March/April 2009

Alzheimer’s Disease Behavioral Concerns
By Marty L. Eng, PharmD, CGP, FASCP
Aging Well
Vol. 2 No. 2

There are no FDA-approved medications for the treatment of behavioral and psychological symptoms of dementia (BPSD). Yet, there are guidelines and strict regulations in place in long-term care institutions providing a framework for their use in the management of BPSD. Extensive literature supports a modest benefit with potentially serious adverse events. Detailed assessment, conservative dosing, and vigilant monitoring with periodic dose reductions are the keys to optimal BPSD treatment.

It’s not unusual to hear dire pleading for help from older adults in long-term care facilities. How do you or your team typically manage this type of behavior? This scenario may be considered a subtype of agitation labeled verbal nonaggression. Symptoms are often differentiated clinically into psychosis, mood disorders, or agitation. However, they may coexist, and differentiation may be challenging in practice. Providing education to staff and learning a common language to describe individual BPSD or symptom clusters may greatly facilitate team interventions for achieving treatment goals.

Although pharmacologic treatments used for managing BPSD involve potential benefits and risks, the use of pharmacologic interventions presupposes that a thorough assessment has identified possible antecedents such as pain, acute illness, urinary tract infections, and hunger and that nonpharmacologic interventions have failed to meet treatment goals.

The definition of the treatment target is critical for optimal treatment and follow-up. However, because of the heterogeneity of BPSD, defining a treatment target is usually based on clinical phenotype—psychosis, mood disorder, or agitation. If it looks like depression, treat depression if no other underlying cause is determined. It’s important to document in detail the actual symptom being treated to enable adequate team follow-up. In most cases, pharmacologic therapies should not be long term.

Potential Benefits of Atypical Antipsychotics
BPSD have been associated with significant negative outcomes. However, clinical trials have focused more on resolving symptoms. This makes the interpretation of benefits difficult because while one symptom may resolve, a separate symptom may arise, and thus, the change in score may not adequately reflect the magnitude of potential efficacy.

There is much controversy and conflicting information regarding the off-label (non–FDA-approved) use of antipsychotics, antidepressants, anxiolytics, and antiepileptic agents. Consider a scenario in which an older adult female complains of seeing men in her room. Assuming that nonpharmacologic interventions have failed and no antecedent was identified to trigger this behavior, what pharmacologic treatment would be acceptable?

Guidelines suggest that atypical antipsychotics such as risperidone, olanzapine, quetiapine, and aripiprazole may be reasonable for psychosis such as hallucinations and delusions, provided there are no contraindications present in the patient. Remember that some serious risks accompany these medications. In the example, a thorough assessment by the director of nursing attempts to determine whether this was a hallucination or a delusion. In fact, the resident saw what she thought was a man but was actually a shadow cast through the window by the cleaners. The director of nursing promptly rearranged the window treatments, and the hallucinations ceased. The situation required no pharmacologic therapy.

Despite numerous studies, there is considerable disagreement in the interpretation of the results. One reason is that earlier clinical trials included mixed populations with a variety of BPSD. Sometimes symptoms may resolve and others may arise. This makes the translation of neuropsychological scores into clinically important terms difficult. More recent trials have sought to focus primarily on agitation and aggression. However, in practice, there is a wide variety of symptoms included under agitation. This underscores the importance of using common terms to target and monitor treatment accurately.
Studies suggest that the mitigation rather than the elimination of symptoms may be the realistic treatment target (i.e., reduction in frequency and severity but not complete elimination). Pharmacologic intervention is consistently described as moderate at best, and many guidelines suggest that nonpharmacologic interventions should be continued even if pharmacologic intervention is deemed necessary.

It’s unclear whether differences in setting account for differences in benefit. For example, in many of the studies, nursing homes trained the nursing staff in dementia care. Based on methodology descriptions, it’s unclear whether the training of caregivers in the community was comparable with that of nursing staff. Presumably, better training of caregivers may result in higher placebo responses and lower treatment effect differences.

Among the atypical antipsychotics, risperidone has been the most studied, and olanzapine is comparable to risperidone. There is considerable controversy about quetiapine, though. The minimum effective dose is not known, and target doses in clinical trials are often not achieved in practice due to dose-limiting side effects. Two studies of aripiprazole resulted in different findings, necessitating additional study. Ziprasidone has not been studied in this population. A recent study compares risperidone, olanzapine, quetiapine, and placebo or (in the second phase) citalopram. Results indicate that tolerability often limits the effectiveness of these agents.

Risks of Atypical Antipsychotics
Among the side effects of atypical antipsychotics are sedation, extrapyramidal symptoms (EPS), orthostatic hypotension, and weight gain. Most of these are dose related. However, EPS may also be duration related. In fact, nursing homes usually monitor psychotropic use with the Abnormal Involuntary Movement Scale every three months to screen for this potential adverse effect. EPS may take anywhere from a few months to more than one year to resolve after discontinuing the antipsychotic. Olanzapine seems to carry the highest risk for metabolic disturbances such as hyperglycemia. It can also be sedating at doses greater than 10 milligrams per day.

Risperidone is perhaps the most used, in part because it has been around longer. Risperidone may be less sedating than olanzapine and quetiapine but carries a slightly higher risk of EPS and stroke. While nursing home regulations allow for up to 2 milligrams per day, it is rare to see an older adult receive 1 milligram per day without side effects.

Quetiapine is virtually devoid of EPS risk until doses approach more than 200 milligrams per day. The usual dose-limiting side effects are sedation and orthostatic hypotension. The side effect profile in this population with aripiprazole and ziprasidone is not known. To date, most studies suggest that conventional and atypical antipsychotics are equivocal in efficacy but that conventional antipsychotics are less tolerable and have significantly higher EPS risk.

Potential Benefits and Risks of Antidepressants
Selective serotonin reuptake inhibitors (SSRIs) have been studied in the treatment of depression and BPSD. SSRIs are the treatment of choice for depression and anxiety in older adult patients with or without Alzheimer’s disease. However, current evidence supporting possible benefits in treating mild BPSD is conflicting. SSRIs that have been studied for BPSD include fluoxetine, citalopram, and sertraline.

There is little clinical difference among SSRIs. Treatment choice is based largely on tolerability, potential drug interactions, and cost. Paroxetine can elevate the levels or effects of medications metabolized through this pathway such as atomoxetine, tamoxifen, tricyclic antidepressants, dextromethorphan, tramadol, and duloxetine. Management of these potential drug interactions involves monitoring and lowering doses or choosing an alternate SSRI. In addition, paroxetine also has mild anticholinergic activity. The clinical implication is that it has the potential to worsen cognition although this is not consistently seen clinically.

Sertraline is primarily serotonergic in pharmacology but has mild norepinephrine and dopaminergic antiagonist activity. Sertraline may increase the effects of warfarin. Potential adverse effects are usually gastrointestinal.

Because of the potential for cognitive adverse effects with fluoxetine, risks may outweigh the potential benefits when other alternatives are available. In fact, fluoxetine appears on the list of potentially inappropriate medications for older adults.

Potential Benefits and Risks of Benzodiazepines
For acute episodes, benzodiazepines may provide quick benefits, but their use should be limited to severe acute episodes. They may be overlapped with the titration of another agent such as an SSRI or atypical antipsychotic, with the ultimate goal of discontinuing the benzodiazepine. As a principle, short-intermediate acting benzodiazepines that undergo phase 2 metabolism, such as lorazepam, oxazepam, or temazepam, are considered preferable in older adults. This is because benzodiazepines that undergo phase 1 reactions have less interindividual predictability with aging and their much longer half life leads to risk of accumulation.

Monitoring Considerations
The documentation of symptoms is critical to optimal BPSD treatment. The resolution of symptoms should occur within the first two weeks of treatment. Dose-related adverse effects may occur at the beginning of treatment and at dose titration. Other adverse effects such as EPS may occur at any time within three months and with longer duration of treatment.

In the nursing home environment, regulations require frequent documentation of pharmacologic treatment effects and monitoring of adverse effects in an ongoing manner. Because of the narrow risk/benefit ratio and the potential for serious adverse effects, vigilance is critical in optimizing pharmacologic treatment: Use the lowest effective dose for the shortest effective duration.