Antidepressant medication to prevent depression relapse in primary care: the ANTLER RCT.

BACKGROUND: There has been a steady increase in the number of primary care patients receiving long-term maintenance antidepressant treatment, despite limited evidence of a benefit of this treatment beyond 8 months. OBJECTIVE: The ANTidepressants to prevent reLapse in dEpRession (ANTLER) trial investigated the clinical effectiveness and cost-effectiveness of antidepressant medication in preventing relapse in UK primary care. DESIGN: This was a Phase IV, double-blind, pragmatic, multisite, individually randomised parallel-group controlled trial, with follow-up at 6, 12, 26, 39 and 52 weeks. Participants were randomised using minimisation on centre, type of antidepressant and baseline depressive symptom score above or below the median using Clinical Interview Schedule - Revised (two categories). Statisticians were blind to allocation for the outcome analyses. SETTING: General practices in London, Bristol, Southampton and York. PARTICIPANTS: Individuals aged 18-74 years who had experienced at least two episodes of depression and had been taking antidepressants for ≥ 9 months but felt well enough to consider stopping their medication. Those who met an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of depression or with other psychiatric conditions were excluded. INTERVENTION: At baseline, participants were taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg. They were randomised to either remain on their current medication or discontinue medication after a tapering period. MAIN OUTCOME MEASURES: The primary outcome was the time, in weeks, to the beginning of the first depressive episode after randomisation. This was measured by a retrospective Clinical Interview Schedule - Revised that assessed the onset of a depressive episode in the previous 12 weeks, and was conducted at 12, 26, 39 and 52 weeks. The depression-related resource use was collected over 12 months from medical records and patient-completed questionnaires. Quality-adjusted life-years were calculated using the EuroQol-5 Dimensions, five-level version. RESULTS: Between 9 March 2017 and 1 March 2019, we randomised 238 participants to antidepressant continuation (the maintenance group) and 240 participants to antidepressant discontinuation (the discontinuation group). The time to relapse of depression was shorter in the discontinuation group, with a hazard ratio of 2.06 (95% confidence interval 1.56 to 2.70; p < 0.0001). By 52 weeks, relapse was experienced by 39% of those who continued antidepressants and 56% of those who discontinued antidepressants. The secondary analysis revealed that people who discontinued experienced more withdrawal symptoms than those who remained on medication, with the largest difference at 12 weeks. In the discontinuation group, 37% (95% confidence interval 28% to 45%) of participants remained on their randomised medication until the end of the trial. In total, 39% (95% confidence interval 32% to 45%) of participants in the discontinuation group returned to their original antidepressant compared with 20% (95% confidence interval 15% to 25%) of participants in maintenance group. The health economic evaluation demonstrated that participants randomised to discontinuation had worse utility scores at 3 months (-0.037, 95% confidence interval -0.059 to -0.015) and fewer quality-adjusted life-years over 12 months (-0.019, 95% confidence interval -0.035 to -0.003) than those randomised to continuation. The discontinuation pathway, besides giving worse outcomes, also cost more [extra £2.71 per patient over 12 months (95% confidence interval -£36.10 to £37.07)] than the continuation pathway, although the cost difference was not significant. CONCLUSIONS: Patients who discontinue long-term maintenance antidepressants in primary care are at increased risk of relapse and withdrawal symptoms. However, a substantial proportion of patients can discontinue antidepressants without relapse. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants and improve shared decision-making. The participants may not have been representative of all people on long-term maintenance treatment and we could study only a restricted range of antidepressants and doses. Identifying patients who will not relapse if they discontinued antidepressants would be clinically important. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15969819 and EudraCT 2015-004210-26. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 69. See the NIHR Journals Library website for further project information.

Antidepressants are used to treat depression when someone is unwell, but are also used as maintenance treatment to prevent the reoccurrence of depression. There has been a large increase in the use of long-term maintenance antidepressant treatment, but the evidence for the benefits of maintenance beyond 8 months is very poor. The ANTidepressants to prevent reLapse in dEpRession (ANTLER) trial was a randomised controlled trial that examined the effectiveness of long-term maintenance treatment with antidepressants. The participants were well enough to consider stopping antidepressant medication, were recruited from primary care and had taken antidepressants for ≥ 9 months. In total, 238 participants were randomised to continue taking antidepressants and 240 were randomised to receive a visually identical tablet that contained no active ingredients after a period when the antidepressants were gradually reduced. Neither the participants nor those interviewing them knew which group they had been placed in, and they were followed up for 1 year. Participants who discontinued antidepressants were more likely to experience relapse than those who continued antidepressants. By 52 weeks, 39% of those who continued antidepressants had experienced a relapse, compared with 56% in the group that discontinued antidepressants. In other words, over a 52-week period, one in every six patients who stopped antidepressants would experience a relapse that may not have occurred if they had remained on their antidepressants. Patients in the discontinuation group reported more symptoms of anxiety and depression and experienced more withdrawal symptoms than those in the maintenance group, mostly in the first 3­4 months after stopping the antidepressants. Participants in the discontinuation group also reported lower quality of life than those in the maintenance group but both groups used similar amounts of health-care and social care resources over the 12-month period. About one-third of participants who were allocated to the discontinuation group in the ANTLER trial decided to restart their antidepressants. However, another one-third of participants in that group remained on trial medication for 12 months and managed without antidepressants. Long-term maintenance treatment with antidepressants is effective in reducing the rate of relapses. For those who are considering stopping their antidepressant, our findings will provide estimates of the likely benefits and harms, to improve shared decision-making and support the regular review of long-term antidepressant prescription.

A randomised controlled trial assessing the use of citalopram, sertraline, fluoxetine and mirtazapine in preventing relapse in primary care patients who are taking long-term maintenance antidepressants (ANTLER: ANTidepressants to prevent reLapse in dEpRession): study protocol for a randomised controlled trial.

BACKGROUND: Antidepressants are used both for treating acute episodes and for prophylaxis to prevent future episodes of depression, also called maintenance treatment. This article describes the protocol for a randomised controlled trial (ANTLER: ANTidepressants to prevent reLapse in dEpRession) to investigate the clinical effectiveness and cost-effectiveness in UK primary care of continuing on long-term maintenance antidepressants compared with a placebo in preventing relapse of depression in those who have taken antidepressants for more than 9 months and who are currently well enough to consider stopping maintenance treatment. METHODS/DESIGN: The ANTLER trial is an individually randomised, double-blind, placebo-controlled trial in which participants are randomised to remain on active medication or to take an identical placebo after a tapering period of 2 months. Eligible participants are those who: are between the ages of 18 and 74 years; have had at least two episodes of depression; and have been taking antidepressants for 9 months or more and are currently taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg but are well enough to consider stopping their medication. The participants will be followed up at 6, 12, 26, 39 and 52 weeks. The primary outcome will be the time in weeks to the beginning of the first episode of depression after randomisation. This will be measured using a retrospective version of the Clinical Interview Schedule-Revised administered at 12, 26, 39 and 52 weeks. Secondary outcomes will include depressive and anxiety symptoms, adverse effects, withdrawal symptoms, emotional processing tasks, quality of life and the resources and costs used. We will also perform a cost-effectiveness analysis based on results of the trial. DISCUSSION: The ANTLER trial findings will inform primary care prescribing practice by providing a valid and generalisable estimate of the clinical effectiveness and cost-effectiveness of long-term maintenance treatment with antidepressants in UK primary care. TRIAL REGISTRATION: Controlled Trials ISRCTN Registry, ISRCTN15969819. Registered on 21 September 2015.