Internet and Telephone Support for Discontinuing Long-Term Antidepressants: The REDUCE Cluster Randomized Trial

IMPORTANCE: There is significant concern regarding increasing long-term antidepressant treatment for depression beyond an evidence-based duration. OBJECTIVE: To determine whether adding internet and telephone support to a family practitioner review to consider discontinuing long-term antidepressant treatment is safe and more effective than a practitioner review alone. DESIGN, SETTING, AND PARTICIPANTS: In this cluster randomized clinical trial, 131 UK family practices were randomized between December 1, 2018, and March 31, 2022, with remote computerized allocation and 12 months of follow-up. Participants and researchers were aware of allocation, but analysis was blind. Participants were adults who were receiving antidepressants for more than 1 year for a first episode of depression or more than 2 years for recurrent depression who were currently well enough to consider discontinuation and wished to do so and who were at low risk of relapse. Of 6725 patients mailed invitations, 330 (4.9%) were eligible and consented. INTERVENTIONS: Internet and telephone self-management support, codesigned and coproduced with patients and practitioners. MAIN OUTCOMES AND MEASURES: The primary (safety) outcome was depression at 6 months (prespecified complete-case analysis), testing for noninferiority of the intervention to under 2 points on the 9-item Patient Health Questionnaire (PHQ-9). Secondary outcomes (testing for superiority) were antidepressant discontinuation, anxiety, quality of life, antidepressant withdrawal symptoms, mental well-being, enablement, satisfaction, use of health care services, and adverse events. Analyses for the main outcomes were performed on a complete-case basis, and multiple imputation sensitivity analysis was performed on an intention-to-treat basis. RESULTS: Of 330 participants recruited (325 eligible for inclusion; 178 in intervention practices and 147 in control practices; mean [SD] age at baseline, 54.0 [14.9] years; 223 women [68.6%]), 276 (83.6%) were followed up at 6 months, and 240 (72.7%) at 12 months. The intervention proved noninferior; mean (SD) PHQ-9 scores at 6 months were slightly lower in the intervention arm than in the control arm in the complete-case analysis (4.0 [4.3] vs 5.0 [4.7]; adjusted difference, -1.1; 95% CI, -2.1 to -0.1; P = .03) but not significantly different in an intention-to-treat multiple imputation sensitivity analysis (adjusted difference, -0.9 (95% CI, -1.9 to 0.1; P = .08). By 6 months, antidepressants had been discontinued by 66 of 145 intervention arm participants (45.5%) who provided discontinuation data and 54 of 129 control arm participants (41.9%) (adjusted odds ratio, 1.02; 95% CI, 0.52-1.99; P = .96). In the intervention arm, antidepressant withdrawal symptoms were less severe, and mental well-being was better compared with the control arm; differences were small but significant. There were no significant differences in the other outcomes; 28 of 179 intervention arm participants (15.6%) and 22 of 151 control arm participants (14.6%) experienced adverse events. CONCLUSIONS AND RELEVANCE: In this cluster randomized clinical trial of adding internet and telephone support to a practitioner review for possible antidepressant discontinuation, depression was slightly better with support, but the rate of discontinuation of antidepressants did not significantly increase. Improvements in antidepressant withdrawal symptoms and mental well-being were also small. There were no significant harms. Family practitioner review for possible discontinuation of antidepressants appeared safe and effective for more than 40% of patients willing and well enough to discontinue. TRIAL REGISTRATION: ISRCTN registry Identifiers: ISRCTN15036829 (internal pilot trial) and ISRCTN12417565 (main trial)

Internet and Telephone Support for Discontinuing Long-Term Antidepressants: The REDUCE Cluster Randomized Trial

Importance: There is significant concern regarding increasing long-term antidepressant treatment for depression beyond an evidence-based duration. Objective: To determine whether adding internet and telephone support to a family practitioner review to consider discontinuing long-term antidepressant treatment is safe and more effective than a practitioner review alone. Design, Setting, and Participants: In this cluster randomized clinical trial, 131 UK family practices were randomized between December 1, 2018, and March 31, 2022, with remote computerized allocation and 12 months of follow-up. Participants and researchers were aware of allocation, but analysis was blind. Participants were adults who were receiving antidepressants for more than 1 year for a first episode of depression or more than 2 years for recurrent depression who were currently well enough to consider discontinuation and wished to do so and who were at low risk of relapse. Of 6725 patients mailed invitations, 330 (4.9%) were eligible and consented. Interventions: Internet and telephone self-management support, codesigned and coproduced with patients and practitioners. Main Outcomes and Measures: The primary (safety) outcome was depression at 6 months (prespecified complete-case analysis), testing for noninferiority of the intervention to under 2 points on the 9-item Patient Health Questionnaire (PHQ-9). Secondary outcomes (testing for superiority) were antidepressant discontinuation, anxiety, quality of life, antidepressant withdrawal symptoms, mental well-being, enablement, satisfaction, use of health care services, and adverse events. Analyses for the main outcomes were performed on a complete-case basis, and multiple imputation sensitivity analysis was performed on an intention-to-treat basis. Results: Of 330 participants recruited (325 eligible for inclusion; 178 in intervention practices and 147 in control practices; mean [SD] age at baseline, 54.0 [14.9] years; 223 women [68.6%]), 276 (83.6%) were followed up at 6 months, and 240 (72.7%) at 12 months. The intervention proved noninferior; mean (SD) PHQ-9 scores at 6 months were slightly lower in the intervention arm than in the control arm in the complete-case analysis (4.0 [4.3] vs 5.0 [4.7]; adjusted difference, -1.1; 95% CI, -2.1 to -0.1; P = .03) but not significantly different in an intention-to-treat multiple imputation sensitivity analysis (adjusted difference, -0.9 (95% CI, -1.9 to 0.1; P = .08). By 6 months, antidepressants had been discontinued by 66 of 145 intervention arm participants (45.5%) who provided discontinuation data and 54 of 129 control arm participants (41.9%) (adjusted odds ratio, 1.02; 95% CI, 0.52-1.99; P = .96). In the intervention arm, antidepressant withdrawal symptoms were less severe, and mental well-being was better compared with the control arm; differences were small but significant. There were no significant differences in the other outcomes; 28 of 179 intervention arm participants (15.6%) and 22 of 151 control arm participants (14.6%) experienced adverse events. Conclusions and Relevance: In this cluster randomized clinical trial of adding internet and telephone support to a practitioner review for possible antidepressant discontinuation, depression was slightly better with support, but the rate of discontinuation of antidepressants did not significantly increase. Improvements in antidepressant withdrawal symptoms and mental well-being were also small. There were no significant harms. Family practitioner review for possible discontinuation of antidepressants appeared safe and effective for more than 40% of patients willing and well enough to discontinue. Trial Registration: ISRCTN registry Identifiers: ISRCTN15036829 (internal pilot trial) and ISRCTN12417565 (main trial)

Internet and telephone intervention to support patients discontinuing long-term 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 minimisation 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 cost-effective 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. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme (NIHR award ref: RP-PG-1214-20004) and is published in full in Programme Grants for Applied Research; Vol. 13, No. 7. See the NIHR Funding and Awards website for further award information

Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy

Purpose: Evaluate response of mismatch repair deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty dMMR rectal cancer patients were identified by immunohistochemistry and/or microsatellite instability analysis, with initial treatment response compared to a matched pMMR rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), 6 (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable to 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome (LS) with enrichment of germline MSH2 and MSH6 mutations when compared to 193 LS-associated colon cancer patients (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < .003). Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for LS in dMMR rectal cancer patients

Measuring progress and projecting attainment on the basis of past trends of the health-related Sustainable Development Goals in 188 countries: an analysis from the Global Burden of Disease Study 2016

The UN’s Sustainable Development Goals (SDGs) are grounded in the global ambition of “leaving no one behind”. Understanding today’s gains and gaps for the health-related SDGs is essential for decision makers as they aim to improve the health of populations. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016), we measured 37 of the 50 health-related SDG indicators over the period 1990–2016 for 188 countries, and then on the basis of these past trends, we projected indicators to 2030

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570