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Platelet and endothelial activity in comorbid major depression and coronary artery disease patients treated with citalopram: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy Trial (CREATE) biomarker sub-study

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Abstract

Background and purpose Major depression is an independent risk factor for increased morbidity and mortality in patients with coronary artery disease (CAD). Increased platelet activity and vascular endothelial dysfunction are possible pathways through which depression may increase cardiovascular risk. Citalopram exhibits strong selective inhibition of human platelet activation, but little is known about its effects on vascular endothelium. We assessed whether treatment of depressed CAD patients with citalopram alters platelet/endothelial biomarkers. The study was performed within the framework of the CREATE trial. Methods We assessed the effect of citalopram on P-selectin, β-thromboglobulin (βTG), soluble intercellular cell adhesion molecule-1 (sICAM-1), and total nitric oxide (tNO). Plasma samples were obtained at baseline and week 12 from subjects randomized to citalopram 20–40 mg daily (n = 36), or placebo (n = 21). Anticoagulants, aspirin, and clopidogrel were permitted. Results Treatment with citalopram was associated with greater increase in tNO over 12 weeks compared to placebo (P = 0.005). There were no differences for the other biomarkers such as P-selectin (P = 0.70), βTG (P = 0.46) and ICAM (P = 0.59). Conclusion Treatment with citalopram for 12 weeks in depressed CAD patients is associated with enhanced production of nitric oxide despite the co-administration of commonly prescribed anti-platelet regimens including aspirin and clopidogrel. Clinical implications of these findings are unclear, but improved endothelial function is implied by the increased NO production, suggesting that citalopram may be of particular benefit for patients with comorbid depression and vascular disease including CAD, stroke, peripheral artery disease, and diabetes.

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Acknowledgments

We would like to thank the following site principal investigators and their research assistants for their contributions to this study through recruitment, clinical input, blood collection, and sample storage and shipping. Montreal Heart Institute: Marc-André Laliberté, MD (PI); Marie-Pierre Leduc, MPs; Aline Masson, MSc; Elaine Kennedy, MPs; Kingston General Hospital and Hotel Dieu Hospital: Joan Bowie and Pilsu-qua Lloyd; Calgary Health Region: Margaret Oakander, MD (PI), Bette Moxham, and Linda Seyler. Dr. Serebruany is listed as an inventor of 2 US Patents (USN 6,245,782 and USN 6,552,014) related to the use of SSRI and metabolites as antiplatelet agents. We also acknowledge valuable assistance with manuscript review received from members of the Montreal Heart Institute Coordinating Center: Ginette Gravel, MSc and Martine Habra, PhD.

Financial disclosure

This study was supported by the Canadian Institutes of Health Research (CIHR) Clinical Trials Program grant MCT50397; Fondation du Centre Hospitalier de l’Université de Montréal; Fondation de l’Institut de Cardiologie de Montréal; HeartDrug Research, LLC.; National Association of Norway for Public Health (the Norwegian Council for Heart and Vessels); Eastern Regional Health Authority of Norway; Grants from the University of Oslo, and the Aker University Hospital Research Foundation. Citalopram and matching placebo were donated by Lundbeck Canada Inc.

Role of sponsors

None of the sponsors participated in the design, conduct, management, analysis, or interpretation of the data or was involved in the preparation, review, or approval of the manuscript.

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Authors and Affiliations

  1. Department of Psychiatry, Queen’s University, Kingston, ON, Canada

    Louis T. van Zyl

  2. Department of Psychiatry, University of Montreal, Montreal, QC, Canada

    Francois Lespérance & Marc-André Laliberté

  3. Research Centres Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada

    Francois Lespérance, Nancy Frasure-Smith & Marc-André Laliberté

  4. Montreal Heart Institute, Montreal, QC, Canada

    Francois Lespérance, Nancy Frasure-Smith & Marc-André Laliberté

  5. Department of Psychiatry and School of Nursing, McGill University, Montreal, QC, Canada

    Nancy Frasure-Smith

  6. HeartDrug™ Research Laboratories, Osler Medical Center, HeartDrug™ Research LLC, 7600 Osler Drive, Ste. 307, Towson, MD, 21204, USA

    Alex I. Malinin & Victor L. Serebruany

  7. Johns Hopkins University, Baltimore, MD, USA

    Alex I. Malinin & Victor L. Serebruany

  8. Division of Cardiology, Aker University Hospital, Oslo, Norway

    Dan Atar

  9. Faculty of Medicine, University of Oslo, Oslo, Norway

    Dan Atar

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  1. Louis T. van Zyl
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Correspondence to Victor L. Serebruany.

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van Zyl, L.T., Lespérance, F., Frasure-Smith, N. et al. Platelet and endothelial activity in comorbid major depression and coronary artery disease patients treated with citalopram: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy Trial (CREATE) biomarker sub-study. J Thromb Thrombolysis 27, 48–56 (2009). https://doi.org/10.1007/s11239-007-0189-3

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