The Efficacy of Citalopram Treatment in Acute Stroke (TALOS)

We wish to conduct a prospective, randomized, double blind, placebo controlled multi center study of the combined neuroprotective and antithrombotic effects of SSRI treatment after stroke. Hypotheses: SSRI treatment commenced in the acute phase of stroke (day 0-7) protects against new thromboembolic events and leads to better rehabilitation. 600 stroke patients will be randomized in a 1:1 ratio. The treatment and follow up period is 6 months. During these 6 months there will be 2 clinical follow up visits, one telephone control and one visit to evaluate compliance regarding medication.

Design TALOS is an investigator-initiated, national multicenter randomized- and placebo-controlled, double blind trial testing citalopram in acute ischemic stroke. Randomization Eligible patients will be randomized 1:1 to treatment with either citalopram or placebo. Treatment allocation is double-blinded based on computer-generated algorithm via a dedicated website. Patients whose treatment is stopped within 31 days after inclusion will be replaced. Intervention and follow-up Patients randomized to citalopram will receive oral treatment with 20 mg tablets (10 mg if age ≥65 and/or reduced liver function) for 6 months with telephone contact after 2 weeks and 3 months and follow-up visits at 1 and 6 months. If patients develop depression dosage is initially doubled, followed by an additional control to evaluate effect and, if necessary, shifted to open-label antidepressant treatment. After 6 months, treatment will either stop or switch to open-label antidepressants at the discretion of the investigator. Substudy 120 of patients will begin treatment within 12 hours after treatment with recombinant tissue plasminogen activator. These patients will receive a standard acute magnetic resonance imaging (MRI) with additional perfusion and angio sequences. The 24-hour control scan will be done using MRI instead of conventional CT. Data monitoring When 300 patients have been included in the trial, an interim analysis will be performed. The unblinded results of this analysis will be reviewed by an independent data monitoring committee.

Stroke, SSRI (Selective Serotonin Reuptake Inhibitors), Serotonin, 5-HT (5-Hydroxytryptamine), Neuroprotection, MRI (Magnetic Resonance Imaging), Platelet, CT (computerized tomography), Post Stroke Depression

Myocardial Infarction: STEMI (ST segment elevation myocardial infarction) and NSTEMI (non-ST segment elevation myocardial infarction)

Using the Global Utilization Of Streptokinase And Tpa For Occluded Arteries definition for bleeding (GUSTO)

STEMI (ST segment elevation myocardial infarction) and NSTEMI (non-ST segment elevation myocardial infarction)

Using the Major Depression Inventory test (MDI), Global depression scale (self and clinician and Hamilton Depression Scale - 6 item (HAM-D6)

Inclusion Criteria: First ever ischemic stroke Age 18 years or above Exclusion Criteria: Hemorrhagic 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 noncompliant behavior Liver failure (increased liver enzyme levels up to or more than 2 times upper limit) Renal failure (eGFR below 30 ml/min per 1.73m2) 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

Siepmann T, Penzlin AI, Kepplinger J, Illigens BM, Weidner K, Reichmann H, Barlinn K. Selective serotonin reuptake inhibitors to improve outcome in acute ischemic stroke: possible mechanisms and clinical evidence. Brain Behav. 2015 Sep 23;5(10):e00373. doi: 10.1002/brb3.373. eCollection 2015 Oct.

Bonaventura A, Liberale L, Vecchie A, Casula M, Carbone F, Dallegri F, Montecucco F. Update on Inflammatory Biomarkers and Treatments in Ischemic Stroke. Int J Mol Sci. 2016 Nov 25;17(12):1967. doi: 10.3390/ijms17121967.

Mortensen JK, Johnsen SP, Larsson H, Andersen G. Early Antidepressant Treatment and All-Cause 30-Day Mortality in Patients with Ischemic Stroke. Cerebrovasc Dis. 2015;40(1-2):81-90. doi: 10.1159/000435819. Epub 2015 Jul 11.

Adelborg K, Sundboll J, Videbech P, Grove EL. The Risk of Thromboembolism in Users of Antidepressants and Antipsychotics. Adv Exp Med Biol. 2017;906:351-361. doi: 10.1007/5584_2016_125.

Kraglund KL, Mortensen JK, Damsbo AG, Modrau B, Simonsen SA, Iversen HK, Madsen M, Grove EL, Johnsen SP, Andersen G. Neuroregeneration and Vascular Protection by Citalopram in Acute Ischemic Stroke (TALOS). Stroke. 2018 Nov;49(11):2568-2576. doi: 10.1161/STROKEAHA.117.020067.