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Depression and Cardiovascular Disease: An Update on How Course of Illness May Influence Risk
Open accessAbstract
Depression constitutes a novel and independent risk factor for cardiovascular disease, which despite extensive support in the literature has been underappreciated. While much of the evidence for depression as a risk factor for cardiovascular disease is based on studies following myocardial infarction, the elevated vascular risk conveyed by depression is not confined to periods following acute coronary syndromes. For that matter, the risk appears across mood disorders with evidence for even greater risk in bipolar disorder. This review summarizes the literature linking depressive disorders to cardiovascular mortality with a focus on how the course of illness of mood disorders may influence this risk. Mood disorders may influence risk over decades of illness in a dose-response to symptom burden, or the persistence of affective symptomatology. This may be mediated through changes in the activity of the autonomic nervous system, the hypothalamic-pituitary-adrenal axis, and inflammatory cytokines. Whether treatment of depression can mitigate this risk is not established although there are suggestions to support this contention, which could be better studied with more effective treatments of depression and larger standardized samples. Directions for future study of mechanisms and treatment are discussed. Regardless of causal mechanisms, persons with depressive disorders and other risk factors for vascular disease represent a neglected, high-risk group for cardiovascular events. In addition to the appropriate treatment for depression, screening and optimized management of traditional risk factors for cardiovascular diseases is necessary.
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“In mood disorders, for example, vasculopathy has been associated with the long-term course of illness and in proportion to symptom burden or the persistence of mood symptoms [45].”
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MethodArterial endothelial function is impaired in treated depression
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“With regard to the most commonly assessed marker CRP, several but not all studies [70, 72], found higher levels in those with mania compared to those who were depressed [66, 68, 71] or euthymic [66, 68, 71, 74].”
BackgroundResultAntidepressant therapy and C-reactive protein levels
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Autonomic Neural Regulation of the Immune System
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“With regard to the most commonly assessed marker CRP, several but not all studies [70, 72], found higher levels in those with mania compared to those who were depressed [66, 68, 71] or euthymic [66, 68, 71, 74].”
BackgroundResultLambert, É., Dawood, T., Straznicky, N. E., Sari, C. I., Schlaich, M. P., Esler, M., & Lambert, G. W. (2010) · Journal of Hypertension · doi:10.1097/hjh.0b013e3283350ea4 · Cited by 123 · cited 1×
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Liu, H., Yang, Y., Chou, Y.-M., Chen, K.-P., Shen, W. W., & Leu, S. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.01.006 · Cited by 118
Impairment of Endothelial Function in Unipolar and Bipolar Depression
Rybakowski, J. K., Wykretowicz, A., Heymann-Szlachcinska, A., & Wysocki, H. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.03.025 · Cited by 105
Tsai, S., Chung, K., Wu, J.-Y., Kuo, C., Lee, H., & Huang, S. (2011) · Journal of Affective Disorders · doi:10.1016/j.jad.2011.08.022 · Cited by 103 · cited 1×
“With regard to the most commonly assessed marker CRP, several but not all studies [70, 72], found higher levels in those with mania compared to those who were depressed [66, 68, 71] or euthymic [66, 68, 71, 74].”
ResultDepression, anxiety, and arterial stiffness
Seldenrijk, A., van Hout, H. P. J., van Marwijk, H. W. J., de Groot, E., Gort, J., Rustemeijer, C., Diamant, M., & Penninx, B. W. J. H. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.12.034 · Cited by 101
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“sample, for instance, those with mood disorders were found to have an increased risk of heart disease independent of age, urbanicity, income, education, smoking, marital status, race, employment, family history of heart disease, obesity, high blood pressure, and diabetes [9].”
BackgroundSelf-citationLate‐Life Depression is Associated with Arterial Stiffness: A Population‐Based Study
Tiemeier, H. W., Breteler, M. M. B., van Popele, N. M., Albert Hofman, D., & Witteman, J. C. M. (2003) · Journal of the American Geriatrics Society · doi:10.1046/j.1532-5415.2003.51359.x · Cited by 95
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Associations Between Psychological Traits and Endothelial Function in Postmenopausal Women
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Depressive Symptoms and Mortality Risk in a National Sample: Confounding Effects of Health Status
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“While some have found the association between depression and cardiovascular mortality does not persist after control of confounding [8], much of the literature has indeed been able to demonstrate an independent contribution of depression, above and beyond that explainable due to confounding variables.”
BackgroundVascular Function in Older Adults with Depressive Disorder
Paranthaman, R., Greenstein, A. S., Burns, A. S., Cruickshank, J. K., Heagerty, A. M., Jackson, A., Malik, R. A., Scott, M. L. J., & Baldwin, R. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.04.017 · Cited by 91
The combined DEX-CRH test in treatment course and long-term outcome of major depression
Hatzinger, M., Hemmeter, U., Baumann, K., Brand, S., & Holsboer‐Trachsler, E. (2002) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(02)00021-3 · Cited by 90 · cited 1×
“Individual level data from two small studies suggests those with more prior episodes of major depression have greater alterations in HPA activity as assessed by the dexamethasone/corticotropin-releasing hormone test [45, 46].”
MethodBaumert, M., Lambert, G. W., Dawood, T., Lambert, É., Esler, M., McGrane, M. T., Barton, D., Sanders, P., & Nalivaiko, E. (2009) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00236.2009 · Cited by 82 · cited 1×
“The low frequency components of heart rate variability are considered a poor measure of sympathetic outflow [49].”
BackgroundDawood, T., Lambert, É., Barton, D., Laude, D., Elghozi, J., Esler, M., Haikerwal, D., Kaye, D. M., Hotchkin, E., & Lambert, G. W. (2007) · Hypertension Research · doi:10.1291/hypres.30.285 · Cited by 77 · cited 1×
“Caution must be exercised in interpreting these findings given results of the third longest study (12 weeks, N=24 treated), in which hsCRP significantly increased, not decreased, on SSRIs despite significant reductions in depression following treatment [82].”
ResultAdverse Impact of Mood on Flow-Mediated Dilation
Cooper, D. C., Milic, M. S., Tafur, J., Mills, P. J., Bardwell, W. A., Ziegler, M. G., & Dimsdale, J. E. (2010) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3181cdbfc0 · Cited by 76
Muscle sympathetic nervous activity in depressed patients before and after treatment with sertraline
Scalco, A. Z., Rondon, M. U. P. B., Trombetta, I. C., Laterza, M. C., Serro‐Azul, J. B., Pullenayegum, E., Scalco, M. Z., Kuniyoshi, F. H. S., Wajngarten, M., Negrão, C. E., et al. (2009) · Journal of Hypertension · doi:10.1097/hjh.0b013e3283310ece · Cited by 75 · cited 1×
“This finding was replicated in another small study which additionally found that treatment with sertraline reduced muscle sympathetic nerve activity both at rest and in response to mental stress [51].”
ResultBaumert, M., Lambert, G. W., Dawood, T., Lambert, É., Esler, M., McGrane, M. T., Barton, D., & Nalivaiko, E. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00301.2008 · Cited by 74
Metyrapone Improves Endothelial Dysfunction in Patients With Treated Depression
Broadley, A., Korszun, A., Abdelaal, E., Moskvina, V., Deanfield, J. E., Jones, C. J. H., & Frenneaux, M. P. (2006) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.12.078 · Cited by 71
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Mania and mortality: Why the excess cardiovascular risk in bipolar disorder?
Murray, D. P., Weiner, M., Prabhakar, M., & Fiedorowicz, J. G. (2009) · Current Psychiatry Reports · doi:10.1007/s11920-009-0072-3 · Cited by 70 · cited 1×
“The majority of studies that assessed the SMR for both mood diagnoses have found a greater burden of cardiovascular mortality in bipolar disorder compared to unipolar major depression [7].”
BackgroundSelf-citationSymptoms of depression and impaired endothelial function in healthy adolescent women
Tomfohr‐Madsen, L. M., Martin, T. M., & Miller, G. E. (2007) · Journal of Behavioral Medicine · doi:10.1007/s10865-007-9141-4 · Cited by 69
Mackay, G., Forrest, C. M., Christofides, J. A., Bridel, M. A., Mitchell, S. L., Cowlard, R., Stone, T. W., & Darlington, L. G. (2008) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2008.05077.x · Cited by 67 · cited 1×
“In the second longest study (18 weeks), CRP showed non-significant increases following treatment with fluoxetine although this study was designed to assess antidepressant-related changes, rather than the effect of changes in mood state, as the comparison group also received active treatment, consisting of counseling f…”
BackgroundLife Stress and Cardiovascular Disorders
Wolff, H. G. (1950) · Circulation · doi:10.1161/01.cir.1.2.187 · Cited by 67 · cited 1×
“studied generations prior, and is intimately tied with ancient folklore about the role of the heart [2].”
BackgroundStraub, R. H., Buttgereit, F., & Cutolo, M. (2011) · PubMed · Cited by 65
Anger, depression and anxiety associated with endothelial function in childhood and adolescence
Osika, W., Montgomery, S. M., Dangardt, F., Währborg, P., Gan, L., Tideman, E., & Friberg, P. (2009) · Archives of Disease in Childhood · doi:10.1136/adc.2008.152777 · Cited by 64
Evaluation of C-Reactive Protein and Total Serum Cholesterol in Adult Patients with Bipolar Disorder
Berardis, D. D., Conti, C., Campanella, D., Carano, A., Scali, M., Valchera, A., Serroni, N., Pizzorno, A. M., D'Albenzio, A., Fulcheri, M., et al. (2008) · International Journal of Immunopathology and Pharmacology · doi:10.1177/039463200802100208 · Cited by 64 · cited 2×
“With regard to the most commonly assessed marker CRP, several but not all studies [70, 72], found higher levels in those with mania compared to those who were depressed [66, 68, 71] or euthymic [66, 68, 71, 74].”
BackgroundResultFiedorowicz, J. G., Coryell, W. H., Rice, J. P., Warren, L. L., & Haynes, W. G. (2012) · Psychotherapy and Psychosomatics · doi:10.1159/000334779 · Cited by 62 · cited 1×
“In the case of bipolar disorder, impairments in vascular function are not seen early in the course of illness [17], but appear to arise over the long-term course of illness [18] and in relation to manic/hypomanic symptom burden [19].”
BackgroundSelf-citationEvidence for accelerated vascular aging in bipolar disorder
Sodhi, S. K., Linder, J., Chenard, C. A., Miller, D. D., Haynes, W. G., & Fiedorowicz, J. G. (2012) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2012.06.004 · Cited by 57 · cited 2×
“In the case of bipolar disorder, impairments in vascular function are not seen early in the course of illness [17], but appear to arise over the long-term course of illness [18] and in relation to manic/hypomanic symptom burden [19].”
BackgroundSelf-citationBarbosa, I. G., Morato, I. B., de Miranda, A. S., Bauer, M. E., Soares, J. C., & Teixeira, A. L. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.12.042 · Cited by 53
History of Major Depressive Disorder and Endothelial Function in Postmenopausal Women
Wagner, J. A., Tennen, H. A., Mansoor, G. A., & Abbott, G. (2006) · Psychosomatic Medicine · doi:10.1097/01.psy.0000195868.68122.9e · Cited by 53 · cited 1×
“Later in the course of illness, even a history of depression has been associated with poorer endothelial function [24, 25].”
BackgroundSu, K., Leu, S.-J. C., Yang, Y., Shen, W. W., Chou, Y.-M., & Tsai, S. (2002) · Journal of Affective Disorders · doi:10.1016/s0165-0327(01)00369-x · Cited by 53
Greenstein, A. S., Paranthaman, R., Burns, A. S., Jackson, A., Malik, R. A., Baldwin, R., & Heagerty, A. M. (2010) · Hypertension · doi:10.1161/hypertensionaha.110.152801 · Cited by 53
Antidepressant Effects on Insulin Sensitivity and Proinflammatory Cytokines in the Depressed Males
Chen, Y.-C., Lin, W., Chen, Y.-J., Mao, W.-C., & Hung, Y.-J. (2010) · Mediators of Inflammation · doi:10.1155/2010/573594 · Cited by 46
Plasma Nitrate Levels and Flow-Mediated Vasodilation in Untreated Major Depression
Garcia, R. G., Zarruk, J. G., Barrera, C., Pinzón, A., Trillos, E., Arenas, W. D., Luengas, C., Tomaz, C. A. B., & López-Jaramillo, P. A. (2011) · Psychosomatic Medicine · doi:10.1097/psy.0b013e31821566cf · Cited by 43 · cited 1×
“Despite using varied measures of vascular function, studies have found a relatively consistent association between impaired vascular function and depression with the two notable negative studies involving young adults [17, 30], predominantly early in their course of illness.”
BackgroundTomfohr‐Madsen, L. M., Murphy, M. L. M., Miller, G. E., & Puterman, E. M. (2011) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3182228644 · Cited by 41
Oulis, P., Kouzoupis, A. V., Kyrkou, K., Masdrakis, V. G., Georgiopoulos, G., Karapoulios, E., Georgiou, S., Karakatsanis, N. A., Lykka, M., Papadimitriou, G. N., et al. (2009) · Journal of Affective Disorders · doi:10.1016/j.jad.2009.08.003 · Cited by 41
Relationship of depression, stress and endothelial function in stable angina patients
Chen, H., Zhang, L., Zhang, M., Song, X., Zhang, H., Liu, Y., & Lv, S. (2013) · Physiology & Behavior · doi:10.1016/j.physbeh.2013.05.024 · Cited by 37
Licht, C. M. M., Penninx, B. W. J. H., & de Geus, E. J. C. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.06.034 · Cited by 33 · cited 1×
“Heart rate variability, an indirect assessment of the autonomic nervous system, appears decreased in those with depression and related to severity of depression [47], although some contest that this may be an effect of antidepressant medications [48].”
BackgroundWagner, J. A., Tennen, H. A., Mansoor, G. A., & Abbott, G. (2008) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2007.11.007 · Cited by 30 · cited 1×
“Later in the course of illness, even a history of depression has been associated with poorer endothelial function [24, 25].”
BackgroundWagner, J. A., Tennen, H. A., Finan, P. H., White, W. B., Burg, M. M., & Ghuman, N. (2011) · International Journal of Behavioral Medicine · doi:10.1007/s12529-011-9190-5 · Cited by 29
Vascular Mortality in Participants of a Bipolar Genomics Study
Fiedorowicz, J. G., Jancic, D., Potash, J. B., Butcher, B. D., & Coryell, W. H. (2014) · Psychosomatics · doi:10.1016/j.psym.2014.02.001 · Cited by 26 · cited 1×
“In a 7-yearmortality follow-up of 1716 persons with bipolar disorder, a measure of depressive symptom burden, the duration of the most severe depression, predicated vascular mortality [16].”
BackgroundSelf-citationVascular function is not impaired early in the course of bipolar disorder
Murray, D. P., Metz, N. S., Haynes, W. G., & Fiedorowicz, J. G. (2012) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2011.12.006 · Cited by 25 · cited 2×
“Despite using varied measures of vascular function, studies have found a relatively consistent association between impaired vascular function and depression with the two notable negative studies involving young adults [17, 30], predominantly early in their course of illness.”
BackgroundSelf-citationDefective Nitric Oxide–Cyclic Guanosine Monophosphate Signaling in Patients With Bipolar Disorder
Fontoura, P. C., Pinto, V. L. M., Matsuura, C., Resende, Â. C., de Bem, G. F., Ferraz, M. R., Cheniaux, E., Brunini, T. M. C., & Mendes‐Ribeiro, A. C. (2012) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3182689460 · Cited by 20 · cited 1×
“With regard to the most commonly assessed marker CRP, several but not all studies [70, 72], found higher levels in those with mania compared to those who were depressed [66, 68, 71] or euthymic [66, 68, 71, 74].”
ResultSantangelo, A., Testaì, M., Barbagallo, P., Crisafulli, C., GRASSO, S. G., Manuele, S., Muscarà, G., Rizzotto, M., Tomarchio, M., & Maugeri, D. (2008) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2008.02.014 · Cited by 20 · cited 1×
“Similar results were seen in a sample of 110 elderly nursing home residents, wherein responders to a SSRI (sertraline or citalopram) exhibited a 60 % reduction in cardiovascular events [91].”
ResultThe National Network of Depression Centers: progress through partnership
Greden, J. F. (2011) · Depression and Anxiety · doi:10.1002/da.20862 · Cited by 16 · cited 2×
“The huge burdens of disease for both cardiovascular and depressive diseases, and the enhancement by their co-occurrence calls for incremental collaborative studies among cardiovascular centers of excellence and depression centers of excellence such as in the National Network of Depression Centers [94].”
BackgroundZhuo, C., Wang, Y., Tian, H., Wang, X., Chen, Y., & Mao, F. (2011) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y11-063 · Cited by 5
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The intriguing relationship between coronary heart disease and mental disorders
Binder, M. D., Detraux, J., & Vancampfort, D. (2018) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2018.20.1/mdehert · Cited by 506
Vascular depression consensus report – a critical update
Aizenstein, H. J., Baskys, A., Boldrini, M., Butters, M. A., Diniz, B. S., Jaiswal, M. K., Jellinger, K. A., Kruglov, L. S., Meshandin, I. A., Mijajlovic, M. D., et al. (2016) · BMC Medicine · doi:10.1186/s12916-016-0720-5 · Cited by 267
“for cardiovascular and cerebrovascular disease is necessary [219, 220].”
BackgroundThe Emerging Field of Nutritional Mental Health
Kaplan, B. J., Rucklidge, J. J., Romijn, A., & McLeod, K. (2015) · Clinical Psychological Science · doi:10.1177/2167702614555413 · Cited by 132
“The autonomic nervous system, HPA axis, and inflammatory cytokines are all being considered now as playing a role in the development of both depression and heart disease (Fiedorowicz, 2014).”
Background“GrimAge,” an epigenetic predictor of mortality, is accelerated in major depressive disorder
Protsenko, E., Yang, R., Nier, B., Reus, V. I., Hammamieh, R., Rampersaud, R., Wu, G. W. Y., Hough, C. M., Epel, E. S., Prather, A. A., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01302-0 · Cited by 118
Lillevang-Johansen, M., Abrahamsen, B., Jørgensen, H. L., Brix, T. H., & Hegedüs, L. (2019) · European Journal of Endocrinology · doi:10.1530/eje-19-0006 · Cited by 100
Metadata
- Authors
- Fiedorowicz, J. G.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Fiedorowicz, Jess G.
- ORCID
- Fiedorowicz, Jess G.
- Venue
- Current Psychiatry Reports
- Published
- 2014-08-28
- Volume
- 16
- Issue
- 10
- Pages
- 492-492
- ISSN
- 1523-3812 (ISSN-L)
- 1535-1645
- PMC
- PMC4153989
- OpenAlex
- W2069214992
- Cited by
- 103
- References
- 99
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 13 · 2023: 11 · 2022: 5 · 2021: 14 · 2020: 7 · 2019: 13 · 2018: 9 · 2017: 5 · 2016: 10 · 2015: 9 · 2014: 3
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Current Psychiatry Reports (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (K23MH083695)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Health and Mental Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- depression, cardiovascular disease, cardiovascular risk factors, mood disorders, bipolar disorder, clinical course, cardiovascular mortality, myocardial infarction, autonomic nervous system, hypothalamic-pituitary-adrenal axis, inflammatory cytokines, antidepressant treatment, cardiovascular screening
- MeSH terms
- Antidepressive Agents, Cardiovascular Diseases, Humans, Hypothalamo-Hypophyseal System, Inflammation, Pituitary-Adrenal System, Risk Factors, Cognitive Behavioral Therapy, Selective Serotonin Reuptake Inhibitors, Disease Progression, Mood Disorders
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