Internet and telephone intervention to support patients discontinuing longterm antidepressants in primary care: the REDUCE research programme including RCT

Background: There is significant concern about increasing long-term antidepressant use in Western countries, much of which is not evidence-based. Median duration of treatment is more than 2 years in the United Kingdom, and more than 10% of adults are taking antidepressants, risking potentially significant adverse effects, particularly for older patients. Objectives: To develop internet-and telephone-based support for practitioners and patients, through a process of co-design, and to determine its effectiveness and cost-effectiveness in helping people discontinue antidepressants without increasing depression, in a randomised controlled trial. Design: Two systematic reviews (one qualitative); qualitative interviews with patients; qualitative interviews and focus groups with healthcare practitioners; co-production of online interventions with patients and practitioners; feasibility randomised controlled trial; definitive non-inferiority cluster randomised controlled trial with health economic evaluation; and quantitative and qualitative process evaluations. A booklet and video version of the patient intervention was also developed in Urdu. Setting: Primary care (131 general practices in England and Wales). Participants: Adults on antidepressant treatment for more than 1 year for a first episode of depression, or more than 2 years for recurrent depression, who were no longer depressed or judged to be at significant risk of relapse. Interventions: Tailored internet support (ADvisor for patients, and ADvisorHP for health professionals), plus three telephone support calls from psychological well-being practitioners. Primary outcome: Depressive symptoms on the Patient Health Questionnaire-9 items questionnaire at 6 months. Secondary outcomes: Depressive symptoms over 12 months, antidepressant discontinuation, anxiety, quality of life, withdrawal symptoms, adverse events, mental well-being, patient enablement, patient satisfaction, health service use and costs over 12 months. Sample size: The original sample size calculation gave a target of 402 patients for 90% power with one-sided significance of 2.5% to determine non-inferiority of the intervention, within 2 points on the Patient Health Questionnaire-9 items. This was reduced to 360 on finding a significant correlation between baseline and follow-up values for the Patient Health Questionnaire-9 items part-way through the trial. Randomisation: Remote cluster randomisation of practices by computerised sequence generation, with minimization by practice size, urban/rural location and deprivation index. Blinding: Participants and researchers could not be blinded given the pragmatic open design, but self-complete measures avoided observer rating bias, and analyses were conducted blind. Analyses: Linear mixed modelling was used to determine differences in outcomes, adjusting for previous depression, baseline outcome values, baseline anxiety, sociodemographic characteristics, and practice as a random effect. Primary analysis was performed by intention to treat, with per-protocol and complier-average sensitivity analyses. Multiple imputation was used to account for missing values. Qualitative interviews: Semistructured topic guides were used for interviews and focus groups, informed by normalisation process theory, which were audio-recorded, transcribed verbatim and analysed using reflexive thematic analysis. Results: Systematic reviews, qualitative interviews and focus groups indicated that barriers to discontinuing treatment include a fear of relapse of depression and withdrawal symptoms. If practitioners do not broach possible discontinuation, patients will usually continue treatment without questioning it. Patients wanted information on antidepressant mechanisms and effects, withdrawal symptoms and coping strategies. Practitioners wanted guidance on initiating discontinuation, antidepressant tapering regimens, and distinguishing withdrawal from relapse. The definitive trial randomised 330 patients (5% of those approached; 178 in intervention practices and 152 in controls), of whom 275 (83%) were followed up at 6 months, and 240 (73%) at 12 months. Mean Patient Health Questionnaire-9 items scores were slightly higher among controls at 6 months [5.0 vs. 4.0; adjusted difference 1.07 (95% confidence interval 0.09 to 2.06; p = 0.033)]. Antidepressant discontinuation rates at 6 months were slightly higher in the intervention arm, but not significantly (45.5% vs. 41.9% in the control arm). Antidepressant withdrawal symptoms and mental well-being were significantly better in the intervention arm. There were no significant differences in anxiety, quality of life, adverse events, patient enablement, or satisfaction with care. The adjusted mean cost of services used was lower in the intervention arm by −£69 (95% confidence interval −£77 to £207). The incremental cost-effectiveness ratio was a mean saving of −£2839 per quality-adjusted life-year gained (95% confidence interval −£30,024 to £22,227). The probability of the intervention being cost-effective compared to review alone, at the National Institute for Health and Care Excellence thresholds of societal willingness to pay of £20,000 and £30,000 per quality-adjusted life-year, was > 89% for both. Qualitative interviews suggested advice to taper slowly, and information on the difference between relapse and withdrawal symptoms, contributed significantly to the success of the interventions. Participants were well and willing to attempt antidepressant discontinuation, and general practitioners excluded people considered at high risk of relapse of depression. This may explain why more than 40% of participants in each arm discontinued. The results may not generalise to an unselected sample of people on long-term antidepressants, including people at greater risk of relapse. Conclusions: Comparatively high rates of discontinuation of long-term antidepressants are achievable through enabling patients, who are ready to consider stopping them, to get tapering advice and support from their general practitioners. Tailored internet and psychologist telephone support may help protect patients coming off long-term antidepressants against depressive and withdrawal symptoms, and conserve mental well-being. The interventions appear highly costeffective at thresholds for societal willingness to pay used by the National Institute for Health and Care Excellence. Trial registration: Workstream 4 (feasibility trial) is registered as International Standardised Randomised Controlled Trial Number ISRCTN15036829 and Workstream 5 (definitive trial of effectiveness and cost-effectiveness) is registered as ISRCTN12417565.