Bruijn 1996.

Study characteristics
Methods	Randomised, double‐blind comparison
Participants	Use of checklist with DSM‐III‐R criteria SADS depression portion was performed in the presence of a second psychiatrist DSM‐III‐R depressive episode; excluded psychotic depression with hallucinations HRSD‐17 > 17 Inpatients. Subgroup psychotic depression. Probably only with delusions 51% of included participants were adequately pretreated during the current episode: adequate dose of an antidepressant during at least 4 weeks
Interventions	Imipramine vs mirtazapine; 37.5 to 450 mg imipramine (blood level: 199 to 400 ng/mL) vs 40 to 100 mg mirtazapine (blood level 49 to 93 ng/mL) Washout: 3 days medication free and 4 days placebo Additional medication: 1 to 6 tablets a day containing 45 mg of an extract of valerian, lorazepam 1 to 5 mg a day, or haloperidol 1 to 15 mg a day Treatment period: 4 weeks after predefined blood levels reached (mirtazapine group: 5 to 21 days; imipramine group: 7 to 25 days)
Outcomes	Dichotomous data: study author defined: response is reduction in HRSD‐17 ≥ 50%. No remission data Continuous data: symptom reduction: no ITT data; global response: no ITT data; QOL: no data Overall dropout rate: yes Dropout due to adverse effects: no ITT data in subgroup Mortality rate: 0
Notes	Worse responding in a group leads to more participants given haloperidol 107 participants included; 6 bipolar; 10 dropouts Subgroup: MDD psychotic; 30 (15 mirtazapine and 15 imipramine) Mirtazapine group: 7 haloperidol treatment (6 non‐responders, 1 responder) Imipramine group: 2 haloperidol treatment (2 non‐responders) Participants treated with haloperidol counted as dropouts Mirtazapine group: 1 dropout + 7 haloperidol treatment = 8/18; imipramine group: 2 dropouts + 2 haloperidol treatment = 4/15 Additional information from study author included
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	As reported: "patients were randomly allocated to a double blind treatment"
Allocation concealment (selection bias)	Unclear risk	No explicit information
Blinding (performance bias and detection bias) of participants	Low risk	As reported: "identical capsules. Dose adjustment by an independent psychiatrist on the basis of blood levels"
Blinding (performance bias and detection bias) of personnel	Low risk	As reported: "identical capsules. Dose adjustment by an independent psychiatrist"
Blinding (performance bias and detection bias) of outcome assessors	Low risk	Side effects were not systematically rated to prevent bias towards unblinding. After completion of the study, the research psychiatrist guessed the medication: 46 correct and 37 incorrect
Incomplete outcome data (attrition bias) All outcomes	Low risk	None
Selective reporting (reporting bias)	Unclear risk	No protocol available. Generally accepted outcomes have been used
Other bias	High risk	Participants with psychotic depression with hallucinations were excluded. So only participants with psychotic depression with delusions were included in the re‐analysed subgroup We re‐analysed the data in the subgroup with psychotic depression. We counted as dropouts: 1 participant with bipolar disorder, 9 participants with haloperidol treatment (7 in mirtazapine group and 2 in imipramine group) Worse responding in psychotic depression leads in this study to more open co‐treatment with haloperidol 1 to 15 mg, especially in the mirtazapine group. Only 1 of these 9 participants (mirtazapine group) was a responder. So haloperidol probably was not instrumental in the recovery of those participants