Antidopaminergic medications (ADMs; VMAT2 inhibitors and neuroleptics)  are commonly used for the management of Huntington’s Disease (HD). ADMs are associated with side effects that impact measures of cognition and function, and may lead to worse outcomes on measures of clinical progression of HD.

Causal analysis included participants (N = 1172) off-ADMs at baseline. The exposed group (n = 380) began ADM use during the two-year follow-up, while the unexposed group (n = 792) remained ADM-free. To control for 27 covariates, we applied a doubly-robust target maximum likelihood estimation in two analyses: one assessing ADM effects at two years for 12 outcome measures and another on dose-dependent impact by higher or lower ADM dosage.

Participants on ADMs had worsening measures of clinical outcome at 2 years for Total Functional Capacity (TFC), cUHDRS, cognitive measures (SWR, SDMT), bradykinesia scale, gait and balance, and hand movements. Similar results were observed for patients on VMAT2 inhibitors only or  neuroleptics only. Dose analysis showed higher doses of ADMs were associated with greater decline of cognitive measures  and cUHDRS. No reliable dose effect was found for TFC, TMS, or motor sub-scores.

ADM use was strongly associated with accelerated worsening of clinical measures of cognitive, function and cUHDRS. However, assumptions required to establish causation between ADM use and these measures were not fully met, and further research is warranted.