant to prevention and symptomatic treatment: blockade of amyloid precursor protein processing or neuroprotection, synaptic plasticity and improvement in both cognitive deficits and NPS. Multi-radiotracer PET studies of beta-amyloid (Aβ), tau and 5-HT have been performed longitudinally in amnestic, multi -domain, MCI (aMCI-MD) and cognitively normal elderly. Cortical and limbic 5-HT degeneration was a more powerful predictor of longitudinal memory decline than Aβ or Tau. Elucidating the role of 5-HT, in relation to Tau and Aβ in cognitive decline in aMCI-MD will have fundamental implications for the design of prevention and intervention studies targeting 5-HT.

Pimavanserin for the treatment of psychosis in Alzheimer's disease: A literature review.

BACKGROUNDAlzheimer’s disease (AD) is among the most prevalent forms of dementia in the world and neuropathological studies suggest similar high prevalence of mixed (AD + vascular) dementias. Approximately 25%-50% of individuals with AD develop psychosis sometime during their illness. The presence of psychosis in AD worsens outcomes. Currently there are no United States Food and Drug Administration (FDA) approved medications for the treatment of psychosis in AD. Pimavanserin, a novel atypical antipsychotic medication, was approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson disease psychosis and is currently in clinical trials for the treatment of psychosis in AD.AIMTo evaluate the existing literature regarding the use of pimavanserin for treating psychosis among individuals with AD.METHODSA literature review of clinical studies of pimavanserin treatment for psychosis in individuals with AD was performed using the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Trials were identified by systematically searching PubMed, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2019. The 5-point Jadad scoring system was used to assess the methodologic quality of the randomized placebo-controlled trials.RESULTSA total of 499 citations were retrieved and pooled in EndNote and de-duplicated to 258 citations. This set was uploaded to Covidence for screening. Two separate screeners (Srinivasan S and Tampi RR) evaluated the titles, abstracts, and full text of eligible articles. Of the identified 258 abstracts, 98 articles underwent full text review and 2 publications from 1 randomized controlled trial (RCT) were included in the final analysis. The quality of evidence was assessed to be of good methodologic quality, scoring 4 out of 5 using the 5-point Jadad questionnaire with the Jadad Scoring calculation. This systematic review found only one RCT that evaluated the use of pimavanserin for the treatment of psychosis among individuals with AD. This phase 2 trial resulted in two publications, the second of which was a subgroup analysis from the original study. The evidence from these two publications showed that pimavanserin improves psychotic symptoms among individuals with AD when compared to placebo at week 6.CONCLUSIONPimavanserin may be a pharmacologic consideration for the treatment for psychosis in AD. Additional RCTs are needed to assess the evidence of effectiveness before pimavanserin is considered a standard treatment.

New antipsychotic drugs for the treatment of agitation and psychosis in Alzheimer's disease: focus on brexpiprazole and pimavanserin.

Behavioral and psychological symptoms of dementia are symptoms of disturbed perception, mood, behavior, and thought content that occurred frequently. These symptoms, which include apathy, depression, anxiety, psychosis, agitation, and aggression, can serve as predictors of and early clinical diagnostic markers for Alzheimer’s disease (AD) and are common precipitants of institutional care. Agitation and psychosis are associated with accelerated disease progression and increased tau phosphorylation in patients with AD. Current guidelines recommend the use of second-generation antipsychotics for the treatment of agitation and psychosis in AD, but only after first-line non-pharmacological interventions and for no longer than 12 weeks because long-term use of these drugs is associated with an increased risk of mortality and an increased frequency of cerebrovascular events. Therefore, new antipsychotic drugs with improved efficacy and safety are needed as an alternative to current antipsychotic drugs. In this report, we discuss some of the most relevant advances in the field of agitation and psychosis in AD and focus on the recent positive clinical evidence observed with two new antipsychotics drugs: brexpiprazole and pimavanserin. Brexpiprazole is a receptor partial agonist (D2, D3, 5-HT1A), receptor antagonist (5-HT2A/B, α1B/α2C) according to the neuroscience-based nomenclature. Two recent phase III clinical trials have shown that brexpiprazole 2 mg/day is effective for the treatment of agitation in patients with AD and has an improved tolerability and safety profile compared with currently available second-generation antipsychotics. Pimavanserin is a receptor antagonist (5-HT2A, 5-HT2C) that has been given market authorization for psychosis occurring in Parkinson’s disease. Recent phase II studies suggest that this drug is effective in AD patients with more severe psychosis, although further long-term studies are needed to better define the efficacy and long-term safety profile of pimavanserin for the treatment of psychosis in AD.

Network Systems Pharmacology-Based Mechanism Study on the Beneficial Effects of Vitamin D against Psychosis in Alzheimer\u2019s Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease with significant financial costs and negative impacts on quality of life. Psychotic symptoms, i.e., the presence of delusions and/or hallucinations, is a frequent complication of AD. About 50% of AD patients will develop psychotic symptoms (AD with Psychosis, or AD + P) and these patients will experience an even more rapid cognitive decline than AD patients without psychosis (AD-P). In a previous analysis on medication records of 776 AD patients, we had shown that use of Vitamin D was associated with delayed time to psychosis in AD patients and Vitamin D was used more by AD-P than AD + P patients. To explore the potential molecular mechanism behind our findings, we applied systems pharmacology approaches to investigate the crosstalk between AD and psychosis. Specifically, we built protein-protein interaction (PPI) networks with proteins encoded by AD- and psychosis-related genes and Vitamin D-perturbed genes. Using network analysis we identified several high-impact genes, including NOTCH4, COMT, CACNA1C and DRD3 which are related to calcium homeostasis. The new findings highlight the key role of calcium-related signaling pathways in AD + P development and may provide a new direction and facilitate hypothesis generation for future drug development.