Yonkers 2008.

Study characteristics
Methods	Study design: RCT, parallel‐group Location: USA Setting: community/secondary care No. of centres: 4: Yale University School of Medicine, Bridgeport Hospital, University of Texas Southwestern Medical Center, and Massachusetts General Hospital Dates of study: 1997‐2004 Total duration of study: 7 years Recruitment: women were recruited by advertisement or referral from obstetric care providers Randomisation method: predetermined with a computer‐generated schedule in blocked sets of 4 and was stratified by site Analysis by ITT: yes (LOCF for response and remission analyses) Power calculation: yes
Participants	Inclusion criteria: aged ≥ 16 years, met diagnostic criteria for MDD with an onset in the 3 months post‐delivery, had given birth within the previous 9 months and had a score on the 17‐item HAM‐D of at least 16 at the initial visit. Women who were breastfeeding were allowed to participate Exclusion criteria: onset of MDD prior to delivery, current suicidal ideation with intent, current (within the last 6 months) alcohol or drug abuse or dependence, current psychotic symptoms, lifetime diagnosis of schizophrenia, bipolar disorder or schizoaffective disorder, currently receiving treatment (pharmacotherapy or psychotherapy) for a psychiatric disorder, currently pregnant, unwilling to be randomised or unable to attend treatment visits at a participating site Number recruited: 70 women (35 active treatment, 35 placebo) Number dropped out by final week (week 8 ± 7 days): paroxetine: 20/35 (57%); placebo: 23/35 (66%) Number analysed: paroxetine N = 35; placebo N = 35. ITT analysis and evaluation at week 8 for results from 17 women in paroxetine group and 14 women in the placebo group Age, mean (SD) years: paroxetine: 26.1 (6.5); placebo: 25.9 (6.5) Severity of PND, mean (SD) score: HRSD‐17: paroxetine 23.6 (4.7); placebo 24.7 (5.0) IDS‐SR: paroxetine 38.6 (8.4); placebo 42.8 (8.4) CGI‐S: paroxetine 4.2 (1.0); placebo 4.5 (0.9) Duration of PND: not reported Physical health co‐morbidities: not reported Mental health co‐morbidities: paroxetine N = 15 (46.9%); placebo N = 15 (53.1%). Comorbid psychiatric conditions = lifetime alcohol abuse, alcohol dependence, drug abuse, drug dependence, anxiety disorder Ethnicity: paroxetine: white: 18 (51.4%), black: 5 (14.3%), Hispanic: 11 (31.4%), other 1 (2.9%); placebo: white: 16 (45.7%), black: 4 (11.4%), Hispanic: 14 (40.0%), other 1 (2.9%) Socioeconomic status: paroxetine: < 12 years of education: 11 (37.9%), > 12 years of education: 18 (62.1%); placebo: < 12 years of education: 15 (53.6%), > 12 years of education: 13 (46.4%)
Interventions	Women were randomly assigned to 1 of 2 groups Paroxetine: week 1 and 2: 1 capsule (10 mg) of immediate‐release paroxetine daily; week 3 and 4: 2 capsules (20 mg) of immediate release paroxetine daily unless side effects limited an increase. Further increments to 30 mg by week 4 and then 40 mg by week 6 were encouraged if improvement was assessed as < 30% compared with baseline Placebo: identical placebo administered according to same protocol as paroxetine
Outcomes	Primary outcome: change in depressive symptoms measured by the HAM‐D, CGI and the Inventory of Depressive Symptomatology ‐ Self‐report scale Secondary outcomes: rates of remission, defined as a HAM‐D score of ≤ 8, and response, defined as a CGI‐Improvement scale score of 1 or 2; predictors of remission defined as above; Social Adjustment as measured by the SAS; SF‐36 Time points: weeks 1, 2, 3, 4, 6 and for a final visit, at week 8 (± 7 days)
Notes	This study was supported by a Collaborative Research Trial, Investigator‐Initiated grant from GlaxoSmithKline to Drs Yonkers and Cohen and by National Institute of Mental Health grant MH01648 to Dr Yonkers.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Subjects were randomly assigned to take identical capsules of either paroxetine or placebo. Random assignment was predetermined with a computer‐generated schedule in blocked sets of 4 and was stratified by site. A study statistician was responsible for random assignment"
Allocation concealment (selection bias)	Unclear risk	Insufficient details provided to be sure of allocation concealment
Blinding of participants (performance bias)	Low risk	"Subjects were instructed to take 1 capsule (10mg of immediate‐release paroxetine or identical placebo)"
Blinding of personnel (performance bias)	Low risk	"A study statistician was responsible for random assignment, and remaining study staff were blind to group assignment."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"..remaining study staff were blind to group assignment"
Incomplete outcome data (attrition bias) All outcomes	High risk	"Seventy women qualified for the study, and 31 completed study treatment… Subjects withdrew from the active treatment for the following reasons: 1 due to an adverse event (nausea), 6 due to lack of efficacy, including 1 subject who was psychiatrically hospitalised, 6 who were lost to follow‐up, 5 who felt well and no longer desired treatment, 1 who became pregnant and 1 who was noncompliant In subjects randomly assigned to placebo, 4 left the study because of perceived adverse events (rash, nausea, diarrhoea, headache), 7 discontinued because of lack of efficacy, including 1 subject who required hospitalisation, 9 were lost to follow‐up, 2 improved and no longer desired treatment, and 1 subject moved" "Given the high rate of dropout, we explored additional models to assess the robustness of remission results. These models first assumed that all dropouts were remitters and then that they were all non‐remitters. In both models, treatment with paroxetine remained significantly better than treatment with placebo" Dropout numbers are similar in the 2 groups and some reasons account for similar numbers across the 2 groups but for a substantial proportion 'lost to follow up' the reason for dropout is unknown. Sensitivity analyses only performed for the primary outcome
Selective reporting (reporting bias)	High risk	The SAS and SF‐36 were included in the methods but not reported in the results
Other bias	Unclear risk	"Pill counts revealed that, among women assigned to paroxetine, 7 were noncompliant (took less than 80% of prescribed pills at 1 visit, and 4 were non‐compliant at 2 visits. One subject assigned to active treatment was discontinued due to on‐going lack of compliance; of the remaining subject, no others fell below the 80% compliance rate at more than 2 visits. Among subjects assigned to placebo, 10 were noncompliant at 1 visit, 3 were noncompliant during at least 2 visits, and 1 was noncompliant on 4 occasions" The potential bias was unclear as we do not know whether non‐compliant women were taking 0% or 79% of their medication. It is also not clear whether the numbers of non‐compliant participants were reported for the study as a whole (26/70 women) or only for those who did not drop out (26/31 women) Funded by GlaxoSmithKline but it is unclear if they provided the study medication.

BAME: Black, Asian and minority ethnic; BAI:  Beck Anxiety Inventory; BDI: Beck Depression Inventory; BDP: brief dynamic psychotherapy; CBT: cognitive behavioural therapy; CGI‐I: Clinical Global Impressions‐Improvement; CGI‐S: Clinical Global Impressions‐Severity; CIS‐R: Revised Clinical Interview Schedule; DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; EPDS: Edinburgh Postnatal Depression Scale; EQ‐5D: EuroQol‐5 Dimenion; GAS: Global Assessment Scale; GHQ: General Health Questionnaire; GP: general practitioner; GRIMS: Golombok Rust Inventory of Marital State; HAM‐A: Hamilton Rating Scale for Anxiety; HAM‐D: Hamilton Rating Scale for Depression; HDRS/HRSD: Hamilton Rating Scale for Depression; ICD‐10: International Classification of Disease Tenth Revision; IDAS‐GD: Inventory of Depression and Anxiety Symptoms, General Depression scale; IPT: interpersonal psychotherapy; ITT: intention to treat; LOCF: last observation carried forward; MADRS: Montgomery‐Åsberg Depression Rating Scale; MAMA: Maternal Adjustment and Maternal Attitudes; MDD: major depressive disorder; MHI: Mental Health Index; PAPA: Preschool Age Psychiatric Assessment; PND: postnatal depression; PPAQ: Postpartum Adjustment Questionnaire; PSI: Parenting Stress Index; RCT: randomised controlled trial; SAS: Social Adjustment Scale; SCID: Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; SD: standard deviation; SF‐12: 12‐item Short Form; SIGH‐ADS: Structured Interview Guide for the Hamilton Depression Rating Scale—Atypical Depression Symptoms Version; SPQ: Social Problems Questionnaire; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant; TSH: thyroid‐stimulating hormone; YBOCS: Yale‐Brown Obsessive Compulsive Scale