Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates

Abstract

Along with cognitive decline, 90% of patients with dementia experience behavioral and psychological symptoms of dementia, such as psychosis, aggression, agitation, and depression. Atypical antipsychotics are commonly prescribed off-label to manage certain symptoms, despite warnings from the regulatory agencies regarding the increased risk of mortality associated with their use in elderly patients. Moreover, these compounds display a limited clinical efficacy, mostly owing to the fact that they were developed to treat schizophrenia, a disease characterized by neurobiological deficits. Thus, to improve clinical efficacy, it has been suggested that patients with dementia should be treated with exclusively designed and developed drugs that interact with pharmacologically relevant targets. Within this context, numerous studies have suggested druggable targets that might achieve therapeutically acceptable pharmacological profiles. Based on this, several different drug candidates have been proposed that are being investigated in clinical trials for behavioral and psychological symptoms of dementia. We highlight the recent advances toward the development of therapeutic agents for dementia-related psychosis and agitation/ aggression and discuss the relationship between the relevant biological targets and their etiology. In addition, we review the compounds that are in the early stage of development (discovery or preclinical phase) and those that are currently being investigated in clinical trials for dementia-related psychosis and agitation/aggression. We also discuss the mechanism of action of these compounds and their pharmacological utility in patients with dementia.

Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions

“…Brexpiprazole is a second-generation antipsychotic, occasionally referred to as a third-generation antipsychotic with partial agonist properties at the D2 receptor. The compound is FDA-approved for treating schizophrenia and major depressive disorder as add-on therapy (217). Compared with aripiprazole and brexpiprazole, the molecule shows less activity at the D2 receptor, thereby generating a more tolerable side effects profile.…”

“…A selective M4 receptor agonist, HTL0016878, is being tested in one phase I clinical trial. Several compounds, acting on pharmacologically relevant targets, such as the 5-HT6 receptor (5-HT6R) and M1/M4R, have also progressed to advanced preclinical development stages (217). Therefore, one can envision drugs targeting mGluR, NMDA receptors, cannabinoid receptor type 1 (CB1R), M1/M4R, and 5-HT6R to be soon part of the pharmacological armamentarium employed for dementia-related agitation.…”

Relieving Caregiver Burden Through Evidence-Based Treatment for Dementia-Related Psychosis

“…[36][37][38] Although atypical antipsychotics may play a limited role in the short-term management of psychosis in patients with dementia, 39,40 any benefit has to be balanced against the risk of significant harms (Figure 2 41,42 ). 38 Dr Ballard noted that the US Food and Drug Administration (FDA) requires a "black box" warning 43 on atypical antipsychotic labels indicating an increased risk of mortality, other known harms, and limited efficacy in patients with dementia, 4 and European agencies have similar warnings. 44 Cholinesterase inhibitors may provide a pharmacologic treatment alternative for psychosis in people with DLB, 45 but benefits are less clear in people with other dementias.…”

“…3 Along with cognitive decline, 90% of patients with dementia experience behavioral and psychological symptoms of dementia, such as psychosis, aggression, agitation, and depression. 4 Dementia-related psychosis (DRP), which includes delusions and hallucinations, contributes to institutionalization, cognitive decline, and caregiver burden. 5 In this Academic Highlights, Drs Ballard and Aarsland will address best practices for improving outcomes for people living with DRP and their care partners.…”

Real-World Treatment Patterns and Characteristics Among Patients with Agitation and Dementia in the United States: Findings from a Large, Observational, Retrospective Chart Review

“…Historically, first-and second-generation antipsychotics have been used off-label as the first-line treatment of choice [24,25]. However, there have been concerns about the risk of adverse events associated with antipsychotics, as well as concerns about their limited clinical efficacy in alleviating agitation [26]. In 2005, the U.S. Food and Drug Administration (FDA) issued an advisory warning after reports of a 60% to 70% increased risk of death associated with the use of atypical antipsychotics compared with placebo in older patients with dementia-related psychosis [27].…”