CHRISTINE ARENSON, MD is Clinical Assistant Professor and Director, Division of Geriatric Medicine, Department of Family Medicine, Jefferson Medical
College, Philadelphia, Pa; and Medical Director, Social Service and Health Independence Program, a joint program of the Jefferson
Health System and the Philadelphia Senior Center, Philadelphia.
CONCETTA FORCHETTI, MD, PhD is Medical Director, Memory Disorder Center, Alexian Neurosciences Institute, Hoffman Estates, Ill.
ERIC G. TANGALOS, MD is Professor of Medicine; and Chair, Primary Care Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn.
The idea that Alzheimer's disease (AD) is unresponsive to drug therapy appears to be changing but a combination of environmental
and drug therapy remains an effective strategy for patients with disruptive behaviors. Treating underlying depression and
pain may alleviate restlessness and aggression.
Common behavioral disorders associated with AD include depression, sleep disturbances, anxiety, agitation, aggression, and
sundowning. Families or caregivers are usually motivated to seek help for patients with these conditions when the behavior
becomes disruptive. The most difficult situation is when patients become belligerent and resist daily care because they feel
threatened. Functional issues, such as difficulty following directions and managing activities of daily living (ADLs), can
also be a problem. Families and caregivers sometimes interpret behavioral problems as stubbornness, although the cause is
usually cognitive decline.
Other difficult behavioral manifestations include demanding attention, constant complaining, pacing, and repetitive behaviors.
By the time those with AD are placed in a nursing home or assisted care facility, these behaviors may have taken more resistive
forms such as biting, grabbing, screaming, and striking people because patients no longer have control of their emotions and
inhibitions. Admissions to nursing homes can be delayed and quality of life improved when behavioral disturbances are managed
appropriately.
MANAGEMENT OPTIONS Management of mild behavioral disorders in AD patients includes nonpharmacologic approaches. Some possible tactics for caregivers
include maintaining a brightly lit home environment without a noisy background, offering simple instructions for meals and
bathing, adherence to a stable daily routine, and installing motion detectors in bathrooms so that lights turn on automatically.
Information about a nonpharmacologic approach to AD can be found in the recently reported findings of the Resources for Advancing
Alzheimer's Caregiver's Health (REACH) trial, the largest randomized controlled clinical trial to date, involving 1222 caregiver
and care recipients recruited from 6 different sites in the United States. The authors' descriptions of occupational-based
interventions can help caregivers who are looking for solutions to behavior problems.1 Questions to consider before beginning pharmacologic intervention include
- Is drug therapy appropriate for the symptom?
- As a rule, does the symptom respond to pharmacologic intervention?
- What drug category is most efficacious in treating this symptom?
- What are the possible side effects of the drug?
- What is the appropriate duration of drug therapy?
Pharmacotherapy is appropriate as an adjunctive treatment when behavior problems are not found to have any physical cause,
are not believed to be the side effect of medication, become so acute that the safety of patients and those around them is
threatened, or do not respond to nonpharmacologic efforts.
Management of depression Depression is a common comorbidity in all stages of AD, although it is most easily identifiable before the disease has progressed.
Symptoms are expressed differently depending on how advanced the disease is. Initially, symptoms are similar to those seen
in a cognitively intact adult and include feelings of guilt, sadness, grief, and worthlessness. Patients may also become socially
isolated and withdrawn.
AD patients may also experience frustration and anxiety. As the disease progresses through the intermediate stages, anxiety
and frustration may increase, and patients may become more and more agitated. Later, as the terminal phase approaches, agitation
and anxiety may be compounded by openly aggressive behavior.
Table1: Recommended dosages for drugs commonly used in AD
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Pharmacotherapy is useful for treating depression in AD patients. Selective serotonin reuptake inhibitors (SSRIs) are usually
the first-line therapy. SSRIs such as citalopram and sertraline are usually very well-tolerated in the elderly, with few side
effects, and low dosages are usually sufficient for providing at least partial relief from depression (see Table 1). Compared
to cognitively normal persons, AD patients have more side effects from medications in general, but particularly from psychoactive
drugs, so low-dosage regimens are important. If an SSRI is ineffective or is not tolerated, alternatives may include bupropion,
venlafaxine, or nortriptyline (in patients who do not have cardiac disease). Nortriptyline, however, has an increasingly restricted
treatment role in elderly patients. One suggestion is to use mirtazapine starting at 7.5 mg and increasing to 15 or 22.5 mg
qhs.
Coping with sleep disturbances Sleep disturbances in AD patients may be attributable in part to concomitant depression and in part to the disease itself
as it disrupts sleep patterns. Also, circadian rhythms may become disturbed because these patients no longer have the cognitive
skills and manual abilities to engage in activities that would normally keep them occupied during the day, such as reading
a book or completing minor repairs around the house. Patients may become bored as a result of their decreased activity level
and fall asleep. Such excessive sleeping, which may be compounded by interruption of the brain's sleep center, disrupts the
natural sleep-wake cycle, so that patients may lie awake at night and become disoriented. They may then grow anxious, agitated,
and even wander from home.
Nonpharmacologic efforts to improve sleep hygiene include keeping the patient mentally occupied during the day, adhering to
a structured daily schedule, and providing opportunities for physical exercise. Medication may be necessary if these strategies
fail. Zolpidem, zaleplon, or trazodone may be used for sleeplessness in AD patients.*
Managing anxiety Anxiety is another common problem in all stages of AD and, like insomnia, may be related to depression stemming from a subjective
understanding of mental decline. It may also be provoked by confusion correlated with cognitive, memory, or language deficiencies;
delusions associated with paranoia; or sleep disorders.
If the anxiety is related to depression, an SSRI may be effective. Trazodone's sedating effects make it particularly useful
when anxiety occurs in the evening and insomnia results.* Anxiety and agitation together may be treated with valproic acid
or carbamazepine.* If symptoms do not respond to therapy with these drugs or if delusions and hallucinations are causing or
worsening anxiety, very low dosages of atypical antipsychotics such as olanzapine, risperidone, or quetiapine can be used.*
Buspirone or a short-acting benzodiazepine such as lorazepam may have some use for alleviating anxiety in patients with AD.
In this population, however, the side effects of these drugs, including confusion and increased potential for falling, can
prove problematic. Their use is thus best kept brief and limited to certain stressful episodes such as a change in residence
or a medical procedure that may cause anxiety.
Dealing with agitation and aggression Agitation is common in persons with AD as the disease progresses through the middle and later stages. Much like anxiety, agitation
may be caused by sleep disorders or confusion and frustration associated with diminishing mental faculties. Illness or depression
may also be communicated through agitated behavior in cognitively impaired patients.
Aggression and combativeness are behaviors associated with agitation that serve as a means of expressing feelings of depression,
frustration, illness, or discomfort. Biting, verbal abuse, and striking people are common disruptive behaviors and are usually
responses to particular situations, such as attempts to provide personal care. Patients may become frustrated and resentful
if they do not understand what the caregiver wants when giving them instructions or assisting them in ADLs, including dressing
and bathing. They may display aggression as an outlet for their feelings. Patients with AD usually respond best to simple,
one-step commands, such as "take off your slippers" and then "put on your socks," as opposed to a general command, such as
"get dressed."
Among these patients, physical discomfort and illness may also be expressed as belligerence. Physicians thus need to be aware
of pain syndromes in older persons with dementia, because pain in these patients is not manifested in standard ways. Those
with AD are not able to relate to their body as well as cognitively normal people, and so they use aggression and other behaviors,
such as screaming and refusing to eat to communicate pain or feeling ill. In such cases, simply curing the physical ailment
or alleviating the pain may put an end to the aggressive episodes.
*Unlabeled use.
Pharmacologic intervention for agitation and aggression becomes necessary when environmental modifications, such as clearly
labeling drawers and cabinets or limiting menu and clothing options, are no longer sufficient to reduce or eliminate the aggressive
behavior. SSRIs or trazodone is effective if behavior is associated with depression. Low dosages of atypical antipsychotics
can also be used to treat agitation and aggression, particularly when psychoses are present. Cholinesterase inhibitors may
reduce behaviors directly correlated with cognitive decline by slowing down intellectual deterioration.
A recent review of the responsiveness to pharmacotherapy of patients with established AD found that cholinesterase therapy
was associated with quality-of-life improvements that included reduced behavioral disturbances. Cholinesterase inhibitors
may have found a place in the treatment of AD at all stages; whether it be impact cognition, function, or behavior.
Memantine can be used either in combination or alone for moderate to advanced disease.2 However, Dr Forchetti, one of the consultants for this update, disagrees with this approach—adding memantine to modify behavior—because
the clinical trials did not show a significant effect on the Neuropsychiatric Institute Inventory, the instrument used to
measure changes in behavioral and psychiatric symptoms.
Management of delusions and hallucinations Delusions and hallucinations are seen most often in patients with mid- to late-stage AD and may also cause aggressive behaviors.
Events depicted on TV, such as a gunfight or other form of violence, may be disturbing or frightening for these patients.
They may believe that these events are actually occurring or happening to them and express their fears by physically lashing
out. It is important that their caregivers are aware of this problem and monitor television-viewing.
Paranoid delusions are also common in patients with AD, because paranoia can fill in the gaps when memory is failing. These
delusions are upsetting and can also precipitate violent behavior. Patients may suspect spouses of infidelity or family members
of trying to steal their possessions. They may also believe that their home is being burglarized or that relatives have been
replaced by impostors (Capgras's syndrome).
Hallucinations experienced by AD patients are commonly visual and may or may not trigger an aggressive outburst. If the hallucination
is one that patients find frightening, such as the belief that they are being assaulted, they may grow agitated and resort
to aggression. Hallucinations are often more upsetting to caregivers, however.
Atypical antipsychotics at very low dosages can be used to control delusions, paranoia, and hallucinations. A study found
that, compared with placebo, risperidone at 1 mg/d significantly improved symptoms of psychosis and aggression in older patients
with dementia.3 Atypical antipsychotics should not be used on an as-needed basis, however, but should be given consistently over a short
period at a particular dosage at the time of day when the behavior is most likely to occur or tends to worsen. If the behavior
appears to be under control, it may be possible to discontinue or begin tapering the antipsychotic medication, and perhaps
replace it with an SSRI.
Gender is also an important consideration. There is evidence that men are more likely than women to be given psychotropic
medication, particularly antipsychotic drugs, because of their greater predisposition to certain behaviors such as wandering.4
Treatment of sundowning This behavioral manifestation of AD incorporates many of the disorders already discussed. Patients with sundowning become
increasingly agitated and anxious in the late afternoon or early evening, after functioning and behaving well earlier in the
day. The agitation and anxiety may then cause patients to become aggressive. Sundowning may be caused by decreased sensory
stimulation as the daylight fades or by fatigue related to the natural downturn in body cycles. The atypical antipsychotics
have a sedative side effect so this drug class is particularly useful in the treatment of sundowning and confusion in the
evening.
CONTRAINDICATIONS AND SIDE EFFECTS Certain prescription drugs should be avoided or prescribed only on a limited basis in AD patients because their side-effect
profile may be exacerbated in those with dementia. In addition, even drugs commonly used to treat the behavioral problems
of AD may cause side effects that need to be addressed. The best way to minimize or avoid the deleterious effects of any drugs
used in older persons with dementia is to restrict their use to certain situations, prescribe them at the lowest possible
dosages, and limit the duration of treatment.
Drugs to avoid in AD Any drug that has a significant anticholinergic profile or has a potential cognitive side effect should be avoided in patients
with AD, unless there is a very clear indication for its use. This would include diphenhydramine for sleep problems or allergies,
since it can cause sedation and confusion.
Tricyclic antidepressants should probably not be prescribed for AD patients taking cholinesterase inhibitors because the opposing
effects on acetylcholine metabolism could exacerbate dementia. In addition to confusion, the anticholinergic effects of the
tricyclic antidepressants include dry mouth and severe constipation. These drugs can also cause cardiac arrhythmias or even
sudden cardiac death. If the decision is made to use tricyclics, when SSRI therapy fails, for example, patients must be monitored
closely with ECG testing and serum drug level measurements. In addition, baseline and periodic WBC counts with differential,
as well as liver function studies, should be done.
Side effects of commonly used drugs The atypical antipsychotics have a better adverse-effect profile than older antipsychotics such as haloperidol, including
a lower risk of extrapyramidal side effects and tardive dyskinesia. It is thus prudent to limit the use of haloperidol in
favor of the atypical antipsychotics, particularly in patients with Parkinson's disease in addition to AD. Some of the atypical
antipsychotics, such as olanzapine and quetiapine, can sometimes cause orthostasis, however. Orthostasis is also a problem
with trazodone and this drug can cause priapism, although this side effect occurs relatively infrequently. As mentioned, benzodiazepines
can increase risk of falling because these drugs can decrease muscle tone and cause balance problems.
Table 2: Common adverse events associated with cholinesterase inhibitors compared with PBO
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SSRIs can cause diarrhea and anorexia in older patients, although these problems often resolve within 2 weeks of initiating
therapy. GI side effects can be minimized by starting with very low dosages and then gradually increasing them. These drugs
can also cause hallucinations or delusions, although this is an extremely rare occurrence. Table 2 lists commonly reported
adverse events associated with cholinesterase inhibitors compared with placebo .
How long should pharmacologic treatment continue? It is important to reassess patients' cognitive functional and behavioral status on a regular basis—at least every 3 to 6
months if they are outpatients. Those who are inpatients or in a nursing home setting should be monitored more frequently,
because as cognitive decline continues, problem behaviors are likely to change. Behavioral symptoms that were present earlier
in the course of the disease may diminish, and new ones may develop. In the later stages, patients may become more apathetic
and less aggressive than previously.
No rule of thumb exists for the duration of pharmacotherapy because the course of disease is extremely variable among individuals.
Patients go through phases in which they may be aggressive and then enter other phases of relative calmness and complacency.
Duration of therapy usually depends on the clinical situation and on the types of behavior that the caregiver is reporting.
It is thus a good idea to communicate often with the caregiver to monitor behavior. In most situations, behaviors are improved
or reduced—but not completely eradicated—by drug treatment. If the behavior has been modified to the point at which it rarely,
if ever, occurs, it may be possible to try reducing the dosage or begin gradually tapering off the medication. Should the
behavior reemerge, treatment can be initiated again as quickly as possible.
This consensus article was written by Charlotte LoBuono in consultation with Drs Arenson, Forchetti, and Tangalos.
Dr Tangalos discloses that he has served as a consultant for Lilly, Abbott, Jansson, and Forest.
Dr Arenson discloses that she has no relationship with any manufacturer in this therapeutic area.
REFERENCES 1. Schulz R, Belle SH, Czaja SJ, et al. Introduction to the special section on Resources for Enhancing Alzheimer's Caregiver
Health (REACH). Psychol Aging. 2003;18:357-360.
2. Standbridge JB. Pharmacotherapeutic approaches to the treatment of Alzheimer disease. Clin Ther. 2004;26:615-630.
3. Katz IR, Jeste DV, Mintzer JE, et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances
associated with dementia: a randomized, double-blind trial. The Risperidone Study Group. J Clin Psychiatry. 1999;60:107-115.
4. Ott BR, Lapane KL, Gambassi G. Gender differences in the treatment of behavior problems in Alzheimer's disease. SAGE Study
Group. Systemic Assessment of Geriatric drug use via Epidemiology. Neurology. 2000;54; 427-432.
SUGGESTED READING Borson S, Raskind MA. Clinical features and pharmacologic treatment of behavioral symptoms of Alzheimer's disease. Neurology. 1997;48(suppl 6): S17-S24.
Cummings JL, Donohue JA, Brooks RL. The relationship between donepezil and behavioral disturbances in patients with Alzheimer's
disease. Am J Geriatr Psychiatry. 2000;8:134-140.
Daly MP. Diagnosis and management of Alzheimer disease. J Am Board Fam Pract. 1999;12:375-385.
De Deyn PP, Rabheru K, Rasmussen A, et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms
of dementia. Neurology. 1999;53:946-955.
Jeste DV, Rockwell E, Harris MJ, et al. Conventional vs. newer antipsychotics in elderly patients. Am J Geriatr Psychiatry. 1999;7:70-76.
Parnetti L. Therapeutic options in dementia. J Neurol. 2000;247:163-168.
Raskind MA. Psychopharmacology of noncognitive abnormal behaviors in Alzheimer's disease. J Clin Psychiatry. 1998;59(suppl 9):28-32.
Tariot PN, Farlow MR, Grossberg GT, et al. Memantine Study Group. Memantine treatment in patients with moderate to severe
Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004; 291:317-324.
Drugs mentioned in this article
Bupropion (Wellbutrin)
Buspirone (BuSpar)
Carbamazepine
Citalopram (Celexa)
Diphenhydramine
Donepezil (Aricept)
Escitalopram (Lexapro)
Galantamine (Reminyl)
Haloperidol (Haldol)
Lorazepam (Ativan)
Memantine (Namenda)
Mirtazapine (Remeron)
Nortriptyline (Aventyl, Pamelor)
Olanzapine (Zyprexa)
Paroxetine (Paxil, Pexeva)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Rivastigmine (Exelon)
Sertraline (Zoloft)
Tacrine (Cognex)
Trazodone (Desyrel)
Valproic acid
Venlafaxine (Effexor)
Zaleplon (Sonata)
Zolpidem (Ambien)
