Some antidepressants may do a better job preventing relapse

Clinical takeaway: When selecting an antidepressant for major depressive disorder, clinicians may want to consider long-term outcomes alongside acute symptom relief. Escitalopram, duloxetine, and agomelatine were associated with higher rates of sustained response, with escitalopram and duloxetine also demonstrating favorable treatment acceptability.

Major depressive disorder affects nearly 6% of adults worldwide, and many patients remain vulnerable to relapse even after symptom improvement. Although antidepressants are effective for acute treatment, less is known about which agents are most likely to help patients maintain recovery over time. To address that gap, researchers conducted the first large-scale comparison of antidepressants designed to evaluate sustained response.

Researchers analyzed data from 115 randomized clinical trials involving 30,428 adults with major depressive disorder. Compared with fluoxetine, escitalopram, duloxetine, and agomelatine (the latter not approved in the US) were more likely to produce sustained response, defined as achieving improvement and maintaining it without relapse through study completion.

Escitalopram and duloxetine also demonstrated better acceptability than fluoxetine, as reflected by lower rates of all-cause treatment discontinuation. Agomelatine likewise emerged as a leading option for sustained response, although it did not show superior treatment acceptability. In a separate analysis of maintenance studies, approximately 62% of patients who continued antidepressant therapy maintained a sustained response compared with about 45% of patients who received placebo, supporting the role of ongoing treatment after clinical improvement.

The authors emphasized that differences between treatments were generally modest. They also noted that evidence certainty was limited by the relatively small number of direct head-to-head comparisons and the high risk of bias in more than half of studies included in the primary analysis.

This systematic review and network meta-analysis evaluated double-blind randomized trials of 21 antidepressants used for longer than 12 weeks in adults with unipolar major depressive disorder. The primary outcomes were sustained response and acceptability, measured by all-cause treatment discontinuation.

The investigators called for additional long-term comparative trials, particularly studies extending beyond 12 months and those evaluating newer antidepressants with limited long-term evidence. Future research may help clarify whether the observed differences persist across broader patient populations and longer treatment durations.

Source: van Haaren PCF, et al. (2026 Nov 10) Lancet Psychiatry. Comparative efficacy and acceptability of antidepressants in the long-term treatment of major depressive disorder: a systematic review and network meta-analysis