Bauer 2009 (ONYX).

Methods	Parallel group RCT
Participants	Country: Australia, Canada, Europe, South Africa Setting: Outpatient care N randomised: (n = 329 (67.6%) female (of 487 included in analyses)) Age: Mean 45.44 years (SD 10.53). Inclusion: Patients aged 18 to 65 years with a documented DSM‐IV‐TR diagnosis of MDD (single episode [296.2x] or recurrent [296.3x]). Diagnoses confirmed by the Mini‐International Neuropsychiatric Interview. HAM‐D‐17 total score > 20 and HAM‐D item 1 (depressed mood) score ≥ 2 at enrolment and randomisation. Exclusion: Any DSM‐IV Axis I disorder other than MDD within 6 months prior to enrolment; any DSM‐IV Axis II disorder significantly impacting the patient’s current psychiatric status; duration of current MDD episode > 12 months or < 4 weeks from enrolment; substance or alcohol abuse or dependence, as defined by DSM‐IV criteria, within 6 months prior to enrolment; any clinically significant medical illness, such as renal or hepatic impairment, or coronary artery disease; conditions that could affect absorption or metabolism of study medication risk of suicide or homicide; HAM‐D item 3 score of ≥ 3; or suicide attempt within the past 6 months. Patients requiring psychotherapy (other than supportive therapy), unless psychotherapy had been ongoing for ≥ 3 months before randomisation. Drugs that induce or inhibit the hepatic metabolising cytochrome P450 3A4 enzymes within 2 weeks prior to randomisation. Quetiapine > 25 mg/d for insomnia within 7 days before randomisation, known lack of response following 4 weeks’ treatment with quetiapine ≥ 50 mg/d for depression or were receiving quetiapine ≥ 50 mg/d at enrolment
Interventions	Group 1: Augmentation of current antidepressant with quetiapine XR (150 mg/d) for six weeks Group 2: Augmentation of current antidepressant with quetiapine XR (300 mg/d) for six weeks Group 3: Augmentation of current antidepressant with placebo for six weeks
Outcomes	Post‐treatment assessment (6 weeks): 1. Depressive symptoms, continuous (MADRS, HAM‐D) 2. Dropouts 3. Response, dichotomous (≥ 50% reduction in MADRS total score from randomisation) 4. Remission, dichotomous (MADRAS total score ≤ 8) 5. Quality of life, continuous (Q‐LES‐Q‐SF) 6. Adverse events
Definition of TRD	Inadequate response during the current episode to amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine given for ≥ 6 weeks at adequate doses (minimum effective dose according to label and including at least 1 dose increase as permitted by label)
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 randomisation sequence was generated. "eligible patients ... were randomly assigned (1:1:1 ratio) to receive 6 weeks of double‐blind treatment with 1 of 3 treatment regimens".
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided to enable a judgment ''eligible patients ... were randomly assigned ..".
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. "This was a 6‐week, randomized, double‐blind, parallel‐group, placebo‐controlled, phase III, double‐dummy study."
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 interventions that were identical in appearance."'This was a 6‐week, randomized, double‐blind, parallel‐group, placebo‐controlled, phase III, double‐dummy study."
Incomplete outcome data (attrition bias) All outcomes	Low risk	LOCF used to account for missing data. MITT analysis carried out. Six randomised participants could not be included in it. Missing data balanced across groups. "Efficacy analyses were based on the MITT [modified intention to treat] population; a last‐observation‐carried‐forward (LOCF) approach was used for missing data ... modified intent‐to‐treat (MITT) population (all patients assigned to randomized treatment who took study medication and who had a MADRS assessment at randomization and at least 1 valid MADRS assessment after randomization)."
Selective reporting (reporting bias)	Unclear risk	Very limited information in the protocol about which outcomes will be assessed but all those mentioned were reported in the paper. Additional outcomes reported that did not appear in the protocol (e.g. adverse events)
Other bias	Low risk	No other concerns identified