The science behind Simtriyo, the first ADHD medication to target three major neurotransmitters

A new medicine for attention-deficit hyperactivity disorder (ADHD) has just entered the treatment toolbox: centanafadine, a once-a-day tablet sold under the brand name Simtriyo.

It has been approved in the United States for adults and children aged six years and older but isn’t yet available in Australia.

So how does it work? How is it different to other ADHD medications? And what are the potential side effects?

It belongs to a new class of ADHD drugs

Centanafadine belongs to a new class of ADHD medicines. It’s the first to affect three brain chemicals: noradrenaline (known as norepinephrine in the US), dopamine and serotonin. Others usually only target two: dopamine and noradrenaline.

Brain cells use chemicals, called neurotransmitters, to send messages to each other:

• dopamine and noradrenaline are involved in attention, motivation and self-control
• serotonin helps regulate things such as mood, sleep and appetite.

Normally, after a neurotransmitter sends its message, the brain cell takes it back up. This is called reuptake.

Think of it like sending a text message and then quickly deleting it. Centanafadine slows down the brain’s deleting process. This leaves more of these chemicals available for longer, helping brain cells communicate.

By increasing the activity of dopamine, noradrenaline and serotonin, centanafadine may help reduce problems with attention, hyperactivity and self-control.

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How does it differ from ADHD stimulants?

Most ADHD medicines are stimulants. These include dexamfetamine, lisdexamfetamine and methylphenidate.

Stimulants mainly increase the activity of two brain chemicals: dopamine and noradrenaline.

Centanafadine works in a similar way, but also affects serotonin. This makes centanafadine different from existing stimulant medicines.

However there is debate about whether centanafadine is a stimulant or not. The pharmaceutical company that made the drug called it a non-stimulant back in 2017. But the US Food and Drug Administration calls it a stimulant in the product information.

In any case, having another treatment option is useful because not everyone responds to ADHD medicines in the same way.

How is it different to antidepressants?

Centanafadine affects serotonin, but that doesn’t make it an antidepressant.

Most commonly used antidepressants mainly affect serotonin, although some also affect noradrenaline. These are important for mood regulation

Commonly used antidepressants generally don’t increase dopamine activity enough to treat the main symptoms of ADHD. Although some of the older antidepressants do affect dopamine activity, they haven’t been extensively studied to treat symptoms of ADHD.

Centanafadine affects reuptake of all three chemicals: dopamine, noradrenaline and serotonin. This is what makes it different from most common antidepressants.

How is it different to Strattera?

Strattera is the brand name for atomoxetine.

Atomoxetine mainly increases the amount of noradrenaline available in the brain. It has much less effect on dopamine and serotonin.

Because it has less of an effect on dopamine reward pathways in the brain, it’s not considered a stimulant.

How effective is it?

Centanafadine was tested in four large phase-3 clinical trials before it was approved in the US. These studies found people taking centanafadine had improved ADHD symptoms. The medicine was also generally well tolerated.

But the studies compared centanafadine with a placebo, rather than directly comparing it with medicines such as methylphenidate, dexamfetamine or atomoxetine.

This means we cannot yet say if centanafadine works better than existing ADHD medicines.

Only some of the results from these studies have been made publicly available. For most of the trials, researchers have reported their own ratings of people’s symptoms. We have less information about how participants themselves felt the medicine affected them.

One study in teenagers found ADHD symptoms improved within about a week of starting centanafadine. The medicine was generally well tolerated, but some participants experienced side effects such as a reduced appetite, a headache, nausea and a rash.

Another study compared the results of centanafadine trials with previous studies of medicines such as lisdexamfetamine and atomoxetine. It suggested centanafadine may cause less insomnia, anxiety, dry mouth and loss of appetite than lisdexamfetamine.

However, this was an indirect comparison. That means the medicines were not tested against each other in the same clinical trial. So these results should be interpreted carefully.

What are the most common side effects?

The most common side effects reported with centanafadine include reduced appetite, insomnia, dry mouth and headache.

These side effects can also occur with other ADHD medicines.

The prescribing information also includes a warning about suicidal thoughts and behaviours. Similar warnings are made for other medicines used to treat ADHD and depression.

Researchers and the company that makes the drug will continue to monitor the medicine as more people use it.

Why isn’t it available in Australia?

Centanafadine has not been approved by Australia’s Therapeutic Goods Administration (TGA). Nor has it been listed on the Pharmaceutical Benefits Scheme (PBS).

If it passes Australia’s regulatory process, it may become available through normal treatment pathways. However, medicines need to be approved by the TGA before they can be considered for PBS subsidies.

Could it help with anxiety or depression too?

Possibly, but we don’t fully know yet.

Because centanafadine affects serotonin as well as dopamine and noradrenaline, researchers are interested in whether it could help people who have ADHD plus anxiety or depression.

Early research has shown some promising results, but the full findings of a study looking at ADHD and anxiety have not yet been published.

More research and real-world experience will help us understand where it fits among the current treatments available for ADHD and for those who also have ADHD plus anxiety or depression.

This article is republished from The Conversation under a Creative Commons license. Read the original article.