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Innovations: Geriatric Psychiatry: Diagnosis and Treatment of Neuropsychiatric Symptoms in Alzheimer's Disease
Helen Lavretsky, M.D.; Lang Hai Nguyen, B.S.
Psychiatric Services 2006; doi: 10.1176/appi.ps.57.5.617

The authors review research on the treatment of behavioral disturbances and psychiatric symptoms of patients with dementia, including pharmacological treatment with antipsychotics, antidepressants, cholinesterase inhibitors, and other psychotropic drugs. They conclude that although these medications have some beneficial effects, no intervention is currently able to eradicate behavioral disturbances and psychiatric symptoms of demented patients. Research suggests that multiple interventions for an individual patient are likely to replace the use of a single treatment. Such interventions include caregiver training and support, antipsychotics, antidepressants, and cholinesterase inhibitors, along with other drugs developed for the treatment of Alzheimer's disease. (Psychiatric Services 57:617-619, 2006)

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The authors are affiliated with the department of psychiatry and biobehavioral sciences at the University of California, Los Angeles. Send correspondence to Dr. Lavretsky at UCLA-Neuropsychiatric Institute and Hospital, 760 Westwood Place, Los Angeles, California 90095 (e-mail, hlavrets@ucla.edu). Marion Zucker Goldstein, M.D, served as guest editor of this column.

The assessment and management of the acutely agitated or depressed patient with dementia can be challenging because of coexisting cognitive and behavioral symptoms, comorbid medical conditions, polypharmacy, and complicated social circumstances compounding patient's ability to function independently. In his column we discuss nonpharmacological and pharmacological treatment of behavioral and psychological symptoms of patients with dementia.

Behavioral management strategies should be instituted before intervention with medications (1). Teri and colleagues (2) used the following five-step nonpharmacologic approach: identify the target symptoms, determine when symptoms are likely to occur, determine precipitants of symptoms, plan interventions to reduce the precipitants, and consider alternative approaches if the first approach fails.

Adjusting the physical environment, redirecting distressed patients, talking calmly with patients, and promoting appropriate social interactions and activities, combined with caregiver education and support, can ameliorate problem behaviors and their impact (3). Environmental changes in lighting, noise level, and temperature can reduce agitation (4). Adjustment of the patient's schedule, introduction of structured activities, and avoidance of diuretics, caffeine, and alcohol are also important. Music therapy, dancing, exercise, and pet therapy may be effective in reducing agitation. Physical restraints should be avoided because they are associated with injury, not protection, when used with patients who are confused (1,2,3,4). Caregivers can also intensify agitation by being confrontational, angry, or critical. Training them to be supportive by using redirection can be very useful.

Drug therapy for elderly patients with or without dementia should take into account age-related physiological changes in the structure and function of the brain and other organs. In general, older people are more sensitive than younger adults to both therapeutic and toxic effects of psychotropic medications, necessitating lower dosages and slower dosage titration. Pharmacokinetic and pharmacodynamic effects of drugs may be different among older patients with dementia, who may require lower dosages for therapeutic response or a longer titration to the therapeutic dosage. Not only are controlled pharmacological studies in this group of patients scarce, but also no therapies have been approved by the Food and Drug Administration (FDA) for treatment of neuropsychiatric symptoms in Alzheimer's disease and related dementias. Most clinicians use the rule of "target symptoms" in making decisions about pharmacotherapy. [A list of psychoactive drugs and the target symptoms for which they are used is available in the online version of this column, along with a table summarizing the recommended dosages of antidepressants and antipsychotics that are commonly used for older patients with dementia.]

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Antipsychotic medications

Many studies have explored the efficacy of antipsychotic medication treatment for psychosis and agitation among patients with dementia. Approximately two-thirds of patients with agitated behavior improve with antipsychotic treatment, although the response is generally modest and some patients do not benefit. No difference in efficacy among first-generation antipsychotic drugs has been consistently demonstrated, although few comparison trials have been conducted (5). However, extrapyramidal symptoms, gait disturbance, peripheral anticholinergic effects, or cognitive decline often complicate treatment (6). In this medication group, high-potency agents are preferred, and most patients respond to a low dosage.

Clinicians have used second-generation antipsychotics "off-label" to treat neuropsychiatric symptoms among elderly demented patients. Several studies, summarized in a Cochrane Review and in a recent systematic review published in JAMA (3), cite the modest but significant reductions in neuropsychiatric symptoms demonstrated among elderly patients treated with risperidone or olanzapine. However, second-generation antipsychotics are associated with an increased risk of stroke.

Risperidone has been shown to be effective in trials lasting three months (7); however, treatment led to the development of extrapyramidal side effects with a daily dosage of up to 2 mg. Olanzapine has also been shown to effective and well tolerated at dosages of 5 to 10 mg per day (8). Data for quetiapine, ziprasidone, and aripiprazole are limited, although preliminary studies suggest that quetiapine is effective and well tolerated in this population with dosage titration up to about 150 mg per day. Clozapine at 12.5 to 100 mg per day, with careful titration, may improve psychosis or aggression among some elderly patients with dementia, although the medication is not routinely recommended because of frequent adverse effects. Results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), which was recently completed, may reduce the uncertainty about risks and benefits of these drugs when used to treat patients with dementia (9). The complete results of the study have not been released.

In the past year several public safety warnings have been issued by various agencies, including the FDA, about use of second-generation antipsychotics on the basis of pooled analyses of the existing studies. The issued warnings were related to the increased risk of cerebrovascular events among patients taking risperidone and olanzapine and to increased metabolic syndrome among those taking second-generation antipsychotics (3,9,10). Recently, the FDA issued a public health advisory to notify health care providers, patients, and patient caregivers of a newly identified concern associated with the off-label use of second-generation antipsychotics for treatment of dementia-related behavioral disorders in the elderly population. This advisory was based on an analysis of data from 17 placebo-controlled trials of aripiprazole, olanzapine, quetiapine, and risperidone that involved 5,106 elderly patients with dementia-related behavioral disorders. The analysis found that these medications were associated with a 1.6- to 1.7-fold increase in the mortality rate compared with the rate for placebo-treated patients. The mortality rate associated with placebo use in these acute trials was 2.6 percent, compared with 4.5 percent for patients who received second-generation antipsychotics (10,11).

Although no placebo-controlled trials of ziprasidone or clozapine have been conducted and the rates of associated mortality are not known, it is reasonable to view the increased mortality as a class effect and to assume that older, first-generation antipsychotic medications may present equal or greater mortality risks. In a recent article, similar mortality rates were quoted for the first-generation antipsychotic agents (12). Unfortunately, no such data are available for other classes of psychotropic drugs.

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Antidepressant medications

Nine placebo-controlled efficacy studies of antidepressants from several different classes have been conducted among elderly persons with dementia. Four of eight studies reported greater efficacy of antidepressants, and four found no differences in response compared with placebo. Improvements in depression occurred in 50 to 75 percent of patients treated with antidepressants, with mean reductions in standardized scale scores for depression of 30 to 60 percent. The placebo response in this population has been found to be about 30 to 40 percent.

Antidepressants have been used to treat agitation in dementia. Trazodone, citalopram, other serotonergic medications, and anticonvulsants are effective and well tolerated when prescribed to treat agitated behavior of patients with dementia, although data from controlled trials is limited (13). Five trials of antidepressants have been conducted, and results showed no efficacy for treating neuropsychiatric symptoms other than depression, with the exception of one study of citalopram (3). Three randomized trials of valproate showed no advantage over placebo (3). Two small randomized controlled trials of carbamazepine also had conflicting results (3).

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Cholinesterase inhibitors

Growing evidence suggests that the neurobiological basis of behavioral disturbances of Alzheimer's disease and related dementias is a loss of cholinergic neurons and a resultant decline in acetylcholine in brain regions that regulate behavioral and emotional responses, such as the limbic system (12). This cholinergic deficit can be partially corrected by inhibiting cholinesterase enzymes. Two meta-analyses and six randomized controlled trials of cholinesterase inhibitors generally showed a low but statistically significant level of efficacy in the improvement or stabilization of existing behaviors and a delay in the emergence of new behavioral symptoms (3).

Donepezil has shown efficacy for cognitive and behavioral symptoms among outpatients with moderate to moderately severe illness over a period of 24 weeks but did not demonstrate efficacy in mild-to-moderate Alzheimer's disease and among institutionalized patients with severe disease. Galantamine has been shown to delay the onset of behavioral and psychological symptoms among patients with mild-to-moderate Alzheimer's disease in one placebo-controlled study and to improve behavioral and psychological symptoms in a similar study of patients with cerebrovascular disease or probable vascular dementia. Studies with rivastigmine have shown efficacy in placebo-controlled studies of patients with mild- to-moderate Alzheimer's disease and patients with Lewy body variant. Institutionalized patients with severe disease also experienced symptomatic benefits with rivastigmine, resulting in a reduction of concomitant use of psychoactive medications (14).

All cholinesterase inhibitors improve apathy, depression, and anxiety, and rivastigmine also improves hallucinations and delusions, possibly as result of dual inhibition of acetylcholinesterase and butyrylcholinesterase. The presence of hallucinations has been shown to predict response to rivastigmine. A recent meta-analysis of the efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer's disease demonstrated a modest beneficial effect on behavioral or neuropsychiatric symptoms and on functional abilities (14). Two randomized controlled trials of memantine for treatment of neuropsychiatric symptoms produced conflicting results (3).

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Other psychotropic drugs

Benzodiazepines are not part of the recommended management of neuropsychiatric symptoms and should be avoided, especially for long-term management (15). The report published by the Expert Consensus Panel for Agitation in Dementia (1) generally recommends against the use of benzodiazepines except for short-term or occasional use for anxiety symptoms. In addition, no psychoactive medication prescribed to treat neuropsychiatric symptoms of dementia should be continued indefinitely, and attempts to withdraw the drug should be made regularly.

Dopaminergic and stimulant medications can be used in the treatment of apathy, lack of motivation, and social withdrawal, but the efficacy of dopaminergic drugs is unknown (16). Kaufer (17) concluded that behavioral and motor symptoms in dementia of Lewy bodies are less amenable to dopaminergic therapy, and psychosis may emerge as a result of their use.

Currently, no intervention is able to completely stop the progression of dementia or eradicate depression and associated behavioral and psychological disturbances. No treatment can arrest neurodegenerative processes and cell loss. It is expected that over the next five years most patients will present with fairly mild memory and psychological complaints, which could allow for initiation of early treatment. Multiple interventions for an individual patient are likely to replace the use of a single treatment.

Interventions will include psychosocial treatments; caregiver training and support; cognitive enhancers, such as acetylcholinesterase inhibitors; as well as other drugs developed for the treatment of Alzheimer's disease and neuroprotective agents, antioxidants, and lipid-lowering drugs (although at this time the use of lipid-lowering drugs remains controversial. Augmentation with other medications or alternative medicines will become more popular and will be supported by better research evidence. A healthy lifestyle, a healthy diet, and exercise, as well as memory training, will be employed to enhance cognition, mood, and resistance to further decline. Future research should focus on improvements in long-term outcomes, such as quality of life, institutionalization, and caregiver burden.

Dr. Lavretsky received grant support through the University of California, Los Angeles, from Forest Laboratories and honoraria from Pfizer, Inc., Eisei, Inc., and Janssen Pharmaceutica Inc. She also was supported by grant K23-MH01948 from the National Institute of Mental Health.

The Expert Consensus Panel for Agitation in Dementia: treatment of agitation in older persons with dementia. Postgraduate Medicine 103(Apr special issue):1-88, 1998
 
Teri L, Logsdon RG, Uomoto J, et al: Behavioral treatment of depression in dementia patients: a controlled clinical trial. Journals of Gerontology: Series B, Psychological Sciences and Social Sciences 4:159-166, 1997
 
Sink KM, Holden KF, Yaffe K: Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 293:596-608, 2005
 
Lavretsky H: Therapy of depression in dementia. Expert Review of Neurotherapeutics 3(5):89-97, 2003
 
Schneider LS, Pollock VE, Lyness SA: A meta-analysis of controlled trials of neuroleptic treatment in dementia. Journal of the American Geriatrics Society 38:553-563, 1990
 
Byerly MJ, Weber MT, Brooks DL, et al: Antipsychotic medications and the elderly: effects on cognition and implications for use. Drugs and Aging 18:45-61, 2001
 
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. Journal of Clinical Psychiatry 60:107-115, 1999
 
Street JS, Clark WS, Gannon KS, et al: Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer's disease in nursing care facilities. Archives of General Psychiatry 57:968-976, 2000
 
Schneider LS, Tariot PN, Lyketsos CG, et al: National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology. American Journal of Geriatric Psychiatry 9:346-360, 2001
 
Schneider LS, Dagerman K, Insel PS: Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. American Journal of Geriatric Psychiatry 14:191-210, 2006
 
Schneider LS, Dagerman KS, Insel P: Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 294:1934-1943, 2005
 
Wang PS, Schneeweiss S, Avorn J, et al: Risk of death in elderly users of conventional vs atypical antipsychotic medications. New England Journal of Medicine 353:2335-2341, 2005
 
Sultzer DL, Gray KF, Gunay I, et al: Does behavioral improvement with haloperidol or trazodone treatment depend on psychosis or mood symptoms in patients with dementia? Journal of the American Geriatrics Society 49:1294-1300, 2001
 
Trinh N-H, Hoblyn J, Mohanty S, et al: Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer's disease. JAMA 289:210-216, 2003
 
Meehan KM, Wang H, David SR, et al: Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 26:494-504, 2002
 
Lavretsky H, Kumar A: Clinically significant non-major depression: old concepts, new insights. American Journal of Geriatric Psychiatry 10:239-255, 2002
 
Kaufer DI: Pharmacological therapy of dementia with Lewy bodies. Journal of Geriatric Psychiatry and Neurology 15:224-232, 2002
 
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References

The Expert Consensus Panel for Agitation in Dementia: treatment of agitation in older persons with dementia. Postgraduate Medicine 103(Apr special issue):1-88, 1998
 
Teri L, Logsdon RG, Uomoto J, et al: Behavioral treatment of depression in dementia patients: a controlled clinical trial. Journals of Gerontology: Series B, Psychological Sciences and Social Sciences 4:159-166, 1997
 
Sink KM, Holden KF, Yaffe K: Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence. JAMA 293:596-608, 2005
 
Lavretsky H: Therapy of depression in dementia. Expert Review of Neurotherapeutics 3(5):89-97, 2003
 
Schneider LS, Pollock VE, Lyness SA: A meta-analysis of controlled trials of neuroleptic treatment in dementia. Journal of the American Geriatrics Society 38:553-563, 1990
 
Byerly MJ, Weber MT, Brooks DL, et al: Antipsychotic medications and the elderly: effects on cognition and implications for use. Drugs and Aging 18:45-61, 2001
 
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. Journal of Clinical Psychiatry 60:107-115, 1999
 
Street JS, Clark WS, Gannon KS, et al: Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer's disease in nursing care facilities. Archives of General Psychiatry 57:968-976, 2000
 
Schneider LS, Tariot PN, Lyketsos CG, et al: National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology. American Journal of Geriatric Psychiatry 9:346-360, 2001
 
Schneider LS, Dagerman K, Insel PS: Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. American Journal of Geriatric Psychiatry 14:191-210, 2006
 
Schneider LS, Dagerman KS, Insel P: Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 294:1934-1943, 2005
 
Wang PS, Schneeweiss S, Avorn J, et al: Risk of death in elderly users of conventional vs atypical antipsychotic medications. New England Journal of Medicine 353:2335-2341, 2005
 
Sultzer DL, Gray KF, Gunay I, et al: Does behavioral improvement with haloperidol or trazodone treatment depend on psychosis or mood symptoms in patients with dementia? Journal of the American Geriatrics Society 49:1294-1300, 2001
 
Trinh N-H, Hoblyn J, Mohanty S, et al: Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric symptoms and functional impairment in Alzheimer's disease. JAMA 289:210-216, 2003
 
Meehan KM, Wang H, David SR, et al: Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology 26:494-504, 2002
 
Lavretsky H, Kumar A: Clinically significant non-major depression: old concepts, new insights. American Journal of Geriatric Psychiatry 10:239-255, 2002
 
Kaufer DI: Pharmacological therapy of dementia with Lewy bodies. Journal of Geriatric Psychiatry and Neurology 15:224-232, 2002
 
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