Keller 1998.

Study characteristics
Methods	Design: multi‐phase double‐blind placebo‐controlled trial Prerandomisation phases Phase 1: acute treatment with sertraline (12 weeks) Phase 2: continuation treatment with sertraline (16 weeks) Duration post randomisation: 76 weeks Aim: to determine if maintenance therapy with sertraline hydrochloride can prevent recurrence of depression in the high‐risk group of patients experiencing chronic major depression or major depression with antecedent dysthymic disorder
Participants	Country: USA Setting: 10 academic centres and 2 clinical research centres Type of AD: sertraline Duration of antidepressant treatment prerandomisation: 28 weeks Duration of antidepressant post stabilisation: 16 weeks Number of participants in phase 1: 426; 209 entered continuation phase, 169 response at end of continuation treatment Total number of randomised participants: 161 (77 sertraline, 84 placebo) Primary diagnosis ‐ chronic major depression (at least 2 years' duration): 43% placebo, 52% antidepressant ‐ double depression (dysthymic disorder with concurrent diagnosis of major depression): 57% placebo, 48% antidepressant Number of previous episodes: 1.9 (2.1) placebo, 1.8 (2.2) sertraline Severity of depressive symptoms at randomisation (HAMD‐24), mean (SD): 6.3 (3.7) placebo, 5.5 (4.2) sertraline History of comorbidities ‐ anxiety disorder ‐ placebo: panic disorder 5%, social phobia 13%, GAD 2%, any anxiety disorders 22% ‐ antidepressant: panic disorder 16%, social phobia 10%, GAD 3%, any anxiety disorders 30% ‐ history of alcohol abuse: 24% placebo, 36% antidepressant ‐ history of substance abuse: 30% placebo, 43% antidepressant ‐ comorbid Axis II personality disorder: 51% placebo, 44% antidepressant Gender distribution (F): 69% placebo, 62% antidepressant Mean age, years (SD): 42.4 (9.7) placebo, 40.8 (9.0) antidepressant Inclusion criteria ‐ SCID‐I chronic MDD of 2 years' duration or dysthymic disorder with concurrent diagnosis of MDD (double depression) (DSM‐III criteria) ‐ patients entered continuation phase if full remission/response or satisfactory therapeutic response to acute treatment ‐ patients were eligible to enter the RCT if they had sustained at least a satisfactory antidepressant response to sertraline through the end of continuation therapy Defintion of response/remission: full remission/response (HAM‐D score ≤ 7 and CGI improvement 1 or 2) or satisfactory therapeutic response (reduction of 50% in HAM‐D total score plus HAM‐D ≤ 15 and CGI improvement ≤ 2 and CGI severity ≤ 3) Exclusion criteria ‐ not reported
Interventions	Intervention 1: placebo Tapering scheme: tapered sertraline over 4 weeks; 50 mg/week reduction Intervention 2: sertraline hydrochloride (at a flexible daily dose of 50 to 200 mg)
Outcomes	Primary ‐ time to recurrence of a major depressive episode Definition of recurrence: (1) DSM criteria for major depression for at least 3 weeks, (2) CGI severity score ≥ 4 (at least moderate severity), (3) CGI improvement score ≥ 3 (minimally improved or less), and (4) increase in HAM‐D score to a score ≥ 4 points higher than the maintenance phase baseline and within 1 week (total duration of clinical worsening criteria of at least 4 weeks) to meet all criteria and judged as recurrence of major depression by an investigator ‐ double‐blind titration to maximum dose of 200 mg per day was used for participants meeting recurrence criteria; no change in study medication was needed ‐ experiencing exacerbation but did not meet criteria Secondary ‐ time to re‐emergence of clinically significant depression: blinded review of HAM‐D, GCI, and overall clinical picture of all patients who discontinued the study prematurely. Agreement among 6 (75%) of 8 senior investigators was required for a patient to be categorised as having met this clinical endpoint (less stringent post hoc endpoint) ‐ time to re‐emergence of first symptoms of depression: blinded review of HAM‐D, GCI, and overall clinical picture of all patients who discontinued the study prematurely. Agreement among 6 (75%) of 8 senior investigators was required for a patient to be categorised as having met this clinical endpoint (less stringent post hoc endpoint) ‐ HAM‐D 24, CGI severity and improvement scale (every 2 weeks during first 12 weeks, then monthly) ‐ MADRS, Cornell Dysthymia Scale, Beck Depression Inventory (monthly) ‐ quality of life ‐ psychosocial functioning: SAS‐SR, SF‐36, LIFE (reported in Kocsis 2002)
Notes	Funding: study is supported by a grant from the pharmaceutical industry COI: main study author is a consultant from the pharmaceutical company, has received grants, and serves on the advisory board. Co‐authors received grants from the pharmaceutical industry
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: information insufficient to permit judgement
Allocation concealment (selection bias)	Unclear risk	Comment: information insufficient to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: trial described as double‐blind Quote: “to maintain blinding, this group of patients continued (as a parallel but non‐randomised group) to receive imipramine during subsequent continuation and maintenance phases… the integrity of the study’s double‐blind component was not compromised”
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: information insufficient
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: high dropouts and imbalance across treatment groups (placebo group 60/84 (71%) and sertraline group 42/77 (54.5%))
Selective reporting (reporting bias)	High risk	Comment: study protocol not available; adverse events and withdrawal symptoms not an outcome of the study
Other bias	Unclear risk	Comment: grant received from the pharmaceutical industry