Freeman 2004.

Methods	Randomised double‐blind, placebo‐controlled, 3‐arm parallel study (intermittent or continuous dosing or placebo) Study flow: 167 women were randomised: 56 to intermittent (35 completed, 45 analysed), 56 to continuous (40 completed, 48 analysed), 55 to placebo (43 completed, 50 analysed). Refer to table of bias for details of attrition
Participants	Country: USA Site: University based Premenstrual Syndrome Program Inclusion: PMS or PMDD. Age 18‐45 years, regular menstrual cycles of 22‐35 days, positive urine test for ovulation, persistent premenstrual symptoms for at least 6 months, global report of at least moderate to severe impairment in work, family life or social activity; general good health; no major psychiatric diagnosis within past year, meeting stated PMS criteria based on prospective daily rating of symptoms. Required a total premenstrual Daily Symptom Rating Score >/80 and an increase of >/50% over the postmenstrual score for the mean of the three screen cycles and for the single blind placebo cycle. Mean age continuous dosing 34.5±6.2, placebo group 33.4±6.5 years. Exclusion: Any major Axis 1 psychiatric diagnosis, including major depression, currently or within previous year as assessed by SCID; use of psychotropic medications that could not be discontinued for the duration of the study, use of any prescription, non‐prescription, herbal or other therapies for PMS, pregnancy, lactation, hysterectomy, symptomatic endometriosis, irregular menstrual cycles, not using medically approved contraception, serious health problems, suicide risk, alcohol or drug abuse within the past year.
Interventions	Screening: Two screening cycles followed by one single blind placebo run in cycle Interventions: 1. 50mg sertraline taken orally until day 2 menses (n=56) 2. 50 ‐100mg of sertraline taken throughout cycle orally (n=56) (mean dosage during trial was 75mg/day +/‐25) for three cycles versus 3. placebo taken orally (n=55) for three cycles In the absence of improvement dose could be increased to 100mg sertraline or 2 tablets (sertraline or placebo) Timing of administration: Bottle A started on Day 3 of menses, switching to bottle B at 14 days before the expected date of menses and continuing through day 2 of menses Summary measures: Data is presented as end of treatment, LOCF, mean values Timing of administration: Bottle A started on Day 3 of menses, switching to bottle B at 14 days before the expected date of menses and continuing through day 2 of menses Summary measures: Data presented at end of treatment, LOCF, mean values
Outcomes	Daily Symptom Rating Form Subject Global Ratings of Functioning
Notes	Daily symptom rating Funding: National Institute of Child Health and Human Development. Drugs provided by Pfizer Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation using random number tables
Allocation concealment (selection bias)	Low risk	Allocation conducted by a technician at the beginning of the study with no clinical contact
Blinding (performance bias and detection bias) All outcomes	Low risk	Double blind, medication taken from Bottle A and Bottle B on the same day of the menstrual cycle whatever the allocation. "Sertraline and placebo tablets were identical in appearance"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	29% of women (49/167) did not complete treatment, including 24/167 (14%) who provided no outcome data. The remaining 86% were included in analysis, using last‐observation‐carried‐forward Dropout rate variable across groups. Reasons for dropouts as follows: intermittent: 21/56 (adverse event =5, lack of efficacy =2, withdrawn consent = 8, medical problem =2, non‐compliance = 1, loss to follow up = 3); continuous: 16/56 (adverse event = 7, withdrawn consent = 4, medical problem =2, non ‐compliance =1, loss to follow up = 2); placebo 12/56 (adverse event =1, lack of efficacy =1, withdrawal of consent =5, noncompliance = 2, loss to follow‐up = 3)
Selective reporting (reporting bias)	Unclear risk	Adverse events not a predefined outcome and not all prospectively recorded ‐ AEs were recorded at each visit, plus women had a medication checklist to report at home any side effects experienced "while taking tablets from Bottle A" (i.e. non‐luteal phase) to identify discontinuation‐related symptoms. Individual adverse effects not reported
Other bias	Unclear risk	Exclusion of placebo responders