​​An Old Drug, New Tricks: Sertraline May Lighten the Load in HD by Targeting Protein Production

Depression and anxiety are common symptoms of Huntington’s disease (HD), and they can make everything harder. New research explores how sertraline, a widely-used antidepressant, affects protein production in HD cells and mice, finding that it prevents motor problems in HD mice and is linked to slower functional decline in people with HD. This study raises an intriguing question: could treating HD with sertraline do more than just improve mood? 

The Depression Factor

Living with HD is challenging enough, but depression and anxiety, two of the most common psychiatric symptoms in HD, can make everything exponentially harder. 

Imagine trying to navigate your daily life while carrying a heavy backpack filled with rocks. Even simple tasks become exhausting, your movements feel more labored, and your brain has less energy for everything else. 

That backpack represents depression and anxiety, and new research on sertraline, a commonly prescribed antidepressant, gives us an opportunity to think about how treating these conditions might lighten the load in meaningful ways.

The Protein Production Problem

The research team, led by scientists at the University of Barcelona, set out to study the molecular effects of sertraline on a specific problem in HD cells: abnormal protein production. Scientists have known for a while that cells in HD produce proteins differently than regular cells. 

Specifically, in some models of HD, some scientists have reported too much activity in a process called translation initiation, which is the initiation of protein production. Think of translation as the cellular assembly line that turns genetic instructions into functional proteins. In some HD models, this assembly line seems to run too fast, like a factory churning out products without proper quality control.

The researchers knew that sertraline can slow down protein production in cancer cells, so they wondered if it could do the same in HD. This study looked at the molecular effects of what sertraline does to protein-making machinery in HD cells and how this affects mice, and potentially people. 

Testing in striatal neurons (the brain cells most affected in HD) from mice that model HD, they found that sertraline appeared to normalize the elevated protein production this team saw. When they treated HD mice with sertraline for four weeks, the mice showed improved learning on motor tasks and coordination compared to untreated HD mice.

From Mice to People

Since the mouse results were promising, the researchers wanted to better understand the effects sertraline might be having in people with HD. So they turned to Enroll-HD, the world’s largest observational study of people with HD, which tracks tens of thousands of people over time. 

They compared people with HD taking sertraline (either alone or with other antidepressants) to people taking other medications or no antidepressants at all. They found that people taking sertraline showed a slower decline in functional capacity, meaning they maintained their ability to work, manage finances, handle domestic chores, and care for themselves better over time. Specifically, people taking sertraline showed better scores on tests measuring total functional capacity, functional assessment, and independence. 

However, the researchers didn’t see improvements in total motor scores, meaning sertraline doesn’t seem to influence movement symptoms that many people with HD experience. This could be due to the relatively small number of people in some groups or because doses used in mouse studies are much, much higher than the doses doctors prescribe to people.

They found that people taking sertraline showed a slower decline in functional capacity, meaning they maintained their ability to work, manage finances, handle domestic chores, and care for themselves better over time.

A Cellular Clue

The researchers also made an intriguing discovery about protein production in easily accessible cells. When they looked at skin cells (fibroblasts) from people with HD, they found signs of increased protein production, but only in people whose expanded HTT had fewer than 42 CAG repeats. Treating these cells with sertraline brought protein production back to normal levels.

This cellular finding suggests that the abnormal protein production the researchers are studying may occur in a small subset of people or in select models of HD. Whether this predicts who might benefit most from sertraline’s molecular effects remains an open question. Future research could explore whether measuring protein production in fibroblasts might serve as a biomarker for certain treatments.

Molecular Effects or Mood Effects?

Here’s where interpretation becomes important. This paper primarily focuses on the molecular story of how sertraline affects protein production in HD cells. The research suggests that sertraline can normalize abnormal translation in neurons and in skin cells from some people HD, suggesting the drug may be having a direct effect on cellular machinery that goes awry in HD. This finding is of interest because it could point toward new therapeutic targets.

But it’s equally important to consider sertraline’s primary job: treating depression and anxiety. When depression lifts and anxiety eases, everything becomes more manageable. Your energy improves, your motivation returns, you sleep better, and daily stressors don’t hit as hard. All of these changes can improve how well you function day-to-day, even if the underlying HD pathology hasn’t changed.

Lightening the Load

Consider how depression and anxiety might worsen HD symptoms. If you’re depressed and anxious, stress hormones course through your body, your muscles stay tense, you move less because you lack motivation, and you’re more likely to avoid activities that could maintain your skills. You might struggle more at work, find household tasks overwhelming, or withdraw from social connections that provide support. It can be like trying to function day-to-day while carrying around a 40 pound backpack. 

But what happens if you put that backpack down? Remove the depression and anxiety, and suddenly you’re more likely to stay active, engage with therapies, maintain your job, and participate in activities that keep both your mind and body working well.

The motor symptoms of HD haven’t disappeared, the actual disease progression hasn’t changed, but you’ve removed barriers that were piling onto existing challenges. This doesn’t make the benefits any less real or important, it just means the mechanism might be indirect. Like removing that heavy backpack, treating psychiatric symptoms might make it easier to maintain function and navigate daily life with HD.

Finding Your Right Combination

It’s important to note that sertraline is just one tool in the toolbox for managing HD symptoms. The researchers couldn’t identify clear effects on motor function in the Enroll-HD dataset, which reminds us that no single medication addresses all aspects of this complex disease. Finding the right combination of medications to improve both mood and motor symptoms often takes trial and error for each person.

If you’re experiencing depression, anxiety, or worsening motor symptoms, working closely with your healthcare provider(s) to find the right medication combination is crucial. Several medications can help with depression and anxiety, and different medications can address motor symptoms. 

What works beautifully for one person might not work as well for another, so open communication with your medical team about what’s working and what isn’t helps guide adjustments.

What This Means Clinically

This research doesn’t suggest that sertraline is a disease-modifying treatment for HD. What it does suggest is that sertraline may have some effect on abnormal cellular processes in HD, and people taking it appear to maintain function better over time. 

Whether the functional benefits come from correcting molecular abnormalities, from treating depression and anxiety, or from both, the practical implication is the same: addressing psychiatric symptoms in HD matters.

Depression and anxiety in HD aren’t just uncomfortable side effects that people should be expected to tolerate. They’re treatable conditions that, when left unaddressed, can worsen the challenges HD creates. Treating these symptoms is legitimate medical care that could have broader benefits than we might expect.

If you’re experiencing depression, anxiety, or worsening motor symptoms, working closely with your healthcare provider(s) to find the right medication combination is crucial.

Talk to Your Doctor

If you or your loved one is living with HD and experiencing symptoms of depression or anxiety, persistent sadness, loss of interest in activities, excessive worry, difficulty sleeping, or changes in appetite, talk to your healthcare provider. 

These symptoms aren’t just uncomfortable; they may actively worsen the functional challenges people with HD are facing. Effective treatments exist, and addressing these symptoms might help more than you think.

Your doctor can help determine whether medications for depression, anxiety, or motor symptoms make sense for you or your loved one, considering your specific situation, other medications being taken, and overall health. Finding the right combination might take some adjustment, but the effort is worthwhile.

The Bottom Line

This research offers molecular insights into how sertraline could affect protein production in HD cells, showing that it could be able to normalize changes in neurons and in cells from some people with HD. The finding that people taking sertraline maintained better function over time is encouraging, whether those benefits come from molecular effects, from treating depression and anxiety, or from both.

The most immediate takeaway is that treating psychiatric symptoms in HD is important medical care, not optional comfort. Whether sertraline proves to have unique disease-modifying properties or simply works exceptionally well at treating depression and anxiety in HD, people who received it maintained better function. That’s meaningful, and it reinforces the value of comprehensive symptom management in HD.

Summary

• Researchers studied how sertraline (an antidepressant) affects abnormally fast protein production in Huntington’s disease (HD) cells 
• Sertraline normalized protein production in HD mouse brain cells and prevented motor coordination problems in mice
• Analysis of the Enroll-HD database showed people taking sertraline maintained better functional capacity (ability to work, manage daily tasks, stay independent) over time, though motor scores didn’t improve
• Sertraline normalized abnormal protein production in skin cells from people with HD with fewer than 42 CAG repeats, suggesting additional work could look at the potential of protein production as a biomarker
• Benefits in people could come from sertraline’s molecular effects on protein production, from treating depression and anxiety (which themselves worsen HD symptoms), or potentially both
• Sertraline is one tool in the toolbox against HD to treat depression and anxiety. Finding the right combination of medications for mood and motor symptoms takes trial and error with your doctor
• Whether sertraline helps by fixing cellular problems or by lifting the “backpack” of depression and anxiety (or both), treating psychiatric symptoms in HD is important medical care that may have broader benefits than expected

Learn More

Original research article: “Sertraline treatment prevents motor dysfunction in a Huntington’s disease mouse model and functional decline in patients” (open access).