Brexpiprazole entered psychiatry with a confident promise:
a calmer, smoother, more tolerable version of aripiprazole—without the activation, without the akathisia, and with stronger antidepressant properties.

For a while, many clinicians believed it would sit right between aripiprazole and quetiapine, balancing clarity with calmness.

It didn’t quite land that way.

What Made Brexpiprazole Look Special?

Brexpiprazole has a refined pharmacology:

• Partial agonist at D2/D3 receptors, but far less activating than aripiprazole

• Higher affinity for 5-HT1A, leading to an anxiolytic edge

• Strong 5-HT2A blockade, giving smoother emotional control

• Alpha-1 and H1 effects, offering some calming

In theory, this was perfect for:

• Major depression augmentation

• Irritability

• Anger outbursts

• Social anxiety

• Mixed mood states

Mechanistically, it promised what aripiprazole couldn’t:
calming without flattening, augmenting without agitating.

But pharmacology is only half the story. Real life is the other half.

Why It Lost Momentum

1. The Weight Gain Was Unexpected

Brexpiprazole was marketed as aripiprazole’s “gentler, cleaner” sibling.

Then real-world data showed:

• Weight gain

• Increased appetite

• Sedation

• Metabolic creep

Not as heavy as olanzapine, but heavier than what people expected from a third-generation partial agonist.

For patients and psychiatrists, this felt like a mismatch.

2. It Was Too Slow to Impress

The antidepressant augmentation effect takes 4–8 weeks, sometimes longer.

Aripiprazole works faster.
Quetiapine works faster.
Even buspirone augmentation feels more immediate.

In a field where patients want relief yesterday, an ultra-slow medication loses traction quickly.

3. It Became “Too Expensive for Too Subtle”

In India and globally, brexpiprazole is priced much higher than:

• aripiprazole

• quetiapine

• lurasidone

• risperidone

• even newer molecules like lumateperone

When a drug is:

• slow

• subtle

• mildly sedating

• more expensive

…it struggles in a competitive environment.

4. A Branding Problem After US Litigation

A major blow came when its manufacturer faced legal and PR consequences over marketing for agitation in dementia.

This damaged the molecule’s global reputation—even though the molecule itself wasn’t the culprit.

Psychiatry is sensitive to optics, and the enthusiasm dulled.

Where Brexpiprazole Still Works Well

It’s not a failed drug.
It’s simply a niche drug.

It works beautifully for:

• Depression with anxiety

• Irritability in personality disorders

• Patients who develop akathisia with aripiprazole

• Chronic low-grade agitation

• Mixed depressive states

In the right patient, it provides:

• gentle emotional smoothing

• reduced reactivity

• controlled mood lability

• less internal tension

• more social ease

It is a slower, subtler, softer psychopharmacological tool.

For patients who are hypersensitive to activation, brexpiprazole still has a place.

Where It Stands in 2025

Brexpiprazole sits in the “use when needed, not first-line” zone.

It lost mainstream traction because:

• it didn’t outperform aripiprazole

• it didn’t match quetiapine’s mood power

• it didn’t match lumateperone’s tolerability

• it didn’t match lurasidone’s clarity

• it cost more and moved slower

What was once seen as a “future favourite” has settled into being a specialised augmentation molecule for selective situations.

About the Author

Dr. Srinivas Rajkumar T, MD (AIIMS), DNB, MBA (BITS Pilani)
Consultant Psychiatrist & Neurofeedback Specialist
Mind & Memory Clinic, Apollo Clinic Velachery (Opp. Phoenix Mall)
✉ srinivasaiims@gmail.com 📞 +91-8595155808