Vasopressin 1a Receptor Antagonists for Pathological Aggression in Neurodegenerative and Other CNS Diseases

Background: Neurodegenerative diseases are a major health problem, and the neuropsychiatric symptoms seen in these diseases adversely impact the lives of patients, families, and caregivers. Inappropriate aggressive behavior is a highly disruptive symptom and a leading cause of institutionalization. There are no approved drugs specifically for the treatment of problematic aggression, and the off-label use of antipsychotics has limited benefit with significant side effects and safety risks. This review discusses dysregulated arginine vasopressin (AVP) signaling in fear-threat circuitry as a key driver of inappropriate aggression. Because the AVP 1a receptor (V1aR) is the dominant subtype in the CNS, the selective antagonism of this receptor represents a well-rationalized target for the treatment of aggression across neurodegenerative, psychiatric, and neurodevelopmental disorders. Objectives: Our goal was to summarize the basis for using V1aR antagonists as a treatment for irritability and aggressive behavior. We describe its discovery, biosynthesis, receptor pharmacology, and CNS distribution, emphasizing V1aR localization in central fear-threat circuits. Translational evidence from animal studies, pharmacological neuroimaging, and lesion network mapping is presented. These data support the suggestion that heightened vasopressinergic tone biases socioemotional information processing toward negative valence, increasing threat sensitivity and the likelihood of inappropriate aggressive responses. Emerging clinical data support this framework. Highly selective, CNS-penetrant V1aR antagonists reduced aggressive behavior and had an excellent safety profile in phase 2 studies in Huntington's disease and intermittent explosive disorder, with efficacy signals across caregiver-reported, clinician-rated, and incident-based measures. Furthermore, pharmacological neuroimaging showed that V1aR antagonism normalizes AVP-induced alterations in activity within fear-threat circuitry. Conclusions and Future Directions: Preclinical, translational, and clinical findings to date support V1aR antagonism as a promising strategy for treating pathological aggression across disorders. Additional experimental medicine studies and clinical trials are needed to conclusively establish efficacy in various disease populations, and we note the need for improved trial designs and analytical methods as part of the development process.