Antidopaminergic treatment is associated with reduced chorea and irritability but impaired cognition in Huntington's disease (Enroll-HD)

Abstract

Objectives: Alterations in dopamine neurotransmission underlie some of the clinical features of Huntington's disease (HD) and as such are a target for therapeutic intervention, especially for the treatment of chorea and some behavioural problems. However, justification for such an intervention is mainly based on case reports and small open label studies and the effects these drugs have on cognition in HD remain unclear.

Methods: In this study, we used the Enroll-HD observational database to assess the effects of antidopaminergic medication on motor, psychiatric and cognitive decline, over a 3-year period. We first looked at the annual rate of decline of a group of HD patients taking antidopaminergic medication (n=466) compared with an untreated matched group (n=466). The groups were matched on specified clinical variables using propensity score matching. Next, we studied a separate group of HD patients who were prescribed such medications part way through the study (n=90) and compared their rate of change before and after the drugs were introduced and compared this to a matched control group.

Results: We found that HD patients taking antidopaminergic medication had a slower progression in chorea and irritability compared with those not taking such medications. However, this same group of patients also displayed significantly greater rate of decline in a range of cognitive tasks.

Conclusion: In conclusion we found that antidopaminergic treatment is associated with improvements in the choreic movements and irritability of HD but worsens cognition. However, further research is required to prospectively investigate this and whether these are causally linked, ideally in a double-blind placebo-controlled trial.

Figure 1

Graphs showing average annual change in UHDRS total motor score, PBA irritability and composite cognitive score per group. Group 1. (A) There is no difference in the annual increase in UHDRS total motor score between HD antidopaminergic medication takers and HD non-antidopaminergic medication takers. (B) HD patients taking antidopaminergic medication had a significantly reduced increase in chorea score compared with HD controls not taking antidopaminergic medication. (C) Antidopaminergic medication takers had a significantly smaller increase in reported irritability on the PBA compared with patients not on DA altering medications.(D) HD antidopaminergic medication takers had a statistically faster rate of cognitive decline than HD patients not taking these drugs. Groups were compared using univariate analysis with age, CAG and gender as covariates. Mean and SE of the mean are shown. ***p<0.001. n=466 per group. DA, dopamine; HD, Huntington’s disease; PBA, problems behavioural assessment; UHDRS, Unified Huntington Disease Rating Scale.

Figure 2

Graphs showing average annual change in UHDRS total motor score, PBA irritability and composite cognitive score per group. Group 2. (A) HD patients who had a period of assessment before being prescribed antidopaminergic medications did not show a significant difference in annual change in motor score pre-antidopaminergic and post-antidopaminergic medication introduction. Matched controls also did not show a significant difference across the two time intervals. (B) HD patients showed a diminished increase in chorea score in the period after they were prescribed the antidopaminergic medication. In contrast, matched controls did not show significant changes in chorea score between the two time intervals. (C) The onset of antidopaminergic medication did not have a significant effect on PBA irritability scores. Matched controls also did not display significant changes in irritability score. (D) HD patients who began antidopaminergic medication showed a significantly faster rate of cognitive decline in the period after medication introduction. In contrast, matched controls did not show any change in cognitive score. A paired t-test compared scores of time interval 1 (pre-antidopaminergic medication) with time interval 2 (post-antidopaminergic medication). A univariate ANOVA compared scores of each group during each time interval with age, CAG and gender as covariates. p<0.05. n=81 pairs. HD, Huntington’s disease; PBA, problems behavioural assessment; UHDRS, Unified Huntington Disease Rating Scale.