Andersen 2013.

Study characteristics
Methods	Multicentre Study type: interventional (clinical trial) Intervention model: parallel assignment Primary purpose: treatment
Participants	642 participants Country: Denmark Setting: inpatient At randomisation number allocated: citalopram n = 319; placebo n = 323 % male at baseline: citalopram n = 199/319 (62%); placebo n = 222/323 (69%) Age at baseline: mean age, citalopram 68 ± 13 (n = 319); placebo 68 ± 13 (n = 323) Subtype of stroke at baseline: not available Severity of stroke at baseline: NIHSS, citalopram 5.3 ± 5.6; placebo 4.8 ± 4.8 Time since stroke onset: mean time from last known 'well' to first treatment 1.7 days (median 1, IQR 0 to 6) Inclusion criteria: First ever ischaemic stroke Age > 18 years Exclusion Criteria Haemorrhagic stroke Dementia or other neurodegenerative disease Antidepressant medical treatment within 6 months of admission Acute need for antidepressant treatment Drug abuse or other conditions that may indicate non‐compliant behaviour Liver failure (increased liver enzyme levels up to or more than 2 times upper limit) Renal failure (eGFR below 30 mL/min per 1.73 m2) Hyponatremia (S‐potassium below 130 mmol/L Actively bleeding ulcer Fatal stroke or other severe co‐morbidity that markedly decreases expected life span Prolonged corrected QT‐interval (QTc above 480 ms) Ongoing treatment with drugs known to prolong the QTc interval
Interventions	Experimental: citalopram 20 mg (10 mg if aged ≥ 65 years or having reduced liver/kidney function) or placebo once daily for 6 months Comparator: ½ to 2 tablets with no intrinsic drug activity per day for 6 months
Outcomes	Primary outcomes Vascular death, TIA/stroke and myocardial infarction within 6 months Functional status at 6 months (mRS) Secondary outcomes within or at 6 months Vascular death Death of any cause TIA/stroke Bleeding Myocardial infarction Disability/dependence (mRS and BI) Physical activity (PASE) Cognitive and organic cerebral impairment (MMSE and the Symbol Digit Modalities Test) Fatigue (Multidimensional Fatigue Inventory) Post‐stroke depression (Major Depression Inventory test (MDI), Global depression scale (self and clinician and Hamilton Depression Scale ‐ 6 item (HAM‐D6)) Pathological crying (Pathological Crying Scale) Lesion size (FLAIR positive lesion size on MRI 24 hours after treatment with Alteplase)
Funding source	TrygFonden, the Danish Council for Independent Research, the Regional Medicine Fund, and the Aarhus University Research Foundation
Notes	Dates study conducted: September 2013 to December 2016 Declarations of Interest: Dr Kraglund received speaker honoraria from Bristol‐Meyers Squibb and Pfizer. Dr Iversen received speaker honoraria from Boehringer Ingelheim, Bristol‐Myers Squibb, Bayer, AstraZeneca, and Pfizer and has previously participated in advisory board meetings for Boehringer Ingelheim, Bristol‐Myers Squibb, Pfizer, Bayer, AstraZeneca, and Amgen. Dr Grove has received speaker honoraria from AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, MSD, and Pfizer and has previously participated in advisory board meetings for AstraZeneca, Bayer, Boehringer Ingelheim, and Bristol‐Myers Squibb. Dr Andersen reports other from MSD, personal fees from AstraZeneca, outside the submitted work
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A computer‐generated randomization code was used to randomize patients in blocks of 10."
Allocation concealment (selection bias)	Low risk	Quote: "Citalopram was commercially available (Sandoz, Denmark) and production of the placebo and randomization was prepared by a pharmacy independently of the investigators (Glostrup Pharmacy, Denmark). The tablets were indistinguishable and were supplied in numbered containers."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participant, care provider, and investigator assured and unlikely that the blinding could have been broken
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessor assured and unlikely that the blinding could have been broken
Incomplete outcome data (attrition bias) All outcomes	High risk	Attrition/exclusions reported with reasons provided (including did not start on study medication, consent withdrawn, side effects, indication for open label, other reasons (no detail provided)). At < 31 days of study medication, twice as many participants in the citalopram group withdrew consent (n = 29/318 (9%)) compared to the placebo group (n = 14/320 (4%)). However, at < 31 days twice as many participants in the placebo group (n = 12/318(4%)) compared to the citalopram group (n = 6/320 (2%) were switched to open label. Attrition/exclusions: 51/319 (16%) in the citalopram group and 39/319 (11%) in the placebo group. The investigators use LOCF in their intention‐to‐treat analysis. LOCF assumes that missing values are missing completely at random and ignores improvements or deteriorations in the participants condition since dropout and therefore stops improvements or declines in outcome measures. LOCF introduces risk of false or biased conclusions (Molnar 2008)
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study's prespecified (primary and secondary) outcomes that are of interest to the review have been reported in the prespecified way
Other bias	Low risk	The study appears to be free of other sources of bias