Derubeis 2019.

Study characteristics
Methods	Design: multi‐phase randomised controlled trial Prerandomisation phases Phase 1a: acute treatment with antidepressants (and any of the augmenting or adjunctive agents) with and without cognitive‐behavioural therapy (CBT) lasted until the patient met the criteria for remission (at least 4 consecutive weeks of minimal symptoms) (up to 19 months of treatment was allowed for remission). Results of phase 1 were reported in Hollon 2016 Phase 1b: continuation treatment with antidepressants (and any of the augmenting or adjunctive agents) with and without CBT lasted until the patient met the criteria for recovery (another 26 consecutive weeks without relapse) (up to 42 months for recovery was allowed) Duration post randomisation: 156 weeks Aim: to determine the effects of combining CBT with antidepressants and antidepressants alone for prevention of depressive recurrence when antidepressants were withdrawn or maintained after recovery in patients with major depressive disorder
Participants	Country: USA Setting: community adults (3 outpatient research clinics) Type of AD: 4 different classes of antidepressants (sertraline, venlafaxine, 2 others not reported) Duration of antidepressant treatment before randomisation: up to 42 months, mean 80.3 (40.0) weeks (reported for the combination and antidepressants alone study arms; data not separately reported for each study arm) + mean (SD) number of CBT sessions in the combination group during phase 1 was 33.3 (22.8) Duration of antidepressant treatment post stabilisation: minimum 30 weeks Number of participants: participants with CBT: 227 randomised to phase 1, 170 responded to phase 1, 155 randomised to RCT; participants without CBT: 225 randomised to phase 1, 148 responded to phase 1, 137 randomised to RCT Total number of randomised participants: 155 participants with CBT (70 discontinuation, 85 antidepressant), 137 participants without CBT (69 discontinuation, 68 antidepressant) Primary diagnosis ‐ in participants with CBT: chronic major depressive disorder: 35% discontinuation, 31% antidepressant; recurrent depression: 84% discontinuation, 89% antidepressant ‐ in participants without CBT: chronic major depressive disorder: 34% discontinuation, 50% antidepressant; recurrent depression: 88% discontinuation, 82% antidepressant previous episodes Severity of depressive symptoms at randomisation (HDRS), mean (SD): participants with PCT: discontinuation 5.4 (3.9), antidepressant 5.8 (4.0); participants without PCT: discontinuation 6.0 (4.4), antidepressant 5.4 (4.0) Gender distribution (F): participants with PCT: discontinuation 59%, continuation 56%; participants without PCT: discontinuation 62%, continuation 37% Mean age, years (SD): participants with PCT: discontinuation 43.9 (11.8), antidepressant 45.6 (13.0); participants without PCT: discontinuation 43.9 (11.8), antidepressant 45.6 (13.0) Inclusion criteria ‐ DSM‐IV major depressive disorder (MDD) either chronic (episode duration ≥ 2 years) or recurrent (with an episode in the past 3 years if only the second episode) ‐ 17‐item Hamilton Rating Scale for Depression (HDRS) score ≥ 14 ‐ ≥ 18 years of age at entry to phase 1 ‐ English speaking ‐ willing and able to provide informed consent Patients were previously randomised in phase 1 of the clinical trial, which compared patients who received antidepressant treatment with patients who received antidepressant treatment in combination with PCT. Patients from phase 1 were eligible to participate in phase 2 if they met the criteria for recovery before the maximum allowable time (3.5 years) Response/remission criteria: 4 consecutive weeks of LIFE Problem Symptom Rating (PSR) Scale values ≤ 2 and HDRS scores ≤ 8 for 4 consecutive weeks (with partial remission defined as LIFE PSR values ≤ 3 and HDRS scores ≤ 12 after month 12 only) Recovery criteria: 6 consecutive months following remission without relapse (2 weeks of elevated LIFE PSR scores ≥ 4 and HDRS scores ≥ 14) Exclusion criteria ‐ history of bipolar disorder or non‐affective psychosis ‐ substance dependence in the past 3 months ‐ DSM‐IV Axis I disorders requiring non‐protocol treatment ‐ DSM‐IV Axis II disorders poorly suited to study treatments (antisocial, borderline, and schizotypal) ‐ suicide risk requiring immediate hospitalisation ‐ medical condition precluding the use of study medications (including pregnancy) ‐ current medications that induce depression ‐ mandated treatment or compensation issues
Interventions	Intervention 1: discontinuation of antidepressant (without placebo) and discontinuation of CBT Tapering scheme: 4‐week period or longer if clinically indicated Intervention 2: continuation of antidepressant (adjustment or augmentation of the medication regimen was permitted) and discontinuation of CBT Co‐intervention: participants in both treatment groups received CBT sessions 2x weekly for at least the first 2 weeks, at least weekly thereafter during acute treatment, and then at least monthly during continuation phase and delivered by therapist. Therapists were free to vary the frequency to meet the needs of patients. Sessions were based on a treatment manual for CT of depression augmented when indicated for participants with comorbid Axis II disorders. CBT ended before entry to the discontinuation trial
Outcomes	Primary outcomes ‐ estimates of the recurrence of depression. Recurrence of depression was measured by the Longitudinal Interval Follow‐up Evaluation (LIFE) (every 4 weeks for the first 12 weeks and every 12 weeks thereafter); the LIFE tool measures psychiatric status rating on a scale of 1 to 6, with score of 5 or 6 indicating the patient met DSM‐IV symptom criteria for MDD that week Definition of relapse/recurrence ‐ 3 consecutive weeks with LIFE rating of 5 or 6 during the first 8 weeks ‐ LIFE rating of 5 or 6 for 2 consecutive weeks at any time after the first 8 weeks Secondary outcome Serious adverse events Results were separated for participants with and without PCT
Notes	Funding: study was supported by 3 grants from the National Institute of Mental Health; 2 pharmaceutical companies provided sertraline and venlafaxine for the trial COI: 2 study authors received grants from the pharmaceutical industry Note: a principle‐based algorithm was implemented that could involve up to 4 different classes of ADMs and any of the augmenting or adjunctive agents commonly used in clinical practice. Study authors did not report the 4 different classes nor the augmenting agents
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: a random component is used Quote: "random assignment to treatment was implemented using an adaptive (urn) randomisation procedure"; "adaptive randomisation algorithms for phase 2 assignment were..."
Allocation concealment (selection bias)	Unclear risk	Comment: insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: medication withdrawn was not accompanied by the use of placebo. Due to the nature of the trial (monotherapy vs combination therapy), blinding would not be possible for patients and providers Quote: "because medication withdrawal was not accompanied by the use of placebo, phase 1 assignments were not blinded for patients or pharmacotherapists"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: blinding of outcome assessment ensured; likely that blinding was successful Quote: "interviewers who were blinded to the patients’ treatment conditions assessed patient status using the LIFE ..."
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: dropout rates different across groups (28.5% discontinuation group, 35.5% antidepressant group); reasons for dropout not accounted for
Selective reporting (reporting bias)	High risk	Comment: study protocol is available; predefined outcomes were not reported (types of serious adverse events). Other adverse events and withdrawal symptoms were not an outcome
Other bias	Unclear risk	Comment: grant from pharmaceutical industry