Judith A. Neugroschl, MD

Although cognitive and functional decline are the car­dinal features of dementia syndromes, the associated neuropsychiatric symptoms are some of the most common and troubling manifestations of these debilitating diseases. These symptoms include agitated or aggressive behaviors, such as yelling, biting, and hitting, and psychotic symptoms, such as paranoia and hallucinations. Given that an estimated 5.4 million Americans have Alzheimer disease and that neuropsychiatric symptoms eventually develop in 60% of community-dwelling patients and more than 80% of nursing home patients, one can appreciate the scope of this problem. Moreover, these symptoms are exceedingly difficult for both clinicians and families to manage, making this a particularly relevant aspect of caring for patients with dementia.

These common dementia-associated neuropsychiatric symptoms carry risks for decreased quality of life, increased cost of care, more rapid cognitive decline, and tremendous caregiver burden. Caregivers often neglect their own physical and emotional needs, which can lead to depression, anxiety, irritability, and insomnia.

 When caregivers are burned-out and symptomatic themselves, the risk of substandard patient care, not to mention neglect and abuse, becomes much higher.

Increased caregiver burden, in particular, carries with it significant repercussions for patients and families, because caregiver stress is clearly associated with more rapid patient institutionalization. Apart from the often difficult emotional repercussions from placing a loved one in a nursing home, early institutionaliza­tion has obvious financial implications for the entire health care system. Indeed, neuropsychiatric symptoms can shorten the time to nursing home placement by as much as 2 years. Although the data are conflicting, some studies have shown a connection between neuropsychiatric symptoms and increased mortality.

As common and debilitating as these symptoms are, clinicians have few ways of adequately addressing them. There are no FDA-approved treatments for patients with dementia-related agitation or psychosis. Moreover, historical accounts of treatment of nursing home patients with such mental disorders (including dementia-related neuropsychi­atric symptoms) and recent data on the risks of using antipsychotic medications in this population have made choosing a course of action even more complex.

Until quite recently, the psychiatric conditions of nursing home residents were often misdiagnosed or ignored. This led to the related problems of neglect or inappropriate treatment, often with physical and so-called chemical restraints. Early data indicated that 25% of 1.3 million nursing home residents were in physical restraints for the control of behavioral problems, despite the potential adverse effects of injury, skin breakdown, and demoralization, as well as the fact that physical restraints do not decrease behavioral disturbances.

Studies from the 1970s and 1980s indicated that between 20% and 50% of nursing home residents were receiving psychotropic medications.

 Unfortunately, there was little concern for documenting residents’ psychiatric diagnoses, recording results of mental status examinations, and obtaining psychiatric consultation. Specific concern was expressed that neuroleptic medications were being used as a form of chemical restraint, without consideration of less burdensome and risky forms of treatment, such as alternative classes of drugs or behavioral interventions. Moreover, once treatment with a neuroleptic medication was started, patients frequently continued the regimen long term, without any clear indication or attempts to taper the dosage or discontinue use once acute symptoms were stable.

The misuse and abuse of these forms of restraint were major antecedents for the sweeping nursing home reform enacted in 1987. The Omnibus Budget Reconciliation Act’s (OBRA) Nursing Home Reform Act led to federal regulations requiring preadmission screening for mental disorders, prohibiting the inappropriate (eg, for discipline) use of restraints, and creating specific indications and guidelines for the use of antipsychotics.

 In general, studies have shown that the OBRA regulations had the intended effect on antipsychotic medication use: a substantial decrease in use without a signif-icant concomitant increase in the use of other medications.

Antipsychotics for neuropsychiatric symptoms of dementia?

It was long believed that atypical antipsychotics were the drugs of choice for the treatment of behavioral disturbances in dementia. Thus, clinicians faced with patients with difficult behavioral problems and no FDA-approved treatments often used these medications as first-line treatment.

In aggregate, atypical antipsychotics appear to have moderate efficacy in treating the neuropsychiatric symptoms of Alzheimer dementia, although several studies have not found their effects to be significantly different from those of placebo.

 In a meta-analysis of 15 randomized controlled trials of atypical antipsychotics in which psychosis and/or agitation in dementia were outcome measures, global assessments of neuropsychiatric symptom status improved only in a pooled analysis for risperidone and aripiprazole.

 Scores specifically related to psychosis improved only in trials using risperidone.

 Full interpretation of these data is difficult, because these trials were done in a variety of settings using a variety of outcomes measures.

The recent Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer Disease (CATIE-AD) attempted to assess the effectiveness of atypical antipsychotics for the treatment of psychosis or agitation in dementia, with a seemingly more relevant outcome in the initial phase of the trial: time to discontinuation for any reason. Patients were randomized to olanzapine, quetiapine, risperidone, or placebo. Interestingly, the atypical antipsychotics did not prove to be superior to placebo on the primary (time to discontinuation for any reason) or secondary (Clinical Global Impression scale) outcome measure at 12 weeks.

Although the trial was designed to answer the question of efficacy, there are a number of interesting issues. For example, patients in the placebo arm most often switched because of lack of efficacy, whereas those in the various treatment arms had higher switching rates because of adverse effects. However, the drugs that patients were switched to and often continued had similar rates of adverse effects. This suggests that there are some medications that do show efficacy for some patients, and that for them, adverse effects were considered tolerable in light of efficacy. In addition, the primary outcome measure was time to discontinuation (including switching drugs), and clinicians knew that only the first phase of the trial included a placebo arm. Thus, in the first phase, the rate of switching drugs may have been higher than that of adjusting the dosage.

Results of studies suggest a differential pattern of response to antipsychotics. Schneider and colleagues

found a better global neuropsychiatric response in patients without psychosis, which suggests that atypical antipsychotics may be more efficacious in patients with agitation alone. Although some randomized controlled trials seemed to show a modest effect in treating aggressive behavior and agitation, others did not. The atypical antipsychotics that were reported to have some efficacy included risperidone, olanzapine, and aripiprazole.

Although the adverse-effect profile of older, conventional (typical) antipsychotics has discouraged many clinicians from using them, they remain widely used in elderly patients with dementia. However, when typical antipsychotics were compared with atypical antipsychotics in 4 randomized controlled trials, there was no evidence to suggest that conventional agents were better at treating psychotic or behavioral symptoms in Alzheimer disease.

 Three of these studies compared risperidone with haloperidol, and 1 study compared quetiapine with halo­peridol. While there is no proven advantage in efficacy for atypicals, conventional antipsychotics are well known to carry greater risk of extrapyramidal symptoms, such as tremor and rigidity, akathisia, and tardive dyskinesia, particularly in elderly populations.

Elderly patients are generally more sensitive to medication adverse effects, partly because of age-related changes in pharmacokinetics.

 Adverse events specifically related to the use of antipsychotic medications in elderly patients with dementia have come to light in recent years. Some of the most concerning adverse effects related to these medications are cerebrovascular events.

 The 2003 warning by the FDA referred to cerebrovascular adverse events (stroke, transient ischemic attack), some of which were fatal, in elderly patients with dementia-related psychosis and/or agitation in trials of risperidone. The manufacturer of risperidone added a warning to the prescribing information with respect to stroke risk in elderly patients with dementia. Similar warnings were later applied to the other atypical antipsychotics, and since 2005, the FDA has required a black box warning for all second-generation antipsychotic medications.

In a meta-analysis, pooled rates of cerebrovascular events were 1.9% in patients treated with atypical antipsychotics compared with 0.9% in patients who received placebo, and the risk of all-cause mortality was approximately 1.6 times greater in the treated patients.

 The first-generation (typical) antipsychotics seem to carry at least the same level of risk, and in 2008, the FDA required a similar warning for these medications.

The conundrum of treating patients with neuropsychiatric symptoms of Alzheimer disease remains: extreme­ly common symptoms, coupled with attendant morbidities, that lack an effective and safe treatment strategy.

Many clinical situations are not dangerous; therefore, with the idea of “first do no harm” in mind, before consideration of atypical antipsychotics, other interventions should be tried. First, potential organic etiologies of a patient’s behavioral problems should be ruled out. For example, untreated pain or urinary tract infections are common causes for changes in behavior. Nonpharmacological interventions, such as cognitive stimulation, as well as behavioral management paradigms, such as reassuring, repeating and redirecting, looking for antecedents to behaviors and seeing how they can be modulated, and breaking tasks into simpler parts or limiting choices, may all be very helpful. Other interventions that have been tried, although not rigorously studied, include modulation of room lighting and ambient noise levels, aromatherapy, music therapy, pet therapy, art therapy, and structured exercise programs.

Multiple classes of medications besides antipsychotics have been used to try to address the behavioral symptoms of dementia. Antidepressants, including SSRIs and trazo­done; anticonvulsants, such as gaba­pentin, lamotrigine, and valproic acid; and even the cholinesterase inhibitors and memantine have all been used with variable success.

 Although there is no real evidence to support which intervention will be most helpful for which patient, a rational approach that involves identifying target symptoms and closely monitoring for efficacy and adverse effects should be employed. In general, mild or infrequent symptoms that are predictable (eg, “sundowning”) or those that can be treated “prn” can often be managed with low-dose trazodone or gabapentin. Other, mild to moderate symptoms, particularly those with associated anxiety or depression, can be targeted with an initial trial of an SSRI.

If symptoms are severe, a trial of antipsychotic therapy is appropriate if other methods of treatment have been exhausted. The decision to use an antipsychotic is typically made when the anticipated benefit of such a trial outweighs the potential risks. This decision should always involve a discussion with the family or caregivers to assess the goals of care (eg, avoiding hospitalization or nursing home placement, managing severe aggression). It is important to have a sensitive and informed discussion with the family or caregivers, addressing the palliative nature of this intervention as well as the potential risks. Target symptoms should be identified, quantified (frequency and severity), and tracked, and the patient should be closely monitored for potential adverse effects (eg, with periodic ECGs to check the QT interval and with recommended metabolic tests).

With distressing symptoms so common, and treatments that are only modestly effective and yet potentially harmful, the conundrum of how best to help patients and families remains elusive.

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Articles

 Although the adverse-effect profile of older, conventional (typical) antipsychotics has discouraged many clinicians from using them, they remain widely used in elderly patients with dementia. 

Author | Judith A. Neugroschl, MD

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