Integrated Approach Best for Alzheimer’s-Associated Agitation

Non-cognitive neuropsychiatric symptoms of dementia and Alzheimer’s disease, including agitation, may lead to excess morbidity and mortality, greater healthcare use, and earlier nursing home placement, as well as caregiver stress, depression and difficulty with employment.1

“Non-cognitive neuropsychiatric symptoms [NPS] are among the most complex, stressful, and costly aspects of care, leading to frequent hospitalizations, early nursing home placement, and increased mortality,” Helen Kales, MD, of the University of Michigan in Ann Arbor told Psychiatry Advisor. “Because these behaviors are so stressful and difficult […] to manage, they pose threats to caregivers’ own health, employment income and quality of life.”

According to Kales, agitation is a very common symptom associated with Alzheimer’s disease (AD), with more than 20% of outpatients with dementia and 40% to 60% of those with dementia in care settings experiencing the symptom. 

The incidence of agitation also increases with AD severity and becomes more common as the disease progresses.

Anti-psychotics for NPS symptoms

Currently, there are no FDA approved treatments for neuropsychiatric symptoms of AD, however, anti-psychotics are commonly used to control symptoms.

“Antipsychotics show only modest efficacy in improving symptoms like aggression and agitation and often carry substantial risks (such as falls, over-sedation, worsened memory problems and even mortality),” said Kales.

D.P. Devanand, MD, of Columbia University in New York and colleagues, evaluated the effect of citalopram on agitation as compared with placebo in the Citalopram for Agitation in Alzheimer Disease (CitAD) randomized clinical trial.

Citalopram proved to be moderately better than placebo on some indicators of efficacy, the researchers found.4

“However, two-thirds of the way through the study, the FDA made a new recommendation that elderly patients should not be on a citalopram dose higher than 20 mg per day, as it can lead to QT prolongation on the electrocardiogram,” Devanand said.  

“The study continued with citalopram 30 mg per day dosing but with additional EKG monitoring, and QT prolongation was, in fact, observed on the EKG in patients receiving citalopram. Therefore, while citalopram showed efficacy at 30 mg daily it remains unclear if the lower dose of 20 mg daily would have had a comparable effect.”

The effect of discontinuation on agitation

Currently, there is a federal mandate to discontinue antipsychotics among patients with dementia after four months of treatment, so doctors need to make the case to continue treatment with antipsychotics for those with AD and agitation.

In the Antipsychotic Discontinuation in Alzheimer’s Disease (ADAD) trial, Devanand and colleagues evaluated the effects of continuing versus discontinuing risperidone in patients with AD who had agitation or psychosis at eight U.S. clinical trial sites.

The investigators treated 180 patients openly with risperidone for four months, and then 110 responders were randomly assigned to risperidone or placebo for the next four months. After this four-month period, patients who had not relapsed were then again randomly assigned to continue on risperidone or switch to placebo.2

During the first four months after randomization, the likelihood of relapse among the placebo group was nearly twice the rate of patients in the risperidone group, and in the next four months the relapse risk was four times greater for placebo compared with risperidone.3

“The results indicate that patients who improve on risperidone, and probably other antipsychotic medications, need to be on the medication for an extended period of time because discontinuation is associated with an increased risk of relapse in patients who previously responded to risperidone,” Devanand said.

Nonpharmacological management with multidisciplinary teams

Multiple medical organizations and expert groups recommend nonpharmacological strategies as the preferred first-line treatment approach to managing behavioral symptoms, except in emergency situations when behaviors could result in imminent danger or otherwise compromise safety.

However, nonpharmacological approaches are currently underused in standard of care. In an effort to improve NPS management in dementia, Kales and colleagues developed the Describe, Investigate, Create, Evaluate (DICE) approach.

The approach provides clinicians with an evidence-based structured approach to addressing the patient’s needs.5

“We have designed DICE to be used by any health professional and to work well within a team-care setting which facilitates coordination among the implementation of medical, medication and nonpharmacologic strategies,” said Kales.

There are several challenges using DICE in current care setting. “Even if health professionals are adequately trained, the current system does not allow for reimbursement for time spent in such approaches. So, writing a prescription for a medication that might be modestly effective at best and dangerous at worst, is the most common first-line action,” Kales said.

“It is our hope that the medical system, perhaps through the new Medicare Pay for Performance guidelines might compensate providers for time spent in DICE or similar approaches.”


Overall, there remains a need for an evidence-informed standardized approach to detecting and managing behavioral symptoms that integrates pharmacological and non-pharmacological treatments.


Kales HC, Gitlin LN, et al. Management of neuropsychiatric symptoms of dementia in clinical settings: Recommendations for multidisciplinary expert panel. J Am Geriatr Soc. 2014; 62(4): 762-769.

Devanand DP, Mintzer J, et al. The Antipsychotic Discontinuation in Alzheimer Disease Trial: Clinical Rationale and Study Design. Am Geriatr Psychiatry. 2012; 20(4): 362-373.

Devanand DP, Mintzer J, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s disease. NEJM. 2012; 367(16): 1497-1507.

Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, et cal. Effect of citalopram on agitation in Alzheimer’s disease: The CitAD randomized clinical trial. JAMA. 2014; 311(7): 682-691.

Fraker J, Kales HC, et al. The role of the occupational therapist in the management of neuropsychiatric symptoms of dementia in clinical setting. Occup Ther Health Care. 2014; 28(1): 4-20.Fra