You probably know someone who takes an antidepressant, or you take one yourself. Most people hear the same question when they start. Which pill works, and once it works, which one keeps working?
A new study in The Lancet Psychiatry suggests the second answer may not be the same as the first. Researchers pooled 115 randomized trials covering more than 30,000 adults with major depression.
They compared 21 antidepressants against the best known one, fluoxetine, sold as Prozac.
Three drugs stood out for keeping people well over the longer term. Escitalopram (Lexapro), duloxetine (Cymbalta) and agomelatine (Valdoxan) all outperformed fluoxetine for sustained response.
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Escitalopram ranked at the top for keeping people free of symptoms during follow-up. Users were also less likely to drop out of the trials, a sign the drug was reasonably well tolerated.
Why staying well is a different question from getting better
For decades, most antidepressant comparisons measured how many patients felt better in the first eight to twelve weeks.
Treatment guidelines, though, recommend staying on the medication for at least six to twelve months after that, to lower the chance of relapse.
The new review focused on that longer window. The main head-to-head analysis pulled together 35 trials that followed roughly 9,900 patients for six months or more.
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Paul van Haaren of Radboud University Medical Center is the study's first author, writes EurekAlert.
He noted in the Radboud press release that escitalopram is already widely used, while duloxetine is less familiar and less often prescribed as a first-line option.
The team also flagged that agomelatine performed well but carries a known risk of serious liver injury, which limits how broadly it can be used. Agomelatine is not approved in the United States.
What this finding means for people already on an SSRI
For American readers, the comparison lands close to home.
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Escitalopram is among the top three most prescribed antidepressants in the country, with 41.7 million prescriptions dispensed in 2024, according to the ClinCalc DrugStats database.
Fluoxetine remains one of the most familiar names in the class.
"Of these SSRIs, escitalopram now appears to be the most effective, also for long-term use," said Eric Ruhé in the Radboud according to EurekAlert. He is professor of difficult-to-treat depression at Radboud University Medical Center.
Ruhé added that medication choice still has to weigh benefits against side effects for each patient.
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Escitalopram and fluoxetine are both SSRIs with broadly similar tolerability. Duloxetine is an SNRI and comes with its own warnings about blood pressure and withdrawal.
The authors stressed that this is a population-level finding, not a verdict on any one person's prescription. The paper also notes that only six of the included trials ran longer than six months, which limits what can be said about much longer treatment.
Anyone thinking about a change should raise it with the prescribing clinician first. Stopping or swapping SSRIs on your own can trigger withdrawal symptoms and raise the short-term risk of relapse.
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This article is made and published by Ida-Marie Palm Varbæk, who may have used AI in the preparation.