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Taking long-term antidepressants can prevent depression recurring (relapse). But new research shows that almost half of those who stop taking the medication do not relapse.

Depression is a major cause of ill health and disability worldwide. It causes emotional distress and interferes with everyday life. Many people with depression continue taking antidepressant drugs for months or even years after their symptoms have resolved. This so-called maintenance therapy aims to reduce the risk of relapse.

The numbers of people taking maintenance therapy for depression is increasing. However, there is little research to show how effective these drugs are in preventing relapse in people who have been taking them long-term.

This study included people who had two previous relapses of depression. Researchers compared rates of relapse in those who continued on antidepressants with those who stopped. They found that people who stopped medication were more likely to relapse. However, more than 4 in 10 people who stopped taking antidepressants had no relapse of their depression.

More information about depression is available on the NHS website.

What’s the issue?

Most people feel down from time to time, but people with depression have a low mood that lasts for weeks or months. They typically have little interest in things they used to enjoy and can withdraw socially, sleep and eat more or less than usual, and have poor concentration.

More than 300 million people worldwide have depression. Most recover with the right treatment and support. But around half of those who have recovered go on to relapse.

The condition is usually treated with antidepressants. However, these drugs sometimes have side-effects including indigestion, and feeling agitated. Side-effects usually improve over time.

Guidance from the National Institute of Health and Care Excellence recommends that antidepressants are used as ‘maintenance’ treatment for up to 2 years to prevent their depression returning (relapse). It also recommends cognitive-behavioural therapy to change habits of thought and behaviour.

An increasing number of people are taking antidepressants as long-term maintenance. The chance of relapse is reduced by staying on the drugs for a few months after depression has cleared. However, there is little evidence that these drugs prevent relapse when taken for longer than 8 months.

In this study, researchers explored relapse rates among people who had taken them for more than 9 months.

What’s new?

The study included 478 people aged 18 - 74 years, who were treated at 150 general practices in Bristol, London, Southampton, and York. Participants had all had two previous relapses of depression. They had been taking one of the 4 most commonly prescribed antidepressants (citalopram, sertraline, fluoxetine, or mirtazapine) for at least 9 months, and were well enough to consider stopping.

Half (238 people) continued taking their usual antidepressant (treatment group), while the others in the discontinuation group (240 people) took dummy pills (placebo). These dummy pills looked identical to people’s usual pills and initially contained their normal dose of antidepressant. This dose was gradually reduced over 1-2 months until the placebo contained no antidepressant at all.

Participants’ depressive symptoms were assessed at the start of the trial, and then again at various time points (12, 26, 39 and 52 weeks).

The study found that:

  • by 52 weeks, more people on placebo relapsed (56%) than those who continued with treatment (39%)
  • more than 4 in 10 people (44%) on placebo did not relapse
  • most relapses occurred 12 to 26 weeks after the study started
  • people in the placebo group had worse anxiety and depression scores than those in the treatment group, particularly at 12 and 26 weeks
  • discontinuing treatment cost marginally more than continuing over 12 months (because people who re-start treatment have more healthcare appointments, which cost more than continuing on treatment).

Not everyone who relapsed went back on to medication. Of 134 people in the placebo group who relapsed, most (53%) went back on to antidepressants prescribed by their doctor. But 49 people (37%) remained on placebo in the trial, and a further 14 (10%) chose not to take any medication.

More people on placebo had withdrawal symptoms (which can feel similar to anxiety and depression and include sleeping problems and restlessness) than in the treatment group.

Why is this important?

The study suggests that some people who would have remained free of depression with treatment, relapse when they discontinue. But more than 4 in 10 are likely to remain well without treatment. These findings should inform discussions between doctors and people who have had depression. Both need to be aware of the likely benefits and harms of stopping long-term treatment with antidepressants.

Follow-up during the study identified the time points at which people might have worse anxiety or depression or be more vulnerable to relapse. Knowing in advance that these symptoms may appear - and then resolve - is helpful. For instance, many people discontinuing medication felt their mood worsening at 12 weeks, but this may have not been severe enough for them to restart treatment.

What’s next?

The researchers say their results should be interpreted with care since the study included only people who had had two previous relapses. The findings might not apply to people receiving treatment for their first depressive episode.

Participants were mostly White, married and employed, and were recruited from moderately sized general practices in urban areas. Whether the same patterns are seen in other groups (people who are younger, unemployed or from minority ethnic groups) needs to be explored.

Outstanding questions include:

  • does reducing the dose of antidepressant more gradually (over a longer period) have benefits
  • what is the relapse rate after 12 months
  • since this study looked at 4 antidepressants, would other antidepressants that work in different ways have different relapse rates.

It would also be useful to explore the reasons behind individual decisions to stop medication during the study.

You may be interested to read

The paper this NIHR Alert was based on: Duffy L, and others. Antidepressant medication to prevent depression relapse in primary care: the ANTLER RCT. Health Technology Assessment 2021;25:69

National Institute for Health and Care Excellence (NICE). Depression in adults: recognition and management. NICE guideline [CG90]. 2009

The cost-effectiveness analysis from the ANTLER study: Clarke CS, and others. Cost utility analysis of discontinuing antidepressants in England primary care patients compared with long term maintenance: the ANTLER study. Applied Health Economics and Health Policy 2022;20:269-282

Funding: This study was funded by the NIHR Health Technology Assessment programme.

Conflicts of Interest: Several authors report competing interests.

Disclaimer: NIHR Alerts are not a substitute for professional medical advice. They provide information about research which is funded or supported by the NIHR. Please note that views expressed in NIHR Alerts are those of the author(s) and reviewer(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

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