Advancing therapeutic approaches for agitation: A neurorelational perspective

Agitation is a common, distressing, and difficult-to-treat symptom in dementia, linked to emotional dysregulation and interpersonal stress. Degenerative and compensatory changes in the locus coeruleus-noradrenergic (LC-NA) system have been implicated in agitation in Alzheimer's disease. However, substantial interindividual variability in the emergence of agitation over the course of dementia suggests that neuropathological changes alone are unlikely to fully account for individual differences in susceptibility to agitation. We explore how mentalizing capacity (the ability to understand one's own and others' thoughts, feelings, beliefs, and intentions) in both care recipients and caregivers may influence agitation propensity. Mentalizing supports adaptive emotion regulation and may underpin person-centered care, but becomes less effective under conditions of heightened arousal and interpersonal stress. It is proposed that LC-NA regulation of arousal may influence the capacity to sustain mentalizing under stress, potentially contributing to agitation and increasing the likelihood of escalation of care. Notably, mentalizing may be compromised by different processes in care recipients and caregivers. In care recipients, neurodegeneration may impair mentalizing, potentially in part through dysregulation of the LC-NA system. In caregivers, distress, burden, and emotionally challenging interactions may undermine the capacity to maintain mentalizing. As disease progression is likely to increasingly constrain mentalizing capacity in care recipients, we consider pharmacological modulation of care recipients' LC-NA function and psychosocial interventions to strengthen caregiver mentalizing as complementary and potentially modifiable targets for intervention. This conceptualization is best understood within a relationship-centered care perspective, which extends beyond person-centered care by emphasizing care as embedded in the dynamic relationships between caregivers and care recipients, rather than focusing solely on individual patient preferences. Taken together, these considerations inform a neurorelational framework for understanding and addressing agitation, integrating neurobiological and socio-emotional perspectives to provide a basis for personalized intervention approaches to potentially mitigate the effects of neurodegeneration on "neuropsychiatric reserve."