Study Number Study Title S1202: Duloxetine Hydrochloride to Treat Muscle, Bone, and Joint Pain in Pts W/Early-Stage Breast Cancer Receiving ClinicalTrials.gov Identifier Condition RATIONALE: Duloxetine hydrochloride may lessen muscle, bone, and joint pain caused by hormone therapy. It is not yet known whether duloxetine hydrochloride is more effective than a placebo in tr
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Usvh.orgUSVH Disease of the Week #3: Dementia in Older Adults and Veterans “Managing Common Behavioral Problems in Dementia: How to Improve Quality of Life forPatients and Families” James R. Burke, MD, PhD; Joel C. Morgenlander, MD VOL 106 / NO 5 / OCTOBER 15, 1999 / POSTGRADUATE MEDICINE Although memory loss is an early and prominent finding in most patients with dementia, thechief factor leading to institutionalization is disruptive behavior related to the disease. Commonbehavioral symptoms include depression, sleep disturbance, agitation, aggression, and psychoticfeatures (delusions and hallucinations).
Behavioral symptoms can arise as a result of the dementing illness, a concomitant medicalillness, or iatrogenic causes. A common error in management of behavioral disturbances is totreat them without identifying the symptom precipitant. Before treatment is instituted, disruptivebehavior should be categorized and underlying causes sought. Unless both the physician and thepatient's family have a clear understanding about the behavior being treated and the goals oftreatment, the results are often unsatisfactory.
Depression affects up to 20% of patients with dementia. In Alzheimer's disease, depression maybe due to disease-related neuronal loss or, less frequently, a reaction to the disease process (1). Inpatients with vascular dementia, depression commonly follows left cerebral hemisphere stroke.
The prevalence of depression is also increased in patients with dementia related to Parkinson'sdisease. The diagnosis of depression in patients with dementia can be difficult, because apathy iscommon to both disorders.
Patients with dementia commonly have impaired insight, which makes psychotherapy useless.
Thus, treatment primarily consists of pharmacotherapy, but physical and mental activity can behelpful in minimizing symptoms. When drug therapy is required, a selective serotonin reuptakeinhibitor (SSRI) is a reasonable first-line treatment. Paroxetine hydrochloride (Paxil) andsertraline hydrochloride (Zoloft) are well tolerated by patients with dementia and have afavorable ratio of efficacy to side effects. When marked apathy is present, a more activatingantidepressant that stimulates both the serotonergic and adrenergic neurotransmitter systems (eg,fluoxetine hydrochloride [Prozac], venlafaxine [Effexor]) is useful. For patients in whominsomnia is a prominent feature of depression, trazodone hydrochloride (Desyrel) is an effectivesedating antidepressant. However, this agent should be used with care in men, because it cancause priapism, which may require surgical intervention.
Tricyclic antidepressants with low anticholinergic activity (eg, desipramine hydrochloride[Norpramin], nortriptyline hydrochloride [Aventyl HCl Pulvules, Pamelor]) are effective inpatients with dementia and are less expensive than SSRIs. Tricyclic agents with prominent anticholinergic activity (eg, amitriptyline hydrochloride [Elavil]) should be avoided, becauseanticholinergic drugs tend to worsen cognitive impairment and precipitate delirium.
Selected drugs with prominent anticholinergic activity to avoid in patients with dementia: Tricyclic antidepressantsAmitriptyline HCl (Elavil), trimipramine maleate (Surmontil), protriptyline HCl (Vivactil) Low-potency antipsychoticsChlorpromazine HCl (Thorazine) AntispasmodicsOxybutynin chloride (Ditropan), hyoscyamine sulfate (eg, Cystospaz, Levsin) and relatedcompounds (eg, Donnatal) AntiemeticsPromethazine HCl (Phenergan), diphenhydramine HCl (eg, Benadryl), prochlorperazine(Compazine) AnticholinergicsTrihexyphenidyl HCl (eg, Artane), benztropine mesylate (Cogentin) Successful treatment of depression should be continued for at least 6 months, then the dosageshould be slowly tapered. When response to treatment is inadequate, the most common reason isinadequate dosage. The dose should be increased every 1 to 2 weeks until depressive symptomsresolve, side effects occur, or the maximum allowable dose is reached. If depressive symptomspersist after a reasonable therapeutic trial, an antidepressant from a different class should beprescribed. When no response is achieved despite adequate trials of multiple agents, thediagnosis of depression should be reconsidered and the patient referred to a psychiatrist. Moreaggressive treatment in patients with refractory depression may include use of a monoamineoxidase inhibitor, stimulants, or electroconvulsive therapy. The need for continued therapyshould be reassessed often, because worsening dementia may resolve depressive symptoms andsigns.
Families of patients with dementia can often tolerate agitation, delusions, and wandering as longas nighttime sleep remains uninterrupted. However, when behavioral disturbances occur day andnight, families often feel compelled to resort to institutionalization. Educating families aboutstrategies for preventing or correcting sleep problems may help delay nursing home placement.
Many factors can contribute to poor sleep habits in persons with dementia, including disruptedsleep patterns, alterations in circadian rhythm, concurrent medical problems that cause frequenturination, daytime use of sedating medication, and frequent napping. In our experience, the chiefcauses of sleep disruption are frequent napping and excessive expectation of sleep needs.
Families often report that the patient wakes and dresses for morning activities at 3 AM. Onfurther questioning, they may reveal that the patient naps while watching television during theday and goes to bed at 8 PM. In this common scenario, the patient's early morning awakening isnot abnormal. Daily sleep requirements do not increase as a person ages, and the patient is oftensleeping more than the 7 to 8 hours required for most persons to feel rested. In addition,caregivers often see the patient's nap time as an opportunity to accomplish tasks around thehouse. This is a shortsighted view that many come to regret.
The first step in reestablishing a normal sleep pattern is to limit daytime napping. Leaving apatient with dementia in front of a television set almost always leads to napping. To prevent this,caregivers should engage patients in activities that are tailored to the degree of dementia, such assimple handicrafts, household tasks and, most important, regular physical exercise. Suchactivities can be carried out at home, but many patients and families benefit from the addedstructure of adult day care.
Once poor sleep hygiene has become established, it is much more difficult to eradicate. The firststeps in correcting sleep problems are to set a more reasonable bedtime and prevent napping. Thepatient's activity level should be increased, and fluid intake should be decreased in the hoursbefore bedtime. After a few difficult nights, the patient will begin to sleep for longer periods. Forfamilies who cannot accept the possibility that the problem will worsen before improving,limited use of a hypnotic or sedating drug (eg, trazodone, zolpidem tartrate [Ambien], a short-acting benzodiazepine) may be considered. However, long-term reliance on sleeping medication,especially benzodiazepines, is rarely successful.
Environmental lighting may also have a role in sleep disturbance. Light is an importantmodulator of circadian rhythms, which may be disrupted in dementia. Increased lighting duringafternoon and early evening hours may improve sleeping patterns. Van Someren and associates(2) studied the effect of increased daytime illumination in 22 patients with dementia.
Improvement in the rest-activity rhythm occurred in patients with intact vision but not in visuallyimpaired patients. A clinical trial assessing the efficacy of melatonin in the treatment of sleepdisturbance in Alzheimer's disease is under way, but results are not yet available.
The most difficult part of managing sleep problems is the need for continued adherence to a rigidschedule. Families should be taught that periodic disruption of the schedule will likely result in areturn to irregular sleep patterns. Authorizing use of a hypnotic agent for periodic administrationis helpful and provides families with a sense of control.
Agitation and aggression Agitation occurs at some time in about half of all patients with dementia (3). Associatedbehaviors include aggression, combativeness, disinhibition, and hyperactivity. As with allbehavioral problems, the first step in treatment is to identify the precipitants. Evaluation shouldinclude assessment for common systemic causes (eg, infection, dehydration, constipation, otherillnesses) as well as changes in medication.
Families should be informed about potential causes of agitation, such as excessive stimulation,and about the need to make educated guesses about circumstances that trigger inappropriate behavior. Patients with dementia often become agitated when rushed; therefore, avoiding time-critical events, if possible, is useful. The patient's day should be structured to provide apredictable routine. Orientation materials (eg, calendar, clock, family pictures) should beprominently displayed, and the living environment should be well lit, even in the daytime, toavoid misperception of stimuli. Behaviors that are disruptive but not harmful (eg, pacing) shouldbe tolerated. Physical restraint is rarely necessary and usually serves to escalate the degree ofagitation.
If environmental measures are insufficient to control agitated or aggressive behavior, medicationis needed. High-potency neuroleptics (eg, haloperidol [Haldol], thioridazine hydrochloride[Mellaril]) are effective for controlling agitation, especially when psychotic features are present(3). Although there is no evidence to suggest that one neuroleptic agent is more effective thananother, the atypical antipsychotics (ie, clozapine [Clozaril], risperidone [Risperdal], olanzapine[Zyprexa], and quetiapine fumarate [Seroquel]) have a lower frequency of extrapyramidal sideeffects (eg, parkinsonism, tardive dyskinesia). They are very useful in patients with Parkinson'sdisease because their selective dopaminergic blockade does not interfere with dopamine'stherapeutic effect in the basal ganglia. However, atypical antipsychotics are expensive.
Benzodiazepines can also be used to treat anxiety or infrequent agitation, but they are lesseffective than other agents for long-term treatment.
In general, when agitation is a consistent problem and neuroleptic treatment is required, startwith a low dose (eg, 0.5 mg of haloperidol or 1 mg of risperidone) and administer it on a regularbasis rather than attempting to treat specific episodes of agitation. Trying to treat a patient who isalready agitated makes administering medication difficult, requires larger doses, and is likely tocause sedation and further clouding of thought.
The anticonvulsants carbamazepine and divalproex sodium (Depakote) are effective in treatingbehavioral disturbances in dementia and have a different side-effect profile than that ofneuroleptics. In a double-blind study, Tariot and colleagues (4) examined the effect ofcarbamazepine on agitation in 51 nursing home patients. Global improvement was noted in 77%of patients receiving carbamazepine and 21% of those receiving placebo. Analysis of the dataconfirmed that the positive changes were due to decreased agitation and aggression. The drugwas well tolerated, and no change in cognition or functional status occurred. The modalcarbamazepine dose was 300 mg a day, and the mean serum level was 5.3 micrograms/mL.
Carbamazepine also appears to be effective when added to neuroleptic therapy in patients withrefractory agitation (5). Divalproex is an effective treatment for mania in bipolar affectivedisorder (6) as well as agitation in dementia (7).
Other classes of drugs are useful for treating agitation. Antidepressants, especially SSRIs andtrazodone, are effective even in the absence of clear depressive symptoms. Theacetylcholinesterase inhibitors, donepezil hydrochloride (Aricept) and tacrine hydrochloride(Cognex), decrease agitation, possibly by stimulating attention and concentration (8). The betablocker propranolol hydrochloride (Inderal) inhibits impulsive behavior after frontal lobe injuryand can be used to decrease agitation and aggressive behavior in dementia, but it may causebradycardia and hypotension (9).
The need for continued pharmacologic treatment of agitation should be regularly reassessed.
Medication for agitation should not be viewed as long-term therapy (10). In one study,neuroleptic treatment was discontinued after agitation was successfully treated in nine patientswith dementia (10). A placebo was then administered, and behavior was monitored for the next 6weeks. Eight of the nine patients did not need additional pharmacologic treatment. Interestingly,five of the patients were less agitated after drug treatment was stopped.
Delusions and hallucinations Delusions (ie, false fixed beliefs) are common in dementia. Patients with Alzheimer's diseaseoften become suspicious of family members and may accuse them of stealing. Some patientsbelieve that intruders are trying to break into their house or that long-dead family members arealive. Visual and auditory hallucinations may also occur. Some hallucinations, such as seeing animaginary child playing on the floor, are nonthreatening, whereas other hallucinations arethreatening and may precipitate agitation or violence.
Before pharmacotherapy is initiated, the cause of the psychosis (eg, onset of another illness, amedication effect) should be determined, if possible. If no cause is found, environmentalchanges, such as increased lighting and decreased social isolation, can help. An increase inenvironmental noise (eg, from a radio or television) is beneficial in some patients but mayincrease delusions in other patients.
Psychotic features are disturbing to caregivers, even when the patient does not appear to bebothered by them. Nonthreatening delusions and hallucinations need not be treated. Familiesshould be reassured about the benign nature of these features and informed of the potential sideeffects of drug therapy. When short-term pharmacologic treatment is needed, it should beinitiated with low doses of a high-potency or atypical antipsychotic. Haloperidol is effective inpatients with dementia, but dosages higher than 3 mg a day often lead to excessive sedation andparkinsonian side effects. Low-potency antipsychotics should be avoided because of theiranticholinergic effects. For long-term treatment, we use one of the drugs suggested for agitation(eg, an SSRI, acetylcholinesterase inhibitor, or anticonvulsant) and begin tapering theantipsychotic medication as soon as possible.
Behavioral problems in patients with dementia are common. Fortunately, nonpharmacologic andpharmacologic therapies are often effective and can dramatically improve the quality of life forpatients as well as their families. However, treatment is rarely successful immediately. The oldtreatment adage "start low and go slow" is a key to success.
1. Katz IR. Diagnosis and treatment of depression in patients with Alzheimer's disease and other dementias. J Clin Psychiatry 1998;59 (Suppl 9):38-44 2. Van Someren EJ, Kessler A, Mirmiran M, et al. Indirect bright light improves circadian rest-activity rhythm disturbances in demented patients. Biol Psychiatry 1997;41(9):955-63 3. Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for GeriatricPsychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA1997;278(16):1363-71 4. Tariot PN, Erb R, Podgorski CA, et al. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry 1998;155(1):54-61 5. Lemke MR. Effect of carbamazepine on agitation in Alzheimer's inpatients refractory to neuroleptics. J Clin Psychiatry 1995;56(8):354-7 6. Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania: the Depakote Mania Study Group. JAMA 1994;271(23):1830 7. Narayan M, Nelson JC. Treatment of dementia with behavioral disturbance using divalproex or a combination of divalproex and a neuroleptic. J Clin Psychiatry1997;58(8):351-4 8. Levy ML, Cummings JL, Kahn-Rose R. Neuropsychiatric symptoms and cholinergic therapy for Alzheimer's disease. Gerontology 1999;45(Suppl 1):15-22 9. Shankle WR, Nielson KA, Cotman CW. Low-dose propranolol reduces aggression and agitation resembling that associated with orbitofrontal dysfunction in elderly dementedpatients. Alzheimer Dis Assoc Disord 1995;9(4):233-7 10. Borson S, Raskind MA. Clinical features and pharmacologic treatment of behavioral symptoms of Alzheimer's disease. Neurology 1997;48(5 Suppl 6):S17-24 Dr Burke is assistant professor of medicine, division of neurology, Duke University School ofMedicine, and director of clinical dementia trials, Joseph and Kathleen Bryan Alzheimer'sDisease Research Center and Deane Laboratory, Durham, North Carolina. Dr Morgenlander isassistant professor of medicine, division of neurology, and director, Neurology ResidencyTraining Program, Duke University School of Medicine. Correspondence: James R. Burke, MD,PhD, Duke University Medical Center, Box 2900, Durham, NC 27710. E-mail:[email protected]
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