Neuroleptics for Behavioral Symptoms of Dementia

CLINICAL QUESTION: What is the efficacy and tolerability of risperidone for treating elderly demented patients with aggression and other behavioral symptoms?

BACKGROUND: Aggression and other behavioral symptoms of dementia are significant predictors of caregiver burden and may underlie the decision to institutionalize demented patients. Conventional neuroleptics are often used to manage disruptive behaviors. Adverse drug effects, however, such as movement disorders, extrapyramidal symptoms (EPS), anticholinergic effects, and drug-drug interactions limit their usefulness. Atypical antipsychotics such as risperidone may offer added benefit in elderly patients with dementia.

POPULATION STUDIED: The study recruited 371 nursing home patients from 51 centers in 8 countries. All had been given a diagnosis of primary degenerative dementia of the Alzheimer’s type, vascular dementia, or mixed dementia. Ages ranged from 56 to 97 years; 99% were white; and 56% were women. The median duration of institutionalization was 4 months. According to standardized measures, these patients had cognitive and functional deficits severe enough to affect basic daily activities. Mean Mini-Mental State Examination (MMSE) scores were 7.9 to 8.8.

STUDY DESIGN AND VALIDITY: Following a 1-week single-blind washout phase during which all psychotropic medications were discontinued, 344 patients were randomized to double-blind treatment with risperidone, haloperidol, or placebo. The study groups were comparable at baseline. The 12-week treatment period started with 0.25 mg (1 mg/mL oral solution) per day of risperidone or haloperidol. The dose was increased by 0.25 mg every 4 days up to a maximum of 2 mg twice daily. Efficacy was judged using several established behavioral assessment tools. Assessment of tolerability included evaluation for EPS, the level of sedation, Functional Assessment Staging, MMSE score, and the incidence of adverse drug effects. Outcomes were analyzed both by intention to treat (end point data) and observed case analysis that included only the 223 patients who continued treatment for 12 weeks (week 12 data). Of note, supplemental lorazepam was allowed in the first 4 weeks of the study, but concomitant use of antipsychotics, antidepressants, lithium, carbamazepine, and valproic acid was not otherwise permitted. This study was funded in part by Janssen Pharmaceuticals, maker of Risperdal (risperidone).

OUTCOMES MEASURED: The primary outcome was clinically significant improvement of disturbing behavior defined as a 30% or greater change on the Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) total score. Many secondary outcomes were reported regarding the efficacy of risperidone compared with placebo and its tolerability compared with both placebo and haloperidol.

RESULTS: The percentage of patients with clinical improvement (30% improvement in BEHAVE-AD total score) in the risperidone, haloperidol, and placebo groups was 54%, 63%, and 47% respectively by intention-to-treat analysis. This difference was not statistically significant (P = .25 with 80% power to detect a difference of 20%). The high placebo response may explain the poor effect overall of active treatment.¹ Non-intention-to-treat analysis and secondary measures of behavior, particularly those assessing aggression, showed a statistically significant benefit of risperidone over placebo. This study was not intended to compare the efficacy of risperidone with that of haloperidol although a post hoc analysis was reported. In terms of tolerability, the severity of EPS was significantly greater with haloperidol than risperidone. There was no significant difference in the occurrence of serious adverse events. Dropout rates for the risperidone, haloperidol, and placebo groups were high (41%, 30%, and 35%, respectively). The most common reasons cited for discontinuation were adverse events (50.4%) and lack of efficacy (43.8%). The mean dose of medication was approximately 1 mg per day in both active groups.