The best studied medications for the treatment of behavioural and psychological symptoms of dementia are the antipsychotics, which may, in part, account for the fact that they are among the most frequently used medications for control of most types of behavioural and psychological symptoms of dementia including psychosis, aggression and agitation. Antipsychotics have preferentially been recommended as first-line pharmacotherapy for behavioural and psychological symptoms of dementia by various reviews and guidelines. The symptoms which are most likely to respond to antipsychotics include delusions, hallucinations, aggression, agitation and sleep disturbance.
The largest number of published randomized controlled trials compare typical antipsychotics (e.g. haloperidol) with placebo. Seventeen randomized controlled trials enrolled approximately 500 patients treated with typical antipsychotics and 235 controls treated with placebo. Meta-analyses of these trials suggest a response rate >60 per cent for the antipsychotic with a significant therapeutic effect of 18-26 per cent compared to placebo. While these meta-analyses suggest the efficacy rate is approximately equivalent to the side effect rate, patients with dementia are at significant risk of developing parkinsonism and tardive dyskinesia, even when treated with low doses of typical antipsychotics. There is also some evidence that typical antipsychotics may increase the rate of cognitive decline in patients with Alzheimer’s disease and hasten mortality in patients with dementia with Lewy Bodies.
While there are fewer published trials of the atypical antipsychotics, over 2000 patients were included in the seven randomized controlled trials of risperidone, olanzapine and quetiapine. The studies of risperidone and olanzapine demonstrated efficacy greater than placebo. There was some evidence for a dose-response effect, and two studies which utilized an active haloperidol-treated arm suggested equal efficacy with less tendency to cause extrapyramidal symptoms (EPS). In the only published quetiapine RCT, quetiapine, up to 100 mg/day, was no more effective than placebo and was associated with worsening of cognition. The lack of efficacy may have been due to the low dose of quetiapine as unpublished data suggest that only doses of approximately 200 mg per day are associated with efficacy greater than placebo.
After reviewing data from published and unpublished behavioural and psychological symptoms of dementia RCTs, health regulatory agencies have recently raised concerns about serious adverse events including cerebrovascular adverse events (CVAEs) and death. For example, in 11 randomized controlled trials of olanzapine and risperidone (five published, six unpublished), 48 of 2187 (2.2 per cent) drug-treated patients experienced CVAEs compared with 10 of 1190 (0.8 per cent) placebo-treated patients for a relative risk of 2.7 (95 per cent CI, 1.4-5.3). The FDA (Food and Drug Administration of the USA) recently warned that analyses of 17 placebo-controlled trials of olanzapine, aripiprazole, risperidone and quetiapine with 5106 dementia patients with behavioural and psychological symptoms of dementia suggested a 4.5 per cent mortality rate in drug-treated patients compared with 2.6 per cent of placebo-treated patients. The publication of these warnings must be concerns for clinicians from two perspectives: (1) Are these drugs truly safe? (2) How can clinicians be assured of their efficacy given that the majority of the studies reviewed by the FDA have not been published? The latter is a question that plagues evidence-based practitioners of all aspects of medicine. The question would probably equally apply to non-pharmacological interventions as there is no reason to assume there is not an equal proportion of unpublished studies of these modalities. Clinical trial registration and access to study data submitted for drug registration, available to all researchers and clinicians, would significantly advance the cause of evidence-based medicine.
With respect to the safety of antipsychotics for behavioural and psychological symptoms of dementia, the increased incidence of CVAEs appears to be accounted for by non-specific vascular events rather than completed strokes. For example, in a review of the risperidone trials, while the percentage of patients with any CVAEs was statistically greater in risperidone-treated patients compared with placebo, there were no significant differences in the rates of serious CVAEs (defined as death, life threatening, requiring hospitalization, leading to persistent disability, etc.). Furthermore, large observational administrative health database studies also suggest no differences in the rates of hospitalization for strokes when comparing olanzapine to risperidone and typical antipsychotics. Because many patients in the randomized controlled trials had numerous treated and untreated vascular risk factors, clinical recommendations might include avoiding the use of atypicals in Alzheimer’s disease patients with vascular risk factors. While this recommendation appears reasonable, data from a study of over 32 000 elderly dementia patients treated with either typical or atypical antipsychotics suggested no differences in the risk of stroke associated with either class of drugs when analysed for other stroke risk factors such as history of previous stroke and atrial fibrillation.
Similar data from randomized controlled trials led health regulatory agencies to issue warnings about increased mortality in atypical AP-treated dementia patients compared to placebo. In a meta-analysis of 15 published and unpublished behavioural and psychological symptoms of dementia trials, 118/3353 (3.5 per cent) atypical AP-treated patients died compared with 40/1757 (2.3 per cent) placebo-treated patients. There was no evidence that risk varied by drug, severity or diagnosis. In two studies that included haloperidol arms, a similar increased magnitude of risk was noted. These results conflict with four observational studies which suggested there was no increased risk of mortality compared with untreated patients or patients treated with typical antipsychotics.
In summary, as a class, the antipsychotics are the best studied of any intervention for behavioural and psychological symptoms of dementia with numerous, relatively small, high quality studies of the typical antipsychotics, and a smaller number of high quality randomized controlled trials of atypical agents with much larger sample sizes supporting their efficacy. Use of typical antipsychotics is plagued by concerns about the tendency to cause extrapyramidal symptoms (both acute extrapyramidal symptoms and tardive dyskinesia), while use of atypical antipsychotics appears to increase the risk of CVAEs and mortality. Given that emerging data suggest no differences between typical and atypical antipsychotics with respect to stroke risk and increased mortality, there is no rationale for clinicians to return to the use of typical antipsychotics. If pharmacological management in behavioural and psychological symptoms of dementia is required, use of atypicals would still appear to be the most reasonable first-line pharmacological intervention for psychosis, agitation and aggression, especially when patient and caregiver safety are concerns. Full disclosure of the relative risks and benefits with substitute decision-makers is clearly essential.