Behavioral and psychological symptoms of dementia (BPSD) frequently arise in people with Alzheimer's disease (AD) and other dementias. They cause significant distress and confer risk to the person and others, in addition to presenting a complex clinical challenge for treatment (Ballard et al., 2009b). There is good evidence for the value of first-line management strategies such as psychological interventions and treatment of concurrent medical conditions, particularly pain, which are known to be effective (Ballard et al., 2009b). However, there are limited pharmacological treatment options for severe aggression, which causes significant risk, and for other severe BPSD which do not respond to first-line approaches. The only pharmacological intervention with an adequate evidence base is the prescription of atypical antipsychotics, where 18 placebo-controlled trials have evaluated the effect of treatment over 6–12 weeks. The literature indicates modest but significant benefits in the treatment of aggression and psychosis with risperidone and aripiprazole (Cohen's d standardized effect size of 0.2), uncertain benefits with olanzapine, and no benefits with quetiapine (Ballard and Howard, 2006; Schneider et al., 2006a; Ballard et al., 2009b; Corbett et al., 2012). Unfortunately, the benefits of longer term prescribing are more limited (Schneider et al., 2006b; Ballard et al., 2008) and there have been increasing concerns regarding the potential for serious adverse outcomes, including accelerated cognitive decline, stroke, and death (Schneider et al., 2006b; Ballard et al., 2009a). There is therefore an urgent imperative to identify more effective pharmacological treatments for severe BPSD which have a better safety profile, particularly for long-term treatment and prophylaxis. Despite this urgency, there has been very little effort toward developing or evaluating potential novel therapies for the treatment of key symptoms such as aggression, psychosis, restlessness, and apathy.
