Huntington’s: antidopaminergic drugs associated with greater decline, without proven causality

A comparison within the placebo group

Antidopaminergic drugs include vesicular monoamine transporter type 2 inhibitors, known as VMAT2 inhibitors, and antipsychotics. They are used in Huntington’s disease to manage motor and psychiatric symptoms.

The researchers conducted a post hoc analysis of participants in the placebo group of PROOF-HD, a trial investigating pridopidine. Of these participants, 135 took antidopaminergic drugs and 112 did not, based on their exposure during the study.

This distinction is crucial: PROOF-HD is a randomized trial, but this comparison between users and non-users of antidopaminergic drugs is not randomized. It examines an association, not the causal effect of prescribing a drug.

Differences across several clinical measures

Exposed participants showed greater deterioration in global, functional, cognitive and motor measures. For the composite cUHDRS score and total functional capacity, known as TFC, differences favored unexposed participants between weeks 39 and 78.

At week 52, the mean difference in change was 0.66 points for cUHDRS, with a 95% confidence interval of 0.31 to 1.01, and 0.85 points for TFC, with an interval of 0.47 to 1.22. These group averages do not predict an individual’s course.

Analyses examining antipsychotics, VMAT2 inhibitors and higher doses separately also found an association with greater decline. Sensitivity analyses pointed in the same direction.

The role of disease severity remains difficult to disentangle

Patients with more symptoms may be precisely those who receive these drugs. Disease severity may therefore help explain their less favorable course, even after statistical adjustments.

Another nuance: all motor score subdomains favored unexposed participants, except chorea. The abstract does not allow this exception to be translated into an estimate of the treatments’ symptomatic benefit.

A finding mainly useful for interpreting trials

This analysis highlights the importance of accounting for exposure to antidopaminergic drugs, their class and their dose in Huntington’s trials. Otherwise, differences in concomitant treatments can complicate the interpretation of results.

It is not sufficient to recommend stopping or changing treatment. Such a decision should be discussed with the neurologist, taking into account the symptoms being targeted and the benefit observed.

What we can take away

The association deserves consideration in Huntington’s trials, but it does not support the conclusion that antidopaminergic drugs accelerate the disease.