Rouillon 2000.

Study characteristics
Methods	Design: multi‐phase double‐blind randomised placebo‐controlled trial Prerandomisation phases Phase 0: placebo washout period 4 to 7 days Phase 1: open‐label treatment with milnacipran 2 mg bid (6 weeks) Phase 2: open continuation treatment with milnacipran (18 weeks) Duration post randomisation: 52 weeks Aim: to compare the efficacy and assess the tolerability of milnacipran 50 mg bid to placebo for prevention of recurrence in depressed patients who had responded to acute treatment and had remained in remission after a 4‐month continuation phase
Participants	Country: France Setting: 104 centres Type of AD: milnacipran Duration of antidepressant treatment prerandomisation: 24 weeks Duration of antidepressant treatment post stabilsation: 18 weeks Number of participants: 500 entered phase 1, 323 entered phase 2, 227 completed phase 2 and recovered Total number of randomised participants: 214 (104 milnacipram, 110 placebo) Primary diagnosis: recurrent depressive disorder Number of previous episodes (SD): placebo group 2.7 (2.3); milnacipran group 3.1 (2.3) Severity of depressive symptoms at randomisation (HDRS), mean (SD): 4.58 (2.42) placebo, 4.77 (2.99) antidepressant Gender distribution (F): placebo 68.2%, milnacipran 66.3% Mean age, years (SD): placebo 44.6 (10), milnacipran 46.1 (10.2) years Inclusion criteria ‐ 18 to 70 years of age ‐ history of MDD ‐ current major depressive episode without psychotic symptoms (DSM‐III‐R) ‐ HDRS‐21 ≥ 18 at baseline of phase 0 For entry into maintenance phase: HDRS ≤ 8, improvement or disappearance of initial symptoms, very much improved/much improved on CGI‐I Definition of remission: HDRS ≤ 8 Exclusion criteria Mania, hypomania, dysthymia, depression secondary to schizophrenia, schizoaffective disorder, alcoholism or drug addiction, suicidal intent, treatment‐resistant depression, cardiac rhythm disorders requiring antiarrhythmic treatment, kidney failure, past history of epilepsy, past history of serious allergic reaction or toxic reaction to a drug, life‐threatening disorders, abnormalities in clinical chemistry, haematology or urinalysis, pregnancy, lack of effective birth control or breastfeeding
Interventions	Intervention 1: placebo Tapering scheme: not described Intervention 2: milnacipran 50 mg twice a day
Outcomes	Recurrence, every 2 months Defintion of recurrence: return to diagnostic criteria required for entry into the trial (depression according to DSM‐III‐R, ≥ 18 on HDRS with need to treat recurrence) Adverse events, every 2 months Quality of life, measured by DIP
Notes	Funding: study supported by a grant from the pharmaceutical industry COI: not reported Mean number of previous major depressive episodes significantly lower in placebo group (2.7 (2.3)) than in milnacipran group (3.1 (2.3)); P < 0.05 Number of hospitalised patients at the moment of inclusion: 19.2% in antidepressant group and 20.7% in placebo group
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	Unclear risk	Comment: information insufficient to permit judgement
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: 25% (28/110) placebo and 18% (20/104) milnacipran patients discontinued for reasons other than relapse; reasons not stated
Selective reporting (reporting bias)	High risk	Comment: adverse events were reported incompletely (not separated for each treatment group; no numbers for increased sweating); withdrawal symptoms were not measured
Other bias	Unclear risk	Comment: grant from the pharmaceutical industry