TORDIA.

Methods	Design: treatment of individuals after remission/recovery from an acute episode of depression to prevent relapse/recurrence Phases: acute phase: 12 weeks treatment with either venlafaxine, another SSRI, venlafaxine + CBT or another SSRI + CBT maintenance phase (weeks 13 to 24): those who had responded to treatment continued in same blinded treatment arm. *NB: non‐responders also included in trial and were treated with open‐label treatment after 12 weeks, which could consist of a switch to another SSRI, augmentation or addition of CBT/another psychotherapy Comparison groups: SSRI versus venlafaxine versus SSRI + CBT versus venlafaxine + CBT Relapse prevention phase: 12 weeks Follow‐up assessment point of relapse prevention: 24 weeks post‐baseline Funded by: National Institute of Mental Health
Participants	Acute phase N = 334 Maintenance phase Responders: N = 144 Non‐responders: N = 131 Child and adolescent or adolescent only or first episode population: adolescents only (12 to 18 years) What depression diagnoses (DSM or ICD) were included: DSM‐IV defined MDD, with a CDRS‐R total score of ≥ 40 and a CGI score of ≥ 4 Criteria for remission: at least 3 consecutive weeks without clinically significant depressive symptoms, corresponding to a score of 1 on the Adolescent Longitudinal Interval Follow‐Up Evaluation. Criteria for response: a CGI rating of ≤ 2 (much or very much improved) and a ≥ 50% decrease from baseline in CDRS‐R score. Criteria for relapse: at least 2 consecutive weeks with probable or definite depressive disorder (score of 3 or 4 on the Adolescent Longitudinal Interview Follow‐Up Evaluation) Are those at risk of suicide excluded from the trial? Not stated as an exclusion reason Suicide risk: mean (SD) SIQ‐Jr score at acute stage (all randomised participants): venlafaxine = 40.4 (22.6); SSRI = 42.8 (22.0); no CBT = 41.9 (21.1); CBT = 41.3 (23.5) Baseline severity of depression: mean (SD) CDRS‐R score at acute stage (all randomised participants): venlafaxine = 57.8 (10.1); SSRI = 59.9 (10.6); no CBT = 58.4 (9.7); CBT = 59.2 (11.0) Mean (SD) length of index episode in months at start of acute stage: (all randomised participants) venlafaxine = 21.4 (19.0); SSRI = 23.5 (21.6); no CBT = 22.6 (21.4); CBT = 22.3 (19.4) % first episode at start of acute stage (all randomised participants): venlafaxine = 73.0; SSRI = 74.8; no CBT = 73.5; CBT = 74.4 Age of onset in years (SD): at start of acute stage (all randomised participants) venlafaxine = 12.8 (2.4); SSRI = 12.6 (2.6); no CBT = 12.5 (2.6); CBT = 12.9 (2.4) Comorbidity of the participants included: anxiety (including PTSD), ADHD, oppositional/conduct, dysthymia Mean (SD) age: 15.9 (1.6) Sex (M:F): 101:233 Family SES: no information Setting: outpatient What psychiatric diagnoses were excluded: bipolar spectrum disorder, psychosis, pervasive developmental disorder, autism, eating disorders and substance abuse or dependence Country: USA
Interventions	Medication (SNRI) Acute phase N = 83 Responders (blind) in maintenance phase N = 31 Name (class and type): venlafaxine (SNRI) Dose (mg/day)/length: weeks 1, 2, 3 and 4 to 6: 37.5 mg, 75 mg, 112.5 mg and 150 mg. Non‐responders at week 6 could receive 225 mg. Delivered how: by psychiatrists or master's degree prepared nurses working with the supervision of a psychiatrist. Medication sessions were 30 to 60 minutes and included monitoring of vital signs, adverse effects, safety and symptomatic response, and were weekly for the first 4 weeks, every other week during acute treatment and monthly during the continuation phase. *NB: family psychoeducation also provided by a nurse or psychiatrist. Discussion around symptoms of depression, causes, treatments and potential adverse effects. Medication (SSRI) Acute phase N = 85 Responders (blind) in maintenance phase N = 26 Name (class and type): SSRI Dose (mg/day)/length: 10 mg at week 1 and 20 mg for weeks 2 to 6. Non‐responders at week 6 could receive 40 mg. Delivered how: as above *NB: family psychoeducation also provided by a nurse or psychiatrist. Discussion around symptoms of depression, causes, treatments and potential adverse effects. Combination: psychotherapy + venlafaxine Acute phase N = 83 Responders (blind) in maintenance phase N = 36 Name (description): CBT. Focuses on cognitive restructuring, behavioural activation, emotional regulation, social skills and problem solving sessions.  # sessions/length: acute phase: up to 12 sessions. Every other week for 2 months and monthly thereafter. Manualised (Y/N): yes Individual or group: individual Parent involvement: family psychoeducation provided by a nurse or psychiatrist. Discussion around symptoms of depression, causes, treatments and potential adverse effects. Fidelity check: Cognitive Therapy Rating Scale used by 3 raters: 94.9%, 94% and 93.9% of taped sessions were rated as acceptable Delivered by: therapists with at least a master's degree in a mental health field Medication: venlafaxine as above Combination: psychotherapy + SSRI Acute phase N = 83 Responders (blind) in maintenance phase N = 35 Psychotherapy: as above Medication: SSRI as above
Outcomes	Prevention of second or next episode defined as: at least 2 consecutive weeks with probable or definite depressive disorder (score of 3 or 4 on the Adolescent Longitudinal Interview Follow‐Up Evaluation) All other outcomes not reported for the subset of participants who responded to acute treatment
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Randomization was balanced both within and across sites using a variation of Efron’s biased coin toss”. pg. 904 (Brent 2008)
Allocation concealment (selection bias)	Unclear risk	No information
Blinding (performance bias and detection bias) Blinding of outcome assessor	Low risk	“independent evaluators were blind to medication type. Independent evaluators were also blind to CBT treatment” NB: “In 64 cases, the blinding of the independent evaluator was compromised, most commonly because of participant disclosure of receiving CBT”. pg. 785 (Emslie 2010)
Blinding (performance bias and detection bias) Blinding of participants/care providers	High risk	“Participants were blind to medication type”. NB: unlikely that participants were blind if receiving adjunctive CBT treatment. pg. 785 (Emslie 2010)
Incomplete outcome data (attrition bias) ITT analysis	Low risk	Indicated ITT analysis in Figure 1 consort diagram
Incomplete outcome data (attrition bias) Number of drop‐outs in each group reported	Unclear risk	Number randomised to acute phase: venlafaxine: 83; venlafaxine + CBT: 83; SSRI alone: 85; SSRI with CBT: 83; total: 334 Number of drop‐outs during acute phase: venlafaxine: 22; venlafaxine + CBT: 30; SSRI alone: 25; SSRI with CBT: 25; total: 102 Number of responders in maintenance phase: venlafaxine: 34 (31 blind); venlafaxine + CBT: 40 (36 blind); SSRI alone: 31 (26 blind); SSRI with CBT: 39 (35 blind); total: 144 Number analysed post‐continuation (24 weeks): venlafaxine: 83; venlafaxine + CBT: 83; SSRI alone: 85; SSRI with CBT: 83; total: 334
Incomplete outcome data (attrition bias) Reasons for drop‐out in each group reported	Low risk	Venlafaxine group: 19 had an inadequate response to medication, 1 had an adverse event Venlafaxine + CBT group: 1 had an adverse event, 1 had a family conflict SSRI alone: 2 withdrew due to lack of efficacy, 2 received paroxetine, 1 had ancillary treatment co‐morbidity, 2 were non‐compliant and 1 was lost to follow‐up SSRI + CBT: 3 had adverse events, 2 received paroxetine, 1 had ancillary treatment co‐morbidity, 2 were non‐compliant and 2 withdrew consent
Selective reporting (reporting bias)	High risk	CDRS‐R scores only reported in graph form Drop‐outs across blind treatment and open treatment not clearly reported
Other bias	Unclear risk	Not enough information to make a judgement

AA: annual assessments; ADHD: attention deficit hyperactivity disorder; BDI: Beck Depression inventory; CBT: cognitive behavioural therapy; CD: Conduct Disorder; CDRS‐R: Children's Depression Rating Scale‐Revised; C‐GAS: Children’s Global Assessment Scale; CGI: Clinical Global Impression; DSM: Diagnostic and Statistical Manual of Mental Disorders; F/F: fluoxetine/fluoxetine; F/P: fluoxetine/placebo; FA: frequent assessments; FDA: Food and Drug Administration (US); FLX: fluoxetine; GAF: Global Assessment of Functioning; HAM‐D: Hamilton Rating Scale for Depression; ICD: International Classification of Diseases; INR: initial non‐responders; IR: intermediate responders; ITT: intention‐to‐treat; K‐SADS‐PL: Kiddie Schedule for Affective Disorder and Schizophrenia Present and Lifetime Version LIFE: Longitudinal Interval Follow‐Up Evaluation; MD: Mean Difference; MDD: major depressive disorder; MM: medication management (antidepressant); N/A: not applicable; NST: Nondirective Supportive Therapy; ODD: Oppositional Definant Disorder; P/P: placebo/placebo; PTSD: post‐traumatic stress disorder; RER: Random Effects Regression; RP: relapse‐prevention; RR: rapid responders ; SAE: serious adverse event; SBFT: Systemic Behaviour Family Therapy; SD: standard deviation; SES: socioeconomic status; SSRI: selective serotonin re‐uptake inhibitors