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Peer-reviewedCC BY-NC-ND 4.0Neurology

Antidopaminergic Medications and Clinical Outcomes in Huntington Disease

  • Karen E. Anderson1
  • Andrew M. Tan2,3
  • Andrew Feigin4
  • Ralf Reilmann5,6,7
  • Anne E. Rosser8,9
  • Lynn A. Raymond10
  • Sandra K. Kostyk11
  • Carsten Saft12
  • Kelly Chen3
  • Randal Hand3
  • Michal Geva3
  • Michael R. Hayden3,13
1 more authors
  • for the PROOF-HD study investigators
13 affiliations
  1. 1Departments of Psychiatry and Neurology, Georgetown University, Washington, DC
  2. 2Department of Neurology, Yale University School of Medicine, New Haven, CT
  3. 3Prilenia Therapeutics B.V., Naarden, the Netherlands
  4. 4Department of Neurology, NYU Langone Health, New York
  5. 5George-Huntington Institute, Münster, Germany
  6. 6Department of Clinical Radiology, University of Münster, Germany
  7. 7Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany
  8. 8Cardiff University Brain Repair Group, School of Biosciences, Cardiff, United Kingdom
  9. 9Advanced Neurotherapeutics Centre, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, United Kingdom
  10. 10Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, Canada
  11. 11Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH
  12. 12Department of Neurology, Huntington-Centre NRW, St. Josef Hospital, Ruhr-University Bochum, Germany ; and
  13. 13Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, Canada .
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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.

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.

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Cite

BibTeXRIS
BibTeX
@article{anderson2026antidopaminergic,
  title = {{Antidopaminergic Medications and Clinical Outcomes in Huntington Disease}},
  author = {Karen E. Anderson and Andrew M. Tan and Andrew Feigin and Ralf Reilmann and Anne E. Rosser and Lynn A. Raymond and Sandra K. Kostyk and Carsten Saft and Kelly Chen and Randal Hand and Michal Geva and Michael R. Hayden and for the PROOF-HD study investigators},
  journal = {Neurology},
  year = {2026},
  month = oct,
  doi = {10.1212/wnl.0000000000218627},
  url = {https://doi.org/10.1212/wnl.0000000000218627},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Antidopaminergic Medications and Clinical Outcomes in Huntington Disease
AU  - Karen E. Anderson
AU  - Andrew M. Tan
AU  - Andrew Feigin
AU  - Ralf Reilmann
AU  - Anne E. Rosser
AU  - Lynn A. Raymond
AU  - Sandra K. Kostyk
AU  - Carsten Saft
AU  - Kelly Chen
AU  - Randal Hand
AU  - Michal Geva
AU  - Michael R. Hayden
AU  - for the PROOF-HD study investigators
PY  - 2026
DA  - 2026/10/22
JO  - Neurology
DO  - 10.1212/wnl.0000000000218627
UR  - https://doi.org/10.1212/wnl.0000000000218627
AB  - 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.  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.
SN  - 0028-3878
SN  - 1526-632X
ER  -