Keller 2007.

Study characteristics
Methods	Design: multi‐phase double‐blind randomised placebo‐controlled trial Prerandomisation phases Phase 1: acute treatment with venlafaxine ER (75 mg to 300 mg/d) (10 weeks) Phase 2: continuation treatment with venlafaxine ER (24 weeks) Phase 3: maintenance treatment with venlafaxine ER (52 weeks) (reported in Kocsis 2007); those who responded to venlafaxine entered this study and were randomised to venlafaxine or to placebo Duration post randomisation: 52 weeks Aim: to report second‐year results from the 2‐year maintenance phase of a long‐term study to evaluate the efficacy and safety of venlafaxine extended release (ER) in preventing recurrence of depression
Participants	Country: USA Setting: 29 clinical sites Type of antidepressant: venlafaxine 100% Duration of antidepressant treatment prerandomisation: 86 weeks Duration of antidepressant treatment post stabilisation: 76 weeks Number of participants: 821 entered phase 1, 530 entered phase 2, 409 completed phase 2 in remission or improved response, 336 entered phase 3, 136 completed phase 3 Total number of randomised participants: 83 (40 placebo, 43 AD); third arm (48 continued placebo) (not relevant for this review) Primary diagnosis: recurrent depression Number of previous episodes: not reported Severity of depressive symptoms at randomisation (HAM‐D 17 score), mean (SD): 4.1 (3.7) placebo, 4.8 (2.6) antidepressant Gender distribution (F): 70% placebo, 60% antidepressant Mean age, mean, years: 42.8 placebo, 44.8 antidepressant Inclusion criteria ‐ 18 years or older ‐ DSM‐IV diagnostic criteria for MDD confirmed by structured diagnostic interview at entry of phase 1. Experienced depressive symptoms for ≥ 1 month before the start of phase 1. ‐ met the following criteria for recurrent depression: history ≥ 3 episodes of major depression, with ≥ 2 episodes in the past 5 years (including the current episode), and an interval ≥ 2 months between the end of the previous episode and the beginning of the current episode ‐ had a response (HAM‐D 17 total score ≤ 12 and ≥ 50% decrease from acute phase baseline) or a remission (HAM‐D 17 score ≤ 7) of the intake episode of MDD at the end of maintenance phase 3. Patients achieving a response (therapeutic response, defined as a HAM‐D 17 total score ≤ 12 and ≥ 50% decrease from baseline, or remission, defined as HAM‐D 17 score ≤ 7) during the acute phase 1 were eligible to enter the 6‐month continuation phase 2. Patients who continued to demonstrate a response at the end of the continuation phase 2 entered maintenance phase 3. Patients continuing to respond at the end of maintenance phase 3 were eligible to enter the RCT Definition of response/remission: response: HAM‐D 17 total score ≤ 12 and ≥ 50% decrease from acute phase baseline, remission (HAM‐D 17 score ≤ 7) of the intake episode of MDD Exclusion criteria ‐ patients for whom an adequate trial of fluoxetine, venlafaxine, or venlafaxine ER had failed during the current episode of MDD, or who had treatment‐resistant depression (for whom ≥ 3 previous adequate trials of ≥ 2 classes of antidepressant medication, ECT, or 2 adequate trials of psychotherapy in the past 3 years had failed) were not eligible to participate. Patients with known hypersensitivity to venlafaxine or fluoxetine were excluded, as were those with histories or presence of any of the following: clinically significant hepatic, cardiovascular, renal, or other serious medical disease that might compromise the study; seizure disorder other than a single childhood febrile seizure; bipolar disorder; OCD; eating disorder (if not remitted for ≥ 5 years); drug or alcohol dependence or abuse within 6 months before screening; current postpartum depression; any psychotic disorder, including psychotic depression; significant Axis II disorders; or any organic mental disorder. Patients were not eligible to participate if they met DSM‐IV criteria for a primary diagnosis of panic disorder, OCD, GAD, social phobia, or PTSD. Patients were excluded if the investigator judged them to be at risk for suicide to such a degree that precautions against suicide were required, or if they had clinically significant abnormalities on pre‐study physical examination, ECG, or laboratory tests; had diagnoses of cancer in the past 3 years (excluding squamous or basal cell carcinoma) and/or had active neoplastic disease; or were women of childbearing age who were pregnant, breastfeeding, or not using a medically acceptable method of birth control
Interventions	Intervention 1: placebo Tapering scheme: 4‐week taper period Intervention 2: venlafaxine ER 75 to 300 mg/d with dose increases allowed to optimise treatment response
Outcomes	Primary outcomes ‐ time to recurrence of major depression Definition of remission Primary definition HAM‐D 17 total scores > 12 and HAM‐D 17 reduction from acute phase baseline that was not more than 50% at 2 consecutive visits or at the last valid visit before discontinuation. Participants also had to meet DSM‐IV criteria for MDD and had to be judged by the investigator to have had a recurrence Secondary definition Participants who, at 1 visit, had HAM‐D 17 scores > 12 and HAM‐D 17 reductions from acute phase baseline that were not more than 50% but did not meet the primary definition of recurrence and were reviewed by a committee of experienced psychiatrists, which assessed whether each of these patients experienced recurrence after a review of blinded clinical data. This clinical definition of recurrence therefore included all patients who met the primary definition and patients whom the committee determined had experienced recurrence Secondary outcomes ‐ Hamilton Rating scale for Depression (HAM‐D), Inventory for Depressive Symptomatology Self‐Report (monthly), Rothschild Scale for Antidepressant Tachyphylaxis (monthly), 3‐monthly Hamilton Rating Scale for Anxiety (HAM‐A), Clinical Global Impressions‐Severity of Illness (CGI‐S) Scale (monthly), Longitudinal Internal Follow‐up Evaluation ‐ quality of life measured 3‐monthly with 36‐item Short Form Health Survey (SF‐36), Quality of life Enjoyment and Satisfication Questionnaire (Q‐LES‐Q), Life Enjoyment Scale‐Short version ‐ Social Adjustment Scale Self‐Report (SAS‐SR) ‐ adverse events monitored via reports of adverse events, vital sign measurements (supine pulse and standing and supine blood pressure), and laboratory evaluations. Standard 12‐lead electrocardiography was performed at screening for all patients at least 50 years of age and those for whom the investigator considered this medically indicated. Comprehensive physical examinations were performed at screening. Discontinuation to adverse events ‐ health service utilisation questionnaire
Notes	Funding: study was supported by a grant from the pharmaceutical industry COI: study authors are employees of the drug company or have received grants from pharmaceutical companies
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: computer random number generator Quote: "...were randomly assigned in a double blind fashion in a 1:1 ratio to receive either venlafaxine or placebo..." For each phase of the study, randomisation records were stratified by site and were generated using a block size of 4. A central randomisation scheme was implemented using Quintiles' IVR system
Allocation concealment (selection bias)	Low risk	Comment: central allocation Quote: "after a site deemed a patient eligible to enrol/continue in the study, they contacted the IVR system, which ascertained the site where the patient was located and then the patient was allocated to the next available treatment assignment (i.e. next sequence number) in the randomisation schedule for that site"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: described as double‐blind (in Kocsis 2007); unlikely that blinding could have been broken Quote: "patients and investigators remained blinded to treatment assignment"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: not enough information to permit a judgement Quote: "HAM‐D 17 ratings were performed by individuals who had been trained and certified. Abstracts of the data, including mood ratings and clinical notes from the case report forms were presented to the recurrence review committee: a committee of experienced psychiatrist who assessed whether each of these patient experienced recurrence after a review of the blinded clinical data"
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: dropout rates were higher in the placebo group (25/40) than in the venlafaxine group (12/43)
Selective reporting (reporting bias)	High risk	Comment: adverse events reported; withdrawal symptoms not an outcome
Other bias	Unclear risk	Comment: grant from the pharmaceutical industry