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.

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