Update on neuropsychiatric symptoms of dementia: evaluation

and management
Evaluation

The first step to evaluation of a new-onset behavioral disturbance is the evaluation and
treatment of any underlying medical/physical precipitant. The differential diagnosis of
the neuropsychiatric symptoms of dementia is broad. Agitation can result from an occult
general medical condition, infection, untreated or undertreated pain, bladder distention,
constipation, or fecal impaction.3,6 A chaotic living situation, an untrained or impaired
caregiver, hunger, sleep deprivation, boredom, loneliness, overstimulation, multiple
coexisting medical problems, a history of a personality disorder, substance use, and side
effects from medications, such as anticholinergics and sedatives, can also lead to
agitation, disinhibition, or psychosis.3,6

A thorough medical evaluation may reveal an underlying medical condition that, when
treated, may lead to the resolution of neuropsychiatric symptoms.3 History, work-up, and
risk factors should guide the selection. Examples include:

• A complete blood count (CBC) with differential/platelets may reveal an

underlying infection.
• A comprehensive metabolic profile may uncover physiological changes, such as
renal or hepatic insufficiency, that may change medication levels.
• Thyroid function abnormalities may cause mood instability.
• A urine toxicology screen, gamma-glutamyl transferase, or carbohydrate-deficient
transferrin may expose unreported substance use.
• A urinalysis/urine culture may rule out a urinary tract infection. Asymptomatic
bacteruria may be a more likely explanation and is not related to agitation unless
there are symptoms.
• A review of current medications may reveal anticholinergic medications, such as
diphenhydramine or oxybutynin, which may be contributing to anticholinergic
toxicity.1
• A critical review of current medications, psychical symptoms, and laboratory
results may obviate the need for further medication intervention to address the
behavioral symptoms.

Another important component of the evaluation is a detailed exploration of the

neuropsychiatric symptoms, which can help guide treatment and help the clinician and
family follow target symptoms appropriately. A recommendation to caregivers to
maintain a log of specific behaviors, documenting the intensity, frequency, precipitants,
and consequences, can be helpful in treatment planning and monitoring treatment
effectiveness.3 Carefully describing the symptom, such as where, when, and how often it
occurs, is the first step.3 Important descriptors can be chronic or episodic timing, such as
morning or evening; consistency of timing; and frequency.6 Next, assessing the specific
antecedents and consequences of each symptom often can suggest specific strategies for
management.3 Examples of antecedents include arguments, caregiver anger,

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overcorrection by caregiver, or the patient's frustration at the inability to perform a task.6
If symptoms are determined to be severe and dangerous to the patient or others, certain
safety measures, such as hospitalization, may need to be acutely considered.3

Empirically validated assessment instruments can be used to obtain baseline symptom

data, including symptom frequency and severity. Such assessment instruments should be
corroborated by interviews with family caregivers to determine functional abilities,
neuropsychiatric symptoms, and caregiver distress. Examples of scales include the
Activities of Daily Living Scale, the Instrumental Activities of Daily Living Scale, the
Neuropsychiatric Inventory Questionnaire, and the Caregiver Burden Scale.7

Nonpharmacological interventions

Nonpharmacological interventions in patients with dementia can generally be divided

into behavior-oriented, cognition-oriented, emotion-oriented, and stimulation-oriented
approaches.3 Sadly, the evidence for the efficacy of interventions for neuropsychiatric
symptoms is limited. Published studies have many limitations, such as a mild symptom
burden among study subjects and adverse outcomes not systematically evaluated as in
medication trials.1

In a review of 162 studies, treatments with purported promise of long-lasting benefit were
cognitive stimulation therapy (CST), caregiver and residential staff education, and
behavioral management techniques, although many studies focused on outcomes other
than psychosis or agitation.8 In a multicenter randomized controlled trial of CST, the 14-
session program began with a gentle, noncognitive warm-up activity, such as a softball
game. Sessions encouraged using information processing instead of factual knowledge; in
a "faces" activity, subjects were asked questions such as "who looks the youngest" and
"what do these people have in common." Other interventions included using money,
word games, and the present day.9 A significant improvement in scores on cognitive
function and quality of life scales was observed. In another systematic review of
nonpharmacologic interventions, only 3 randomized controlled trials met strict inclusion
criteria suggested by the American Psychological Association, and the results were
inconclusive.10

Positive results with education of health care personnel have been obtained in some
studies. A comprehensive program to decrease antipsychotic use through education of
physicians, nurses, and nursing home staff decreased the number of days of antipsychotic
use by 72% in nursing homes that used this education, compared with13% in control
nursing homes.11 Another study showed that training and support intervention to nursing
home staff decreased antipsychotic use.Although published studies of
nonpharmacological interventions have many limitations, lack of evidence is not equal to
evidence of lack of efficacy for nonpharmacologic interventions.Sufficiently powered
studies are needed to assess the efficacy of nonpharmacologic interventions and to
recommend evidence-based treatment. In the meantime, an individualized strategy for
treating neuropsychiatric symptoms using nonpharmacologic interventions is warranted.

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Behavioral management interventions

Two general approaches to behavioral management include the three R's and the ABC's.13
The three R's refer to repeat, reassure, and redirect. For example, if a patient is upset
because he believes he must go to dinner at his mother's house, then reassuring him that
the dinner isn't until much later and redirecting to another task (eg, looking at a television
program, listening to music, or stuffing envelopes) could obviate the need for a
medication intervention.The ABC's (antecedents, behaviors, consequences) involve
identifying the antecedent conditions and consequences of a behavior to modify the
environment to improve behavior. For example, changing the environment may help
minimize the negative consequences of bathing, such as switching the bath time to allow
supervision by a particular home health aide or family member, or changing the location
of baths to decrease aggressive outbursts on family members or other patients. Multistep
activities, such as dressing or eating, that result in aggression may need to be simplified
with strategies such as Velcro clothing and serving several nutritious snacks instead of
one large meal.3 Another strategy is to break down a multistep task to component parts
and walk the patient through them. For example, instead of saying "go brush your teeth,"
the caregiver might say "let's go get the toothbrush, let's put it under the water, let me put
on some toothpaste, now brush your bottom teeth, now brush your top teeth, spit, rinse
your mouth." Still another strategy is to limit the choices a patient has to make.
Regardless of the intervention, the level of demand on the patient must be matched with
the patient's current capacity.Training programs for family caregivers, such as the Savvy
Caregiver, Staff Training in Assisted-Living Residences-Caregivers, and Resources for
Enhancing Alzheimer's Caregiver Health, have decreased agitation in patients with
dementia who live at home and have reduced feelings of burden and depression for
family caregivers.For wandering, environmental changes, such as a more complex or less
accessible door latch, may need to be implemented. Electronic locks or electronic devices
that sound an alarm when the patient tries to leave may need to be used in institutional
settings.3 If wandering does occur, provisional measures to locate patients include sewing
or pinning identifying information on clothes, placing medical-alert bracelets on patients,
and filing photographs with local police departments. A referral to the Safe Return
Program of the Alzheimer's Association or a similar program should be considered for all
patients with dementia.3 The Alzheimer's Association, in conjunction with MedicAlert,
has a low cost program that provides vital medical information to emergency responders,
live 24-hour emergency response service for wandering and medical emergencies, 24-
hour family notification service, and 24-hour care consultation services provided by
master's level counselors.

Pharmacological interventions

Multiple classes of medications have been used to treat the neuropsychiatric symptoms
of dementia . The antipsychotics have been the traditional class of medications used to
treat such symptoms, but due to the emergence of the FDA's "black box" warnings for
atypical antipsychotics in April 200515 and conventional antipsychotics in June
2008,exploring other potential treatments for these symptoms is importantAlthough the
evidence base is not strong for most of these medications, anecdotal evidence supports

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trials of medications for behaviorally disturbed patients, with close monitoring of both
positive and adverse effects. From a clinical perspective, treatment of behavioral
disturbance does not allow for a "one size fits all" approach, as it seems as though
different medications may work for different individuals. Some clinical trials do report
that a portion of patients respond very well to any given intervention, but the
heterogeneity of response decreases the overall effect size. A review of the options and
the evidence supporting their use follows.

Antidepressants The American Psychiatric Association's Practice Guideline for the

treatment of patients with Alzheimer's disease and other dementias states that a selective
serotonin reuptake inhibitor (SSRI) or trazodone may be helpful for some nonpsychotic
but agitated patients, patients who are intolerant or do not respond to antipsychotics, or
those patients with relatively mild symptoms.3 From a clinical standpoint, particularly
with patients who appear anxious, frustrated, or sad, an SSRI may be a good choice of
medication.

In addition, some evidence suggests similar efficacy between antipsychotics and

citalopram, even in patients with psychosis associated with dementia as a presenting
symptom.17 Of the 40% of patients who remained in the trial, citalopram was equally
effective for psychotic symptoms as was risperidone.17 Given the metabolic and
cardiovascular concerns about risperidone, citalopram also may be an alternative as a
first-line agent.

In general, the evidence for SSRIs for the treatment of agitation is mixed, with some
studies showing benefit and others showing no benefit.1,3 The evidence for trazodone is
limited to data from case series or small clinical trials.1,3

Risks of SSRIs include headache and gastrointestinal distress, such as nausea and
vomiting. Other risks of concern include hyponatremia and a rare risk of bleeding.

The most dangerous side effect of SSRIs is the serotonin syndrome, caused by excessive
serotonergic activity, frequently as a result of serotonergic medications being combined.
Symptoms of the serotonin syndrome include delirium, autonomic instability, and
increased neuromuscular activity, such as myoclonus.In patients who display
inappropriate sexual behaviors, SSRIs may reduce libido and are likely safer than
hormonal agents, such as medroxyprogesterone, that sometimes are recommended for
such behaviors.

Risks of trazodone include postural hypotension, sedation, dry mouth, and rare priapism.
Trazodone may be used for sleeplessness or nighttime agitation before bedtime, but it can
be divided into two to three doses per day.3 In patients with predictable "sundowning" or
afternoon/evening agitation, a dose of trazodone (25 to 50 mg) prior to the usual time of
worsening symptoms may be helpful.

Anticonvulsants Numerous anticonvulsants have been used for the treatment of agitation
in dementia. Carbamazepine and valproate have the most data to support their use, but

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gabapentin and lamotrigine also have been used. Gabapentin is increasingly being
considered for use due to its more favorable safety profile than other anticonvulsant
medications. Case reports, case series, and open-label studies have found gabapentin to
be well-tolerated and to improve agitation in most patients with dementia, other than
possibly in patients with Lewy Body dementia. Gabapentin may be helpful in dementia
patients who have a significant anxiety component, due to its potentiation of GABAergic
activity. Common side effects include somnolence, dizziness, ataxia, and
fatigue.Lamotrigine may benefit patients with dementia who have agitation or aggression,
and anecdotal evidence also suggests that it may favorably affect psychosis. As
lamotrigine is FDA-indicated for the maintenance treatment of bipolar I disorder to delay
the time to occurrence of mood episodes in patients treated for acute mood episodes with
standard therapy, it may be helpful in patients with dementia who have a significant
mood component. Common side effects include headache, nausea, diarrhea, somnolence,
and dizziness, with a rare rash from Stevens-Johnson syndrome

The American Psychiatric Association's Practice Guideline for the treatment of patients
with Alzheimer's disease and other dementias states that valproate and carbamazepine
may be considered in patients who are sensitive or unresponsive to antipsychotics, who
have significant vascular risk factors, or who do not have psychosis but are mildly
agitated. Given the possible toxicity of these medications and the FDA's issuance of a
warning on the emergence or worsening of suicidal thoughts or behavior or depression
with anticonvulsant treatment, it is important to identify and monitor target symptoms
and to discontinue these medications if no improvement is observed.

Valproate is not routinely recommended to treat behavioral symptoms in patients with

dementia, as most randomized placebo-controlled trials, but not all, have showed no
benefit. Again, in select cases, valproate may be tried. Side effects include sedation,
gastrointestinal disturbances, confusion, ataxia, falls, bone marrow suppression,
hepatotoxicity, thrombocytopenia, and hyperammonemia, and many clinicians
periodically monitor the complete blood count and liver function tests. We recommend
monitoring CBC and liver function tests and the valproate level.

Low doses of carbamazepine may modestly reduce the severity of agitation, but its
routine use for treatment of agitation in patients with dementia is not recommended due
to the known tolerability problems with long-term use, the high risk of drug-drug
interactions, and the scant evidence of efficacy from clinical trials. Side effects include
ataxia, falls, sedation, confusion, rare hyponatremia, and rare bone marrow suppression,
and many clinicians periodically monitor the CBC and electrolytes.

Cholinesterase inhibitors and memantine. These medications generally have a small to

medium effect on neuropsychiatric symptoms, including psychosis and agitation. A
recent evidence-based review found treatment of dementia with cholinesterase inhibitors
and memantine to have statistically significant but only clinically marginal improvement
in measures of cognition and global assessment of dementia. However, secondary
outcome measures and post hoc analyses of patients who often had no clinically
significant baseline behavioral symptoms were used to obtain these data, and some

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studies found no effect of these medications on behavior. One 12-week randomized
placebo-controlled study of donepezil showed no effect on treating agitation in patients
with Alzheimer's dementia who had clinically significant agitation and no response to a
brief psychosocial treatment program. Another trial of donepezil in outpatients with mild
to moderate Alzheimer's dementia showed improvement in global neuropsychiatric
symptoms during the open-label phase for 3 months and symptom worsening in placebo-
treated patients during the discontinuation phase of the trial.

The data with memantine are conflicting. Clinically, most patients already are on a
cholinesterase inhibitor at the time agitation presents, so memantine is often not an option
as an additional medication. Anecdotal evidence certainly supports the idea that some
patients do respond to memantine with improved behavioral control, although
occasionally it can be associated with more confusion or behavioral changes.

Benzodiazepines Although not usually recommended, these medications are

occasionally helpful in treating agitation in patients with dementia who especially have
significant anxiety. Due to risks of disinhibition, oversedation, ataxia, falls, respiratory
suppression, amnesia, confusion, and even delirium, benzodiazepine use should be kept
to a minimum. An 8-week randomized double-blind comparison trial of haloperidol,
oxazepam, and diphenhydramine found these 3 medications to be equivalent for short-
term management of agitated behavior in severely demented patients. Because of
anticholinergic side effects, diphenhydramine is not recommended in the elderly. Due to
the risk of withdrawal, benzodiazepines prescribed for greater than 1 month should be
tapered rather than suddenly discontinued. Long-acting benzodiazepines with active
metabolites, such as diazepam or chlordiazepoxide, are not recommended for use in the
elderly.

Other classes Many other medications have been tried as treatments for these troubling
symptoms, including buspirone, lithium, and beta-blockers. The data to support the use of
any of these medications are limited, but their safety profiles differ markedly.

• Buspirone is probably the best tolerated of the 3, but efficacy data are lacking.
• Beta-blockers have been reported to be helpful for treatment of agitation in
patients with dementia, but are associated with risks such as bradycardia,
hypotension, and delirium, thereby precluding a recommendation of routine use
for treatment of agitation in patients with dementia
• Lithium carbonate has the greatest amount of adverse effects, including a small
therapeutic window and increased risk of toxicity in the elderly with changes in
renal function. Delirium, confusion, ataxia, and tremor are common side effects,
and thus, routine use of lithium carbonate for treatment of agitation in patients
with dementia is not recommended. nicopetrus

Conclusion

The differential diagnosis of neuropsychiatric symptoms associated with dementia is

broad, and a thorough evaluation can help guide treatment.

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Caregiver stress has significant repercussions for patients and families, such as early
patient institutionalization, substandard care, and neglect or abuse of patients. Signs such
as depression, anxiety, irritability, and poor physical health can indicate that caregivers
are in need of evaluation and psychosocial support.

Excluding antipsychotics, pharmacological interventions that may be helpful include

antidepressants, anticonvulsants, cholinesterase inhibitors, memantine, and
benzodiazepines. Although there is no real evidence to support which intervention will be
most helpful for which patient, a rational approach that involves frequent monitoring of
symptoms for improvement or worsening and a flexible approach on the part of the
clinician to stop a given treatment and try another can be beneficial in this complex and
challenging patient population.