McIntyre 2007.

Methods	Parallel group RCT
Participants	Country: Canada Setting: Outpatient N randomised: 58 Age: 44.5 years (SD 11) Inclusion: Adults (18–65 years of age) with a DSM‐IV diagnosis of major depression; a 17‐item Hamilton Depression Scale (HAM‐D) score of ≥ 18; a Clinical Global Impression of Severity (CGI‐S) score of ≥ 4 (moderately ill); and a 14‐item Hamilton Anxiety Scale (HAM‐A) score of ≥ 14. These criteria had to be met both at screening and baseline. In addition, all patients had been treated for their current episode of major depressive disorder with a single SSRI/venlafaxine tablet at a therapeutic dose for at least 6 weeks. Exclusion: Exclusion criteria included: a DSM‐IV diagnosis of substance abuse or dependence within 6 months of screening, and patients who received an antipsychotic or benzodiazepine 7 days prior to entering the study, or a potent cytochrome P450 inhibitor or inducer 14 days prior to entering the study. Patients who were pregnant, breastfeeding, or at risk of suicide in the investigator’s opinion were also excluded.
Interventions	Group 1: Augmentation of SSRI/venlafaxine with quetiapine (mean 182 mg/d) for 8 weeks Group 2: Augmentation of SSRI/venlafaxine with placebo for 8 weeks
Outcomes	Post‐treatment assessment (8 weeks): 1. Depressive symptoms, continuous (HAM‐D‐17) 2. Dropouts 3. Response, dichotomous (≥ 50% reduction in HAM‐D score from baseline) 4. Remission, dichotomous (HAM‐D total score ≤ 7) 5. Adverse events
Definition of TRD	Inadequate response to at least six weeks of a single SSRI or venlafaxine at an acceptable therapeutic dose
Notes	Funding: Study funded by AstraZeneca
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Described as randomised but no information given about how the sequence was generated
Allocation concealment (selection bias)	Unclear risk	No information about how allocation was concealed
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Described as double‐blind and placebo given to control group so unlikely that either participants or study personnel would have been aware of treatment allocation
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not specifically stated that outcome assessors were blind to treatment allocation but study described as double‐blind and placebo given to control group
Incomplete outcome data (attrition bias) All outcomes	Low risk	All randomised participants were included in the analyses. "The intent‐to‐treat (ITT) population (any randomized patient who received at least one dose of study medication) was used in all statistical analyses... LOCF analyses are reported for the above measures".
Selective reporting (reporting bias)	Unclear risk	Study protocol did not provide details of the outcomes to be assessed. All outcomes and time points described in the methods were reported in the results.
Other bias	Low risk	No other concerns identified