Brexpiprazole for Agitation Associated With Dementia Due to Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT1A and dopamine D2 receptor agonist activity and serotonin 5-HT2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used "as needed" or as a "PRN" treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials.

Review of valiltramiprosate (ALZ-801) for the treatment of Alzheimer's disease: a novel small molecule with disease modifying potential.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, functional impairments, and neuropsychiatric symptoms. Valiltramiprosate is a tramiprosate prodrug being investigated as a novel treatment for AD. AREAS COVERED: The online databases PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'ALZ-801' or 'valiltramiprosate.' Alzheon press releases were reviewed for emerging clinical information. Valiltramiprosate is an oral, well-tolerated synthetic valine-conjugate prodrug of tramiprosate. Valiltramiprosate's active metabolite include tramiprosate and 3-sulfopropanoic acid. Proposed mechanism of action is multiligand binding to Aß42 which stabilizes amyloid monomers to prevent peptide aggregation and oligomerization. Pharmacokinetic studies show 52% oral bioavailability, rapid absorption, approximately 40% brain-drug exposure, and near complete renal clearance. Compared to tramiprosate, valiltramiprosate extends plasma tramiprosate half-life and improves interindividual pharmacokinetic variability. Interim analyses from valiltramiprosate's phase II biomarker trial show: (1) significant reductions in plasma p-tau181 and related AD fluid biomarkers; (2) brain structure preservation and reduced hippocampal atrophy by MRI; and (3) improvements on cognitive assessments at multiple timepoints. Its phase III clinical trial in ApoE ε4 homozygotes is near completion. EXPERT OPINION: Valiltramiprosate's clinical trial data show early indications of efficacy with potential disease modifying effect in AD.

A 2023 update on the advancements in the treatment of agitation in Alzheimer's disease.

INTRODUCTION: Neuropsychiatric symptoms (NPS) in Alzheimer's Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is a common and distressing NPS, without safe and effective treatments. Nonpharmacological interventions are first line treatment, but not effective or appropriate for every patient. Current pharmacological treatments of agitation in AD include off-label use of antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. Despite prevalent use, efficacy and safety concerns remain. AREAS COVERED: Better understanding of neurobiological mechanisms of agitation have fueled recent clinical trials. This article is an update to our 2017 review. Comprehensive search of ClinicalTrials.gov was completed from January 2017 to February 2023 using the search terms "Alzheimer's Disease" and "Agitation". Subsequent scoping review was completed in PubMed and Google Scholar. Several agents were identified, including: brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin. EXPERT OPINION: Clinical trials utilize both novel and repurposed agents for agitation in AD. With increasing understanding of the neurobiological mechanisms that fuel development of agitation in AD, use of enahanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval, we advance closer to safe and efficacious treatment options for agitation in AD.

Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study.

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire.HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.