Putting Huntington’s disease medications to the test: results from the Neuro-HD trial

Doctors have been prescribing drugs to help manage Huntington’s disease (HD) symptoms like chorea (involuntary movements) and irritability for decades. But surprisingly, there are not many studies directly comparing these medications head-to-head. A new study called Neuro-HD, published in Parkinsonism & Related Disorders, helps to fill this gap. Researchers compared three commonly used drugs over one year in people with HD: tetrabenazine, olanzapine, and tiapride. Their findings support a more personalised, symptom-by-symptom approach to treatment, and suggest that olanzapine may have advantages for some people.

Why was this study needed?

Tetrabenazine is a type of drug called a VMAT2 inhibitor, one of the only classes of drug that has clearly proven benefits for movement symptoms of HD in large placebo-controlled trials. In many countries VMAT2 inhibitors have been the “default” option for doctors to prescribe to people with HD. However, tetrabenazine can have negative side effects, like worsening mood and sleepiness. It’s also not designed to help with behavioural symptoms, like irritability.

Antipsychotic drugs (also known as neuroleptics) such as olanzapine and tiapride are widely used in HD, especially in Europe, but mostly based on clinician-patient interactions or clinician preference rather than strong trial data. These medications are typically prescribed to help manage symptoms including involuntary movements, irritability, aggression, anxiety, and psychosis, which can be distressing for both people with HD and their families.

Until now, no large randomized study had directly compared these treatments over a meaningful length of time. That’s where Neuro-HD comes in. 

How was Neuro-HD designed?

Neuro-HD was a randomized clinical trial run across 11 centres in France that enrolled 179 adults with manifest HD who had a clinical reason to start or change an antipsychotic drug. Participants were randomly assigned to receive one of three treatments: olanzapine, tetrabenazine, or tiapride.

They were then followed for 52 weeks. Importantly, this was an open-label study, so   everyone knew which drug they were taking, and doctors were allowed to adjust doses or switch medications if needed, reflecting real clinical practice.

One of the main outcomes the researchers looked into was a measure called the Independence Scale, which gives a readout of how much help a person needs in daily life. They also carefully tracked motor symptoms (including chorea), behavioural symptoms (like irritability and depression), thinking abilities, and side effects.

Did any drug slow disease progression?

In short: no. But nor did we expect these drugs to; these are symptom management drugs not disease-modifying drugs. 

Over one year, all three groups showed a similar decline in independence that is expected with HD progression. None of the drugs slowed overall disease progression or preserved independence better than the others.

Effects on movement: who improved most?

Movement symptoms improved in all three groups, but the clearest benefits were seen with tetrabenazine and olanzapine. Both drugs led to significant reductions in some measures of movement changes in HD over one year, although not Total Motor Score (TMS), a commonly used metric to track HD symptom progression. Olanzapine also came with a trade-off: people taking it experienced a small but measurable increase in rigidity (stiffness). 

Tiapride showed smaller and less consistent improvements.

Effects on irritability and behaviour

This is where the drugs really differed. Olanzapine significantly improved irritability and overall behavioural scores, which measure changes in irritability, depression, apathy, anxiety, obsessive behaviours, and psychosis. 

Tiapride also helped irritability, but less strongly, while tetrabenazine did not improve irritability and was more often linked to mood problems, particularly depressive symptoms and sedation.

For families struggling with anger, impulsivity, or aggression, symptoms that can be incredibly distressing, this finding is especially relevant.

Side effects of these drugs

All three drugs caused side effects, but their profiles were different. Tetrabenazine was most often linked to, depression, suicidal thoughts as well as drowsiness and fatigue. These side effects led to more people stopping or switching treatment.

Meanwhile olanzapine was associated with weight gain and mild increases in cholesterol. These effects were usually manageable, and fewer people stopped olanzapine overall. Notably, far fewer people stopped olanzapine because of depression or suicidal thoughts, giving it a more favourable mood-related safety profile in this study

Tiapride sat somewhere in between, helping irritability but with fewer benefits for chorea.

What does this mean for people with HD?

The Neuro-HD trial reinforces an important message: that HD can impact each person in a unique way and there is no single “best” drug for managing HD symptoms. Instead it suggests that:

• Tetrabenazine remains effective for chorea, but mood needs close monitoring.
• Olanzapine may be a strong option when movement and behavioural symptoms, especially irritability, occur together.
• Tiapride may help irritability, particularly in settings where it’s commonly used.

The results support individualised treatment, where doctors consider the full symptom picture (movement, mood, behaviour, sleep, and weight) rather than focusing on chorea alone.

Why this study matters

Large, long-term, head-to-head trials like Neuro-HD are important studies for the HD community. This study reflects real-world care, includes people with complex psychiatric histories, and provides practical evidence clinicians can use today.

For many people with HD, these medications remain a critical part of symptom management. They are commonly used to help manage challenging symptoms such as irritability, aggression, anxiety, or psychosis, and for some individuals they can make a meaningful difference to daily life and safety. 

That said, it’s still fairly common for many people with HD to be prescribed certain medications simply because they have HD. But that approach can lead to unnecessary side effects without real benefit. Instead, this study suggests that treatments should be targeted to specific symptoms with a clear goal in mind. This way, clinicians can weigh the potential benefits against possible harms and make decisions that truly improve quality of life.

Decisions about starting, stopping, or changing these medications should always be made through open and honest conversations between people with HD, their families, and their clinical care teams. It can be harmful to suddenly stop these drugs or change how you take them without first talking to a clinician, and anyone experiencing side effects or new symptoms should speak with a clinician rather than making changes on their own

This study also highlights the need for future trials comparing other commonly prescribed drugs, such as risperidone, aripiprazole, or newer VMAT2 inhibitors like deutetrabenazine, using outcomes that matter to patients and families. For now, Neuro-HD offers something the HD community has long needed: clearer evidence to guide everyday treatment decisions.

Summary

• Neuro-HD was a year-long, head-to-head clinical trial comparing three commonly prescribed Huntington’s disease medications—tetrabenazine, olanzapine, and tiapride—in 179 people with HD across France.
• No drug slowed HD progression, but all three helped manage symptoms in different ways.
• Tetrabenazine and olanzapine improved movement, while tiapride had smaller effects.
• Olanzapine best improved irritability and behaviour, with fewer mood problems than tetrabenazine.
• The takeaway: treatment should be personalised, based on each person’s mix of movement, mood, and behavioural symptoms