Kessler 2018.

Methods	Parallel group RCT
Participants	Country: UK Setting: Primary care N randomised: 480 Age: 50.15 years (SD 13.16) Inclusion: Aged 18‐75 years. Treated for depression with any of the following SSRI or SNRI antidepressants for at least 6 weeks at recommended (British National Formulary, BNF) doses: fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, paroxetine, duloxetine or venlafaxine; scored 14 or more on the Beck Depression Inventory (BDI) and have adhered to their medication and meet ICD‐10 criteria for depression (assessed using the Computerised Interview Schedule – Revised version (CIS‐R). Exclusion: Currently taking combined or augmented antidepressant treatment, having their medication managed by a psychiatrist, dementia (formal diagnosis), bipolar disorder, psychosis or alcohol or substance abuse/dependence, pregnant, planning a pregnancy or breastfeeding, unable to complete the study questionnaires, previous adverse reaction to mirtazapine, currently being treated with a monoamine oxidase inhibitor (MAOI), including moclobemide, or with other medical contraindications to mirtazapine
Interventions	Group 1: Augmentation of current antidepressant with mirtazapine (30 mg/d) for up to 52 weeks Group 2: Augmentation of current antidepressant with placebo for up to 52 weeks
Outcomes	Assessed at 12, 24 and 52 weeks (unless specified): 1. Depressive symptoms, continuous (BDI‐II, PHQ‐9) 2. Dropouts 3. Response, dichotomous (≥ 50% reduction in BDI‐II total score from baseline) 4. Remission, dichotomous (BDI‐II < 10) 5. Social functioning (SF‐12 aggregate mental functioning, SF‐12 aggregate physical functioning) 6. Quality of life, continuous (EQ‐5D‐5L) 7. Economic outcomes (health and social care use, costs to patients/carers, time off work) 8. Adverse events (12 and 52 weeks)
Definition of TRD	Inadequate response to fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, paroxetine, duloxetine or venlafaxine given for at least six weeks at BNF recommended dose and adherent to antidepressant treatment
Notes	Funding: National Institute for Health Research (NIHR) Health Technology Assessment programme, UK
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation sequence generated by a computer. "Participants were randomised using the automated randomisation service provided by the Bristol Randomised Trials Collaboration (BRTC). Randomisation was carried out by means of a computer‐generated code to ensure concealment of allocation."
Allocation concealment (selection bias)	Low risk	Centralised allocation provided by an independent organisation using a computer‐generated code. "Participants were randomised using the automated randomisation service provided by the Bristol Randomised Trials Collaboration (BRTC). Randomisation was carried out by means of a computer‐generated code to ensure concealment of allocation".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Placebo‐administered. Study participants reported to be blind to treatment allocation. "Participants were randomly assigned to one of two treatments: (1) 1 × 15 mg encapsulated mirtazapine tablet daily for 2 weeks followed by 2 × 15 mg encapsulated mirtazapine tablets for up to 50 weeks or (2) identical placebo tablets…. Participants, clinicians, outcome assessors and the research team were blinded to allocation."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Placebo‐administered. Study staff reported to be blind to treatment allocation. "Participants were randomly assigned to one of two treatments: (1) 1 × 15 mg encapsulated mirtazapine tablet daily for 2 weeks followed by 2 × 15 mg encapsulated mirtazapine tablets for up to 50 weeks or (2) identical placebo tablets…. Participants, clinicians, outcome assessors and the research team were blinded to allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analyses carried out. "The primary comparative analyses of clinical effectiveness were conducted according to the principle of intention to treat (ITT) …. A number of sensitivity analyses were conducted to assess the impact of missing primary outcome data on the main findings."
Selective reporting (reporting bias)	Unclear risk	PHQ‐9 measured at 12, 24 and 52 weeks but only data for 12 weeks was reported.
Other bias	Low risk	No other concerns identified