Conventional antipsychotics have been approved in the 1950s mainly for the treatment of schizophrenia. Since then, these agents have been systematically used for the treatment of BPSD in spite of a substantial lack of scientific evidence supporting their use in dementia. Few trials investigating the efficacy of conventional agents for the treatment of BPSD have been conducted between the 1960s and the late 1980s [6
]. These studies mainly focused on the effect of haloperidol and thioridazine. They were characterized by small sample sizes and possible lack of power. Data from these early studies showed a modest advantage of conventional antipsychotics over placebo with a nearly 40% placebo response, and only 18% benefit over placebo in the meta-analysis by Schneider et al.
]. Also, according to some of these studies, the observed superiority of conventional antipsychotics over placebo would be limited to symptoms of aggression and it would be absent in other behavioural and psychotic symptoms [60
Atypical antipsychotics have been licensed in the 1990s and approved by The US Food and Drug Administration (FDA) exclusively for the treatment of schizophrenia. Rapidly after their introduction in clinical practice, these medications have become the new standard of care for BPSD due to their reported advantages over conventional agents, particularly with respect to extrapyramidal symptoms (EPS) and tardive diskinesia [19
]. Over the last decade, the off-label use of atypical antipsychotics in dementia has been promoted by clinical practice guidelines although the limited number of clinical trials suggesting the efficacy of these agents in dementia [2
]. In the late 1990s, atypical agents accounted for more than 80% of antipsychotic prescriptions in dementia [37
]. To date 22
randomized placebo-controlled trials have investigated the efficacy of atypical antipsychotics for the treatment of BPSD. Only eleven
of these studies have been published in full at the time of completion of this review (Table
). No data from double blind randomized
clinical trials on patients with dementia are available for amisulpride, clozapine, sertindole, ziprasidone or zotepine.
Published Randomized Clinical Trials of Atypical Antipsychotics among Patients with BPSD
Compared to placebo, risperidone has been shown to be beneficial on psychotic symptoms and aggression at doses of 1 mg and 2 mg per day in three placebo controlled clinical trials [13
]. These studies were conducted on patients with Alzheimer’s disease, vascular dementia or mixed dementia on a 12 weeks time-period.
Olanzapine has been shown significantly effective for improving behavioural symptoms, psychosis and aggression at 5 to 10 mg per day dose compared with placebo [22
]. This evidence derives from two randomized placebo-controlled clinical trials conducted among patients with dementia for a 10 week and 6 week period of time respectively [22
]. In contrast with these data, a recent study on patients with moderate to severe psychotic symptoms of dementia randomly assigned to receive a flexible dose of olanzapine (2.5-10.g per day), risperidone (0.5-2 mg per day) or placebo demonstrated similar improvement of BPSD in the three treatment groups with higher discontinuation rate due to adverse events in the olanzapine and risperidone groups [24
Very recently, a 10-week, double- blind, placebo-controlled study has shown that quetiapine at a fixed dose of 200 mg per day is effective and well tolerated for treating agitation in institutionalized patients with dementia [90
]. Also, one published study involving a small number of patients with dementia has demonstrated no effect of quetiapine or rivastigmine on improving clinically significant agitation and an increased cognitive decline associated with the use of quetiapine [4
]. Finally, a small double-blind, placebo-controlled, randomized study has shown no significant difference between quetiapine and placebo in terms of efficacy on controlling agitation and psychosis among patients with dementia and parkinsonism [53
]. In this study quetiapine was well tolerated and did not worse parkinsonism. As pointed out by the authors of this study, lack of power and a large placebo effect may have contributed to the resulted lack of efficacy.
A single double blind, randomized, placebo-controlled clinical trial has investigated the efficacy and safety of aripiprazole in patients with Alzheimer’s disease and psychosis [21
]. According to this 10-week study, aripiprazole at a mean dose of 10 mg per day appeared to confer no benefit over placebo for controlling delusions and hallucinations and it was well tolerated.
Very recently, the results of a large effectiveness trial, the CATIE-AD (Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer’s Disease), have been published. According to this multicenter, double-blind, placebo-con-trolled trial on outpatients with Alzheimer’s disease and psychosis, aggression or agitation, the effect of olanzapine (mean dose 5.5 mg per day) and risperidone (mean dose 1.0 mg per day) in treating neuropsychiatric symptoms was equally beneficial and superior to the effect of placebo and quetiapine (mean dose 56.5 mg per day) [76
]. However, these benefits were evident only among those patients who tolerated these medications and did not discontinue them due to side effects. Similar rates of treatment discontinuation were reported in the different study groups. However, patients on antipsychotics discontinued mostly because of adverse effects while patients on placebo discontinued mostly because of lack of efficacy. According to authors’ conclusions potential side effect associated with antipsychotic medications in dementia may outweigh possible benefits.
A comprehensive review of the available randomized, double blind, placebo-controlled trials has been conducted by Ballard and White for the Cochrane collaboration to determine the effectiveness of atypical antipsychotics for the treatment of psychiatric and behavioural symptoms in Alzheimer’s disease [5
]. The authors analyzed sixteen placebo-controlled trials among which only six studies were published in full in peer reviewed journals. According to the Cochrane authors, evidence suggests that both risperidone and olanzapine may reduce aggression and risperidone may also reduce psychosis compared to placebo. However, an increased risk of extrapyramidal symptoms and adverse cerebrovascular events associated with atypical antipsychotics would outweigh the modest effectiveness of these medications. According to Cochrane findings, due to the increased risk of adverse effects, the use of atypical antipsychotics in clinical practice would not be suitable and should be limited to those patients presenting with significant distress and risk associated with symptoms.