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

Abstract

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.

Interventions to help patients withdraw from depression drugs: systematic review

“…32 Our updated searches identified one additional eligible study listed with three publications in both databases. [67][68][69] Three of the 13 included studies compared two withdrawal interventions [30][31][32] and ten compared withdrawal with continued drug treatment (tables 1a and 1b). 29,[33][34][35][36][37][38][39][40]67 One study was prematurely stopped following an interim analysis conducted by an independent data monitoring committee due to excessive deterioration upon withdrawal, which was interpreted as relapse.…”

Reliability of the retrospective Clinical Interview Schedule Revised (rCIS-R) to assess relapse in depression in primary care patients

“…The rCIS-R was a modified version of CIS-R and designed as a self-administered computerised questionnaire and asked about the previous 12 weeks [18]. The 12 weeks recall period was chosen because the follow-up appointments were spaced at roughly 3 months or 12 week intervals and it was convenient anchor point for participants to remember what has happened since they last met with the researcher.…”

Esketamine vs Midazolam in Boosting the Efficacy of Oral Antidepressants for Major Depressive Disorder

“…All participants scored 0 points in Clinician-Administered Dissociative States Scale at 2, 4, and 24 hours. At 40 minutes, participants in the esketamine-treated group showed higher level of dissociation compared with the midazolam control group (median [IQR] score, 0 [0-0] vs 6 [3][4][5][6][7][8][9][10][11][12][13]; P < .001). For general side effects assessed by Udvalg for Kliniske Undersogelser, which were defined as an increase of at least 1 on each item, 2 participants (13.3%) had increased dream activity in the group treated with esketamine, and 4 participants (26.7%) had tension or inner unrest and 3 participants (20.0%) had increased dream activity in the midazolam control group (Table 2).…”

“…Treatment guidelines recommend that patients with MDD continue antidepressant therapy for 4 to 9 months after successful acute phase treatment to prevent relapse and recurrence and 2 years or more of maintenance treatment at a full therapeutic dose for patients with an increased risk of MDD recurrence . However, rates of relapse and recurrence remain high even among adherent patients with MDD …”

“…9,10 However, rates of relapse and recurrence remain high even among adherent patients with MDD. [11][12][13] Unlike relapse and recurrence, which occur during the continuation or maintenance phase, loss of a previously effective response while still receiving adequate antidepressant treatment (ADT) occurs in a relatively high proportion of patients with MDD, with rates ranging from 9% to 57%. 14 This concerning phenomenon is known as ADT tachyphylaxis or antidepressant tolerance.…”