Year: 2026
Type: article
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: < 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. DISCUSSION: In this study of the PROOF-HD placebo arm, ADM use was associated with greater worsening across global, functional, cognitive, and motor outcome measures as compared with off-ADM participants. Residual confounding by disease severity cannot be fully excluded, although sensitivity analyses were directionally consistent. Taken together, ADM exposure, class, and dose should be systematically considered when designing and interpreting HD clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT04556656. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with HD, the use of ADMs is associated with greater worsening across global, functional, cognitive, and motor outcome measures as compared with patients not on ADMs.
Source: Neurology
Institutions: Georgetown University, Yale University, NYU Langone Health, University of Münster, Hertie Institute for Clinical Brain Research, George Huntington Institute, University of Tübingen, Cardiff University, The Ohio State University Wexner Medical Center, St. Josef-Hospital, Ruhr University Bochum, University of British Columbia
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W7223221580