Brexpiprazole: Pioneering medication for managing agitation in Alzheimer's disease

Abstract

Alzheimer's disease poses intricate challenges, affecting cognition and behavior, notably marked by agitation. The FDA's approval of brexpiprazole, an atypical antipsychotic, stands as a milestone, representing the first treatment for Alzheimer's-related agitation. brexpiprazole's modulation of serotonin-dopamine activity has proven effective in clinical trials, reducing agitation as measured by CMAI scores. Gradual dosage escalation is recommended, with potential side effects including nasopharyngitis, urinary tract infections, dizziness, somnolence, headache, and insomnia. Also useful for schizophrenia and treatment-resistant depression, providing ongoing treatment and potential well-being enhancement by managing agitation and other symptoms.

Introduction

Alzheimer's disease (AD) is a neurodegenerative condition that involves the buildup of amyloid-β (Aβ) plaques, primarily from the Aβ₄₂ variant, and the development of tau neurofibrillary tangles. ¹ The epidemiology of AD highlights its widespread impact. Globally, an estimated 55 million people are living with dementia, with AD accounting for 60–70% of cases. This number is projected to rise to 78 million by 2030 and 139 million by 2050, underscoring the urgent need for effective treatments for both cognitive and behavioral symptoms. ²

Neuroinflammation, which is a hallmark of AD, significantly contributes to Aβ accumulation. Pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6, and interleukin-1β) inhibit Aβ clearance and promote its production. Furthermore, Aβ damages the neurovascular unit and compromises the blood-brain barrier, leading to increased permeability and the release of more inflammatory substances, thus fueling chronic neuroinflammation. ³ The aging-related neuropathological process disrupts the dopaminergic system, leading to synaptic dysfunction, neurotransmission impairment, and cell loss. ⁴

Several factors, such as genetic predispositions, inflammation, free radicals, cholinergic alterations, metal ions, infections, oxidative stress, and reduced estrogen levels, contribute to the development of AD. Research has found a significant reduction in neuropeptide Y-like immunoreactivity throughout the cerebral cortex of AD patients compared to healthy individuals. Additionally, plasma neuropeptide Y levels are notably lower in AD patients. Neuropeptide Y regulates brain activity, stress response, digestion, blood pressure, heart rate, metabolism, and immune function. ⁵ It has been determined that oxidative stress significantly contributes to the development of AD. Oxygen free radicals attack lipid membranes, nucleic acids, and proteins, disrupting cellular functions. The brain's high content of polyunsaturated fatty acids makes it particularly vulnerable to lipid peroxidation, a type of oxidative degradation that damages cell membranes and produces neurotoxic substances. Selective serotonin reuptake inhibitors like citalopram and sertraline, known for their antioxidant properties, have been found effective in treating neurological disorders, including AD. ⁶

According to the Alzheimer's Association 2023, it is estimated that around 6.7 million Americans aged 65 and above are grappling with AD dementia. ⁷ Beyond the age of 65, one in ten individuals is affected by AD, and nearly 35% of those aged 85 and above are affected by the disease. ³ AD has far-reaching consequences that go beyond cognitive decline, which includes a variety of neuropsychological signs, in which agitation stands out as a noticeable and unsettling event. Behavioral symptoms in dementia, such as agitation, are thought to be associated with the neurotransmitter systems of serotonin, dopamine, and noradrenaline. With the increasing prevalence of agitation in AD and its association with greater burden on patients and caregiver, makes it a primary objective for therapy. ⁸ Some off-label medications, such as antipsychotics, antidepressants, anxiolytics and carbamazepine, are common for managing these symptoms but demonstrate only modest efficacy against agitation. Agitation in AD manifests as a cluster of symptoms including excessive motor activity, verbal aggression, restlessness, pacing, and emotional lability. ⁹ These behaviors are often unpredictable and can escalate, leading to significant distress for the patient and posing considerable challenges for caregivers. The social impact and caregiver burden associated with AD-related agitation are profound. Caregivers of individuals with agitation experience higher rates of psychological distress, depression, and reduced quality of life compared to those caring for AD patients without agitation. ¹⁰ Agitation is also a leading cause of institutionalization, further increasing healthcare expenditures and diminishing the patient's quality of life. ¹¹ Balancing their limited effectiveness, cost, and potential side effects is a challenge. There is a notable need for U.S. Food and Drug Administration (FDA)-approved, effective, and well-tolerated treatments to alleviate the burden of AD agitation. ⁸ In the quest for a medicated alternative to manage agitation related to AD, the FDA has marked a significant milestone by approving brexpiprazole, a serotonin-dopamine activity modulator, as a treatment, making it the first FDA-approved option for this purpose. ¹² This review aims to discuss the relevance of brexpiprazole in addressing the unmet needs in AD-related agitation, its pharmacological properties, clinical trial evidence, and safety profile, providing a comprehensive overview of its role in managing this challenging symptom, such as agitation.

The first FDA-approved medication: brexpiprazole

Rexulti, also known as brexpiprazole, is classified as an atypical antipsychotic drug. It functions as a novel partial agonist of both D2 dopamine and serotonin 1A receptors (5-hydroxytryptamine [5-HT]) and is referred to as a serotonin-dopamine activity modulator. ¹³ This drug exhibits significant binding affinity towards 5-HT1A, 5-HT2A, D2, and adrenergic 1B, 2C receptors. It shows partial agonistic activities at 5-HT1A and D2 receptors and solid antagonistic effects at 5-HT2A and adrenergic 1B, 2C receptors. Additionally, it demonstrates a certain level of affinity, specifically antagonism, for D3, 5-HT2B, 5-HT7, and adrenergic 1A, 1D receptors, as well as a moderate affinity for H1 receptors and a low affinity for M1 receptors. ¹⁴ Brexpiprazole, despite its structural similarity to Aripiprazole, has distinct binding affinities for dopamine and serotonin receptors. This results in comparable effectiveness while offering improved tolerance, especially for conditions such as akathisia, extrapyramidal symptoms, and activation. This improved tolerance is due to the drug's lower intrinsic activity at D2 receptors. ¹⁵ Furthermore, brexpiprazole demonstrates higher binding affinity for serotonin 5-HT1A and 5-HT2A receptors, as well as noradrenaline alpha1B/2C receptors, compared to aripiprazole. The stronger agonism at 5-HT1A receptors may enhance its antidepressant effects, while increased antagonism at 5-HT2A receptors and alpha1B/2C receptors can contribute to a more favorable side effect profile, including a reduced propensity for extrapyramidal symptoms and potentially less somnolence due to lower antihistaminergic properties. ¹⁶ Beyond its recent approval for agitation associated with AD, brexpiprazole has established efficacy and is approved for other significant psychiatric conditions, demonstrating its versatility as a therapeutic agent. ¹⁷

Clinical trial

With the aim of evaluating brexpiprazole's efficacy in alleviating agitation associated with AD, two 12-week, randomized, double-blind, placebo-controlled, fixed-dose clinical trials have been undertaken. Eligible participants were required to have a confirmed diagnosis of AD and exhibit a Mini-Mental State Examination score within the range of 5 to 22. In Trial 1, 433 participants were randomly assigned to receive either brexpiprazole at fixed doses of 2 mg/day, brexpiprazole at 1 mg/day, or a placebo for a duration of 12 weeks. The primary measure of effectiveness was the change in Cohen-Mansfield Agitation Inventory Total (CMAI) score from baseline to Week 12. The results showed that the group receiving brexpiprazole at 2 mg/day exhibited a statistically significant and greater improvement compared to the placebo group on this primary efficacy endpoint. ⁸

In the second trial, 270 individuals were randomly assigned to either receive flexible doses of brexpiprazole ranging from 0.5 to 2 mg/day or a placebo in a 1:1 ratio over a 12-week period. The brexpiprazole doses within this range did not demonstrate statistical superiority over the placebo overall. However, post hoc analyses revealed a benefit among patients who were titrated to the maximum brexpiprazole dose of 2 mg/day compared to similarly titrated placebo patients. ⁸

On the Clinical Global Impression-Severity scale, Trial 1 showed a greater numerical improvement for brexpiprazole 2 mg/day, while Trial 2 demonstrated a greater improvement for brexpiprazole 0.5–2 mg/day. In terms of treatment-emergent adverse events (TEAEs) in Trial 1, among patients receiving brexpiprazole 2 mg/day, common occurrences with an incidence of 5% or more included headache, insomnia, dizziness, and urinary tract infection whereas in Trial 2, TEAEs with an incidence of 5% or more among patients receiving brexpiprazole 0.5–2 mg/day were headache and somnolence. It is noteworthy that in both studies, the majority of TEAEs were of mild or moderate severity. In both clinical trials, brexpiprazole has shown a noticeable improvement in CMAI Total Scores and Neuropsychiatric Inventory–Nursing Home Agitation/Aggression score, making it favorable for the treatment. ⁸

Dosage and adverse effects

Transitioning to another area of pharmacological research, the recommended dosing regimen for brexpiprazole tablets is as follows ¹² : On Days 1 to 7, a daily dose of 0.5 mg is recommended. From Days 8 through 14, the dosage should be increased to 1 mg once daily. On Day 15, patients are advised to further elevate the dosage to 2 mg once daily, which serves as the recommended target dose. After a minimum of 14 days on the recommended target dose, healthcare providers may consider further increasing the dosage to a maximum of 3 mg once daily based on the patient's clinical response and their ability to tolerate the medication. It is imperative to note that brexpiprazole is not intended for as-needed (pro re nata) treatment and should be taken regularly. ¹³ Special consideration should be given to patients identified as CYP2D6 poor metabolizers, a subgroup comprising approximately 8% of Caucasians and 3–8% of Black/African Americans, who may exhibit elevated brexpiprazole concentrations due to impaired CYP2D6 metabolism. ¹²

In the recent clinical trial, 40.7% of the ninety-two patients receiving brexpiprazole at 2 or 3 mg reported TEAEs (Table 1). Meanwhile, 31.0% of the placebo group experienced such events with no apparent dose occurrence of headache, the sole TEAE with an incidence of 5% or more, was 6.6% in the brexpiprazole group compared to 6.9% in the placebo group. Specific categories of TEAEs, including cardiovascular, cerebrovascular, extrapyramidal symptom–related, somnolence/sedation, accident or injury (including falls), and metabolism and nutrition disorders, were also evaluated for brexpiprazole and placebo. The majority of TEAEs were of mild or moderate severity. Unfortunately, one patient in the brexpiprazole 3 mg subgroup died during the trial due to cardiac failure at the age of 78, having withdrawn after 28 days due to hallucinations, along with serious adverse events of pneumonia and cachexia. The death, occurring 23 days post the last brexpiprazole dose, was determined to be unrelated to the medication based on autopsy findings of coronary atherosclerosis. On the Clinical Global Impression-Severity scale 0.0 kg in the placebo group, and minimal changes were observed in the Mini-Mental State Examination scores. No suicidal ideation or behavior TEAEs were reported during the trial. ¹⁸

Table 1.

Summary of treatment-emergent adverse events.

Events:TEAEs with an incidence ≥2% in the brexpiprazole, 2 or 3 mg, group and an incidence greater than placebo	Placebo, %(n = 116)	Brexpiprazole, %
		2 or 3 mg (n = 226)	2-mg Subgroup (n = 73)	3-mg Subgroup (n = 153)
Somnolence	0.9	3.5	4.1	3.3
Nasopharyngitis	1.7	3.1	4.1	2.6
Dizziness	1.7	2.7	1.4	3.3
Asthenia	0	2.2	0	3.3
Diarrhea	0.9	2.2	4.1	1.3
Urinary tract infection	0.9	2.2	0	3.3
Fall	1.7	1.8	2.7	1.3
Akathisia	0	0.9	0	1.3
Extrapyramidal disorder	0	0.9	1.4	0.7
Hip fracture	0	0.4	0	0.7
Sedation	0	0.4	0	0.7

In drug research, it is essential to discover methods for reducing side effects that pose hurdles in treatment. One strategy involves customizing drug doses based on individual patient traits. Combining various medications can mitigate side effects, and a gradual dosage increase allows patients to adapt—consistent monitoring and health examinations aid in identifying and addressing new side effects promptly. Patient education about potential side effects enables them to identify and manage issues. Lifestyle modifications, such as adjusting diet or exercise, may also alleviate side effects. Robust reporting systems and post-market surveillance play a key role in proactively approaching adverse effects.

FDA approval and company communications

The cumulative positive results from these three pivotal Phase 3 trials (331–12–283 NCT01862640, 331-12-284 NCT01922258, 331- 14-213 NCT03548584) formed the basis for the supplemental New Drug Application submitted by Otsuka Pharmaceutical and H. Lundbeck A/S to the FDA. On May 11, 2023, the FDA granted approval for brexpiprazole for the treatment of agitation associated with dementia due to AD. ¹⁹ This marked a significant milestone, as brexpiprazole became the first and only pharmacological treatment specifically approved for this indication in the United States.

Following the approval, Otsuka and Lundbeck issued joint press releases and engaged in various communications to highlight the importance of this new therapeutic option. They emphasized the substantial unmet medical need for an FDA-approved treatment for AD, underscoring the profound burden this symptom places on patients and their caregivers. The companies consistently referenced the robust clinical trial data, showcasing brexpiprazole's efficacy and generally favorable tolerability profile. They positioned brexpiprazole as a groundbreaking advancement, offering a targeted, evidence-based solution where previously only off-label treatments with known risks were available.^19,20 These communications aimed to inform healthcare professionals and the public about the availability and benefits of this new treatment, reinforcing its role in addressing a critical aspect of AD management.

Clinical uses

Moreover, brexpiprazole exhibits a diverse range of therapeutic applications, extending beyond its role in managing agitation associated with AD. It has proven to be a valuable treatment option for schizophrenia and serves as an adjunct therapy for adults coping with major depressive disorder in conjunction with antidepressants. In the realm of schizophrenia, brexpiprazole monotherapy has demonstrated success in reducing symptom severity, aggression, negative symptoms, and cognitive symptoms. It is also associated with a lower risk of relapse and a longer time to treatment discontinuation compared to other antipsychotics. For patients with treatment-resistant depression, brexpiprazole supplements antidepressant therapy effectively, reducing depressive symptoms and enhancing overall patient functioning, even in cases involving anger or anxiety. ²¹ This multifaceted utility highlights its potential significance in psychiatric therapeutics.

Side effects

Like all pharmacological agents, brexpiprazole is associated with a range of side effects. While generally well-tolerated, particularly in comparison to some older antipsychotics, it is crucial to be aware of its potential adverse effects, especially the serious risks highlighted by the FDA in its Boxed Warning.

Brexpiprazole carries a Boxed Warning, which is the most stringent warning issued by the FDA for prescription drugs, indicating serious or life-threatening risks. This warning has two primary components ¹⁷ :

Increased Mortality in Elderly Patients with Dementia-Related Psychosis:

Antipsychotic drugs, including brexpiprazole, are associated with an increased risk of death when used to treat elderly patients with dementia-related psychosis. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. While the causes of death were varied, most deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. It is important to note that brexpiprazole is not approved for the treatment of patients with dementia-related psychosis not associated with agitation due to AD. ¹⁷

Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults:

Antidepressants, including brexpiprazole when used as an adjunctive treatment for Major Depressive Disorder, increased the risk of suicidal thoughts and behaviors in pediatric patients and young adults (up to 24 years of age) in short-term studies. This risk must be balanced with the clinical need. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Beyond the boxed warning, common adverse events reported in clinical trials for brexpiprazole across its various indications include ²² :

• Akathisia (inner restlessness): While generally lower than with aripiprazole, it can still occur.

• Weight gain: A common side effect with many atypical antipsychotics.

• Headache

• Dizziness

• Somnolence (drowsiness)

• Nausea

• Upper respiratory tract infection

Patients and healthcare providers should discuss the potential benefits and risks of brexpiprazole treatment, especially considering the boxed warnings and individual patient profiles. Regular monitoring for adverse events is recommended during treatment.

Alternative medications for managing Alzheimer's-related agitation

To address agitation or psychosis in AD patients, antipsychotic medications are commonly employed. First-generation (typical) antipsychotics function by inhibiting dopaminergic neurotransmission, particularly by blocking about 72% of D2 dopamine receptors, with additional actions on noradrenergic, cholinergic, and histaminergic systems. However, the notable side effects of first-generation antipsychotics, such as haloperidol, limit their use. Second-generation (atypical) antipsychotics, including olanzapine, quetiapine, and risperidone, demonstrate comparable effectiveness with higher patient tolerance and reduced extrapyramidal side effects. The FDA's warning on antipsychotic use in cognitively impaired individuals has heightened awareness of associated risks, including increased mortality. The European Academy of Neurology recommends atypical antipsychotics only after non-pharmacological measures have proven ineffective. Selective serotonin reuptake inhibitors like citalopram and sertraline have shown efficacy in treating agitation, with citalopram demonstrating acceptability and efficacy over placebo. Escitalopram and sertraline also exhibit clinical benefits, though dose considerations are crucial. Mirtazapine, an antidepressant, and carbamazepine, an anticonvulsant, have shown modest benefits in reducing agitation. Prazosin, while effective, is not recommended for patients with orthostatic hypotension. Thus, a range of pharmacological options, including atypical antipsychotics, selective serotonin reuptake inhibitors, and other agents, presents various approaches to managing agitation in AD, necessitating careful consideration of individual patient profiles and potential side effects. ²³

Conclusion

Brexpiprazole represents a significant advancement in the management of agitation associated with AD, being the first and currently only pharmacological agent specifically approved by the FDA for this challenging indication. The robust evidence from three pivotal Phase 3 clinical trials consistently demonstrated its efficacy in reducing agitation symptoms and a generally favorable tolerability profile compared to existing off-label treatments. This approval addresses a critical unmet medical need, offering a targeted therapeutic option that can potentially alleviate significant distress for patients and reduce the substantial burden on caregivers. Long-term observational studies and registries could provide valuable insights into its sustained efficacy, adherence rates, and long-term safety profile, particularly concerning the boxed warning for increased mortality in elderly patients with dementia-related psychosis. Further research could explore more individualized dosing strategies beyond the currently approved fixed and flexible doses. Identifying patient characteristics (e.g., genetic markers, specific agitation phenotypes) that predict response to brexpiprazole could help optimize treatment outcomes and minimize side effects. While brexpiprazole has shown superiority to placebo, head-to-head comparative effectiveness studies against other commonly used off-label agents (e.g., citalopram, other atypical antipsychotics) would be beneficial. Such studies, carefully designed to account for safety concerns, could provide clearer guidance on its place in the treatment algorithm relative to other options. In summary, brexpiprazole represents a significant step forward in the pharmacotherapy of AD-related agitation. However, its introduction should catalyze further research to refine its use, explore its long-term impact, and continue to address the complex and multifaceted needs of individuals living with AD and their careers.