Antipsychotic drugs for psychosis and agitation in dementia: efficacy, safety, and a possible noradrenergic mechanism of action.

The first patient described by Alzheimer in 1907 had both progressive cognitive deterioration and prominent comorbid signs and symptoms of psychosis and agitation (Alzheimer, 1907, 1987). In this editorial, we use “psychosis” to denote delusions and hallucinations and “agitation” to denote irritability, aggression, pressured motor activity, and active resistance to necessary care. Although advances have been made in the treatment of these non-cognitive symptoms, these psychosis and agitation symptoms continued to be burdensome and costly for dementia patients, caregivers, and society. Among the pharmacologic treatments available for psychosis and agitation, antipsychotic drugs are the drug class most consistently demonstrated effective for psychosis and agitation in dementia (Lyketsos et al., 2006; APA Work Group on Alzheimer’s Disease and Other Dementias et al., 2007). These are widely prescribed for these behavioral problems, but their use remains controversial and their mechanism of action unclear. In this editorial, we attempt to discern from the clinical trial data which non-cognitive symptoms of dementia, if any, are therapeutically responsive to antipsychotics. We argue that despite the descriptor “antipsychotics,” (derived from their clear and substantial efficacy for the complex bizarre delusions and auditory hallucinations of psychosis in schizophrenia), the predominant effect of these drugs in dementia is to reduce agitation rather than psychosis. The most common psychosis symptoms in dementia are simple, memory impairmentinfluenced delusions (e.g., delusions of theft) and visual hallucinations. In contrast to agitation, these common psychosis symptoms in dementia are poorly responsive to antipsychotic drugs (Rabinowitz et al., 2007). We propose a model in which the therapeutic effect of antipsychotic drugs for agitation in dementia is a function of their alpha-1 adrenoreceptor (AR) antagonist activity rather than the dopamine receptor-2 antagonist activity, believed to explain efficacy for the psychosis symptoms of schizophrenia. Although a detailed review of the now large number of randomized controlled trials (RCTs) of antipsychotic drugs for psychosis and agitation in dementia is beyond the scope of this editorial, we will refer to representative studies. In the 1980s and early 1990s, several “conventional” antipsychotics were evaluated for “behavioral disturbance” in dementia patients. Loxapine, thioridazine, and thiothixene were modestly effective, but pseudoparkinsonism and excessive sedation often limited usefulness (Barnes et al., 1982; Petrie et al., 1982; Finkel et al., 1995). The subsequently introduced atypical antipsychotics with lower incidences of extrapyramidal adverse effects became widely prescribed for behavioral disturbance in dementia, particularly in long-term care facilities (Kamble et al., 2009). Because these drugs were still under patent protection, several pharmaceutical companies saw an opportunity to obtain Food and Drug Administration (FDA) approval for risperidone, olanzapine, quetiapine, and aripiprazole as effective treatments for “psychosis of dementia” (Katz et al., 1999; Street et al., 2000; De Deyn et al., 2004; 2005; Mintzer et al., 2006; Tariot et al., 2006; Katz et al., 2007; Mintzer et al., 2007; Zhong et al., 2007; Streim et al., 2008). For both regulatory and diagnostic reasons, psychosis of dementia was designated as the primary outcome measure in these large multicenter RCTs. Drug effects on agitation were also measured, but as secondary outcome measures. Disappointingly, these RCTs generally failed to demonstrate meaningful efficacy for psychosis of dementia, the primary outcome measure upon which the FDA approval depended. In contrast, these RCTs consistently demonstrated efficacy for agitation symptoms in dementia. However, the secondary outcome measure designation of “agitation” and the nonspecifity of agitation as a disorder entity worked against the FDA approval of atypical antipsychotics for agitation in dementia. Further support for efficacy of the atypical antipsychotic risperidone for psychosis and/or agitation in Alzheimer’s disease (AD) is provided by a placebo-controlled study of relapse rate after discontinuing risperidone in treatment responders (Devanand et al., 2012). Discontinuation of