Researchers analyzed 115 randomized controlled trials, identifying these three medications as having higher efficacy in preventing relapse over periods of six months or longer.
This study, led by researchers at Adelaide University, provides a granular look at long-term pharmacological management. While antidepressants are a cornerstone of treatment for millions, the clinical community has long debated the comparative efficacy of these agents beyond the acute phase of a depressive episode. The findings offer a new framework for clinicians to consider when optimizing maintenance therapy, though they remain subject to limitations regarding study design and duration.
- Sustained Response: Escitalopram, duloxetine, and agomelatine demonstrated a higher likelihood of maintaining symptom improvement compared to fluoxetine.
- Individual Variability: These results represent group averages; clinical “acceptability” is subjective, involving a complex trade-off between symptom relief, side-effect profiles, and daily functioning.
The research, which synthesized data from over 30,000 participants, focused on two primary metrics: the likelihood of sustained response and the rate of treatment discontinuation. By examining 35 head-to-head trials, the authors sought to move beyond the traditional “efficacy” focus and toward “acceptability”—a measure of how well a patient tolerates and stays on a prescribed regimen.
Escitalopram, commonly marketed as Lexapro, was the 13th most dispensed medication under the Pharmaceutical Benefits Scheme (PBS) in the 2024–2025 period. Despite the high volume of use, the review highlights that data on long-term outcomes remain sparse. Most trials analyzed followed participants for only six months, whereas real-world data indicates that the average duration of antidepressant use in Australia is approximately four years, according to research published in 2022.
| Medication | Key Finding (Relative to Fluoxetine) | Reported Adherence |
|---|---|---|
| Escitalopram | Higher sustained response | Higher retention |
| Duloxetine | Higher sustained response | Higher retention |
| Agomelatine | Higher sustained response | Neutral |
While the data suggests a hierarchy of efficacy, the study authors caution against interpreting these results as definitive clinical guidelines. Over half of the trials included in the analysis were identified as having a high risk of bias. This classification typically stems from issues such as lack of blinding, incomplete outcome data, or small sample sizes, which can skew the perceived effectiveness of a drug.
With only six of the 115 trials extending beyond the six-month mark, little is known about how these medications perform over the multi-year span required for chronic management.
Clinical guidelines generally recommend continuing antidepressant therapy for six to 12 months following a successful response to an acute depressive episode. Any decision to taper or discontinue medication must be done under the direct supervision of a healthcare provider.
Determining the “best” antidepressant is a highly personalized process that accounts for pre-existing comorbidities, potential drug-drug interactions, and patient preference. As noted by the research team at Adelaide University, these findings reflect group-level trends and cannot predict the specific outcome for any individual patient.
- Janetzki, J., & Cortis, L. (2026). Comparative efficacy and acceptability of antidepressants for long-term treatment. The Lancet Psychiatry. https://doi.org/10.1016/S2215-0366(26)00326-3
- Australian Institute of Health and Welfare (2025). Mental health prescriptions data.
- Queensland Health.
- Hancock, N., et al. (2022). Antidepressant prescribing patterns and duration in Australia. BJPsych Open.
