Montgomery 2004.

Study characteristics
Methods	Design: multi‐phase double‐blind randomised placebo‐controlled trial Prerandomisation phase Phase 0: single‐blind placebo lead (4 to 10 days) Phase 1: open‐label treatment with venlafaxine IR 100 to 200 mg (8 weeks) Phase 2: continuation treatment with venlafaxine IR 100 to 200 mg (16 weeks) Duration post randomisation: 52 weeks Aim: to investigate the efficiency of venlafaxine for prevention of recurrence of depression among patients who have responded to treatment
Participants	Country: USA and Europe (countries not described) Setting: community adults (outpatients from psychiatric clinics) Type of antidepressant: venlafaxine immediate release (IR) Duration of antidepressant treatment prerandomisation: 24 weeks Duration of antidepressant treatment post stabilisation: 16 weeks Number of participants: 496 entered phase 1, 286 completed open treatment Total number of randomised participants: 235 (placebo 123, venlafaxine 112) Primary diagnosis: recurrent major depression Number of previous episodes: 2 or 3 episodes: 72% placebo, 71% antidepressant; 4 or 5 episodes: 25% placebo, 23% antidepressant Severity of depressive symptoms at randomisation HAM‐D 21 total score, mean (SE): 4.9 (3.7) placebo, 4.5 (3.4) venlafaxine IR MADRS total score, mean (SE): 5.2 (4.8) placebo, 4.3 (3.5) venlafaxine IR Gender distribution (F): 67% placebo, 71% venlafaxine Mean age, years (SD): 43.5 (11.2) placebo, 43.8 (11) venlafaxine Inclusion criteria ‐ ≥ 18 years ‐ meet diagnosis of recurrent major depression (≥ 1 previous episode in the last 5 years with a symptom‐free period > 6 months between episodes) (DSM‐III criteria) ‐ responders to acute open‐label treatment and remained relapse‐free during continuation treatment with venlafaxine Definition of response and remission: HAM‐D 21 score ≤ 12 on Day 56 of acute treatment; no more than 2 HAM‐D 21 scores > 10; and no CGI‐S ≥ 4 between Months 2 and 6 during continuation treatment Exclusion criteria ‐ history of drug and alcohol dependence within 2 years of the start of open treatment ‐ recent myocardial infarction ‐ history of hepatic or renal disease ‐ seizure disorder ‐ psychotic disorder ‐ bipolar disorder ‐ concomitant psychiatric diagnosis meeting DSM‐III criteria ‐ pregnant and breastfeeding women
Interventions	Intervention 1: placebo Intervention 2: venlafaxine IR 100 to 200 mg per day Tapering scheme: tapering over 2 weeks Concomitant treatment ‐ psychotropic medication not permitted with the exception of chloral hydrate in USA and short‐acting benzodiazepines in Europe ‐ those with established psychotherapy or counselling were allowed to enter open treatment, but initiation or change in intensity of either modality was not permitted
Outcomes	Primary outcomes ‐ number of participants with major depression (cumulative probability of recurrence) Definition of relapse/recurrence: CGI‐S ≥ 4 (moderate to severe depression) ‐ time to recurrence Secondary outcomes ‐ time to discontinuation in patients who withdrew from the study because of lack of efficacy ‐ time to recurrence excluding those who discontinued during the first 28 days of the RCT ‐ depressive symptoms and global severity of illness using mean HAM‐D 21, total HAM‐D, MADRS total, CGI‐S scores Safety: assessed by physical examinations, vital signs, ECGs, clinical laboratory tests, monitoring of adverse events, and patient reports throughout the study
Notes	Funding: study was supported by a grant from the pharmaceutical industry COI: not reported by study authors; 4 of 5 study authors were employees in 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 Quote: "patients were randomly assigned to venlafaxine or placebo"
Allocation concealment (selection bias)	Unclear risk	Comment: information insufficient to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: described as double‐blind but information insufficient to permit judgement Quote: "...double blind...placebo substitution..."; "randomly assigned to either venlafaxine or receive placebo under double blind conditions..."; "those assigned to the placebo group had their venlafaxine dose tapered off in a blinded fashion..."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: information insufficient to permit judgement
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: dropout rates were higher in the placebo group (76%) than in the venlafaxine group (50%); LOCF analysis
Selective reporting (reporting bias)	High risk	Comment: no protocol available; relevant outcomes measured; adverse events reported; no withdrawal symptoms
Other bias	Unclear risk	Comment: grant from the pharmaceutical industry