Pharmacological Management Of Behavioral Disturbance in Dementia: Mood Stabilizers

27 Feb
2010

Mood Stabilizers

Anticonvulsant mood stabilizers such as valproic acid (divalproex [Abbott]) have long been used to treat BDD, especially in patients with agitation, aggression, mood lability, disinhibition, and manic-like symptoms. Studies of valproic acid have revealed a mixed picture.

Several studies have shown benefit, but a large placebo-controlled study of nursing-home patients did not. A meta-analysis of valproic acid in dementia suggested limited efficacy at low doses and problems with adverse effects at higher doses. Another review of the literature on revealed a conflicting picture of controlled trials; three studies showed some limited benefits, whereas another did not. Sink et al. concluded that the literature did not support the use of valproate.

(Canadian Tegretol, Novartis) showed modest but conflicting results in several studies, but concerns persist over its tolerability and side effects. Several reports have suggested some utility in managing symptoms of sexual aggressiveness.

Other anticonvulsant mood stabilizers have been used anec-dotally. Lithium has not been well studied in BDD, but it has generally been regarded as poorly tolerated in this population.

Antidepressants

Antidepressants have been used to treat depressive symptoms, anxiety, and agitation in dementia. Older studies showed benefits (Desyrel, Apothecon), especially for sleep. Several selective serotonin reuptake inhibitors (SSRIs), including sertraline (Zoloft, Pfizer) and citalopram (Celexa, Forest), have shown benefits in clinical trials. These drugs have shown some efficacy for depressive symptoms and anxiety and modest evidence of utility in agitation in some studies. In several small-scale studies, verbal aggression responded to citalopram.

Other antidepressants, including (Organon), have been widely utilized, although not thoroughly studied. Mirtazapine is sometimes used as a sleep or appetite aid. (Wyeth) as well as bupropion (Well-butrin, GlaxoSmithKline) and other newer antidepressants have also been used anecdotally, especially when a medication with an activating effect on behavior is needed. Tricyclic anti-depressants should be avoided, primarily because of their anticholinerg ic properties.

Benzodiazepines

Benzodiazepines have been widely prescribed to treat BDD despite admonitions against their use. Anxiety, agitation, and sleep disturbances in patients are common reasons for their use. These drugs may be given orally or by injection. Recent concerns about atypical antipsychotic drugs may have contributed to renewed interest in the benzodiazepines.

Objections to the use of benzodiazepines in elderly patients include concerns about sedation, ataxia, falls, cognitive clouding, dependency, and paradoxical excitation. Despite these potential effects, benzodiazepines in BDD have not been well studied. Long-acting benzodiazepines such as diazepam (Valium, Roche), chlordiazepoxide (Librium, ICN), and clon-azepam (Klonopin, Roche) have proved to be poorly tolerated in elderly patients. These drugs have been associated with increased confusion, falling, fractures, and accidents in this population, although a cause-and-effect relationship has not been clearly established. Generally, clinicians prefer the short-term use of shorter-acting drugs with few active metabolites, such as lorazepam (Ativan, Wyeth) or oxazepam (Serax, Fauld-ing). Benzodiazepines may occasionally prove useful in the treatment of catatonia, which can mimic or complicate dementin g disorders.

( Bristol-Myers Squibb), a non-benzodi-azepine anxiolytic agent, has also been used empirically for anxiety and agitation in patients with dementia. Unlike the benzodiazepines, buspirone is not sedating or habit-forming and it does not affect memory or motor function. In clinical practice, however, it seems to have limited efficacy for BDD.

Sleep Medications

Sleep problems are extremely common in dementia and are often chronic in nature. Typically, sleeping becomes more fragmented and less entrained to the usual circadian cycle as dementia progresses. Patients also frequently have sleep disorders such as sleep apnea and rapid-eye movement (REM) disorder. Comorbid medical conditions such as cardiovascular disease, pulmonary disorders, and arthritis may complicate sleep as well.

Unlike other forms of insomnia, neurodegeneration is the primary underlying cause of sleep disturbances in dementia. Therefore, data from medication studies of insomnia might not be applicable to dementia-related sleep deficits. In fact, even the definition of insomnia is problematic in dementia. Insomnia is typically viewed as a subjective complaint of a sleep deficit. The patient is unable to sleep despite a desire to do so. However, patients with dementia often do not perceive their sleep deficits as a problem, even though they can be a major source of distress for their caregivers.

Nonpharmacological management of sleep disturbance in dementia focuses on sleep hygiene. Maintaining a reasonable level of daytime activity and exercise is helpful. Exposure to bright light during daylight hours may also be useful. Caffeine and alcohol consumption can affect sleep as well. If patients with dementia are permitted to sleep during the day, they are less likely to sleep at night.

Few studies have specifically addressed the pharmacother-apy of sleep disorders in dementia. Nevertheless, medications are frequently prescribed for these disorders on an empirical basis. Sedating antidepressants (Desyrel) and mirtazapine (Remeron) are sometimes used. Sleep disturbances complicated by sundowning, psychosis, or agitation are often managed with atypical antipsychotic agents such as que-tiapine. Hypnotic medications such as zolpidem (Ambien, Sanofi-Synthelabo) are often prescribed.

Melatonin has been used anecdotally, and melatonin agonist agents such as ramelteon (Rozerem, Takeda) may prove useful, but they have not been systematically studied. Melatonin agonists are an appealing choice, because they are not believed to induce dependence or to affect motor function.

Conclusion

Because cure of BDD is not possible, its treatment should focus on maintaining and improving quality of life for patients as well as their caregivers and those around them. Environmental triggers should be identified, and nonpharmacological approaches should be considered before medication is prescribed. Frequently, these approaches are used alongside pharmacological approaches. The treatment flows from a careful assessment considering pre-existing psychiatric illnesses, current medications, and possible delirium or pain. The spectrum of symptoms needs to be identified, and the targets for treatment should be identified. Pharmacotherapy then focuses on managing these targets, with some objective means of outcome measurement used wherever possible.

The medications for Alzheimer’s disease, including cho-linesterase inhibitors and memantine, can be useful in reducing symptoms. Informed consent, usually from a surrogate, should be obtained, keeping in mind the lack of an FDA-approved indication for psychiatric drugs in BDD, the non-specificity of patient responses, and the concept of risk-benefit analysis.

The use of multiple psychiatric medications should be avoided whenever possible. Patients taking these medications require close monitoring and a high index of suspicion for adverse effects, which can have a negative impact on their qual­ity of life. As the dementing illness progresses, the medication requirements evolve over time. Avoidance of anticholinergic medications deserves special emphasis.

The atypical antipsychotic agents have become a special area of controversy because of their wide use as well as ongoing concerns about their limited efficacy, their association with mortality, and their side effects. Recent changes in labeling, including FDA-mandated boxed warnings, have heightened these concerns. Although these agents continue to be prescribed, a clear consensus on how to utilize them is lacking. However, many patients with BDD have serious behavioral problems that have not responded to other measures, and some individual patients have benefited from atypical agents.

Alternative treatments also have limited efficacy and have raised potential concerns about adverse effects. In this setting, it might be prudent to limit antipsychotic agents to patients who have not responded to other treatments or who have shown elements of significant physical aggression or combat-iveness. The presence of demonstrable psychotic symptoms seems to be a logical rationale for prescribing these medications, although clinical trials have yet to show convincing evidence of their utility.

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