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

ABSTRACT: 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, ?1B/?2C) 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.

SUBMITTER: Caraci F

PROVIDER: S-EPMC7344175 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Caraci Filippo F Santagati Mario M Caruso Giuseppe G Cannavò Dario D Leggio Gian Marco GM Salomone Salvatore S Drago Filippo F

F1000Research 20200708

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 phosphorylatio ...[more]

PMID: 32695312

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Project description:ImportanceAgitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment.ObjectiveTo confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia.Design, setting, and participantsThis randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.InterventionsIn this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio.Main outcomes and measuresThe primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events.ResultsA total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, -22.6; placebo baseline, 79.2, mean change, -17.3; least-squares mean difference, -5.32; 95% CI, -8.77 to -1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo.Conclusions and relevanceIn this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population.Trial registrationClinicalTrials.gov Identifier: NCT03548584.

Project description:BACKGROUND:Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies. RESULT:A computational method based on ligand-protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski's rule. CONCLUSION:The present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.

Project description:The purpose of this study is to identify factors that predict nursing home placement among community-dwelling Alzheimer's disease (AD) patients with psychosis and/or agitation in a randomized clinical trial (ClinicalTrials.gov number, NCT00015548).418 participants with AD enrolled in the Clinical Antipsychotic Trial of Intervention Effectiveness - AD (CATIE-AD) trial of anti-psychotic medications and having no evidence of nursing home use at baseline were followed at 9 months post-random assignment using data provided by caregiver proxy. ?2 tests, t-tests and Cox proportional hazard modeling were used to examine the baseline correlates of nursing home use.Of outpatients with no prior nursing home use, 15% were placed in a nursing home in the 9 months following baseline, with the average time to placement being 122 days. Bivariate analyses indicate that those with prior outpatient mental health use at study entry were more likely to be admitted; so too were those with worse physical functioning - i.e. lower scores on the AD Cooperative Study Activities of Daily Living Scale (ADCS-ADL), lower utility scores on the Health Utility Index (HUI)-III, and worse cognition on the Mini-mental State Examination. Controlling for other factors, non-Hispanic white race (hazard ratio [HR] = 2.16) and prior mental health use (HR = 1.87) increased the likelihood of admission. Those with higher ADCS-ADL scores were less likely to be placed (HR = 0.97).Factors leading to nursing home entry among psychotic/agitated AD patients are similar to the general population, though high incidence of nursing home entry highlights the importance of accounting for such utilization in health economic studies of AD outcomes. It also highlights the importance of using information on ADLs and other characteristics to develop profiles identifying those at greater or lesser risk of nursing home entry and, in so doing, inform population planning associated with AD and identification of those patients and caregivers who might benefit most from interventions to prevent eventual placement.

Dataset Information

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

Publications

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

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