The Circadian Antidepressant That Never Reached Its Potential**

Agomelatine was one of the most intriguing antidepressants to enter the field.
Sold internationally as Valdoxan, and in India as Melitor, Agotab, Agovance, Agomenta, Agoprex, it promised a refreshing approach:

Instead of boosting serotonin directly, fix the body clock—and mood will follow.

This concept appealed immediately to clinicians treating:

• depression with insomnia

• depression with fatigue

• circadian rhythm disruption

• atypical depression

• shift workers

• burnout-related mood disorders

For a brief moment, agomelatine felt like the future.

But despite the excitement, it slowly faded into obscurity.

Let’s explore why.

Why Agomelatine Looked Revolutionary

Agomelatine has a unique mechanism:

• MT1 and MT2 agonism → improves circadian rhythm

• 5-HT2C antagonism → boosts dopamine & norepinephrine in frontal regions

This suggested:

• better sleep

• better morning energy

• improved emotional resilience

• restored biological rhythm

• minimal sexual side effects

• no weight gain

• cognitive clarity

Compared to SSRIs and SNRIs, which often worsen:

• sleep

• energy

• motivation

• sexual functioning

…Agomelatine felt refreshingly different.

But everyday clinical realities told a different story.

Where Agomelatine Lost Traction

1. Efficacy Was Weaker Than Expected

Although initial studies were positive, real-world data revealed:

• mild-to-moderate antidepressant effect

• less potency in moderate–severe depression

• slow onset

• smaller mood improvements compared to SSRIs/SNRIs

Patients often said:
“I sleep better… but I’m still depressed.”

It became clear that Agomelatine improves sleep more reliably than mood.

2. Liver Monitoring Killed Its Momentum

Agomelatine carries a risk of:

• elevated liver enzymes (AST/ALT)

• rare hepatotoxicity

Guidelines require regular LFTs:

• baseline

• 6 weeks

• 12 weeks

• 24 weeks

This created huge practical barriers:

• patients forgot

• clinics didn’t enforce

• people disliked repeated blood tests

• many psychiatrists avoided prescribing altogether

In India, where follow-up compliance is low, this was an even bigger issue.

3. It Was Too Gentle for Severe Depression

For patients with:

• melancholic depression

• suicidal ideation

• psychomotor slowing

• high anxiety depression

…agomelatine felt like a soft whisper in a hurricane.
It simply couldn’t deliver the intensity required.

4. Cheaper Alternatives Outperformed It

Compared to escitalopram, sertraline, venlafaxine, desvenlafaxine, mirtazapine, and bupropion, agomelatine:

• worked slower

• worked weaker

• cost more

• required blood tests

In India, brands like Melitor or Agoprex cost significantly more than standard SSRIs.

Patients didn’t see the value.

5. It Became a “Sleep Medicine in Disguise”

Many patients reported:

• better sleep

• more regular cycles

• gentler mornings

But mood improvement lagged behind.
This reputation reduced agomelatine’s positioning to:

“an expensive sleep-regulating antidepressant.”

Not the image it hoped for.

Where Agomelatine Still Works Beautifully

Despite fading from prominence, agomelatine is excellent for a very specific patient profile.

It works well for:

• mild-moderate depression with insomnia

• jet lag–related depression

• shift workers

• burnout with circadian disruption

• patients intolerant to SSRIs

• individuals wanting a “natural-feeling” antidepressant

• those who value emotional clarity over sedation

In these contexts, patients often say:
“I feel more like myself,”
“I wake up fresher,”
“My routine stabilised,”
“My emotions feel normal again.”

But the group benefitting is narrow.

Agomelatine’s Legacy

Agomelatine teaches psychiatry an important lesson:

Fixing the body clock is powerful—but it isn’t enough for most depressions.

Mood disorders are too complex for a pure circadian approach, unless the depression is primarily circadian.

The molecule was visionary.
But real-world depression needs more horsepower.

Where It Stands in 2025

Today, agomelatine (Melitor, Agovance, Valdoxan) is:

• respected

• gentle

• ideal for circadian-linked depression

• excellent for sleep-wake correction

• safe when monitored

But it remains:

• under-prescribed

• overshadowed

• avoided due to LFT monitoring

• limited in potency

• too mild for severe depression

A fascinating molecule that carved out a niche but never transformed the field.

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