Optimizing Outcomes in AAD in Community PCP and LTC Clinics

Agitation in Alzheimer’s Disease

Impact of Agitation on Patients: Agitation in Alzheimer's disease (AAD) significantly affects patients throughout the disease's progression.¹ Approximately 60% of patients with mild cognitive impairment (MCI) and 76% of patients with Alzheimer's experience neuropsychiatric symptoms, including agitation.^1,2 This agitation often manifests early and can increase in severity as the disease state progresses. Symptoms may include restlessness, pacing, hand wringing, irritability, resisting assistance or care, verbal outbursts, and, in severe cases, physical aggression.³ These symptoms not only reduce the quality of life for patients but can lead to increased healthcare resource utilization and higher hospitalization rates​. Patients displaying agitation are also more likely to be institutionalized, particularly as their agitation intensifies​.

AAD is linked to frontal lobe dysfunction, particularly involving the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC).⁴ These brain regions are responsible for emotional regulation, decision-making, and responses to stimuli. Damage in these areas leads to increased sensitivity to stimuli, contributing to the restlessness and aggressiveness seen in AD patients​.⁴ Moreover, agitation is associated with changes in neurotransmitter systems, particularly serotonergic and noradrenergic dysregulation, which further exacerbates behavioral symptoms​.

Impact of Agitation on Caregivers: The burden on caregivers is profound. As agitation worsens, caregivers—often family members or spouses—face emotional stress, physical exhaustion, and mental health issues like depression and anxiety​.⁵ Caregivers of patients with agitation report significantly more hours spent caring for their loved ones, often up to 48 hours per week​. This extended caregiving time, coupled with the emotional toll, leads many caregivers to experience burnout, which is a major contributor to the decision to institutionalize the patient​.⁶ The increased physical aggression in agitated patients also poses safety risks, further straining caregiver well-being​. Institutionalization is more likely when caregiver burden becomes unmanageable, and studies have shown that agitation significantly raises the likelihood of hospitalizations and early placement in long-term care​.^5,7 Studies have shown that prolonged exposure to high levels of caregiver burden is associated with increased rates of anxiety, depression, and even mortality among caregivers​.⁷

Recognizing Early Symptoms of Agitation: Agitation is often mistakenly believed to occur only in the later stages of AD, but it can manifest early, even during the MCI stage, in the form of subtle behavioral changes such as frustration, irritability, and anxiety​.^8,9 These early symptoms may progress to more severe agitation, including verbal and physical aggression, especially if not addressed early. Primary care physicians (PCPs) are the front-line clinicians who will see and report agitation for the first time in many patients and are crucial in recognizing these early signs and diagnosing agitation. Tools such as the Mini-Mental State Examination (MMSE), Cohen-Mansfield Agitation Inventory (CMAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q) are essential for diagnosing and monitoring AAD​.^10,11

Another valuable tool in primary care settings is the Agitation in Alzheimer’s Screener for Caregivers (AASC).¹² The AASC is a simple, one-page questionnaire designed to help caregivers identify and report symptoms of agitation seen within their loved ones. This tool is particularly effective because it enables caregivers to describe the frequency and intensity of behaviors such as restlessness, verbal outbursts, physical aggression, and resistance to care. The structured nature of the AASC provides a common language for caregivers and HCPs, making it easier to detect subtle changes in behavior.¹² Caregivers often hesitate to discuss these behaviors due to feelings of shame, guilt, or the belief that agitation is a normal part of the disease. The AASC helps overcome these barriers by focusing on clear, observable behaviors and facilitating more open communication between caregivers and clinicians.

The AASC aids in early detection and intervention by promoting ongoing communication between caregivers and HCPs. The tool’s simplicity allows it to be completed quickly in a clinical setting or at home, providing critical insights into the patient’s behavior and ensuring that agitation is addressed before it becomes a crisis.

Recognizing early agitation and intervening with non-pharmacological approaches can improve patient outcomes and delay the escalation of severe behaviors​. However, when agitation severely affects patient safety and caregiver well-being, pharmacological interventions, such as antipsychotics and antidepressants, may be required​.

Treatment Approaches for AAD

Managing AAD requires a multifaceted approach that includes both non-pharmacological and pharmacological interventions. Given AD's complexity and impact on various neurotransmitter systems, treatment plans must be individualized, taking into account the patient’s medical history, current medications, and caregiver capacity.

Non-Pharmacological Approaches:
Non-pharmacological strategies are often first-line treatment, especially in mild cases of agitation. These interventions include behavioral therapy, structured routines, environmental modifications, and caregiver education.¹³ Encouraging caregivers to maintain consistent routines and minimize triggers can significantly reduce agitation. In addition, support from social workers, psychologists, and organizations such as the Alzheimer’s Association can provide valuable resources for caregivers, helping them cope with the stress of managing an agitated loved one.

Pharmacological Approaches:
When non-pharmacological interventions are insufficient, pharmacological treatments may be necessary, particularly in moderate to severe cases of agitation or when verbal or physical aggression emerges. The only FDA-approved medication specifically for the treatment of AAD is brexpiprazole, an atypical antipsychotic. Brexpiprazole has been studied in three large clinical trials and has demonstrated efficacy at doses of 2 and 3 mg daily, with a favorable safety and tolerability profile compared to placebo.¹⁴

Brexpiprazole’s approval represents a significant advancement in the treatment of AAD, as it provides clinicians with a medication that has undergone rigorous testing for AAD. However, clinicians must carefully follow the recommended titration schedule, starting at 0.5 mg daily and gradually increasing to a dose of 2 or 3 mg.¹⁴

Despite its benefits, the use of antipsychotics in elderly patients with dementia carries risks, including an increased risk of mortality. For this reason, clinicians are advised to monitor patients closely and reserve pharmacological treatments for those with moderate to severe agitation that significantly impacts their quality of life or the safety of their caregivers.

Emerging Therapies for Agitation in AD

The development of new treatments for AAD is an area of active and ongoing research, with several promising therapies in late-stage clinical trials. These emerging therapies target various neurotransmitter systems and hold the potential to expand the treatment options currently available to clinicians.

Dextromethorphan-Based Therapies¹⁵:
One of the most promising emerging treatments involves dextromethorphan, a common ingredient in cough syrup, combined with a metabolic inhibitor to enhance its efficacy. A combination of dextromethorphan and bupropion has shown promise in clinical trials. This combination is already FDA-approved for the treatment of depression and is now being investigated for AAD. However, other dextromethorphan-based therapies, such as one that includes quinidine, have ceased development for AAD.

Sublingual Dexmedetomidine¹⁶:
Another medication under investigation is sublingual dexmedetomidine, which is being developed for acute agitation in patients with schizophrenia and bipolar disorder. This medication’s potential role in AD is still under evaluation, but early results suggest that it may be useful for managing acute behavioral disruptions in AAD.

Cannabinoids¹⁷:
The potential use of cannabinoids, such as nabilone or THC, is also being explored for the treatment of AAD. While some patients have turned to cannabinoids through medical or recreational dispensaries, concerns remain about the side effects, particularly in patients with cognitive impairments. However, the psychoactive effects of THC may worsen agitation or lead to distress in some patients. More data is needed to determine the safety and efficacy of cannabinoids in AAD.

Conclusion

AAD significantly impacts both patients and caregivers, leading to a decline in quality of life and increased healthcare resource utilization. Early recognition of agitation, even during the mild cognitive impairment stage, is crucial for timely intervention and improved outcomes. Non-pharmacological approaches remain the first-line treatment, but pharmacological options, such as brexpiprazole, are necessary in more severe cases. Emerging therapies targeting various neurotransmitter systems offer hope for expanded treatment options in the future. Ultimately, a multifaceted, individualized approach is essential for managing agitation in AD effectively.

References

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