Vascular and metabolic risk factors of late-life depression

Abstract

Late-life depression (LLD) is a common complex mood disorder with high comorbidity of both psychiatric and physical diseases, cognitive decline, and increased mortality. The mechanisms underlying LLD are incompletely understood. The heterogeneity of depression complicates research into the underlying mechanisms, and factors involved in LLD may differ from those involved in early-life depression. This narrative review provides an overview of (micro-)vascular and metabolic factors involved in the development of LLD. Evidence suggests that cerebral small vessel disease, generalized microvascular dysfunction, and metabolic risk factors, including diabetes and inflammation, may contribute to the development of LLD, while the role of neurodegeneration needs further in-depth investigation. Accordingly, vascular and metabolic factors may provide promising targets for the prevention and improvement of treatment of LLD. Guidelines to screen for LLD in cardiovascular care need further implementation, as do integrated care approaches that treat LLD and diabetes jointly. However, intervention studies are needed to assess which interventions are appropriate and most effective in clinical practice.

Keywords

Depression / etiology / cerebral small vessel disease / microvascular dysfunction / metabolic syndrome / diabetes / inflammation / neurodegeneration

References

[1] Blazer DG.Depression in late life: review and commentary.J Gerontol A Biol Sci Med Sci2003;58:249-65

[2] Diniz BS,Albert SM,Reynolds CF 3rd.Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies.Br J Psychiatry2013;202:329-35 PMCID:PMC3640214

[3] Laborde-Lahoz P,Kinley J,Sareen J.Subsyndromal depression among older adults in the USA: prevalence, comorbidity, and risk for new-onset psychiatric disorders in late life.Int J Geriatr Psychiatry2015;30:677-85

[4] Lenze EJ,Martire LM.The Association of late-life depression and anxiety with physical disability: a review of the literature and prospectus for future research.The American Journal of Geriatric Psychiatry2001;9:113-35

[5] Djernes JK.Prevalence and predictors of depression in populations of elderly: a review.Acta Psychiatr Scand2006;113:372-87

[6] WHO. Depression and other common mental disorders: global health estimates. heepsAvailable form: https://apps.who.int/iris/handle/10665/254610 [Last accessed on 25Mar 2022]

[7] Lenze ,Sheffrin M.Incomplete response in late-life depression: getting to remission.Dialogues Clin Neurosci2009;10:419-30 PMCID:PMC3181898

[8] Paroni G,Fontana A.Klotho gene and selective serotonin reuptake inhibitors: response to treatment in late-life major depressive disorder.Mol Neurobiol2017;54:1340-51

[9] Schaakxs R,Lamers F,Beekman ATF.Associations between age and the course of major depressive disorder: a 2-year longitudinal cohort study.The Lancet Psychiatry2018;5:581-90

[10] Comijs HC,Kok R.The two-year course of late-life depression; results from the Netherlands study of depression in older persons.BMC Psychiatry2015;15:20 PMCID:PMC4329675

[11] Alexopoulos GS.Depression in the elderly.Lancet2005;365:1961-70

[12] Alexopoulos GS,Young RC,Silbersweig D.“Vascular depression” hypothesis.Arch Gen Psychiatry1997;54:915-22

[13] Alexopoulos GS.Mechanisms and treatment of late-life depression.Transl Psychiatry2019;9:188 PMCID:PMC6683149

[14] Krishnan KR,Blazer DG.MRI-defined vascular depression.Am J Psychiatry1997;154:497-501

[15] Souery D,Trivedi MH.Treatment-resistant depression.J Clin Psychiatry2006;67:16-22. Available from: https://www.psychiatrist.com/read

[16] Trivedi MH,Wisniewski SR.STAR*D Study TeamEvaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice.Am J Psychiatry2006;163:28-40

[17] Aizenstein HJ,Boldrini M.Vascular depression consensus report - a critical update.BMC Med2016;14:161 PMCID:PMC5093970

[18] Wardlaw JM,Dichgans M.Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging.The Lancet Neurology2013;12:483-97 PMCID:PMC3836247

[19] Nestler EJ,Dileone RJ,Gold SJ.Neurobiology of depression.Neuron2002;34:13-25

[20] Agtmaal MJM, Houben AJHM, Pouwer F, Stehouwer CDA, Schram MT. Association of microvascular dysfunction with late-life depression: a systematic review and meta-analysis.JAMA Psychiatry2017;74:729-39 PMCID:PMC5710252

[21] Geraets AF,Jansen JF.The association of markers of cerebral small vessel disease and brain atrophy with incidence and course of depressive symptoms - the maastricht study.J Affect Disord2021;292:439-47

[22] van Sloten TT,van Buchem MA.Cerebral small vessel disease and association with higher incidence of depressive symptoms in a general elderly population: the ages-reykjavik study.Am J Psychiatry2015;172:570-8 PMCID:PMC4451386

[23] Perez HC, Direk N, Hofman A, Vernooij MW, Tiemeier H, Ikram MA. Silent brain infarcts: a cause of depression in the elderly?.Psychiatry Res2013;211:180-2

[24] Houben AJHM,Stehouwer CDA.Assessing microvascular function in humans from a chronic disease perspective.J Am Soc Nephrol2017;28:3461-72 PMCID:PMC5698072

[25] Aird WC.Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms.Circ Res2007;100:158-73

[26] Hall, J.E. and A.C. Guyton, textbook of medical physiology. 2011. 12th edn: p. 157-66. ISBN:978-1-4160-4574-8.

[27] Li W,Sörensen BM.Microvascular phenotyping in the maastricht study: design and main findings, 2010-2018.Am J Epidemiol2020;189:873-84 PMCID:PMC7443762

[28] van Sloten TT,Adriaanse MC.Endothelial dysfunction is associated with a greater depressive symptom score in a general elderly population: the Hoorn study.Psychol Med2014;44:1403-16

[29] van Dooren FE,Schalkwijk CG.Associations of low grade inflammation and endothelial dysfunction with depression - the Maastricht study.Brain behav immun2016;56:390-6

[30] Geraets AFJ,Stehouwer CDA.Association of markers of microvascular dysfunction with prevalent and incident depressive symptoms: the Maastricht study.Hypertension2020;76:342-9

[31] Janssen EPCJ,Geraets AFJ.Low-grade inflammation and endothelial dysfunction predict four-year risk and course of depressive symptoms: The Maastricht study.Brain Behav Immun2021;97:61-7

[32] Massardo T,Jaimovich R.Regional brain perfusion is associated with endothelial dysfunction markers in major depressive disorder.Neuropsychobiology2021;80:214-24

[33] Alberti KG,Grundy SM.International Diabetes Federation Task Force on Epidemiology and PreventionHational HeartLungand Blood InstituteAmerican Heart AssociationWorld Heart FederationInternational Atherosclerosis SocietyInternational Association for the Study of ObesityHarmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity.Circulation2009;120:1640-5

[34] Saklayen MG.The global epidemic of the metabolic syndrome.Curr Hypertens Rep2018;20:12 PMCID:PMC5866840

[35] Shu MJ,Zhang DD.Metabolic syndrome, intracranial arterial stenosis and cerebral small vessel disease in community-dwelling populations.Stroke Vasc Neurol2021;6:589-94 PMCID:PMC8717787

[36] Pan A,Okereke OI.Bidirectional association between depression and metabolic syndrome: a systematic review and meta-analysis of epidemiological studies.Diabetes Care2012;35:1171-80 PMCID:PMC3329841

[37] Takeuchi T,Nomura K.Association of metabolic syndrome with depression and anxiety in Japanese men.Diabetes Metab2009;35:32-6

[38] Roy T.Epidemiology of depression and diabetes: a systematic review.Journal of Affective Disorders2012;142:S8-S21

[39] Nefs G,Denollet J.The course of depressive symptoms in primary care patients with type 2 diabetes: results from the diabetes, depression, type D Personality Zuidoost-Brabant (DiaDDZoB) study.Diabetologia2012;55:608-16 PMCID:PMC3268983

[40] Sloten T, Schram M. Understanding depression in type 2 diabetes: a biological approach in observational studies.F1000Res2018;7:1283 PMCID:PMC6092903

[41] Biessels GJ,Teunissen CE,Scheltens P.Understanding multifactorial brain changes in type 2 diabetes: a biomarker perspective.The Lancet Neurology2020;19:699-710

[42] Wardlaw JM,Biessels GJ.Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration.The Lancet Neurology2013;12:822-38 PMCID:PMC3714437

[43] Wang X,Liu J.Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis.Diabetes Care2013;36:166-75 PMCID:PMC3526249

[44] Leonard BE.Inflammation, depression and dementia: are they connected?.Neurochem Res2007;32:1749-56

[45] Pasco JA,Williams LJ.Association of high-sensitivity C-reactive protein with de novo major depression.Br J Psychiatry2010;197:372-7

[46] Tong A,Li F,Li Q.Risk of depressive symptoms associated with impaired glucose metabolism, newly diagnosed diabetes, and previously diagnosed diabetes: a meta-analysis of prospective cohort studies.Acta Diabetol2016;53:589-98

[47] Beran M,Geraets A.European Depression in Diabetes (EDID) Research ConsortiumThe bidirectional longitudinal association between depressive symptoms and HbA_1c : a systematic review and meta-analysis.Diabet Med2022;39:e14671

[48] Meurs M,Wolffenbuttel BH,de Jonge P.Association of depressive and anxiety disorders with diagnosed versus undiagnosed diabetes: an epidemiological study of 90,686 participants.Psychosom Med2016;78:233-41

[49] Geraets AFJ,Muzambi R.The association of hyperglycaemia and insulin resistance with incident depressive symptoms over 4 years of follow-up: The Maastricht Study.Diabetologia2020;63:2315-28 PMCID:PMC7527373

[50] Janssen EP,Stehouwer CD.The patient health questionnaire-9 as a screening tool for depression in individuals with type 2 diabetes mellitus: the Maastricht study.J Am Geriatr Soc2016;64:e201-6

[51] Valkanova V,Allan CL.CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies.J Affect Disord2013;150:736-44

[52] Copeland WE,Worthman C,Costelloet EJ.Cumulative depression episodes predict later C-reactive protein levels: a prospective analysis.Biol Psychiatry2012;71:15-21.

[53] Chocano-Bedoya PO,O’Reilly EJ.C-reactive protein, interleukin-6, soluble tumor necrosis factor α receptor 2 and incident clinical depression.J Affect Disord2014;163:25-32 PMCID:PMC4029945

[54] Baune BT,Reppermund S.Inflammatory biomarkers predict depressive, but not anxiety symptoms during aging: the prospective Sydney memory and aging study.Psychoneuroendocrinology2012;37:1521-30

[55] Wium-Andersen MK,Nielsen SF.Elevated C-reactive protein levels, psychological distress, and depression in 73, 131 individuals.JAMA Psychiatry2013;70:176-84

[56] Zalli A,Hoogendijk WJ,Carvalho LA.Low-grade inflammation predicts persistence of depressive symptoms.Psychopharmacology (Berl)2016;233:1669-78 PMCID:PMC4828485

[57] van den Biggelaar AH,de Craen AJ.Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age.Exp Gerontol2007;42:693-701

[58] Stewart JC,Muldoon MF.A prospective evaluation of the directionality of the depression-inflammation relationship.Brain Behav Immun2009;23:936-44 PMCID:PMC2749896

[59] Dantzer R,Freund GG,Kelley KW.From inflammation to sickness and depression: when the immune system subjugates the brain.Nat Rev Neurosci2008;9:46-56 PMCID:PMC2919277

[60] Romeo HE,Rahman SU,Taylor AN.The glossopharyngeal nerve as a novel pathway in immune-to-brain communication: relevance to neuroimmune surveillance of the oral cavity.Journal of Neuroimmunology2001;115:91-100

[61] Vitkovic L,Bockaert J,Homburger V.Cytokine signals propagate through the brain.Mol Psychiatry2000;5:604-15

[62] Banks WA.The blood-brain barrier in psychoneuroimmunology.Neurol Clin2006;24:413-9

[63] Schiltz JC.Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults.J Neurosci2002;22:5606-18 PMCID:PMC6758199

[64] Schiepers OJ,Maes M.Cytokines and major depression.Prog Neuropsychopharmacol Biol Psychiatry2005;29:201-17

[65] Zunszain PA,Cattaneo A,Pariante CM.Glucocorticoids, cytokines and brain abnormalities in depression.Prog Neuropsychopharmacol Biol Psychiatry2011;35:722-9 PMCID:PMC3513408

[66] Strawbridge R,Danese A,Herane Vives A.Inflammation and clinical response to treatment in depression: a meta-analysis.Eur Neuropsychopharmacol2015;25:1532-43

[67] Baquero M.Depressive symptoms in neurodegenerative diseases.World J Clin Cases2015;3:682-93 PMCID:PMC4539408

[68] Burgut FT,Hencliffe C.Late-life depression: a neuropsychiatric approach.Expert Rev Neurother2006;6:65-72

[69] Tittmann M,Sacher J.Structural brain changes in early-onset and late-onset depression: an update of volumetric MRI findings.Int J Imaging Syst Technol2014;24:149-60

[70] Gudmundsson P,Simoni M.White matter lesions and temporal lobe atrophy related to incidence of both dementia and major depression in 70-year-olds followed over 10 years.Eur J Neurol2015;22:781-8, e49

[71] Cyprien F,Poulain V.Corpus callosum size may predict late-life depression in women: a 10-year follow-up study.J Affect Disord2014;165:16-23

[72] Almeida OP,Ferrier N,O'Brien JT.Depression with late onset is associated with right frontal lobe atrophy.Psychol Med2003;33:675-81

[73] Sapolsky RM.Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders.Arch Gen Psychiatry2000;57:925-35

[74] Disabato BM.Biological basis of late life depression.Curr Psychiatry Rep2012;14:273-9 PMCID:PMC3752388

[75] Scott KM.Prevention of CVD in depression. In: Baune BT, Tully PJ, editors. Cardiovascular Diseases and Depression. Cham: Springer International Publishing; 2016. p. 509-17.

[76] Dooren FE, Nefs G, Schram MT, Verhey FR, Denollet J, Pouwer F. Depression and risk of mortality in people with diabetes mellitus: a systematic review and meta-analysis.PLoS One2013;8:e57058 PMCID:PMC3589463

[77] Perk J,Gohlke H.European Association for Cardiovascular Prevention & Rehabilitation (EACPR)ESC Committee for Practice Guidelines (CPG)European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The fifth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts).Eur Heart J2012;33:1635-701

[78] McMurray JJ,Anker SD.ESC Committee for Practice GuidelinesESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European society of cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC.Eur Heart J2012;33:1787-847

[79] Lichtman JH,Blumenthal JA.American Heart Association Prevention Committee of the Council on Cardiovascular NursingAmerican Heart Association Council on Clinical CardiologyAmerican Heart Association Council on Epidemiology and PreventionAmerican Heart Association Interdisciplinary Council on Quality of Care and Outcomes Research, American Psychiatric Association. depression and coronary heart disease: recommendations for screening, referral, and treatment: a science advisory from the American heart association prevention committee of the council on cardiovascular nursing, council on clinical cardiology, council on epidemiology and prevention, and interdisciplinary council on quality of care and outcomes research: endorsed by the American psychiatric association.Circulation2008;118:1768-75

[80] Stewart A,Hare D.National survey of Australian cardiologists’ beliefs and practice regarding screening, diagnosis and management of depression.Heart, Lung and Circulation2009;18:S5

[81] Young-Hyman D,Hill-Briggs F.Psychosocial care for people with diabetes: a position statement of the American diabetes association.Diabetes Care2016;39:2126-40 PMCID:PMC5127231

[82] Barents ESE,Bouma M.Diabetes mellitus type 2. Available from: https://richtlijnen.nhg.org/standaarden/diabetes-mellitus-type-2 [Last accessed on 25 Mar 2022]

[83] Trangle, M., J. Gursky, and R. Haight, Adult depression in primary care. ICSI Inst Clin Syst Improv. Available from: https://www.icsi.org/guideline/depression/ [Last accessed on 25 Mar 2022]

[84] Stehouwer CDA.Microvascular Dysfunction and hyperglycemia: a vicious cycle with widespread consequences.Diabetes2018;67:1729-41

[85] Ambrose JA.The pathophysiology of cigarette smoking and cardiovascular disease: an update.J Am Coll Cardiol2004;43:1731-7

[86] Fluharty M,Grabski M.The association of cigarette smoking with depression and anxiety: a systematic review.Nicotine Tob Res2017;19:3-13 PMCID:PMC5157710

[87] Trimbos-instituut.ADDENDUM OUDEREN BIJ DE MDR DEPRESSIE. Available from: https://www.trimbos.nl/docs/b0822cf7-b915-44a2-9a55-db6ea341267a.pdf [Last accessed on 25 Mar 2022]

[88] Petrak F,Skinner TC,Holt RIG.Depression and diabetes: treatment and health-care delivery.2015;3:472-85

[89] Bennett S.Depression and dementia: cause, consequence or coincidence?.Maturitas2014;79:184-90

[90] Barnes DE,Byers AL,Schaefer C.Midlife vs late-life depressive symptoms and risk of dementia: differential effects for Alzheimer disease and vascular dementia.Arch Gen Psychiatry2012;69:493-8 PMCID:PMC3704214

[91] Köhler S,Palmer K.Depression, vascular factors, and risk of dementia in primary care: a retrospective cohort study.J Am Geriatr Soc2015;63:692-8

[92] Heintz H,Epstein-Lubow G,Rowlett S.Emerging collaborative care models for dementia care in the primary care setting: a narrative review.Am J Geriatr Psychiatry2020;28:320-30

[93] Köhler-Forsberg O,Hjorthøj C.Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials.Acta Psychiatr Scand2019;139:404-19