Gelenberg 2003.

Study characteristics
Methods	Design: multi‐phase double‐blind randomised placebo‐controlled trial Prerandomisation phases Phase 1: acute treatment with nefazodone alone or nefazodone in combination with cognitive‐behavioral analysis system of psychotherapy (CBASP); sessions twice weekly throughout first 4 weeks and weekly for last 8 weeks; additional twice‐weekly sessions were permitted until Week 8 if a patient was having difficulty mastering the therapy's social problem‐solving approach (12 weeks) (reported in Keller 2000) Phase 2: continuation treatment with nefazodone alone (16 weeks) or continuation treatment in combination with CBASP; sessions were tapered over to every other week for the first 8 weeks and monthly for the subsequent 8 weeks of continuation treatment Duration post randomisation: 52 weeks Aim: to determine the efficacy and safety of nefazodone maintenance treatment for preventing recurrence in chronic depression
Participants	Country: USA Setting: 12 academic centres Type of antidepressant: nefazodone Duration of antidepressant treatment prerandomisation: 28 weeks Duration of antidepressant treatment post stabilisation: 16 weeks Total numbers of participants: 681 and 269 responded to either nefazodone alone or combined treatment; 165 maintained response at end of phase 2 and entered RCT Total numbers of randomised participants: 160 (84 discontinuation, 76 continuation) Primary diagnosis ‐ placebo: chronic depression 28.6%, double depression 42.9%, recurrent depression with incomplete inter‐episode recovery 28.6% ‐ nefazodone: chronic depression 34.2%, double depression 36.8%, recurrent depression with incomplete inter‐episode recovery 29% Severity of depressive symptoms at randomisation (HAM‐D 24), score (SD): 5.6 (4.0) placebo, 5.9 (4.4) nefazodone Duration of current MDD, years (SD): 7.3 (7.5) placebo, 8.4 (10.8) nefazodone Duration of current dysthymia, years (SD): 23.3 (14.3) placebo, 23.5 (15.9) nefazodone Gender distribution (female): 65.5% placebo, 69.7% nefazodone Mean age, years (SD): 44.1 (8.4) placebo, 44.4 (11.1) nefazodone Prior treatment (phases 1 and 2): ‐ placebo group: 28/84 (33.5%) nefazodone, 56/84 (66.7%) nefazodone + CBASP ‐ nefazodone group: 26/76 (34.2%) nefazodone, 50/76 (65.8%) nefazodone + CBASP Inclusion criteria ‐ 18 to 75 years ‐ patients who had responded to nefazodone or continuation treatment in combination with CBASP during a 12‐week acute treatment study and who maintained their response over 16 weeks of continuation treatment ‐ diagnosis of chronic MDD (≥ 2 years’ duration), concurrent MDD superimposed on an antecedent dysthymic disorder (“double depression”), or recurrent MDD with incomplete inter‐episode recovery ≥ 2 years’ duration (DSM‐IV criteria) ‐ ≥ 20 on the HAM‐D 24 both at screening and at baseline after a 2‐week drug‐free period at entry of phase 1 Definition of response: 50% reduction in HAM‐D 24 total score from acute phase baseline achieved at end of acute phase, then maintained at the end of the continuation phase; HAM‐D 24 total score < 16 at end of continuation phase Exclusion criteria ‐ history of seizures, abnormal ECG, stroke, severe head trauma, psychotic symptoms, schizophrenia, bipolar, eating disorders not remitted for 1 year, OCD, dementia ‐ high risk for suicide, antisocial, schizotypal, or severe borderline personality disorders ‐ diagnosis within past 6 months of panic, GAD, PTSD, social phobia, or substance abuse/dependence ‐ did not respond to 3 previous AD trials (of 2 different classes), psychotherapy, or ECT during last 3 years ‐ serious, unstable, concurrent medical conditions ‐ women of childbearing age with inadequate contraception
Interventions	Intervention 1: placebo Intervention 2: nefazodone (300 to 600 mg/d twice daily based on response and tolerability) Tapering scheme: abruptly with no tapering and with identical inactive tablets Co‐intervention ‐ participants could not receive anxiolytics, sedatives, hypnotics, or other pharmacological or behavioural sleep aids during any phase of the study ‐ medication visits in both groups: "the treating physician followed a guideline manual for clinical management (e.g. review of symptoms, side effects, illnesses, and concomitant medications) that proscribed any formal psychotherapeutic interventions (e.g. giving suggestions regarding coping with stressful life events). Medication visits were limited to 15‐20 min" ‐ no CBASP sessions during the trial
Outcomes	Relapse/recurrence every 4 weeks for 52 weeks Definition of relapse/recurrence ‐ HAM‐D 24 ≥ 16 plus MDD (DSM‐IV criteria diagnosed on 2 consecutive visits) ‐ time to recurrence of MDD, in days, every 4 weeks for 52 weeks ‐ HAM‐D 24 mean ‐ dropout any ‐ dropout due to adverse events ‐ treatment‐emergent adverse events
Notes	Funding: study supported by grants from pharmaceutical companies COI: not reported; several trial authors (included first author) report grants from several pharmaceutical companies in Keller 2000
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not enough information to judge Quote: "two separate randomisation schedules were used: one for patients receiving nefazodone monotherapy during the continuation phase and the second for patients receiving combined nefazodone and CBASP during the continuation phase. Within each schedule, patients were randomised in a 1:1 ratio to nefazodone or placebo"
Allocation concealment (selection bias)	Unclear risk	Comment: not reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: insufficient information on blinding of personnel to permit judgement Quote: "...patients assigned to placebo received apparently identical, inactive tablets. Patients were switched abruptly to placebo with no downward taper..."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Comment: blinding of outcome assessment ensured; unlikely that blinding could have been broken Quote: "HAM‐D, which was rated by trained, independent evaluators blind to treatment assignment"; " ...a blinded review of symptom exacerbations by a consensus committee of research clinicians..."
Incomplete outcome data (attrition bias) All outcomes	High risk	Comment: although reasons for withdrawal are stated, the withdrawal rate is much higher in the placebo group (61.9%) compared to the nefazodone group (38.2%). Dropout rates not reported separately for participants who had responded to nefazodone alone or in combination with psychotherapy. ITT analysis on 160/165 patients entered into the RCT with at least 1 post‐baseline assessment Quote: "the distribution of patients discontinuing was unequal between the two treatment groups, with 29 of 76 (38.2%) nefazodone treated patients compared with 52 of 84 (61.9%) placebo treated patients discontinuing before the end of the study"
Selective reporting (reporting bias)	High risk	Comment: the study protocol is not available; information on adverse events was reported. Withdrawal symptoms were not an outcome. None of our secondary outcomes were measured
Other bias	Unclear risk	Comment: grant from pharmaceutical industry