Kornstein 2006.

Study characteristics
Methods	Design: multi‐phase double‐blind randomised controlled trial Prerandomisation phase Phase 1: acute treatment with 1 of 4 SSRIs (fluoxetine, sertraline, paroxetine, citalopram) (8 weeks) Phase 2: continuation treatment with escitalopram 10 to 20 mg (16 weeks) Duration post randomisation: 52 weeks Aim: to examine the efficacy of maintenance escitalopram treatment in preventing depression recurrence in patients who responded to acute SSRI therapy
Participants	Country: USA Setting: 28 centres Type of AD: escitalopram Duration of antidepressant treatment prerandomisation: 24 weeks Duration of antidepressant treatment post stabilisation: 16 weeks Number of participants: 515 entered phase 1, 386 completed phase 1, and 259 responded to phase 1; 234 entered phase 2, 164 completed phase 2, and 139 responded to phase 2 Total numbers of randomised participants: 139 (66 placebo, 73 antidepressant) Primary diagnosis: recurrent major depressive disorder Number of previous episodes, mean (SD): 5.8 (6.0) placebo, 4.7 (3.1) antidepressant Gender distribution (female): placebo 78.8%, escitalopram 79.5% Mean age, years (SD): placebo 43.7 (12.4), escitalopram 42.0 (11.3) Severity of depressive symptoms at randomisation MADRS (mean (SD)): placebo 4.9 (3.6), escitalopram 4.7 (4.0) HAM‐D (mean (SD)): placebo 5.2 (3.8), escitalopram 5.2 (4.0) CGI‐I (mean (SD)): placebo 1.2 (0.4), escitalopram 1.2 (0.5) CGI‐S (mean (SD)): placebo 1.6 (0.7), escitalopram 1.5 (0.6) Inclusion criteria ‐ DSM‐IV criteria for a current major depressive episode ≥ 4 weeks’ duration and ≥ 2 major depressive episodes before the index episode, with 1 of the episodes resolving within the previous 5 years. A MADRS total score ≥ 22 and ≥ 2 on item 1 of the HAM‐D were also required, both at screening and at baseline. Enrolled patients had normal or clinically insignificant findings on physical examination, laboratory tests, and 12‐lead ECGs at the screening visit ‐ responded to acute open‐label treatment and maintained response criteria at the end of the continuation treatment Definition of response/remission: MADRS score ≤ 12 Exclusion criteria ‐ DSM‐IV criteria for bipolar disorder, schizophrenia, or any psychotic disorder ‐ OCD ‐ mental retardation ‐ any pervasive developmental or cognitive disorder ‐ diagnosis of any Axis I disorder other than MDD (including dysthymic disorder) ‐ history of any psychotic disorder ‐ exhibited any psychotic features ‐ significant personality disorder ‐ history of substance abuse or dependence (other than nicotine) in the previous 6 months per DSM‐IV criteria ‐ presenting suicide risk ‐ ≥ 5 on MADRS item 10 (suicidality) ‐ required concomitant psychotropic medication (other than zolpidem for sleep) ‐ women who were pregnant or nursing and were required to practise a reliable method of birth control
Interventions	Intervention 1: placebo Tapering scheme: abrupt, without down‐tapering Intervention 2: escitalopram 10 to 20 mg/d; same dose that was administered at the end of the continuation period
Outcomes	Primary outcome ‐ time to recurrence Definition of relapse: MADRS score ≥ 22 or withdrawal from the study due to insufficient treatment response based on the judgement of the principal investigator Secondary outcomes ‐ depressive symptoms ‐ global severity of illness using HAM‐ D 24, CGI‐I, and CGI‐S ‐ adverse events (treatment‐emergent adverse events and serious adverse events)
Notes	Funding: supported by a grant from the pharmaceutical industry (Forest Research Institute is an affiliate of the pharmaceutical industry) COI: principal study author has received research support and honoraria from the pharmaceutical industry and has served on the advisory board including the funding company. Other co‐authors are employees of the funding company
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “patients were randomly assigned on a 1:1 ratio” 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	Quote: "double‐blind" 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: high dropout in placebo group (45%) and 31% in antidepressant group; 18% of placebo patients (12/66) completed the trial compared to 51% of escitalopram patients (37/73)
Selective reporting (reporting bias)	High risk	Comment: protocol is not available; reports include all expected outcomes, and adverse events were reported. Withdrawal symptoms were not an outcome
Other bias	Unclear risk	Comment: grant from the pharmaceutical industry