European Journal of Epidemiology

, Volume 18, Issue 8, pp 745–750 | Cite as

REVIEW: Biological risk factors for late life depression

  • Henning Tiemeier


Depression in late life is a recognised public health problem. After establishing socio-demographic and psychological risk factors for depression, epidemiological research has focused on biological factors. This review summarises the evidence on the associations of cerebrovascular pathology, inflammation, and endocrine and nutritional status with depression in the elderly. The most consistent finding in biological psychiatry is the disturbance of the hypothalamic–pituary–adrenal axis in depressed persons. About half of the patients with severe depression have a disturbed glucocorticoid feedback mechanism and many exhibit hypercortisolism. Longitudinal studies show that this endocrine dysfunction increases the risk of relapse. More recently, silent brain infarcts and cerebral white matter lesions on MRI were found to be more frequent in the depressed elderly than in controls. Cerebral small vessel disease has been rediscovered as a potential cause of depression. Furthermore, there is evidence of immune activation in depressed persons. However, it remains unclear as to whether inflammation contributes to the pathological process as longitudinal studies are lacking. Clinical studies have also related many nutrients to psychological symptoms, but the evidence in elderly persons is consistent only for some vitamin deficiencies. In conclusion, despite a substantial body of literature on biological correlates of late life depression, little is known about causal relations. Prospective population-based studies are warranted.

Depression Elderly Hormones Inflammation Nutrition Vascular pathology 


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  1. 1.
    Beekman AT, Copeland JR, Prince MJ. Review of community prevalence of depression in later life. Br J Psychiatry 1999; 174: 307–311.Google Scholar
  2. 2.
    Snowdon J. Prevalence of depression in old age. Br J Psychiatry 2001; 178: 476–477.Google Scholar
  3. 3.
    Mendlewicz J. The age factor in depressive illness: Some genetic considerations. J Gerontol 1976; 31: 300–303.Google Scholar
  4. 4.
    Beekman AT, Deeg DJ, van Tilburg T, et al. Major and minor depression in later life: A study of prevalence and risk factors. J Affect Disord 1995; 36: 65–75.Google Scholar
  5. 5.
    Casey DA. Depression in the elderly. South Med J 1994; 87: 559–563.Google Scholar
  6. 6.
    Serby M, Yu M. Overview: Depression in the elderly. Mt Sinai J Med 2003; 70: 38–44.Google Scholar
  7. 7.
    Hickie I, Scott E. Late-onset depressive disorders: A preventable variant of cerebrovascular disease? [editorial]. Psychol Med 1998; 28: 1007–1013.Google Scholar
  8. 8.
    Rothman KJ, Greenland S. Modern Epidemiology. Philadelphia: Lippincott Williams & Wilkins Publishers, 1998.Google Scholar
  9. 9.
    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders-IV. Washington DC, 1994.Google Scholar
  10. 10.
    Beekman AT, Deeg DJ, Geerlings SW, et al. Emergence and persistence of late life depression: A 3-year follow-up of the Longitudinal Aging Study Amsterdam. J Affect Disord 2001; 65: 131–138.Google Scholar
  11. 11.
    Prince MJ, Harwood RH, Thomas A, et al. A prospective population-based cohort study of the effects of disablement and social milieu on the onset and maintenance of late-life depression. The Gospel Oak Project VII. Psychol Med 1998; 28: 337–350.Google Scholar
  12. 12.
    Lepine JP, Bouchez S. Epidemiology of depression in the elderly. Int Clin Psychopharmacol 1998; 13(Suppl. 5): S7–S12.Google Scholar
  13. 13.
    Stein M, Miller AH, Trestman RL. Depression, the immune system, and health and illness. Findings in search of meaning. Arch Gen Psychiatry 1991; 48: 171–177.Google Scholar
  14. 14.
    Delgado PL. Depression: The case for a monoamine deficiency. J Clin Psychiatry 2000; 61(Suppl. 6): 7–11.Google Scholar
  15. 15.
    Owens MJ, Nemeroff CB. Role of serotonin in the pathophysiology of depression: Focus on the serotonin transporter. Clin Chem 1994; 40: 288–295.Google Scholar
  16. 16.
    Benton D, Donohoe RT. The effects of nutrients on mood. Public Health Nutr 1999; 2: 403–409.Google Scholar
  17. 17.
    Moller SE. Tryptophan to competing amino acids ratio in depressive disorder: Relation to efficacy of antidepressive treatments. Acta Psychiatr Scand Suppl 1985; 325: 3–31.Google Scholar
  18. 18.
    Smith RS. The macrophage theory of depression. Med Hypotheses 1991; 35: 298–306.Google Scholar
  19. 19.
    de Beaurepaire R. Questions raised by the cytokine hypothesis of depression. Brain Behav Immun 2002; 16: 610–617.Google Scholar
  20. 20.
    Licinio J, Wong ML. The role of inflammatory mediators in the biology of major depression: Central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999; 4: 317–327.Google Scholar
  21. 21.
    Olff M. Stress, depression, and immunity: The role of defense and coping styles. Psychiatry Res 1999; 85: 7–15.Google Scholar
  22. 22.
    Zorrilla EP, Luborsky L, McKay JR, et al. The relationship of depression and stressors to immunological assays: A meta-analytic review. Brain Behav Immun 2001; 15: 199–226.Google Scholar
  23. 23.
    Ormel J, Neeleman J. Towards a dynamic stressvulnerability model of depression. The role of neuroticism, life events, and gender. In: Harris T (ed.), Where Inner and Outer World Meet. London: Routledge, 2000: 151–169.Google Scholar
  24. 24.
    Stahl SM. Peripheral models for the study of neurotransmitter receptors in man. Psychopharmacol Bull 1985; 21: 663–671.Google Scholar
  25. 25.
    Elliott JM. Peripheral markers in anxiety and depression. Mol Aspects Med 1992; 13: 173–190.Google Scholar
  26. 26.
    Alexopoulos GS, Meyers BS, Young RC, et al. ‘Vascular depression’ hypothesis [see comments]. Arch Gen Psychiatry 1997; 54: 915–922.Google Scholar
  27. 27.
    Gaupp RE. Die Depressionszustände des höheren Lebensalters. Med Wschr 1905; 52: 1531–1537.Google Scholar
  28. 28.
    Krishnan KR, McDonald WM. Arteriosclerotic depression. Med Hypotheses 1995; 44: 111–115.Google Scholar
  29. 29.
    Krishnan KR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry 1997; 154: 497–501.Google Scholar
  30. 30.
    Andersen G, Vestergaard K, Riis J, et al. Incidence of post-stroke depression during the first year in a large unselected stroke population determined using a valid standardized rating scale. Acta Psychiatr Scand 1994; 90: 190–195.Google Scholar
  31. 31.
    Burvill PW, Johnson GA, Jamrozik KD, et al. Prevalence of depression after stroke: The Perth Community Stroke Study. Br J Psychiatry 1995; 166: 320–327.Google Scholar
  32. 32.
    House A, Dennis M, Mogridge L, et al. Mood disorders in the year after first stroke. Br J Psychiatry 1991; 158: 83–92.Google Scholar
  33. 33.
    Turner-Stokes L. Poststroke depression: Getting the full picture. Lancet 2003; 361: 1757–1758.Google Scholar
  34. 34.
    Ramasubbu R. Relationship between depression and cerebrovascular disease: Conceptual issues. J Affect Disord 2000; 57: 1–11.Google Scholar
  35. 35.
    Fujikawa T, Yamawaki S, Touhouda Y. Incidence of silent cerebral infarction in patients with major depression. Stroke 1993; 24: 1631–1634.Google Scholar
  36. 36.
    Yanai I, Fujikawa T, Horiguchi J, et al. The 3-year course and outcome of patients with major depression and silent cerebral infarction. J Affect Disord 1998; 47: 25–30.Google Scholar
  37. 37.
    Steffens DC, Helms MJ, Krishnan KR, et al. Cerebrovascular disease and depression symptoms in the cardiovascular health study. Stroke 1999; 30: 2159–2166.Google Scholar
  38. 38.
    O'Brien J, Desmond P, Ames D, et al. A magnetic resonance imaging study of white matter lesions in depression and Alzheimer's disease. Br J Psychiatry 1996; 168: 477–485.Google Scholar
  39. 39.
    Singh A, Herrmann N, Black SE. The importance of lesion location in poststroke depression: A critical review. Can J Psychiatry 1998; 43: 921–927.Google Scholar
  40. 40.
    Lyness JM, Caine ED, King DA, et al. Cerebrovascular risk factors and depression in older primary care patients: Testing a vascular brain disease model of depression. Am J Geriatr Psychiatry 1999; 7: 252–258.Google Scholar
  41. 41.
    Barrett-Connor E, Palinkas LA. Low blood pressure and depression in older men: A population-based study. Br med J 1994; 308: 446–449.Google Scholar
  42. 42.
    Paterniti S, Verdier-Taillefer MH, Geneste C, et al. Low blood pressure and risk of depression in the elderly. A prospective community-based study. Br J Psychiatry 2000; 176: 464–467.Google Scholar
  43. 43.
    Morgan RE, Palinkas LA, Barrett-Connor EL, et al. Plasma cholesterol and depressive symptoms in older men [see comments]. Lancet 1993; 341: 75–79.Google Scholar
  44. 44.
    Steffens DC, Krishnan KR, Crump C, et al. Cerebrovascular disease and evolution of depressive symptoms in the cardiovascular health study. Stroke 2002; 33: 1636–1644.Google Scholar
  45. 45.
    Baldwin RC, O'Brien J. Vascular basis of late-onset depressive disorder. Br J Psychiatry 2002; 180: 157–160.Google Scholar
  46. 46.
    Barefoot JC, Schroll M. Symptoms of depression, acute myocardial infarction, and total mortality in a community sample. Circulation 1996; 93: 1976–1980.Google Scholar
  47. 47.
    Ford DE, Mead LA, Chang PP, et al. Depression is a risk factor for coronary artery disease in men: The precursors study. Arch Intern Med 1998; 158: 1422–1426.Google Scholar
  48. 48.
    Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: Results from a communitybased longitudinal study. Arch Gen Psychiatry 2001; 58: 221–227.Google Scholar
  49. 49.
    Carroll BJ, Martin FI, Davies B. Pituitary-adrenal function in depression. Lancet 1968; 1: 1373–1374.Google Scholar
  50. 50.
    Plotsky PM, Owens MJ, Nemeroff CB. Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatr Clin North Am 1998; 21: 293–307.Google Scholar
  51. 51.
    Nemeroff CB. Clinical significance of psychoneuroendocrinology in psychiatry: Focus on the thyroid and adrenal. J Clin Psychiatry 1989; 50: 13–20; discussion 21-22.Google Scholar
  52. 52.
    Rush AJ, Giles DE, Schlesser MA, et al. The dexamethasone suppression test in patients with mood disorders. J Clin Psychiatry 1996; 57: 470–484.Google Scholar
  53. 53.
    Newport DJ, Nemeroff CB. Hypothalamic-pituary-adrenal axis: Normal physiology and disturbances in depression. In: Thakore JH (ed.), Physical Consequences of Depression. Petersfield: Wrightson Biomedical Publishing, 2001: 1–22.Google Scholar
  54. 54.
    Zobel AW, Nickel T, Sonntag A, et al. Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: A prospective study. J Psychiatr Res 2001; 35: 83–94.Google Scholar
  55. 55.
    Mullen PE, Linsell CR, Parker D. Influence of sleep disruption and calorie restriction on biological markers for depression. Lancet 1986; 2: 1051–1055.Google Scholar
  56. 56.
    Baghai TC, Schule C, Zwanzger P, et al. Influence of a functional polymorphism within the angiotensin Iconverting enzyme gene on partial sleep deprivation in patients with major depression. Neurosci Lett 2003; 339: 223–226.Google Scholar
  57. 57.
    Parker KJ, Schatzberg AF, Lyons DM. Neuroendocrine aspects of hypercortisolism in major depression. Horm Behav 2003; 43: 60–66.Google Scholar
  58. 58.
    Kirschbaum C, Hellhammer DH. Salivary cortisol in psychoneuroendocrine research: Recent developments and applications. Psychoneuroendocrinology 1994; 19: 313–333.Google Scholar
  59. 59.
    Kirschbaum C, Hellhammer D. Psychoendokrinologie und Psychoimmunologie. Göttingen: Hogrefe, 1999.Google Scholar
  60. 60.
    Gold MS, Pottash AL, Extein I. Hypothyroidism and depression. Evidence from complete thyroid function evaluation. Jama 1981; 245: 1919–1922.Google Scholar
  61. 61.
    Jackson IM. The thyroid axis and depression. Thyroid 1998; 8: 951–956.Google Scholar
  62. 62.
    Poce MM-C, Navas AG, Gomez MM, et al. Prevalence of thyroid disorders in patients diagnosed with depression. Aten Primaria 2000; 26: 176–179.Google Scholar
  63. 63.
    van West D, Maes M. Activation of the inflammatory response system: A new look at the etiopathogenesis of major depression. Neuroendocrinol Lett 1999; 20: 11–17.Google Scholar
  64. 64.
    Maes M, Scharpe S, Van Grootel L, et al. Higher alpha 1-antitrypsin, haptoglobin, ceruloplasmin, and lower retinol binding protein plasma levels during depression: Further evidence for the existence of an inflammatory response during that illness. J Affect Disord 1992; 24: 183–192.Google Scholar
  65. 65.
    Joyce PR, Hawes CR, Mulder RT, et al. Elevated levels of acute phase plasma proteins in major depression. Biol Psychiatry 1992; 32: 1035–1041.Google Scholar
  66. 66.
    Sluzewska A. Indicators of immune activation in depressed patients. In: Dantzer R, Wollman EE, et al. (eds), Cytokines, Stress, and Depression. New York: Kluwer Academic/Plenum Publishers, 1999: 59–73.Google Scholar
  67. 67.
    Seidel A, Rothermundt M, Rink L. Cytokine production in depressed patients. In: Dantzer R, Wollman EE, et al. (eds), Cytokines, Stress, and Depression. New York: Kluwer Academic/Plenum Publishers, 1999: 47–58.Google Scholar
  68. 68.
    Frommberger UH, Bauer J, Haselbauer P, et al. Interleukin-6-(IL-6) plasma levels in depression and schizophrenia: Comparison between the acute state and after remission. Eur Arch Psychiatry Clin Neurosci 1997; 247: 228–233.Google Scholar
  69. 69.
    Leonhard BE, Song C. Stress, depression and the role of cytokines. In: Dantzer R, Wollman EE, et al. (eds), Cytokines, Stress, and Depression. New York: Kluwer Academic/Plenum Publishers, 1999: 251–265.Google Scholar
  70. 70.
    Herbert TB, Cohen S. Depression and immunity: A meta-analytic review. Psychol Bull 1993; 113: 472–486.Google Scholar
  71. 71.
    Reichenberg A, Yirmiya R, Schuld A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001; 58: 445–452.Google Scholar
  72. 72.
    Irwin M. Immune correlates of depression. In: Dantzer R, Wollman EE, et al. (eds), Cytokines, Stress, and Depression. New York: Kluwer Academic/Plenum Publishers, 1999: 1–24.Google Scholar
  73. 73.
    Fava M, Borus JS, Alpert JE, et al. Folate, vitamin B12, and homocysteine in major depressive disorder. Am J Psychiatry 1997; 154: 426–428.Google Scholar
  74. 74.
    Alpert JE, Mischoulon D, Nierenberg AA, et al. Nutrition and depression: Focus on folate. Nutrition 2000; 16: 544–546.Google Scholar
  75. 75.
    Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 2000; 69: 228–232.Google Scholar
  76. 76.
    Maes M, De Vos N, Pioli R, et al. Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defenses in that illness. J Affect Disord 2000; 58: 241–246.Google Scholar
  77. 77.
    Shibata H, Kumagai S, Watanabe S, et al. Relationship of serum cholesterols and vitamin E to depressive status in the elderly. J Epidemiol 1999; 9: 261–267.Google Scholar
  78. 78.
    Peet M, Murphy B, Shay J, et al. Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Biol Psychiatry 1998; 43: 315–319.Google Scholar
  79. 79.
    Adams PB, Lawson S, Sanigorski A, et al. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 1996; 31: S157–S161.Google Scholar
  80. 80.
    Edwards R, Peet M, Shay J, et al. Omega-3 poly-unsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998; 48: 149–155.Google Scholar
  81. 81.
    Penninx BW, Guralnik JM, Ferrucci L, et al. Vitamin B12 deficiency and depression in physically disabled older women: Epidemiologic evidence from theWomen's Health and Aging Study. Am J Psychiatry 2000; 157: 715–721.Google Scholar
  82. 82.
    Tiemeier H, van Tuijl HR, Hofman A, et al. Vitamin B12, folate, and homocysteine in depression: The Rotterdam Study. Am J Psychiatry 2002; 159: 2099–2101.Google Scholar
  83. 83.
    Moller SE, Bech P, Bjerrum H, et al. Plasma ratio tryptophan/neutral amino acids in relation to clinical response to paroxetine and clomipramine in patients with major depression. J Affect Disord 1990; 18: 59–66.Google Scholar
  84. 84.
    Bell C, Abrams J, Nutt D. Tryptophan depletion and its implications for psychiatry. Br J Psychiatry 2001; 178: 399–405.Google Scholar
  85. 85.
    Delgado PL, Charney DS, Price LH, et al. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 47: 411–418.Google Scholar
  86. 86.
    Moreno FA, Gelenberg AJ, Heninger GR, et al. Tryptophan depletion and depressive vulnerability. Biol Psychiatry 1999; 46: 498–505.Google Scholar
  87. 87.
    Benkelfat C, Ellenbogen MA, Dean P, et al. Moodlowering effect of tryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective disorders. Arch Gen Psychiatry 1994; 51: 687–697.Google Scholar
  88. 88.
    Knott VJ, Howson AL, Perugini M, et al. The effect of acute tryptophan depletion and fenfluramine on quantitative EEG and mood in healthy male subjects. Biol Psychiatry 1999; 46: 229–238.Google Scholar
  89. 89.
    Carpenter LL, Anderson GM, Pelton GH, et al. Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 1998; 19: 26–35.Google Scholar
  90. 90.
    Biondi M, Picardi A. Psychological stress and neuroendocrine function in humans: The last two decades of research. Psychother Psychosom 1999; 68: 114–150.Google Scholar

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© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Henning Tiemeier
    • 1
  1. 1.Department of Epidemiology & Biostatistics and Department of Child and Adolescent Psychiatry, Erasmus Medical CentreRotterdamThe Netherlands

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