Antipsychotic drug sensitivity in Alzheimer’s disease due to blood-brain barrier breakdown with considerations for clinical prescribing: a narrative review

Alzheimer’s Disease (AD) is a neurodegenerative condition that affects cognitive function, memory and behaviour. Antipsychotics are used to manage psychosis and agitation in AD, through antagonism of dopamine (D2/3) receptors. However, AD patients exhibit an increased sensitivity to antipsychotics that is not shared with patients of other neuropsychiatric disorders. Importantly, older AD patients using antipsychotics show a clinical response and experience parkinsonian side effects at reduced doses with high D2/3 receptor occupancies and lower blood drug concentrations. Consequently, these patients have higher morbidity and mortality risks. A critical component in AD pathophysiology is the blood-brain barrier (BBB), a highly selective cellular monolayer separating blood from parenchyma. This narrative mini-review aims to explore current literature on the role of BBB dysfunction in altering antipsychotic drug sensitivity in AD and the clinical implications to prescribing. We investigate the relationship between BBB dysfunction in AD, involving tight junction protein loss and change in function and expression of transporters, and an increase in brain antipsychotic bioavailability and hypersensitivity. We note that regulatory agencies discourage antipsychotic drug usage in AD through black box warnings and recommendations of avoidance where possible, and only the lowest dose and shortest duration to be prescribed. We conclude that further BBB and receptor occupancy studies in elderly AD patients are essential to ensure a more tailored approach that integrates biomarkers of BBB integrity and drug sensitivity for optimal and targeted pharmacotherapy.