Beyond motor symptoms: efficacy of pharmacotherapies on motor, functional, and cognitive domains in Huntington's disease - a systematic review.

INTRODUCTION

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, neuropsychiatric, cognitive, and peripheral alterations impairing functional capacity and quality of life (QoL). Pharmacotherapies, including dopaminergic and glutamatergic drugs, primarily target motor symptoms, while cholinergic modulators address cognitive decline. However, the literature lacks comprehensive reviews evaluating the combination of these three drug classes across a broad spectrum of clinical outcomes, extending beyond the total motor score (TMS).

OBJECTIVE

This systematic review aimed to assess the efficacy of dopaminergic, glutamatergic, and cholinergic drugs on motor, functional, cognitive decline, and QoL in HD patients.

METHODOLOGY: Following PRISMA guidelines, searches were performed in MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library until October 2025. Randomized clinical trials evaluating these three classes of drugs in adults with genetically confirmed HD were included. Primary outcomes were Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS), Total Functional Capacity (TFC), and cognitive performance. Secondary outcomes included the Independence Scale (IS) and QoL. Risk of bias was assessed using the Cochrane RoB 2 tool. Due to substantial heterogeneity, results were synthesized descriptively.

RESULTS

From 32,746 studies, 15 were included in the final analysis. Findings showed that UHDRS TMS was improved with dopaminergics (tetrabenazine, deutetrabenazine, and pridopidine) and glutamatergic (riluzole) drugs. Only pridopidine treatment exhibited efficacy on UHDRS TFC, subsequently improving UHDRS IS. For QoL, deutetrabenazine treatment proved effective. In the UHDRS cognitive domain, tetrabenazine improved performance in the Stroop Color and Word test, while rivastigmine (cholinergic) improved verbal fluency.

CONCLUSION

Dopaminergic, glutamatergic, and cholinergic drugs exhibit distinct efficacy profiles across various motor and non-motor UHDRS components. This positions them as therapeutic options for attenuating both the motor and non-motor symptoms in HD.