Antidopaminergic medications in Huntington's disease

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder marked by motor, cognitive, and behavioral impairments. Antidopaminergic medications (ADMs), such as VMAT2 inhibitors and antipsychotics, are commonly used to manage HD motor disturbances and behavioral disorders. For patients and caregivers, ADMs are an important tool for managing symptoms that negatively affect daily life. However, the impact of ADM use in HD is not firmly understood due to a lack of robust, systematic studies that assessed their overall effect on HD disease. A mounting body of evidence suggests these medications may be associated with worse clinical measures of cognitive function and functional impairment. While regulatory guidelines highlight adverse effects like sedation, cognitive dysfunction, and extrapyramidal symptoms, it is unclear whether ADMs directly impact disease progression or if the side effects mimic or exacerbate measures of HD symptoms in clinical trials. Given ADM effects on the central nervous system and biological uncertainty within HD outcomes, clinical trial designs should recognize the impact of ADMs on key outcomes, as measured by acceptable scales including Total Functional Capacity, Stoop Word Reading, Symbol Digit Modality Test, and the composite Unified Huntington's Disease Rating Scale. The development of novel HD interventions requires consideration of concomitant ADM use that may influence measures of disease presentation. In this review, we highlight the role of ADMs in HD management, their symptomatic benefits and potential risks, especially with high dose associated side effects, interactions with CYP2D6 inhibitors, and the individualized need for careful dose monitoring for clinical care and trial design.