Bockting 2018.

Study characteristics
Methods	Design: multi‐centre single‐blind 3‐arm randomised controlled trial Prerandomisation phase: no Duration post randomisation: 104 weeks Aim: to compare the effectiveness of antidepressants alone with preventive cognitive therapy (PCT) while tapering off antidepressants and with PCT added to antidepressants in prevention of relapse and recurrence
Participants	Country: Netherlands Setting: community adults recruited via general practitioners (GPs), pharmacists, secondary mental health care and media, or other means Type of antidepressant: SSRI (≥ 80%), other: SNRI, TCA, atypical AD, MAOI, or more than 1 Duration of antidepressant treatment prerandomisation: at least 24 weeks Duration of antidepressant treatment post stabilisation: in remission for at least 8 weeks and no longer than 104 weeks Primary diagnosis: recurrent major depressive disorder Total number of randomised participants: 289 (85 in PCT + discontinuation, 100 antidepressant alone, 104 antidepressants, and PCT) → discontinuation group was split to allow multiple‐arm comparison in the analysis: 43 → 143  participants for comparison PCT + discontinuation compared to AD and 146 participants for comparison PCT and tapering vs PCT and AD continuation Number of previous depressive episodes, median (IQR): 5 (3 to 6) PCT + discontinuation, 4 (3 to 6) antidepressants, 5 (3 to 6) antidepressant + PCT Psychological or psychotherapeutic treatment at randomisation: 16/85 (19%) PCT + discontinuation, 18/99 (18%) antidepressant, 21/104 (20%) antidepressant + PCT Severity of depressive symptoms at randomisation (HDRS score), mean (SD): 3.6 (3.0) PCT + discontinuation; 3.8 (3.1) antidepressant; 3.6 (3.1) PCT + antidepressant Gender distribution (F): 62% PCT + discontinuation, 64% antidepressant, 69% PCT + antidepressant Mean age, years (SD): 47.7 (11.1) PCT + discontinuation, 47.2 (10.5) antidepressant, 47.0 (9.3) PCT + antidepressant Inclusion criteria ‐ ≥ 2 previous depressive episodes (DSM‐IV‐criteria) in the past 5 years ‐ in remission (according to DSM‐IV criteria) for > 2 months and ≤ 2 years ‐ recovery had to have been achieved with acute antidepressant treatment ‐ remitted on antidepressant treatment and use of antidepressant (delivered in primary or secondary care) ≥ 6 months Definition of response/remission: current score ≤ 10 on HDRS 17 Exclusion criteria ‐ current mania or hypomania ‐ history of bipolar disorder ‐ any history of psychosis, including major depressive episode with psychotic features ‐ current alcohol or drug abuse ‐ predominant anxiety disorder ‐ receiving psychological treatment more than twice a month ‐ diagnosis of organic brain damage
Interventions	Intervention 1: preventive cognitive therapy (PCT) combined with tapering antidepressants (no placebo) Description: PCT, based on a treatment manual, comprised 8 weekly group or individual sessions delivered by therapists. GPs and psychiatrists were advised to taper antidepressants over a period of 4 weeks. The GP or psychiatrist and participant received a letter with instructions to guide tapering and a tapering schedule per type of drug. Participants were asked for an intention to taper antidepressants and were allowed to restart antidepressants at any time, which was monitored. Doses of antidepressants were assessed in all participants with the Trimbos and Institute for Medical Technology Assessment questionnaire on costs associated with psychiatric illness. Participants in the tapering group were also monitored on their progress via telephone by an independent researcher. For all antidepressants, equivalent doses in mg of fluoxetine were computed Providers: therapists were psychologists fully trained in cognitive‐behavioural therapy who received an additional 16 hours of training specific to this study Integrity of delivery: to maintain treatment integrity, therapists followed a PCT manual and were supervised by a fully trained cognitive‐behavioural therapist or a licensed psychologist Adherence to PCT (i.e. completing ≥ 5 sessions): 90% Tapering scheme: 4 weeks; GP and psychiatrists received a tapering schedule per type of drug. Most (60%) individuals tapered antidepressants with their doctors over 6 months, indicating that a time frame of 4 weeks was not considered feasible for many individuals Intervention 2: continuation of antidepressant treatment Description: GPs and psychiatrists were advised to continue guidance and prescription of antidepressants at minimally required adequate doses or higher (≥ 20 mg fluoxetine equivalent), as recommended by guidelines. Participants were encouraged to use antidepressants as prescribed, and GPs and psychiatrists were encouraged to prescribe therapeutic doses and to discuss problems with adherence Intervention 3: antidepressant treatment and preventive cognitive therapy (PCT) Description: GPs and psychiatrists were advised to continue guidance and prescription of antidepressants at minimally required adequate doses or higher (≥ 20 mg fluoxetine equivalent), as recommended by guidelines. Participants were encouraged to use antidepressants as prescribed Co‐intervention: 18 in the antidepressants alone group, 16 in the PCT with tapering of antidepressants group, 21 in the PCT and antidepressants group received additional psychological or psychotherapeutic treatment. Two participants in each group received inpatient treatment
Outcomes	Primary ‐ time to recurrence ‐ remission after 3, 9, 15, and 24 months using DSM‐IV‐TR criteria assessed with SCID‐I, including retrospective parts and information from monthly ratings on the Inventory of Depressive Symptomatology–Self‐Report (IDS‐SR) Definition of recurrence/relapse: DSM‐IV criteria assessed with SCID‐I, including retrospective parts and information from monthly ratings on the IDS‐SR Secondary ‐ number of major depressive episodes (assessed with SCID‐I), severity of the last major depressive episode (assessed with SCID‐I), and level of residual symptoms (assessed with HDRS), median duration of recurrence ‐ cost‐effectiveness and quality‐adjusted life‐years (EQ‐5D every 3 months) ‐ suspected serious adverse events
Notes	Funding: The Netherlands Association for Health Research and Development (ZONMW) and The Netherlands Organisation for Scientific Research Conflicts of interest: first author is a member of the scientific advisory board of the National Insure Institute, for which she receives an honorarium, although this role has no direct relation to this study. CLHB has presented keynote addresses at conferences such as the European Psychiatry Association and the European Conference Association, for which she sometimes receives an honorarium. She has presented clinical training workshops, some of which include a fee. CLHB receives royalties from her books and co‐edited books, and she developed PCT on the basis of the cognitive model of AT Beck. One co‐author has received fees from several pharmaceutical companies and grants from The Netherlands Organisation for Health Research and Development and the European Union. Provider of study drugs is not described
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: randomisation was performed by using a computer random number generator Quote: "...the automated permuted‐block randomisation using a computer‐generated random numbers with a predefined allocation ratio of 10:10:8 to PCT and antidepressants, antidepressants alone and PCT while tapering off antidepressants"
Allocation concealment (selection bias)	Low risk	Comment: an independent research assistant was responsible for allocation (central allocation) Quote: "an independent research assistant masked to the randomisation sequence entered the stratification characteristics and implemented the automated permuted‐block randomisation..."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comments: study is described as single‐blind; participants and physicians were not blinded, and the outcome is likely to be influenced by lack of blinding Quote: "participants and physicians were aware of treatment allocation"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comments: study is described as single‐blind and it is unlikely that blinding could have been broken Quote: "trained assessors masked to treatment allocation did all subsequent follow‐up assessments"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: rates and reasons for dropouts were described in the flow chart. Dropouts were low and were similar in both groups (3/85 discontinuation, 4/100 antidepressant). Primary analysis was done by intention‐to‐treatment principle Quote: "primary analyses were done by intention to treat"; "we also did two per‐protocol analyses"; "in 43 (23%) of 189 participants assigned to PCT, the intervention was not started and follow‐up data were not available because the travel time was too long to visit the PCT group or the group sessions were planned at a time they could not attend ... In addition to these 43 participants, 16 in the PCT groups and 21 in the antidepressants alone group dropped out for other reasons"
Selective reporting (reporting bias)	High risk	Comment: the study protocol is available, and all of the study’s pre‐specified (primary and secondary) outcomes have been reported in the pre‐specified way. Suspected serious adverse events were recorded and were reported to the ethics committee, although they were not mentioned in the report. Withdrawal symptoms were not an outcome
Other bias	Low risk	Comment: none