Agitation in Alzheimer Disease: Alternatives to Antipsychotics May Be at Hand

Citalopram and dextromethorphan-quinidine show promise in trials

By Jeffrey Cummings, MD, ScD, and Kate Zhong, MD

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Agitation is among the most common of behavior changes in Alzheimer disease (AD) and among the most challenging to clinicians, patients and families.

Agitation, a common cause of institutionalization, adversely impacts quality of life for patients and caregivers, increases the cost of care and is associated with accelerated cognitive decline and reduced survival.

Despite the common occurrence and disturbing features of agitation in AD, there are no FDA-approved medications to treat this condition. Clinicians commonly choose atypical antipsychotics as their therapy of choice. These agents have moderate efficacy, but are associated with serious side effects, including an approximately twofold increased risk of death. They also may cause weight gain, diabetes and motor symptoms.

New approaches to therapy are urgently needed, and progress is being made.

Defining agitation in cognitive disorders

A past barrier to conducting clinical trials has been the absence of a consensus definition of agitation. This prevented construction of appropriate trial populations and hampered drug development.

Fortunately, in 2014, the International Psychogeriatric Association (IPA) organized an effort to rectify this problem. In a transparent, inclusive, iterative process, a consensus definition was developed following two surveys with approximately 1,000 respondents and input from an international advisory board, which specialists from Cleveland Clinic Lou Ruvo Center for Brain Health co-led. This provisional consensus definition, which was published early this year and is featured below in Table 1, paved the way for recent trials of two promising nontraditional therapies, both of which are commercially available for other FDA-approved indications.

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Table 1. Consensus provisional definition of agitation in cognitive disorders
A. The patient meets criteria for a cognitive impairment or dementia syndrome (e.g., Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, other dementia, a predementia cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorder).
B. The patient exhibits at least one of the following behaviors that are associated with observed or inferred evidence of emotional distress (e.g., rapid changes in mood, irritability, outbursts). The behavior has been sustained or persistent for a minimum of two weeks’ duration and represents a change from the patient’s usual behavior:

  1. Excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms)
  2. Verbal aggression (e.g., yelling, speaking in an excessively loud voice, using profanity, screaming, shouting)
  3. Physical aggression (e.g., grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things or destroying property)
C. Behaviors are severe enough to produce excess disability which in the clinician’s opinion is beyond that due to the cognitive impairment and includes at least one of the following:

  1. Significant impairment in interpersonal relationships
  2. Significant impairment in other aspects of social functioning
  3. Significant impairment in ability to perform or participate in daily living activities
D. While co-morbid conditions may be present, the agitation is not attributable solely to another psychiatric disorder, suboptimal care conditions, medical condition or the physiological effects of a substance.

Reprinted from Cummings et al, International Psychogeriatrics. 2015;27:7-17, © International Psychogeriatric Association.

Exploring non-antipsychotic agents: Citalopram and DM/Q

Citalopram, a selective serotonin reuptake inhibitor (SSRI), and a combination of dextromethorphan and quinidine (DM/Q; AVP-923; Nuedexta™) have been investigated for agitation in AD with positive results.

In the first study, a multicenter investigation published in JAMA in 2014, 40 percent of patients treated with citalopram had moderate or marked improvement in agitation compared to 26 percent of patients treated with placebo. Statistically significant effects in favor of citalopram also were evident on the Neurobehavioral Rating Scale – Agitation subscale. However, a dose of 30 mg was associated with significant cognitive decline and significant QT interval prolongation, indicating the need for caution in using this dose in agitated AD patients.

In the second study, a phase 2 multicenter trial led by our group at Cleveland Clinic and recently published in JAMA, DM/Q was associated with highly significant reductions in agitation within one week of treatment initiation. Using a placebo-controlled sequential parallel comparative design, we found that the Neuropsychiatric Inventory (NPI) Agitation/Aggression scale showed a 3.6 point decline in the treatment group by week 10, compared to a 1.9 point reduction in the placebo group when both stages were analyzed together according to the prespecified analytic plan. DM/Q reduced the NPI Agitation/Aggression scale score by 47 percent in stage 1 and 26 percent in stage 2 (vs. 22 percent and 6.7 percent, respectively, for placebo).

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Side effects included more falls, diarrhea and urinary tract infections in those receiving DM/Q. This agent will be advanced to phase 3 trials for the treatment of agitation in AD.

Time to consider options beyond antipsychotics

Both citalopram and DM/Q produced significant and clinically important reductions in agitation, demonstrating that classes of agents beyond antipsychotics should be considered for potential anti-agitation treatment in AD.

With the advent of the IPA definition of agitation, progress is being made in identifying new treatment options for agitation. Clinicians will have improved therapies for patients suffering from this disabling aspect of AD.


Dr. Cummings is Director of Cleveland Clinic Lou Ruvo Center for Brain Health. Dr. Cummings has consulted for Avanir Pharmaceuticals.

Dr. Zhong is Senior Director of Clinical Research and Development at Cleveland Clinic Lou Ruvo Center for Brain Health.