Khan 2014.

Study characteristics
Methods	Design: 2‐phase double blind randomised 3‐arm controlled interruption trial Prerandomisation phase Phase 1: treatment with desvenlafaxine 50 mg (24 weeks) Duration post randomisation: 4 weeks Aim: to evaluate the tolerability of a tapering regimen compared with abrupt discontinuation and with continuation of long‐term desvenlafaxine treatment for major depression
Participants	Country: USA Setting: 38 clinical research centres Type of AD: desvenlafaxine Duration of antidepressant prerandomisation (weeks): 24 Duration of antidepressant treatment post stabilisation: not specified Total number of participants: 480 enrolled in phase 1, 362 completed phase 1 Total number of randomised participants: 361 (148 abrupt discontinuation, 140 tapering, 73 antidepressant) → control group was split to allow multiple‐treatment comparison: 36 and 37 → 184 participants in the comparison abrupt discontinuation vs continuation (148 abrupt discontinuation, 36 antidepressant) and 176 participants in the comparison tapering vs continuation (140 taper and 37 antidepressants) Primary diagnosis: single or recurrent depression Severity of depressive symptoms at randomisation (QIDS‐SR16), mean (SD): 6.3 (4.5) abrupt, 6.3 (4.3) taper, 6.8 (4.4) antidepressant Gender distribution (F): 67.6% abrupt discontinuation, 73.6% taper, 67.1% antidepressant Mean age, years (SD): 47.8 (13.7) abrupt discontinuation, 47.9 (11.2) taper, 46.7 (11.3) antidepressant Inclusion criteria ‐ ≥18 years ‐ primary diagnosis of single or recurrent MDD without psychotic features (DSM‐IV criteria), assessed by MINI ‐ depressive symptoms ≥ 30 days before screening visit of phase 1 and HAM‐D 17 ≥ 14 at baseline of phase 1 ‐ participants who completed the 24‐week open‐label treatment of phase 1 were enrolled in the discontinuation trial Exclusion criteria ‐ current primary diagnosis of anxiety disorder ‐ significant risk of suicide based on response to question 4 or 5 on the C‐SSRS at screening or baseline ‐ current psychoactive substance abuse or dependence ‐ unstable hepatic, renal, pulmonary, cardiovascular (including uncontrolled hypertension, unstable angina, or recent myocardial infarction); ophthalmologic or neurologic disorder ‐ other clinically important medical disease (including uncontrolled diabetes)
Interventions	Intervention 1: placebo Tapering scheme: abrupt discontinuation of venlafaxine Intervention 3:  gradually tapering of venlafaxine to placebo; tapering scheme: desvenlafaxine 25 mg/d for 1 week followed by placebo for 3 weeks. Intervention 2: continuation of desvenlafaxine 50 mg/d
Outcomes	Primary ‐ withdrawal symptoms measured with Discontinuation‐Emergent Signs and Symptoms (DESS), during the first 2 weeks Secondary ‐ severity of withdrawal symptoms, measured with Discontinuation Symptoms Severity Index (DSSI), an exploratory scale rating DESS items’ severity and relationship to discontinuation, and DESS score at the end of Weeks 3 and 4 of the double‐blind phase to determine if symptoms were present or worsened ‐ adverse events: incidence and timing of taper/post‐therapy‐emergent adverse events (TPAEs), which are adverse events that started or increased in severity during the double‐blind phase, and rate of study discontinuation due to treatment‐emergent adverse events (adverse events that emerged between first administration of the open‐label study medication and 14 days or fewer after last administration of double‐blind treatment) during the double‐blind phase ‐ proportion of participants with withdrawal syndrome (increase in DESS ≥ 4 during double‐blind baseline) ‐ depressive symptoms measured by Quick Inventory of Depressive Symptomatology Self‐Report (QIDS‐SR16) ‐ DESS and DSSI were administered at the end of the OL period (DB baseline) and at DB Weeks 1 through 4
Notes	Funding: study was supported by a grant from the pharmaceutical industry COI: editorial assistance and medical writing were provided by KMD and were funded by the company that funded the trial; 4 of the 6 study authors were employees of the pharmaceutical company that funded the trial; 1 of the 6 study authors was a former employee, and the head study author is the medical director of a pharmaceutical company
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not enough information to permit a judgement
Allocation concealment (selection bias)	Unclear risk	Comment: not enough information to permit a judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: not enough information to permit a judgement Quote: "double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: not enough information to permit a judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: dropout rates low, balanced; missing data were handled using the last observation carried forward approach
Selective reporting (reporting bias)	Low risk	Comment: the study protocol is available, and all of the study’s pre‐specified (primary and secondary) outcomes have been reported (DSSI and QIDS‐SR in a related paper Ninan 2015)
Other bias	High risk	Comment: grant from the pharmaceutical industry; medical writer paid by the pharmaceutical company that funded the trial