Relapse Risk Increased With Antidepressant Discontinuation

Kate Johnson

September 30, 2021

For primary care patients feeling well enough to discontinue antidepressant medication, there was a higher rate of depressive relapse among those who discontinued therapy, compared with those who did not, a new study shows.

The results of the Antidepressants to Prevent Relapse in Depression (ANTLER) trial also suggest that "many patients can discontinue their antidepressants safely in primary care without relapsing, when there is a tapering regime," said lead investigator Gemma Lewis, PhD, from University College London, in an interview.

The multicenter, randomized, double-blind trial, which was published in the New England Journal of Medicine (2021;385:1257-67), included 478 patients, from 150 primary care practices in the United Kingdom.

The participants (73% female, average age 54 years) had a history of at least two depressive episodes or had been taking antidepressants (citalopram, fluoxetine, sertraline, or mirtazapine) for at least 2 years. The vast majority of patients — 70% — had been using the drugs for more than 3 years, the researchers wrote.

Study participants were randomized to either maintain their antidepressant regimen or to taper off for up to 2 months before switching to a placebo.

Over a follow-up of 52 weeks, relapse occurred in 56% of those who discontinued, compared with 39% of those who maintained their regimen (hazard ratio, 2.06; P < .001). Relapse also occurred sooner in the discontinuation group (13 weeks vs. 19 weeks).

The definition of relapse was answering yes to either of the following two questions:

  • Have you had a spell of feeling sad, miserable, or depressed?

  • Have you been unable to enjoy or take an interest in things as much as you usually do?

Patients also had to report that one of these experiences had lasted for 2 weeks or more, and having had at least one of the following symptoms: depressive thoughts, fatigue, loss of concentration, or sleep disturbance.

By the end of the trial, 39% of patients in the group who discontinued taking an antidepressant had returned to taking that type of drug.

"We found that remaining on antidepressants long-term does effectively reduce the risk of relapse. However, we also found that 44% of those who discontinued their antidepressants did not relapse after a full year," Lewis said.

Who Can Stop Medications Without Relapsing Is Unknown

"Many people can stop their medication without relapsing, though at present we cannot identify who those people are," noted Lewis.

"Our study did not investigate who is at higher risk of relapse…but this is something we will focus on in the future," she said.

For primary care clinicians whose patients are considering discontinuation of antidepressant medication, "current best practice is to engage with patients' priorities and collaborate in coming to a decision," she noted.

"For the individual patient, it is only possible to know about the average likelihood of relapse — and the severity of potential relapses will also be unpredictable. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants to inform shared decision-making in primary care."

Findings Are "Important" but "Disappointing"

In an editorial published alongside the study (N Engl J Med. 2021;385:1327-8), Jeffrey L. Jackson, MD, MPH, from the Zablocki VA Medical Center and the Medical College of Wisconsin in Milwaukee characterized the findings as "important but disappointing."

"They confirm what most primary care physicians already knew or intuited. The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive episodes," he explained.

Jackson also pointed out some unknowns about the trial, including the length trial participants had been in remission for depression.

"It is unclear whether the trial results are generalizable to primary care patients with a first episode of depression," he said, and noted that participants with three or more previous depressive episodes were more than twice as likely to relapse, compared with participants with fewer episodes.

"I encourage patients with a single bout of depression, especially episodes that are triggered by a life event, such as loss of a loved one, to consider weaning antidepressant treatment after at least 6 months of remission," he wrote. "For those with three or more previous bouts of depression, my practice has been to recommend that they anticipate medical treatment for life or, if they wish to stop taking medication, explore nonpharmacologic approaches, such as cognitive-behavior therapy."

Protective Effect of Antidepressants Was Clear

"This is an important paper providing an evidence base to the often-cited recommendation that after two or more episodes of depression, antidepressant medication should be continued indefinitely," said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College, Thomas Jefferson University in Philadelphia, who was not involved in the study.

"The protective effect of antidepressant medication here was clear — those who discontinued antidepressant medication had a clinically and significantly higher rate of relapse at the end of a year."

Side Effects Can Be Significant

"It is important to note, though, that in the discontinuation group, 44% of patients did not experience a relapse," Skolnik said. "While antidepressants work without significant side effects for many patients, for others there are significant side effects that include adverse sexual side effects, effects on appetite and weight, nighttime sweats, and other side effects."

"So, this study should not be confused to mean that all patients who have had recurrent depression should remain on antidepressants long term. The decision about whether to continue an antidepressant is influenced by many things and should be a shared decision-making process between clinician and patient, informed by the important results of this study, the current situation of the patient, and most importantly, the patient's informed decision of what they would like to do," he said.

The study was funded by the U.K. National Institute for Health Research. Lewis, Jackson, and Skolnik reported no conflicts of interest.

This article originally appeared on, part of the Medscape Professional Network.


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