Risk of Relapse After Discontinuation versus Maintenance of Antidepressant Therapy

July 2022

Many patients with depression take antidepressants for many years, but the rate of relapse after discontinuing long-term therapy is unknown. The objective of the ANTLER trial was to determine the risk of relapse of depression in patients in primary care practices who felt well enough to stop their medication.

ANTLER, a phase 4, double-blind, randomized trial, included participants from 150 primary care practices in England. Participants were adults aged 18 to 74 years with ≥2 prior episodes of depression or >2 years of antidepressant use. All had been taking common first-line medications used in the United Kingdom (citalopram, fluoxetine, sertraline, and mirtazapine) for ≥9 months, and they stated that they felt well enough to discontinue medication.

Participants were randomly assigned to either maintain their current therapy (maintenance group) or taper and discontinue therapy (discontinuation group) after 1 month (fluoxetine) or 2 months (citalopram, sertraline, and mirtazapine). The primary outcome was the time to the first depressive episode lasting >2 weeks over the 52-week follow-up. Secondary outcomes were scores on scales for depressive symptoms, anxiety, physical symptoms, withdrawal symptoms, quality of life, time to discontinuation, and global rating of mood.

A total of 478 participants were enrolled. The mean age of participants was 54 years, and 71% (maintenance group) and 70% (discontinuation group) had been taking antidepressants continuously for ≥3 years.

At 52 weeks, significantly more participants who discontinued antidepressants had a relapse compared with participants who maintained antidepressant therapy, 56% versus 39%, respectively (P <.001). Scores for secondary outcomes also suggested worsening of mental health symptoms in the discontinuation group compared with the maintenance group, except for measures of physical health and side effects.

Consistent with a higher rate of relapse with discontinuation, 48% of participants in the discontinuation group stopped taking their trial medication by week 52 compared with 30% in the maintenance group. Of these, almost twice as many in the discontinuation group returned to taking antidepressants prescribed by their primary care physicians compared with the maintenance group.

The rate of adverse events was similar between groups, and no suicide attempts occurred during the trial.

“Among patients in primary care practices who had been treated for depression and who were willing to stop their antidepressant medication, the risk of relapse of depression was higher among the patients in the discontinuation group than among those in the maintenance group during 52 weeks,” the investigators concluded.


Lewis G, Marston L, Duffy L, et al. Maintenance or discontinuation of antidepressants in primary care. N Engl J Med. 2021;385(14):1257-1267.

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