Optimal treatment of Alzheimer’s disease psychosis: challenges and solutions

Abstract

Psychotic symptoms emerging in the context of neurodegeneration as a consequence of Alzheimer’s disease was recognized and documented by Alois Alzheimer himself in his description of the first reported case of the disease. Over a quarter of a century ago, in the context of attempting to develop prognostic markers of disease progression, psychosis was identified as an independent predictor of a more-rapid cognitive decline. This finding has been subsequently well replicated, rendering psychotic symptoms an important area of exploration in clinical history taking – above and beyond treatment necessity – as their presence has prognostic significance. Further, there is now a rapidly accreting body of research that suggests that psychosis in Alzheimer’s disease (AD+P) is a heritable disease subtype that enjoys neuropathological specificity and localization. There is now hope that the elucidation of the neurobiology of the syndrome will pave the way to translational research eventuating in new treatments. To date, however, the primary treatments employed in alleviating the suffering caused by AD+P are the atypical antipsychotics. These agents are approved by the US Food and Drug Administration for the treatment of schizophrenia, but they have only marginal efficacy in treating AD+P and are associated with troubling levels of morbidity and mortality. For clinical approaches to AD+P to be optimized, this syndrome must be disentangled from other primary psychotic disorders, and recent scientific advances must be translated into disease-specific therapeutic interventions. Here we provide a review of atypical antipsychotic efficacy in AD+P, followed by an overview of critical neurobiological observations that point towards a frontal, tau-mediated model of disease, and we suggest a new preclinical animal model for future translational research.

Association Between Psychosis in Elderly Patients With Alzheimer Disease and Impaired Social Cognition

“…Psychotic symptoms in Alzheimer disease are a common but not ubiquitous manifestation of the disease, occurring in 30% to 40% of individuals over the course of the illness. 1 The 92 recruited participants were followed an-nually for up to 6 years, and divided into cohorts depending on whether psychotic symptoms emerged. For analysis, the cohort was divided into 3 diagnostic groups: participants with MCI or Alzheimer disease at baseline who would not become psychotic during the study (n = 38), participants with MCI or Alzheimer disease at baseline who would become psychotic during the study (n = 18), and cognitively healthy elderly controls (n = 36).…”

“…Currently, the development of preclinical models of psychosis relies on a short list of behavioral paradigms with cross-species relevance, among them locomotor hyperactivity and disruption of sensorimotor gating. 1 Expanding this list to include social cognitive outcomes-paradigms that can be employed in murine models in the form of social learning and memory-may promote translational research and antipsychotic drug development. Affect subtasks scores differed over time across groups of HEC, patients with MCI or AD without psychosis, and patients with MCI or AD +P after adjustment for covariates (sex to age to group to education to MMSE and to time [number of annual assessments]).…”

Haloperidol inactivates AMPK and reduces tau phosphorylation in a tau mouse model of Alzheimer's disease

“…However, these data should be interpreted with some caution. A sapient critic of the notion of disease prevention with haloperidol in AD would note that haloperidol is widely prescribed for agitation and psychosis related to AD, a condition that affects nearly half of those suffering with disease, and there has been no suggestion of improvement in cognition as a consequence [69] , [70] . Studies of human disease are certainly required before concluding that haloperidol has any impact on pathology or cognition.…”

Agitation and Irritability in Alzheimer’s Disease: Evidenced-Based Treatments and the Black-Box Warning

“…Atypical antipsychotics are used to treat psychosis in AD, especially when associated with agitated or aggressive behavior. As noted above, however, these agents are not approved for this indication by the FDA and their use in this context is considered “off-label” [46]. …”