Cognitive Dimensions of Depression: Assessment, Neurobiology, and Treatment

  • Sang Won Jeon
  • Yong-Ku Kim


Cognitive impairment in patients with depression has great clinical relevance, as depressed patients with cognitive impairment have more physical diseases, greater reduced social functionality, and, eventually, higher mortality. Although cognitive decline may simply be a symptom of depression, accurate assessment and treatment of cognitive impairment is crucial, as it is considered a key risk factor for the prognosis of possible neurocognitive disorders, such as Alzheimer’s disease. In this review, we investigated psychological and biological mechanisms of cognitive impairment in patients with depression and briefly discuss the methods to assess neurocognitive function in depression. Furthermore, we presented some issues about which to be cautious in the therapeutic setting.


Cognition Cognitive impairment Neurocognitive function Amyloid positron emission tomography 


  1. Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility—linking memory and mood. Nat Rev Neurosci. 2017;18(6):335–46CrossRefGoogle Scholar
  2. Austin MP, Mitchell P, Wilhelm K, Parker G, Hickie I, Brodaty H, Hadzi-Pavlovic D. Cognitive function in depression: a distinct pattern of frontal impairment in melancholia? Psychol Med. 1999;29(1):73–85.CrossRefGoogle Scholar
  3. Baldwin R, Jeffries S, Jackson A, Sutcliffe C, Thacker N, Scott M, Burns A. Neurological findings in late-onset depressive disorder: comparison of individuals with and without depression. Br J Psychiatry. 2005;186:308–13.CrossRefGoogle Scholar
  4. Banerjee S, Hellier J, Dewey M, Romeo R, Ballard C, Baldwin R, Burns A. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):403–11.CrossRefGoogle Scholar
  5. Barch DM, D'Angelo G, Pieper C, Wilkins CH, Welsh-Bohmer K, Taylor W, Sheline YI. Cognitive improvement following treatment in late-life depression: relationship to vascular risk and age of onset. Am J Geriatr Psychiatry. 2012;20(8):682–90.CrossRefGoogle Scholar
  6. Barnes DE, Yaffe K, Byers AL, McCormick M, Schaefer C, Whitmer RA. Midlife vs late-life depressive symptoms and risk of dementia: differential effects for Alzheimer disease and vascular dementia. Arch Gen Psychiatry. 2012;69(5):493–8.CrossRefGoogle Scholar
  7. Basso MR, Bornstein RA. Relative memory deficits in recurrent versus first-episode major depression on a word-list learning task. Neuropsychology. 1999;13(4):557–63.CrossRefGoogle Scholar
  8. Beats BC, Sahakian BJ, Levy R. Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed. Psychol Med. 1996;26(3):591–603.CrossRefGoogle Scholar
  9. Boone KB, Lesser IM, Miller BL, Wohl M, Berman N, Lee A, Back C. Cognitive functioning in older depressed outpatients: relationship of presence and severity of depression to neuropsychological test scores. Neuropsychology. 1995;9(3):390.CrossRefGoogle Scholar
  10. Brendel M, Pogarell O, Xiong G, Delker A, Bartenstein P, Rominger A. Depressive symptoms accelerate cognitive decline in amyloid-positive MCI patients. Eur J Nucl Med Mol Imaging. 2015;42(5):716–24.CrossRefGoogle Scholar
  11. Butters MA, Klunk WE, Mathis CA, Price JC, Ziolko SK, Hoge JA, Meltzer CC. Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh compound-B. Alzheimer Dis Assoc Disord. 2008;22(3):261–8.CrossRefGoogle Scholar
  12. Chung JK, Plitman E, Nakajima S, Chow TW, Chakravarty MM, Caravaggio F, Graff-Guerrero A. Lifetime history of depression predicts increased amyloid-beta accumulation in patients with mild cognitive impairment. J Alzheimers Dis. 2016;49(4):1189–90.CrossRefGoogle Scholar
  13. Comte M, Schon D, Coull JT, Reynaud E, Khalfa S, Belzeaux R, Fakra E. Dissociating bottom-up and top-down mechanisms in the cortico-limbic system during emotion processing. Cereb Cortex. 2016;26(1):144–55.CrossRefGoogle Scholar
  14. Cummings JL, Schneider L, Tariot PN, Kershaw PR, Yuan W. Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer’s disease. Am J Psychiatry. 2004;161(3):532–8.CrossRefGoogle Scholar
  15. Dal Forno G, Palermo MT, Donohue JE, Karagiozis H, Zonderman AB, Kawas CH. Depressive symptoms, sex, and risk for Alzheimer’s disease. Ann Neurol. 2005;57(3):381–7.CrossRefGoogle Scholar
  16. de Vasconcelos Cunha UG, Lopes Rocha F, Avila de Melo R, Alves Valle E, de Souza Neto JJ, Mendes Brega R, Sakurai E. A placebo-controlled double-blind randomized study of venlafaxine in the treatment of depression in dementia. Dement Geriatr Cogn Disord. 2007;24(1):36–41.CrossRefGoogle Scholar
  17. Disner SG, Beevers CG, Haigh EA, Beck AT. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011;12(8):467–77.CrossRefGoogle Scholar
  18. Dotson VM, Beydoun MA, Zonderman AB. Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment. Neurology. 2010;75(1):27–34.CrossRefGoogle Scholar
  19. Feil D, Razani J, Boone K, Lesser I. Apathy and cognitive performance in older adults with depression. Int J Geriatr Psychiatry. 2003;18(6):479–85.CrossRefGoogle Scholar
  20. Flint AJ, Black SE, Campbell-Taylor I, Gailey GF, Levinton C. Abnormal speech articulation, psychomotor retardation, and subcortical dysfunction in major depression. J Psychiatr Res. 1993;27(3):309–19.CrossRefGoogle Scholar
  21. Fuchs A, Hehnke U, Erhart C, Schell C, Pramshohler B, Danninger B, Schautzer F. Video rating analysis of effect of maprotiline in patients with dementia and depression. Pharmacopsychiatry. 1993;26(2):37–41.CrossRefGoogle Scholar
  22. Gauthier S, Feldman H, Hecker J, Vellas B, Emir B, Subbiah P. Functional, cognitive and behavioral effects of donepezil in patients with moderate Alzheimer’s disease. Curr Med Res Opin. 2002;18(6):347–54.CrossRefGoogle Scholar
  23. Geerlings MI, Schmand B, Braam AW, Jonker C, Bouter LM, van Tilburg W. Depressive symptoms and risk of Alzheimer’s disease in more highly educated older people. J Am Geriatr Soc. 2000;48(9):1092–7.CrossRefGoogle Scholar
  24. Geerlings MI, Brickman AM, Schupf N, Devanand DP, Luchsinger JA, Mayeux R, Small SA. Depressive symptoms, antidepressant use, and brain volumes on MRI in a population-based cohort of old persons without dementia. J Alzheimers Dis. 2012;30(1):75–82.PubMedPubMedCentralGoogle Scholar
  25. Green RC, Cupples LA, Kurz A, Auerbach S, Go R, Sadovnic D, Farrer L. Depression as a risk factor for Alzheimer disease: the MIRAGE study. Arch Neurol. 2003;60(5):753–9.CrossRefGoogle Scholar
  26. Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM. Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci. 2006;26(35):9047–56.CrossRefGoogle Scholar
  27. Hammar A, Lund A, Hugdahl K. Long-lasting cognitive impairment in unipolar major depression: a 6-month follow-up study. Psychiatry Res. 2003;118(2):189–96.CrossRefGoogle Scholar
  28. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–5.CrossRefGoogle Scholar
  29. Harrington KD, Lim YY, Gould E, Maruff P. Amyloid-beta and depression in healthy older adults: a systematic review. Aust N Z J Psychiatry. 2015;49(1):36–46.CrossRefGoogle Scholar
  30. Harvey PO, Fossati P, Pochon JB, Levy R, Lebastard G, Lehericy S, Dubois B. Cognitive control and brain resources in major depression: an fMRI study using the n-back task. NeuroImage. 2005;26(3):860–9.CrossRefGoogle Scholar
  31. Herholz K, Ebmeier K. Clinical amyloid imaging in Alzheimer’s disease. Lancet Neurol. 2011;10(7):667–70.CrossRefGoogle Scholar
  32. Herrmann LL, Goodwin GM, Ebmeier KP. The cognitive neuropsychology of depression in the elderly. Psychol Med. 2007;37(12):1693–702.CrossRefGoogle Scholar
  33. Kang JE, Cirrito JR, Dong H, Csernansky JG, Holtzman DM. Acute stress increases interstitial fluid amyloid-beta via corticotropin-releasing factor and neuronal activity. Proc Natl Acad Sci U S A. 2007;104(25):10673–8.CrossRefGoogle Scholar
  34. Lavretsky H, Siddarth P, Kepe V, Ercoli LM, Miller KJ, Burggren AC, Small GW. Depression and anxiety symptoms are associated with cerebral FDDNP-PET binding in middle-aged and older nondemented adults. Am J Geriatr Psychiatry. 2009;17(6):493–502.CrossRefGoogle Scholar
  35. Lyketsos CG, Sheppard JM, Steele CD, Kopunek S, Steinberg M, Baker AS, Rabins PV. Randomized, placebo-controlled, double-blind clinical trial of sertraline in the treatment of depression complicating Alzheimer’s disease: initial results from the depression in Alzheimer’s disease study. Am J Psychiatry. 2000;157(10):1686–9.CrossRefGoogle Scholar
  36. Lyketsos CG, DelCampo L, Steinberg M, Miles Q, Steele CD, Munro C, Rabins PV. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry. 2003;60(7):737–46.CrossRefGoogle Scholar
  37. Madsen K, Hasselbalch BJ, Frederiksen KS, Haahr ME, Gade A, Law I, Hasselbalch SG. Lack of association between prior depressive episodes and cerebral [11C]PiB binding. Neurobiol Aging. 2012;33(10):2334–42.CrossRefGoogle Scholar
  38. Marazziti D, Consoli G, Picchetti M, Carlini M, Faravelli L. Cognitive impairment in major depression. Eur J Pharmacol. 2010;626(1):83–6.CrossRefGoogle Scholar
  39. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Fox PT. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156(5):675–82.PubMedGoogle Scholar
  40. Mayberg H, Keightley M, Mahurin R, Brannan S. Neuropsychiatric aspects of mood and affective disorders, The American Psychiatric Publishing textbook of neuropsychiatry and clinical neuroscience. Washington: American Psychiatric Association; 2002.Google Scholar
  41. McDermott LM, Ebmeier KP. A meta-analysis of depression severity and cognitive function. J Affect Disord. 2009;119(1–3):1–8.CrossRefGoogle Scholar
  42. Mormont C. The influence of age and depression on intellectual and memory performances. Acta Psychiatr Belg. 1984;84(2):127–34.PubMedGoogle Scholar
  43. Munro CA, Brandt J, Sheppard JM, Steele CD, Samus QM, Steinberg M, Lyketsos CG. Cognitive response to pharmacological treatment for depression in Alzheimer disease: secondary outcomes from the depression in Alzheimer’s disease study (DIADS). Am J Geriatr Psychiatry. 2004;12(5):491–8.CrossRefGoogle Scholar
  44. Nebes RD, Butters MA, Mulsant BH, Pollock BG, Zmuda MD, Houck PR, Reynolds CF 3rd. Decreased working memory and processing speed mediate cognitive impairment in geriatric depression. Psychol Med. 2000;30(3):679–91.CrossRefGoogle Scholar
  45. Nelson JC, Devanand DP. A systematic review and meta-analysis of placebo-controlled antidepressant studies in people with depression and dementia. J Am Geriatr Soc. 2011;59(4):577–85.CrossRefGoogle Scholar
  46. Nyth AL, Gottfries CG. The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study. Br J Psychiatry. 1990;157:894–901.CrossRefGoogle Scholar
  47. Olin JT, Katz IR, Meyers BS, Schneider LS, Lebowitz BD. Provisional diagnostic criteria for depression of Alzheimer disease: rationale and background. Am J Geriatr Psychiatry. 2002;10(2):129–41.CrossRefGoogle Scholar
  48. Petracca G, Teson A, Chemerinski E, Leiguarda R, Starkstein SE. A double-blind placebo-controlled study of clomipramine in depressed patients with Alzheimer's disease. J Neuropsychiatry Clin Neurosci. 1996;8(3):270–5.CrossRefGoogle Scholar
  49. Pinheiro D. Anticonvulsant mood stabilizers in the treatment of behavioral and psychological symptoms of dementia (BPSD). Encéphale. 2008;34(4):409–15.CrossRefGoogle Scholar
  50. Pisljar M, Pirtosek Z, Repovs G, Grgic M. Executive dysfunction in late-onset depression. Psychiatr Danub. 2008;20(2):231–5.PubMedGoogle Scholar
  51. Reifler BV, Teri L, Raskind M, Veith R, Barnes R, White E, McLean P. Double-blind trial of imipramine in Alzheimer’s disease patients with and without depression. Am J Psychiatry. 1989;146(1):45–9.CrossRefGoogle Scholar
  52. Roiser JP, Elliott R, Sahakian BJ. Cognitive mechanisms of treatment in depression. Neuropsychopharmacology. 2012;37(1):117–36.CrossRefGoogle Scholar
  53. Rosenberg PB, Drye LT, Martin BK, Frangakis C, Mintzer JE, Weintraub D, Lyketsos CG. Sertraline for the treatment of depression in Alzheimer disease. Am J Geriatr Psychiatry. 2010;18(2):136–45.CrossRefGoogle Scholar
  54. Roth M, Mountjoy CQ, Amrein R. Moclobemide in elderly patients with cognitive decline and depression: an international double-blind, placebo-controlled trial. Br J Psychiatry. 1996;168(2):149–57.CrossRefGoogle Scholar
  55. Saavedra Perez HC, Direk N, Hofman A, Vernooij MW, Tiemeier H, Ikram MA. Silent brain infarcts: a cause of depression in the elderly? Psychiatry Res. 2013;211(2):180–2.CrossRefGoogle Scholar
  56. Savard RJ, Rey AC, Post RM. Halstead-Reitan Category Test in bipolar and unipolar affective disorders. Relationship to age and phase of illness. J Nerv Ment Dis. 1980;168(5):297–304.CrossRefGoogle Scholar
  57. Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, Rafi-Tari S. Limbic-frontal circuitry in major depression: a path modeling meta-analysis. NeuroImage. 2004;22(1):409–18.CrossRefGoogle Scholar
  58. Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry. 2007;61(2):198–209.CrossRefGoogle Scholar
  59. Steffens DC, Potter GG. Geriatric depression and cognitive impairment. Psychol Med. 2008;38(2):163–75.CrossRefGoogle Scholar
  60. Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, Lyketsos CG, Schneider LS. Clinical symptom responses to atypical antipsychotic medications in Alzheimer’s disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry. 2008;165(7):844–54.CrossRefGoogle Scholar
  61. Tariot PN, Erb R, Podgorski CA, Cox C, Patel S, Jakimovich L, Irvine C. Efficacy and tolerability of carbamazepine for agitation and aggression in dementia. Am J Psychiatry. 1998;155(1):54–61.CrossRefGoogle Scholar
  62. Tateno A, Sakayori T, Higuchi M, Suhara T, Ishihara K, Kumita S, Okubo Y. Amyloid imaging with [(18)F]florbetapir in geriatric depression: early-onset versus late-onset. Int J Geriatr Psychiatry. 2015;30(7):720–8.CrossRefGoogle Scholar
  63. Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska S, Jones G, Rowe CC. Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias. J Nucl Med. 2011;52(8):1210–7.CrossRefGoogle Scholar
  64. Wu KY, Hsiao IT, Chen CS, Chen CH, Hsieh CJ, Wai YY, Lin KJ. Increased brain amyloid deposition in patients with a lifetime history of major depression: evidenced on 18F-florbetapir (AV-45/Amyvid) positron emission tomography. Eur J Nucl Med Mol Imaging. 2014;41(4):714–22.CrossRefGoogle Scholar
  65. Zakzanis KK, Leach L, Kaplan E. On the nature and pattern of neurocognitive function in major depressive disorder. Neuropsychiatry Neuropsychol Behav Neurol. 1998;11(3):111–9.PubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Department of PsychiatryKangbuk Samsung Hospital, Sungkyunkwan University School of MedicineSeoulSouth Korea
  2. 2.Department of Psychiatry, College of MedicineKorea University Ansan HospitalAnsanSouth Korea

Personalised recommendations