Clinician Article

Maintenance or Discontinuation of Antidepressants in Primary Care.

  • Lewis G
  • Marston L
  • Duffy L
  • Freemantle N
  • Gilbody S
  • Hunter R, et al.
N Engl J Med. 2021 Sep 30;385(14):1257-1267. doi: 10.1056/NEJMoa2106356. (Original)
PMID: 34587384
Read abstract
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 6/7
  • Psychiatry
    Relevance - 6/7
    Newsworthiness - 5/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 4/7
  • FM/GP/Mental Health
    Relevance - 6/7
    Newsworthiness - 4/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 4/7


BACKGROUND: Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting.

METHODS: We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings.

RESULTS: A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group.

CONCLUSIONS: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).

Clinical Comments

FM/GP/Mental Health

Practice-altering data about relapse of MDD after discontinuing long-term antidepressant therapy.

General Internal Medicine-Primary Care(US)

Depression is a difficult chronic condition. Going off antidepressants does come with risks for recurrence.

General Internal Medicine-Primary Care(US)

It is difficult to understand the high rate of depression in patients in the treatment group who were on antidepressants and continued to take them.

Internal Medicine

This study confirms what we already know. A good thing to know is the rate of relapse, which I wasn't aware of before. Also good to know about the secondary outcomes, which are worse in the discontinuation group.

Internal Medicine

As a hospitalist, I know that recurrent depression is very common. Decisions about whether to continue antidepressants for stable patients with recurrent depression can be an issue, especially when polypharmacy or bleeding are involved. In this very well done trial, patients who had their antidepressants discontinued were twice as likely to have recurrent depression (HR 2.0; 95% CI 1.5-2.7). More than 90% of participants had 3 or more previous bouts of depression. I think this article provides good evidence for the practice of keeping stable patients with recurrent depression on antidepressants.


Most psychiatrists already know this. However, maybe primary care docs don't know. This is a study from primary care, in the UK. It would be interesting to know whether there is pressure on GPs/PCPs from external authorities to discontinue antidepressants after two years. Also the upper age limit for this study was 74 years; I suspect if there had been no upper limit, we would have seen higher relapse rates in both groups.


As a psychiatrist, I find it is my practice to treat patients with antidepressants for many months after remission in hopes of preventing relapse. This study adds further support to that practice and demonstrates the significant risk of relapse (39%) even when taking maintenance medication.

Register for free access to all Professional content

Want the latest in aging research? Sign up for our email alerts.

Support for the Portal is largely provided by the Labarge Optimal Aging Initiative. AGE-WELL is a contributing partner. Help us to continue to provide direct and easy access to evidence-based information on health and social conditions to help you stay healthy, active and engaged as you grow older. Donate Today.

© 2012 - 2020 McMaster University | 1280 Main Street West | Hamilton, Ontario L8S4L8 | +1 905-525-9140 | Terms Of Use