January 2008

Treating Behavioral Problems in Dementia
No drug is clearly efficacious for behavioral problems in dementia, and all are associated with significant risks.

Prolactin Elevation and Antipsychotics
Risperidone (Risperdal) seems to increase prolactin more than conventional and other second-generation antipsychotics; adjunctive aripiprazole (Abilify) may lower antipsychotic-induced hyperprolactinemia.

In Brief
Atomoxetine Effective for ADHD in Preschool Children; Excessive Body Weight Increases Risk of Dementia

Treating Adolescent Mania
Olanzapine (Zyprexa) effectively treats adolescent bipolar disorder but appears to cause harmful medical consequences in young patients.

Isotretinoin and Depression
Depression is a possible side effect of treatment with isotretinoin (Accutane and others).

Treating Behavioral Problems in Dementia

January 2008

Cognitive defects are the signature dysfunctions of Alzheimer's and other dementias. But the greatest burden on caregivers comes from behavioral problems, such as agitation and aggression (BTP 2007;30:1). Howard and associates report on a 12-week trial of the cholinesterase inhibitor donepezil (Aricept) to treat clinically significant agitation in patients with Alzheimer's disease.1

Two hundred seventy-two subjects who did not respond to a brief psychosocial program were assigned at random to take either donepezil, 5 mg/day for 4 weeks followed by 10 mg/day for another 8 weeks, or placebo. No statistically significant differences were observed between donepezil and placebo on an inventory of agitation symptoms nor on any other secondary behavioral or caregiver distress measures. Cognitive scores were slightly better in patients who took donepezil.

In an accompanying editorial, Yaffe tempers these negative conclusions, observing that patients in this trial may have been more difficult to treat than the global population of Alzheimer's patients.2 For example, Howard et al only included subjects who had failed to respond to a psychosocial program, and they excluded those recently treated with an antipsychotic or a cholinesterase inhibitor.

Yaffe notes that the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) data found only modest benefits from second-generation antipsychotics in patients with Alzheimer's disease, which were proportionally offset by adverse effects (BTP 2007;30:43-44, 2005;28:47-48).3-4 She also points out warnings from the US Food and Drug Administration that the use of antipsychotics in this population can cause premature death (BTP 2006;29:5, 2005;28:25-26).

In a separate study, Kales and colleagues compared 12-month mortality rates in patients aged 65 years and older who were treated with antipsychotic medications following a diagnosis of dementia versus those who received treatment with other psychiatric medications.5 All groups taking antipsychotics had significantly higher mortality rates (22.6% to 29.1%) than patients taking non-antipsychotic medications (14.6%). And in another analysis from the CATIE-AD trial, Rosenheck et al found that second-generation antipsychotics actually made health care costs higher than placebo when used to treat aggression and agitation in Alzheimer's patients.6

In addition to the recent American College of Neuropsychopharmacology (ACNP) task force report (BTP 2007;30:39-40),7 other good-practice guidelines similarly call for assessment and nonpharmacological intervention as the first steps to address difficult behavior in patients with dementia. Among the latter are music therapy and aromatherapy, along with caregiver education and training.

A reminder of one risk from cholinesterase inhibitors comes in a case report in the British Medical Journal. Leitch and coauthors write of a 76-year-old woman who had two recent syncopal episodes.8 She had a history of depression and Alzheimer's disease but no previous cardiac problems. The patient was taking donepezil, 10 mg/day; escitalopram (Lexapro), 10 mg/day; and propranolol (Inderal and others), 80 mg/day; as well as omeprazole (Prilosec and others), 20 mg/day, for gastroesophageal reflux. On physical examination, she showed mild hypertension, sinus bradycardia, and paroxysmal ventricular tachycardia (torsades de pointes), with a prolonged QT interval. Her cardiac arrhythmia was treated; donepezil, escitalopram, and propranolol were discontinued; and her electrocardiogram (ECG) normalized. The patient's depression was then treated with mirtazapine (Remeron and others).

Elderly patients are at increased risk of QT prolongation, which can potentially be lethal (BTP 2007;30:49), and they typically take multiple drugs, which can interact with one another. This elderly woman was taking several medications which, singly and particularly in combination, can prolong the QT interval: a cholinesterase inhibitor, escitalopram, and propranolol. In addition, escitalopram can increase donepezil blood levels, while escitalopram's metabolism can be inhibited by omeprazole. When such combinations are employed, periodic ECG monitoring is worthwhile.

The problem of behavioral difficulties in patients with dementia is profound, and the number of such patients is expanding rapidly. There are no simple and easy solutions for this problem, given today's medical knowledge. Diagnostic assessment and nonbiological interventions are wise first steps. As of now, no drug is clearly indicated for this problem, and all are fraught with perils. While we await better treatments, clinicians should carefully balance risks and benefits, discuss them with caregivers and document the discussion, individualize treatment decisions, and monitor vital functions, such as the ECG, as needed.

1Howard RJ, Juszczak E, Ballard CG, Bentham P, Brown RG, Bullock R, Burns AS, Holmes C, Jacoby R, Johnson T, Knapp M, Lindesay J, O'Brien JT, Wilcock G, Katona C, Jones RW, DeCesare J, Rodger M, for theCALM-AD Trial Group: Donepezil for the treatment of agitation in Alzheimer's disease. N Engl J Med 2007;357:1382-1392.

2Yaffe K: Treatment of neuropsychiatric symptoms in patients with dementia. N Engl J Med 2007;357:1441-1443.

3Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223.

4McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK, CATIE Investigators: Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry 2006;163:600-610.

5Kales HC, Valenstein M, Kim HM, McCarthy JF, Ganoczy D, Cunningham F, Blow FC: Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am J Psychiatry 2007;164:1568-1576.

6Rosenheck RA, Leslie DL, Sindelar JL, Miller EA, Tariot PN, Dagerman KS, Davis SM, Lebowitz BD, Rabins P, Hsiao JK, Lieberman JA, Schneider LS; Clinical Antipsychotic Trial of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) investigators: Cost-benefit analysis of second-generation antipsychotics and placebo in a randomized trial of the treatment of psychosis and aggression in Alzheimer disease. Arch Gen Psychiatry 2007;64:1259-1268.

7Jeste DV, Blazer D, Casey D, Meeks T, Salzman C, Schneider L, Tariot P, Yaffe K: ACNP white paper: Update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology, in press.

8Leitch A, McGinness P, Wallbridge D: Calculate the QT interval in patients taking drugs for dementia. BMJ 2007;335:557.