Antidopaminergic medications and clinical outcomes in Huntington disease

Anderson, Karen E., Tan, Andrew M., Feigin, Andrew, Reilmann, Ralf, Rosser, Anne E. ORCID: https://orcid.org/0000-0002-4716-4753, Raymond, Lynn A., Kostyk, Sandra K., Saft, Carsten, Chen, Kelly, Hand, Randal, Geva, Michal, Hayden, Michael R. and investigators, for the PROOF-HD study 2026. Antidopaminergic medications and clinical outcomes in Huntington disease. Neurology 107 (10) , e218627. 10.1212/wnl.0000000000218627

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Abstract

Background and Objectives Antidopaminergic medications (ADMs), including vesicular monoamine transporter-2 (VMAT2) inhibitors and antipsychotics, are widely used to manage motor and psychiatric symptoms in Huntington disease (HD). Observational evidence suggests that ADM use may be associated with accelerated worsening of clinical outcome measures used in HD trials, but this relationship has not been examined in a controlled trial setting. We assessed the association between ADM exposure and longitudinal clinical outcomes in the Pridopidine's Outcome On Function in Huntington Disease (PROOF-HD) placebo arm. Methods This post hoc analysis included placebo-arm participants from PROOF-HD (NCT04556656), a randomized controlled trial in adults with Total Functional Capacity (TFC) 7–13 and cytosine-adenine-guanine (CAG) ≥36. Participants were categorized as on-ADMs or off-ADMs based on concurrent medication use across the study period. Outcomes included TFC, composite Unified Huntington's Disease Rating Scale (cUHDRS), Symbol Digit Modalities Test (SDMT), Stroop Word Reading (SWR), and Total Motor Score (TMS). Primary analyses used mixed-effects models for repeated measures, corroborated by propensity score weighting (PSW) and time-varying sensitivity analyses. Results Of 247 placebo-arm participants (mean age 52.6 years [SD 11.4]; 51% female), 135 (54.7%) were on-ADMs and 112 (45.3%) were off-ADMs. On-ADM participants demonstrated faster clinical decline across multiple outcome measures. Between-group differences in cUHDRS and TFC favored off-ADMs from weeks 39–78; at week 52, the difference in mean change was 0.66 (95% CI 0.31–1.01; p = 0.0002) for cUHDRS and 0.85 (95% CI 0.47–1.22; p < 0.0001) for TFC as compared with on-ADMs. Significant or directionally consistent findings for SDMT, SWR, and TMS emerged from week 39 onward. All TMS subdomain scores, except chorea, directionally favored off-ADMs at all visits. Antipsychotic-only, VMAT2 inhibitor–only, and higher-dose ADMs were each associated with greater clinical decline in cUHDRS and TFC as compared with off-ADMs. PSW-adjusted and time-varying analyses were directionally consistent with primary findings.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Schools > Biosciences
Publisher:	American Academy of Neurology
ISSN:	0028-3878
Date of First Compliant Deposit:	29 October 2026
Date of Acceptance:	27 July 2026
Last Modified:	29 Oct 2026 14:00
URI:	https://orca.cardiff.ac.uk/id/eprint/190525

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