The Case for Antipsychotics in Dementia with Lewy Bodies

Recurrent visual hallucinations are a core feature of dementia with Lewy bodies (DLB). While the spectrum of behavioral and psychological symptoms of dementia in DLB is broader than psychosis alone—also including anxiety, depression, apathy, and agitation—hallucinations and delusions (i.e., psychosis) are common in patients with DLB and are a key issue in living with the disease. Hallucinations were described in 76% and delusions in 57% of patients with DLB in 1 cross-sectional study. When comparing mild versus moderate-severe DLB (as determined by the severity of cognitive impairment), psychosis frequency increased from 50% to over 75%. Specifically, hallucinations increased from 30% to 70%, and delusions increased from 20% to over 50%. Other research shows that delusion and hallucination scores on the Neuropsychiatric Inventory are high in DLB regardless of dementia severity. Delusions are an important determinant of quality of life (QoL) in DLB as assessed by both patients and caregivers. Behavioral disturbances are associated with depression in DLB caregivers and are major contributors to caregiver distress and strain. Although research is lacking with regard to the determinants of institutionalization in DLB, Parkinson’s disease (PD) studies show that psychosis is the main risk factor for nursing home placement. The management of hallucinations and delusions in DLB is challenging, however. Antipsychotics have risks in patients with DLB. “Severe neuroleptic sensitivity” is a suggestive feature in DLB clinical diagnostic criteria, in part based on research showing that 81% of patients with DLB who received typical antipsychotics had adverse reactions, one-half of which were severe. Atypical antipsychotics received a black-box warning from the US Food and Drug Administration (FDA) in 2005 due to an increased risk of death in patients with dementia-related behavioral disturbances. This warning was extended to typical antipsychotics in 2008. Studies demonstrate an increased risk of death in patients with dementia who are treated with antipsychotics in both the short and long term. Recent evidence also shows an increased mortality risk in patients with PD who are treated with typical and atypical antipsychotics. Besides the obvious risk of worsened parkinsonism with antipsychotics, some studies suggest that antipsychotic use is associated with an increased rate of cognitive decline in dementia in both community settings and Alzheimer’s disease clinical trials. The benefits of antipsychotics in DLB are uncertain, but few alternatives exist. A meta-analysis of pharmacologic strategies for the closely related Lewy body dementias (LBDs) (i.e., both DLB and PD dementia [PDD]) found few studies of antipsychotic agents in these conditions. In the small studies cited, often with limited methodologic rigor, there was no evidence for efficacy and also a limited ability to exclude potentially beneficial effects. When considering PDD with psychosis, a Movement Disorder Society evidence-based medicine review concluded that clozapine was “efficacious” and had an acceptable risk with specialized monitoring; quetiapine was considered “investigational” given a lack of supporting evidence; and olanzapine was characterized as “unlikely efficacious” and as having “unacceptable risk” given clearly demonstrated worsening of motor function. In considering antipsychotic alternatives, a systematic review of 22 pharmacologic strategies for DLB found that only cholinesterase inhibitors (donepezil and rivastigmine) had high-level evidence for either cognitive or psychiatric symptoms in DLB, but evidence of benefit on neuropsychiatric symptoms was limited and included the possibility of no effect. Furthermore, 25% of patients with DLB and PDD who were receiving cholinesterase inhibitors withdrew from treatment trials, suggesting that substantial numbers of patients with DLB may not tolerate