Network meta-analysis ranks antidepressants for long-term maintenance of recovery

A systematic review and network meta-analysis in The Lancet Psychiatry has compared 20 antidepressants for long-term treatment of major depressive disorder. It found that escitalopram, agomelatine and duloxetine performed better than fluoxetine at keeping patients well over time. The authors describe it as the first large-scale comparison of antidepressants that considers both short- and long-term use.

Why long-term evidence matters

Depression affects close to 6% of people worldwide. Many patients stay on medication after their symptoms improve, partly to reduce the chance of relapse. Yet most comparisons of antidepressants focus on the first weeks of treatment, so prescribers have had less direct evidence on which drugs best sustain a response.

The international research team, with Paul van Haaren as first author, set out to address that gap. Their question was whether any antidepressants can both bring patients to recovery and keep them there.

What the analysis covered

The work pooled data from 115 previously published randomised clinical trials, with more than 30,000 participants in total. Using network meta-analysis, the researchers compared the 20 drugs with one another and with fluoxetine, the best-known antidepressant. The method allows treatments that were never tested head to head to be ranked through their links to common comparators.

The overall results suggest that antidepressants can maintain wellbeing during long-term use. The analysis also found evidence of differences between individual medications. According to the authors, this should influence which drug is chosen at the start of treatment when long-term use is likely.

Three drugs ahead of fluoxetine

Escitalopram, agomelatine and duloxetine were more effective than fluoxetine over the longer term. Each has a different profile in practice:

• Escitalopram is already widely prescribed.
• Agomelatine works well, but van Haaren notes that one of its side effects is a risk of liver failure.
• Duloxetine is less well known and is prescribed less often as a first-line option.

The agomelatine finding shows why efficacy cannot be considered alone. The study's title refers to both comparative efficacy and acceptability, which reflects the need to weigh benefit against tolerability and safety.

Implications for guidelines and prescribing

Many international guidelines recommend selective serotonin reuptake inhibitors (SSRIs) as first-choice treatment. Eric Ruhé, professor of difficult-to-treat depression at Radboud University Medical Center, says escitalopram now appears to be the most effective SSRI, including for long-term use. He suggests the results may have implications for future guidelines.

Ruhé stresses that the findings do not mean everyone with severe depression should be given escitalopram. The balance of benefits and side effects differs between patients, so the best drug may vary. The study is meant to inform shared decisions between prescribers and patients, with long-term benefit as one of the criteria for choosing a first treatment.

Considerations and next steps

As a meta-analysis of existing trials, the study depends on the design, duration and reporting of the underlying studies, and network comparisons involve indirect evidence for some drug pairs. The source summary does not report effect sizes, follow-up lengths or the certainty of evidence for each comparison. Readers will need the full paper for those details.

For researchers, the results strengthen the case for long-term outcomes such as sustained response to be built into trial design and guideline development. Guideline groups can now test whether the ranking holds across patient subgroups and settings, and whether it changes the balance of recommendations among existing first-line options. Further work on duloxetine's place in first-line care, and on how to manage the liver risk linked to agomelatine, would also follow from the findings.

Source: Study identifies antidepressants that get patients well and keep them well (Medical Xpress, 11 November 2026).

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