More than half of people in primary care practices who stopped taking antidepressants after using them for a long time experienced a relapse in a year, the randomized double-blind ANTLER trial showed.
Primary care patients on long-term medication for depression who felt well enough to consider stopping relapsed sooner if they discontinued their antidepressant instead of maintaining it, reported Gemma Lewis, PhD, of University College London in England, and co-authors in The New England Journal of Medicine.
By the end of the 52-week trial, 39% who continued and 56% of people who stopped using antidepressants had relapse (HR 2.06, 95% CI 1.56-2.70, P<0.001). Earlier relapse was seen in the discontinuation group compared with the maintenance group (13 versus 19 weeks).
At 12 weeks after stopping, patients in the discontinuation group also had more symptoms of depression, anxiety, and withdrawal.
The study aimed to discover whether antidepressants were effective at preventing relapse in primary care patients who have been taking them for several years, Lewis noted in an email to BreakingMED.
“We expected to find that the group who stopped their antidepressants experienced more relapses than the group who kept taking them,” she wrote. “However, this has never been investigated in a large sample of people receiving long-term treatment in primary care.”
The study provides information only about the average probability of relapse, Lewis pointed out.
“We do not yet know why some people seem able to come off their antidepressants and some cannot, so further research may help us to predict who can stop antidepressants safely,” she said. “Our study will help doctors and patients to make an informed decision together on whether or not to stop long-term antidepressant treatment.”
The researchers studied 478 patients from primary care practices in the U.K. with a mean age of about 55; 73% were women and 95% were White. All had at least two depressive episodes or had been taking antidepressants for 2 years or longer, and all were being treated with either 20 mg citalopram, 100 mg sertraline, 20 mg fluoxetine, or 30 mg mirtazapine for at least 9 months, but felt well enough to consider discontinuation.
People taking escitalopram or doses of included medications that differed from typical maintenance doses were excluded. Follow-up at 6 weeks was a mailed questionnaire, with face-to-face interviews conducted at baseline, 12, 26, 39, and 52 weeks.
Participants were randomized to continuing medication (n=238 in the maintenance group) or 3-month taper and discontinuation while taking a substituted placebo (n=240 in the discontinuation group).
The primary outcome was time to relapse of depression during the 52-week trial. Continuous antidepressant use for 3 or more years was present in about 71% of the overall cohort, and 94% of the maintenance group and 92% of the discontinuation group had three or more prior episodes of depression. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group.
Relapse was defined if patients answered yes to either: “Have you had a spell of feeling sad, miserable, or depressed?” or “Have you been unable to enjoy or take an interest in things as much as you usually do?” with such conditions lasting two or more weeks, and at least one concomitant symptom of depressive thoughts (loss of interest in sex, restlessness, feeling guilty, feeling inferior to others, hopelessness, feeling that life was not worth living, or thoughts of suicide), fatigue, loss of concentration, or sleep disturbance.
Patients with three or more previous depressive episodes were more than twice as likely to relapse as people with fewer episodes. There were 17 serious adverse events during the trial (nine in the maintenance group, and eight in the discontinuation group). All were considered unrelated to trial medication or unlikely to be related to trial medication, with no deaths or suicide attempts.
By 52 weeks, 39% of patients in the discontinuation group returned to taking an antidepressant, which “may explain why there was no evidence of between group differences for secondary outcomes at the last follow-up at 52 weeks,” Lewis and co-authors noted.
“These findings represent important but disappointing news,” wrote Jeffrey Jackson, MD, MPH, of the Zablocki VA Medical Center in Milwaukee, Wisconsin, in an accompanying editorial.
The results “confirm what most primary care physicians already knew or intuited,” Jackson noted. “The frequency of relapse after the discontinuation of treatment is high, particularly among patients with several previous depressive 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.”
“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,” Jackson added. “The results of this and many other trials highlight the fact that current treatment options for depressed patients are not ideal.”
Eight secondary outcomes also were measured at 12 weeks: depressive symptoms, generalized anxiety symptoms, physical symptoms that may be due to medication (using the Toronto Side effects scale), withdrawal symptoms, quality of life measures (both mental and physical health assessed with the 12-Item Short-Form Health Survey, or SF-12), interval between starting and stopping an antidepressant or placebo, and the patient’s global rating of mood.
“At 12 weeks, secondary outcomes were generally in the same direction as the primary outcome, except for scores on the SF-12 physical-health component and Toronto Side Effect Scale,” the researchers wrote. “Since there was no plan for adjustment of confidence intervals for multiple comparisons, no definite conclusions can be drawn regarding these or other differences between groups for secondary outcomes.”
An important limitation of the study was that findings pertained only to patients who felt they were ready to discontinue medication, Lewis and colleagues acknowledged. The trial population also lacked ethnic diversity. All patients were being treated in the U.K. health system, and generalizability to other populations may be limited.
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Primary care patients on long-term medication for depression who felt well enough to consider stopping relapsed sooner if they discontinued their antidepressant instead of maintaining it, the ANTLER trial showed.
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By the end of the 52-week trial, 39% of people who continued and 56% of people who discontinued their depression medication had relapse.
Paul Smyth, MD, Contributing Writer, BreakingMED™
This study was funded by the National Institute for Health Research.
Lewis had no interests to disclose.
Jackson had nothing to disclose.
Cat ID: 55
Topic ID: 87,55,730,192,55,921
