Agitation and Irritability in Alzheimer’s Disease: Evidenced-Based Treatments and the Black-Box Warning

Abstract

More than five million Americans suffer from Alzheimer's disease (AD), and this number is expected to triple by 2050. While impairments in cognition, particularly memory, are typically the defining features of the clinical syndrome, behavioral symptoms are extremely common, affecting up to 90% of patients. Behavioral symptoms in AD can be difficult to manage and may require a combination of non-pharmacological and pharmacological approaches. The latter is complicated by FDA "black-box warnings" for the medication classes most often used to target these symptoms, and currently there are initiatives in place to limit their use. In this review, we describe common behavioral symptoms of AD-with a particular focus on the challenging symptoms of "agitation" and "irritability"-and discuss evidence-based approaches to their management. Ultimately, multidimensional approaches must be tailored to the patient and their environment, though evidence-based practices should define the treatment of agitation and irritability in AD.

Altered frontal and insular functional connectivity as pivotal mechanisms for apathy in Alzheimer's disease

“…The only exception was a tendency to show other symptoms such as irritability, anxiety, agitation or depression. Irritability is a complex symptom that may result from other variables linked to traits (e.g., mood) or states (e.g., hunger, pain (Koenig, Arnold, & Streim, 2016)) and may also be secondary to apathy (e.g., part of the patient's reactions to the carer's attempt to increase motivation). For a similar reason some degree of agitation might be expected as secondary to the apathetic state and contingent to situational triggers.…”

The Hyperactivity–Impulsivity–Irritiability–Disinhibition–Aggression–Agitation Domain in Alzheimer’s Disease: Current Management and Future Directions

“…Regarding pharmacotherapy, agents that are currently available are either inefficacious or carry the risk for dangerous side effects that outweigh their benefits (Margallo‐Lana et al, 2001; Schneider et al, 2006; Passmore et al, 2008; Ballard and Corbett, 2010; Maher et al, 2011; Koenig et al, 2016; Kongpakwattana et al, 2018). However, short-term use of these agents during periods of severe symptoms or psychosis may be necessary, and atypical antipsychotics and SSRIs currently have the best evidence.…”

“…Regarding pharmacotherapy, atypical antipsychotics are most commonly prescribed to treat HIDA domain symptoms, but their long-term use in elderly patients is severely limited due to an increased risk of extrapyramidal side effects, stroke, and death (Margallo‐Lana et al, 2001; Schneider et al, 2006; Passmore et al, 2008; Ballard and Corbett, 2010; Maher et al, 2011; Koenig et al, 2016; Kongpakwattana et al, 2018). Moreover, there is poor consensus as to which atypical antipsychotic is most efficacious (Yunusa et al, 2019).…”

“…In addition, the best-studied drug, risperidone, confers a three-fold higher risk of stroke with an NNH of 53, an increased risk of extra-pyramidal side effects at an NNH of 20, and an increased risk of urinary tract symptoms at an NNH of 16–36 (Maher et al, 2011). These concerns for heightened adverse effects—especially risk of death—resulted in a black box warning from the FDA for all atypical antipsychotics in elderly patients, and similar warnings have been issued in Europe and Canada (Koenig et al, 2016). In addition, many programs have aimed to discourage the use of antipsychotics in the elderly, including Beers criteria, Screening Tool of Older Persons’ Prescriptions (STOPP), Screening Tool to Alert Doctors to the Right Treatment (START), and Choosing Wisely (O’Mahony et al, 2015; Koenig et al, 2016; Kirkham et al, 2017; Yunusa et al, 2019).…”

“…These concerns for heightened adverse effects—especially risk of death—resulted in a black box warning from the FDA for all atypical antipsychotics in elderly patients, and similar warnings have been issued in Europe and Canada (Koenig et al, 2016). In addition, many programs have aimed to discourage the use of antipsychotics in the elderly, including Beers criteria, Screening Tool of Older Persons’ Prescriptions (STOPP), Screening Tool to Alert Doctors to the Right Treatment (START), and Choosing Wisely (O’Mahony et al, 2015; Koenig et al, 2016; Kirkham et al, 2017; Yunusa et al, 2019). A recent Cochrane Systematic Review suggests that withdrawal from these medications has little effect or no effect on overall BPSD, mortality, and cognitive function (Leeuwen et al, 2018).…”