A new review published in The Lancet Psychiatry has found that some antidepressants may be more effective than others at maintaining improvements in depression symptoms over the long term, with escitalopram (Lexapro), duloxetine (Cymbalta) and agomelatine (Valdoxan) associated with a greater likelihood of sustained response than fluoxetine (Prozac).
The review, published in The Lancet Psychiatry, analysed 115 randomised controlled trials involving more than 30,000 people to compare how well different antidepressants help people maintain improvements in depression over six months or more.
The findings are based on a main analysis combining 35 trials that directly compared one antidepressant with another. The researchers found that people taking escitalopram, duloxetine or agomelatine were more likely to report improved symptoms over the long term than those taking fluoxetine. For those taking escitalopram or duloxetine, they were also less likely to drop out of the trials.
Around one in seven Australians will experience depression during their lifetime, and in 2024-2025, 3.8 million Australians were dispensed an antidepressant prescription. Clinical guidelines recommend continuing antidepressants for at least six months, and preferably 12 months, after an acceptable response to treatment, but real-world prescribing patterns suggest many people take them longer: a 2022 study found nearly a quarter of those prescribed antidepressants were still receiving prescriptions two years later, and another Australian study found average use was four years.
The researchers assessed how acceptable the medicines were by looking at the proportion of people who stopped treatment for any reason during the study period. They classified long-term use as six months or more.
The findings are far from definitive. More than half of the studies included in the main analysis were assessed as having a high risk of bias, meaning some differences between antidepressants may reflect limitations in the original studies rather than genuine differences. Some medicines were also supported by very few studies, making comparisons less certain.
Additionally, the trials directly comparing antidepressants typically followed participants for around six months after they first started taking medication, with only six following people for longer than six months. This is important given the average time people take antidepressants is much longer.
The findings reflect average outcomes across groups of people and cannot tell which antidepressant will work best for any particular person. People respond differently, and the researchers used trial drop-out rates as a measure of acceptability, which may not capture people's experiences of taking these medicines.
Escitalopram is the most commonly prescribed antidepressant in Australia, ranking number 13 out of all PBS-dispensed prescriptions in 2024-25. Duloxetine was number 45, while agomelatine is not available on the PBS.
The authors said the findings are not a reason to switch for anyone taking an antidepressant that is working well for them, and those considering starting, changing or stopping an antidepressant should discuss their options with a doctor.
Analysis
Why This Matters
- The findings may influence prescribing decisions for the millions of Australians taking antidepressants long-term, potentially shifting choices toward medications with better evidence for sustained response.
- The study highlights the gap between clinical trial evidence, which typically follows patients for six months, and real-world use averaging four years, raising questions about what is known about long-term effectiveness.
- The high risk of bias in many included studies underscores the need for more rigorous long-term trials to guide treatment choices.
Background
Antidepressants are one of several treatment options for depression, alongside psychological therapies, social support and lifestyle changes. Clinical guidelines recommend continuing them for at least six to 12 months after an acceptable response, but many Australians take them for years. The new review aimed to compare how well different antidepressants maintain improvements and how acceptable they are to patients.
Key Perspectives
Adelaide University researchers (Jack Janetzki and Lauren Cortis, authors of the review): Found that escitalopram, duloxetine and agomelatine were associated with a greater likelihood of sustained response than fluoxetine, and that people taking escitalopram or duloxetine were less likely to drop out of trials. However, they caution that more than half of the studies had a high risk of bias, comparisons are less certain for medicines supported by few studies, and the findings cannot tell which antidepressant will work best for any particular person.
What to Watch
- Whether clinical guidelines are updated to reflect these findings despite the high risk of bias in the underlying studies.
- Future long-term trials that follow participants for more than six months to better match real-world prescribing patterns.
- How prescribers and patients weigh these results against individual factors such as side effects, other health conditions and previous medication experiences.
Checked
11 claims in this story checked against 1 source: 9 supported.
Show each claim
- SupportedThe review found that some antidepressants may outperform others over the long term.The Conversation – Articles (AU): “A new review has found some antidepressants may be more effective than others at helping people reduce the severity of their symptoms of depression over the long term.”
- SupportedEscitalopram, duloxetine and agomelatine were associated with a greater likelihood of sustained response than fluoxetine, with limitations to the findings.The Conversation – Articles (AU): “They found that three antidepressants – escitalopram, duloxetine and agomelatine – were associated with a greater likelihood of sustained response than fluoxetine. ... the results are far from definitive.”
- SupportedThe review covered 115 randomised controlled trials involving more than 30,000 people.The Conversation – Articles (AU): “The researchers identified and reviewed 115 randomised controlled trials, involving more than 30,000 people.”
- SupportedThe main analysis combined 35 trials that directly compared antidepressants.The Conversation – Articles (AU): “Their main analysis combined the results of 35 trials that directly compared one antidepressant with another.”
- SupportedPeople taking escitalopram or duloxetine were less likely to drop out than those taking fluoxetine.The Conversation – Articles (AU): “People taking escitalopram or duloxetine were also less likely to drop out of the trials than those taking fluoxetine.”
- Partly supportedClinical guidelines recommend continuing antidepressants for at least six months, preferably 12 months, after an acceptable response to treatment.The Conversation – Articles (AU): “For adults with depression, clinical guidelines recommend continuing antidepressants for at least six months, and preferably 12 months, after an acceptable response to treatment is achieved.”
- SupportedMore than half of the studies in the main analysis had a high risk of bias.The Conversation – Articles (AU): “More than half of the studies included in the main analysis were assessed as having a high risk of bias.”
- SupportedThe trials directly comparing antidepressants typically followed participants for around six months, and only six followed them for longer than six months.The Conversation – Articles (AU): “The trials directly comparing antidepressants typically followed participants for around six months after they first started taking the medication. Only six followed people for longer than six months.”
- SupportedThe findings cannot show which antidepressant will work best for an individual, and trial drop-out rates may not capture people’s experiences of taking the medicines.The Conversation – Articles (AU): “They can’t tell us which antidepressant will work best for any particular person. ... While the researchers used trial drop-out rates as a measure of acceptability, this doesn’t necessarily capture people’s experiences of taking these medicines.”
- SupportedEscitalopram ranked 13th and duloxetine 45th among PBS-dispensed prescriptions in 2024–25; agomelatine is not available on the PBS.The Conversation – Articles (AU): “It ranked number 13 out of all PBS-dispensed prescriptions in 2024–25. Duloxetine was number 45, but agomelatine isn’t available on the PBS.”
- Partly supportedThe authors said the findings are not a reason to switch from a working antidepressant and advised people considering starting, changing or stopping one to discuss it with a doctor.The Conversation – Articles (AU): “If you’re taking an antidepressant that’s working well for you, the findings of this study aren’t a reason to switch. And if you’re considering starting, changing or stopping an antidepressant, discuss your options with your doctor.”
