Depression is primarily a mood disorder, but it can also be viewed as a cognitive disorder for many older adults. In community samples, the co-occurrence of depression and cognitive impairment doubles every 5 years after the age of 70 years, and they are estimated to co-occur among at least 25% of persons older than 85 years.1 One of the clinical implications of the co-occurrence of depression and cognitive impairment is that there is a higher risk of adverse outcomes for physical health, functional status, and mortality than from each condition alone.2 Moreover, research suggests that depression in late life may be a prodromal symptom of Alzheimer disease3,4 or a risk factor for dementia in general.5-7
The clinical challenge of treating geriatric depression with cognitive impairment is determining the extent to which cognitive changes are caused by depression versus underlying brain pathology. With the growing aging population in the United States and many other countries, it is important for mental health professionals to develop skills to diagnose and treat cognitive impairment in older patients with depression.
For the purposes of this article, our use of the term "depression" refers primarily to symptoms that occur in major depressive disorder (MDD), which is defined as 1 or more episodes of neg-ative mood and sadness sufficient to interfere with daily living.8 The prevalence of depression is nearly twice as high in women as it is in men.9 Community-based studies estimate that 30% of individuals first experience depression in later life (at approximately age 60 years), 40% first experience depression earlier in life, and 30% are difficult to categorize reliably because of problems with retrospective recall of past depressive symptoms.10
Late-onset depression is more frequently characterized by medical comorbidities, greater apathy, greater cerebrovascular pathology,11,12 more extensive cognitive impairment, and a stronger association with dementia.3 Early-onset depression is more frequently associated with psychiatric comorbidities, family history of mood disorder,13 and volume loss in the hippo-campus when untreated or recurrent.14,15
Although the assessment of cognitive impairment in geriatric depression is predicated on an accurate assessment of depression itself, a full discussion of the clinical assessment of depression is beyond the scope of this article. Table 1 provides a list of elements that are important to a comprehensive evaluation of geriatric depression. In this article, we focus on interviewing and screening for depression, the influence of medical comorbidities on cognitive impairment and depression, and the differentiation of cognitive impairment secondary to depression from comorbid depression and Alzheimer disease.
The neurobiology of depression
Research on the neurobiology of depression has provided important insights into the interrelationship between dysfunctions in mood and cognition. One neurobiological model proposes that a ventral neural system functions to guide affective responses based on the emotional significance and reward value of a stimulus, while a dorsal neural system functions to analyze, monitor, and regulate affective responses to internal thoughts and external events that have high emotional valence.16,17
The ventral system includes the ventral regions of the anterior cingulate gyrus and prefrontal cortex, the amygdala, insula, and ventral striatum; the dorsal system includes the dorsolateral and dorsomedial prefrontal cortices, the hippocampi, and the dorsal anterior cingulate gyrus. Abnormality or damage in the ventral system can lead to decreased motivation and lack of reinforcement from positive experiences, whereas abnormality or damage in the dorsal system can produce dysregulation of emotional responses and exacerbation of negative affect. This broad neural system receives projections from 3 key neurotransmitters linked to depression: serotonin, dopamine, and noradrenaline.18 Emotional and cognitive processes are regulated by both systems, and dysfunction in one system may produce dysfunction in the other.
While many persons with depression experience slowed thinking and concentration difficulties, the presentation of cognitive deficits is more heterogeneous among older adults. Depressed elderly persons typically perform worse than nondepressed elderly on neuropsychological measures of information processing speed19,20; cognitively demanding processes of selective attention, response inhibition, and performance monitoring (otherwise known as executive functions)21,22; and the ability to learn and recall new information.22,23 In many cases, these underlying deficits are reflected in a patient's subjective complaints (Table 2).
Neurocognitive deficits involving processing speed and executive functions are more common when first onset of depression occurs in late life, and even more so when apathy is a prominent symptom.21,24 In many cases, the combination of slowed processing, executive dysfunction, and apathy are associated with underlying cerebrovascular pathology involving frontal and subcortical brain regions.25,26 Other research suggests that older adults with a history of early chronic depression have a more selective deficit in memory,27 probably caused by reductions in hippocampal volume.14,28,29
Even though elderly persons who are depressed tend to demonstrate more cognitive deficits than nondepressed elderly, a smaller proportion of depressed individuals have impaired cognitive function. Mild cognitive impairment was first proposed to characterize a state of abnormal cognition with a high risk of progression to Alzheimer disease,30 but it is increasingly used in depression to characterize depressed individuals with comorbid cognitive impairment in the absence of dementia.
The prevalence of mild cognitive impairment in depression ranges from approximately 25% to 50%,31-33 which is substantially higher than the 3% to 6% prevalence of conventional mild cognitive impairment in studies of individuals who are not depressed where memory is the focal deficit.31,34 An important clinical implication is that mild cognitive impairment or other cognitive impairment during an episode of depression may persist after improvement from the depression symptoms themselves, ranging from one third of individuals with persistent multiple cognitive deficits 1 year after the onset of depression35 to a 4-fold likelihood for impairments in memory to persist 1 year later among individuals who are in remission.33
With or without cognitive impairment, the occurrence of depression in later life is a clinical concern because it may be either a risk factor for or an early symptom of dementia. Several studies have found a higher risk of dementia among persons with a remote history of depression (10 to 25 years before onset of dementia),7,36,37 but they also reveal an increased risk for dementia with decreased time between depression onset and dementia diagnosis, which suggests that onset of depression in later life is either a prodromal symptom or that it creates susceptibility for later dementia.
Symptoms consistent with a major depressive episode range from 10% to 30% in patients with mild and moderate Alzheimer disease,38,39 with an additional 20% to 30% of individuals having other depression syndromes.40 Higher rates of depression are seen in patients who have vascular dementia.41 It is likely that depression is a dementia risk factor for some individuals, while for others it is an early sign of dementia, particularly when the first onset of depression occurs later in life. The key question is which features of affect and cognition best identify which of these respective groups depressed patients fall into.
Diagnosing depression and cognitive impairment
Clinical screening questionnaires should not be used to formally diagnose depression, but they do provide important information to help identify at-risk individuals by characterizing the nature and extent of symptoms that are associated with depression. The Geriatric Depression Scale (GDS) was developed and validated for use with older adults; as such, it avoids somatic and sexual symptoms, surveys subjective experiences of cognitive impairment, and uses simple yes/no items that decrease cognitive burden.42,43 A 15-item version of the GDS requires 5 to 10 minutes to complete and is satisfactory for most screening purposes,44 with a depression cut-off score of 5 or more.
1. Arve S, Tilvis RS, Lehtonen A, et al. Coexistence of lowered mood and cognitive impairment of elderly people in five birth cohorts. Aging (Milano). 1999;11:90-95.
2. Mehta KM, Yaffe K, Langa KM, et al. Additive effects of cognitive function and depressive symptoms on mortality in elderly community-living adults. J Gerontol A Biol Sci Med Sci. 2003;58:M461-M467.
3. Schweitzer I, Tuckwell V, O'Brien J, Ames D. Is late onset depression a prodrome to dementia? Int J Geriatr Psychiatry. 2002;17:997-1005.
4. Ganguli M, Du Y, Dodge HH, et al. Depressive symptoms and cognitive decline in late life: a prospective epidemiological study. Arch Gen Psychiatry. 2006;63: 153-160.
5. Jorm AF, van Duijn CM, Chandra V, et al. Psychiatric history and related exposures as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies. Int J Epidemiol. 1991;20(suppl 2): S43-S47.
6. Speck CE, Kukull WA, Brenner DE, et al. History of depression as a risk factor for Alzheimer's disease. Epidemiol. 1995;6:366-369.
7. Steffens DC, Plassman BL, Helms MJ, et al. A twin study of late-onset depression and apolipoprotein E epsilon 4 as risk factors for Alzheimer's disease. Biol Psychiatry. 1997;41:851-856.
8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.
9. Blazer DG. Mood disorders: epidemiology. In: Sadock BJ, Sadock VA, eds. Comprehensive Textbook of Psychiatry. New York: Lippincott, Williams & Wilkins; 2000: 1298-1308.
10. Blazer DG. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci. 2003;58: 249-265.
11. Krishnan KR, Hays JC, Tupler LA, et al. Clinical and phenomenological comparisons of late-onset and early-onset depression. Am J Psychiatry. 1995;152: 785-788.
12. Krishnan KR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry. 1997;154:497-501.
13. Lyness SA, Eaton EM, Schneider LS. Cognitive performance in older and middle-aged depressed outpatients and controls. J Gerontol. 1994;49:P129-P136.
14. Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160:1516-1518.
15. Bell-McGinty S, Butters MA, Meltzer CC, et al. Brain morphometric abnormalities in geriatric depression: long-term neurobiological effects of illness duration. Am J Psychiatry. 2002;159:1424-1427.
16. Ochsner KN, Gorss JJ. The cognitive control of emotion. Trends Cogn Sci. 2005;9:242-249.
17. Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception, I: the neural basis of normal emotion perception. Biol Psychiatry. 2003;54: 504-514.
18. Millan MJ, Lejeune F, Gobert A. Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents. J Psychopharmacol. 2000;14:114-138.
19. Nebes RD, Butters MA, Mulsant BH, et al. Decreased working memory and processing speed mediate cognitive impairment in geriatric depression. Psychol Med. 2000;30:679-691.
20. Sheline YI, Barch DM, Garcia K, et al. Cognitive function in late life depression: relationships to depression severity, cerebrovascular risk factors and processing speed. Biol Psychiatry. 2006;60:58-65.
21. Boone K, Lesser B, Miller B, et al. Cognitive functioning in a geriatric depressed population: relationship of presence and severity of depression to neuropsychological scores. Neuropsychology. 1995;9:390-398.
22. Beats BC, Sahakian BJ, Levy R. Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed. Psychol Med. 1996;26:591-603.
23. Austin MP, Mitchell P, Wilhelm K, et al. Cognitive function in depression: a distinct pattern of frontal impairment in melancholia? Psychol Med. 1999;29:73-85.
24. Feil D, Razani J, Boone K, Lesser I. Apathy and cognitive performance in older adults with depression. Int J Geriatr Psychiatry. 2003;18:479-488.
25. Alexopoulos GS, Meyers BS, Young RC, et al. "Vascular depression" hypothesis. Arch Gen Psychiatry. 1997;54:915-922.
26. Krishnan KR, Taylor WD, McQuoid DR, et al. Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression. Biol Psychiatry. 2004; 55:390-397.
27. Rapp MA, Dahlman K, Sano M, et al. Neuropsychological differences between late-onset and recurrent geriatric major depression. Am J Psychiatry. 2005;162: 691-698.
28. MacQueen GM, Campbell S, McEwen BS, et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci U S A. 2003;100:1387-1392.
29. Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. 1999;19:5034-5043.
30. Petersen RC, Smith GE, Waring SC, et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303-308.
31. Lopez OL, Jagust WJ, DeKosky ST, et al. Prevalence and classification of mild cognitive impairment in the cardiovascular health study cognition study, part I. Arch Neurol. 2003;60:1385-1389.
32. Adler G, Chwalek K, Jajcevic A. Six-month course of mild cognitive impairment and affective symptoms in late-life depression. Eur Psychiatry. 2004;19:502-505.
33. Lee JS, Potter GG, Wagner HR, et al. Persistent mild cognitive impairment in geriatric depression. Int Psychogeriatr. 2007;19:125-135.
34. Ganguli M, Dodge HH, Shen C, DeKosky ST. Mild cognitive impairment, amnestic type: an epidemiologic study. Neurology. 2004;63:115-121.
35. Reischies FM, Neu P. Comorbidity of mild cognitive disorder and depression—a neuropsychological analysis. Eur Arch Psychiatry Clin Neurosci. 2000;50:186-193.
36. Broe GA, Henderson AS, Creasey H, et al. A case-control study of Alzheimer's disease in Australia. Neurology. 1990;40:1698-1707.
37. Green RC, Cupples LA, Kurz A, et al. Depression as a risk factor for Alzheimer disease: the MIRAGE Study. Arch Neurol. 2003;60:753-759.
38. Lopez OL, Jagust WJ, Dulberg C, et al. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study. Arch Neurol. 2003;60: 1394-1399.
39. Anderson B. Is alpha-MSH deficiency the cause of Alzheimer's disease? Med Hypotheses. 1986;19: 379-385.
40. Ballard C, Bannister C, Solis M, et al. The prevalence, associations and symptoms of depression amongst dementia sufferers. J Affect Disord. 1996;36:135-144.
41. Park JH, Lee SB, Lee TJ, et al. Depression in vascular dementia is quantitatively and qualitatively different from depression in Alzheimer's disease. Dement Geriatr Cogn Disord. 2007;23:67-73.
42. Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res. 1983;17:37-49.
43. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): recent evidence and development of a shorter version. In: Brink DL. Clinical Gerontology: A Guide to Assessment and Intervention. New York: The Haworth Press; 1986:165-173.
44. Baker FM, Miller CL. Screening a skilled nursing home population for depression. J Geriatr Psychiatry Neurol. 1991;4:218-221.
45. Beck AT, Steer RA, Brown GK. Beck Depression Inventory-II Manual. San Antonio, Tex: The Psychological Corporation; 1996.
46. Yates WR, Mitchell J, Rush AJ, et al. Clinical features of depressed outpatients with and without co-occurring general medical conditions in STAR*D. Gen Hosp Psychiatry. 2004;26:421-429.
47. Mast BT, Yochim B, MacNeill SE, Lichtenberg PA. Risk factors for geriatric depression: the importance of executive functioning within the vascular depression hypothesis. J Gerontol A Biol Sci Med Sci. 2004;59:1290-1294.
48. Dugbartey AT. Neurocognitive aspects of hypothyroidism. Arch Intern Med. 1998;158:1413-1418.
49. Naegele B, Pepin JL, Levy P, et al. Cognitive executive dysfunction in patients with obstructive sleep apnea syndrome (OSAS) after CPAP treatment. Sleep. 1998;21: 392-397.
50. Meadows ME, Kaplan RF, Bromfield EB. Cognitive recovery with vitamin B12 therapy: a longitudinal neu- ropsychological assessment. Neurology. 1994;44: 1764-1765.
51. Patten SB, Love EJ. Drug-induced depression. Incidence, avoidance and management. Drug Saf. 1994;10: 203-219.
52. Nikaido AM, Ellinwood EH Jr, Heatherly DG, Gupta SK. Age-related increase in CNS sensitivity to benzodiazepines as assessed by task difficulty. Psychopharmacology (Berl). 1990;100:90-97.
53. Morrison RL, Katz IR. Drug-related cognitive impairment: current progress and recurrent problems. Annu Rev Gerontol Geriatr. 1989;9:232-279.
54. Stein RA, Strickland TL. A review of the neuropsychological effects of commonly used prescription medications. Arch Clin Neuropsychol. 1998;13:259-284.
55. Jorm AF. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): development and cross-validation. Psychol Med. 1994;24: 145-153.
56. Jorm AF. Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Available at: http://www.anu.edu.au/iqcode. Accessed September 7, 2007.
57. Folstein M, Folstein S, Fanjiang G. Mini-Mental State Examination: Clinical Guide and User's Guide. Lutz, Fla: Psychological Assessment Resources; 2001.
58. Tombaugh TN, McIntyre NJ. The Mini-Mental State Examination: a comprehensive review. J Am Geriatr Soc. 1992;40:922-935.
59. Butters MA, Salmon DP, Butters N. Neuropsychological assessment of dementia. In: Storandt M, VandenBos GR, eds. Neuropsychological Assessment of Dementia and Depression in Older Adults: A Clinician's Guide. Washington, DC: American Psychological Association; 1994:33-59.
60. Lyketsos CG, DelCampo L, Steinberg M, et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry. 2003;60: 737-746.
61. Munro CA, Brandt J, Sheppard JM, et al. 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;12:491-498.
62. Alexopoulos GS, Raue P, Arean P. Problem-solving therapy versus supportive therapy in geriatric major depression with executive dysfunction. Am J Geriatr Psychiatry. 2003;11:46-52.
63. Olin JT, Katz IR, Meyers BS, et al. Provisional diagnostic criteria for depression of Alzheimer disease: rationale and background. Am J Geriatr Psychiatry. 2002;10: 129-141.