Cognitive Difficulties Associated With Depression What Are the Implications for Treatment?

Mar 11, 2009

Subjective complaints of impaired concentration, memory, and attention are common in people with major depressive disorder (MDD), and research shows that a variety of structural brain abnormalities are associated with MDD.1 These findings have intensified the interest in quantitative assessment of cognitive and neuropsychological performance in patients with mood disorders. Many studies that used standardized cognitive tests have found that mild cognitive abnormalities are associated with MDD and that these abnormalities are more pronounced in persons who have MDD with melancholic or psychotic features

In This Special Report:

Cognitive Difficulties Associated With Mental Disorders, by Rami Kaminski, MD

Cognitive Remediation for Psychiatric Patients, by Alice Medalia, PhD

Cognitive Difficulties Associated With Depression, by Pedro L. Delgado, MD and Jason Schillerstrom, MD

Cognitive Impairments With ADHD, by Joel T. Nigg, PhD

Subjective complaints of impaired concentration, memory, and attention are common in people with major depressive disorder (MDD), and research shows that a variety of structural brain abnormalities are associated with MDD.1 These findings have intensified the interest in quantitative assessment of cognitive and neuropsychological performance in patients with mood disorders. Many studies that used standardized cognitive tests have found that mild cognitive abnormalities are associated with MDD and that these abnormalities are more pronounced in persons who have MDD with melancholic or psychotic features.2,3 Older patients with MDD, especially those with onset of illness after age 55 years and patients who have signs of vascular injury to the brain, were also shown to have cognitive abnormalities.4-6

In this article, we review the scientific literature that addresses neuropsychological and cognitive impairments in patients who have MDD.

Pathophysiology
A few key conceptual issues need to be considered when evaluating research on MDD in general and on the association of cognitive dysfunction with MDD in particular. It is increasingly clear that MDD is a genetically complex syndrome with multiple causal pathways involving gene-environment interactions.7 In addition, pathology associated with co-occurring drug and alcohol abuse and some general medical disorders, such as diabetes, cardiovascular disease, and

autoimmune disorders, may further contribute to the pathology of MDD or lead to mental states that share many of the same symptoms but arise from markedly different neurobiological origins.

MDD as currently defined may be an overly broad category to use when investigating genetic and neurobiological mechanisms. On the basis of available literature, MDD is most parsimoniously assumed to be a syndrome-a “collection of symptoms that often occur together but for which there is no known cause.”8 Once causal mechanisms are better understood, MDD might be subdivided into a more narrowly defined set of diseases or disorders that make up the syndrome. Such thinking has added some urgency to the search for subtypes of MDD or for subsets of the MDD syndrome that might be more likely to result from a narrower set of causal pathways and be associated with a more discrete neurobiology. Such narrower subsets are frequently referred to as intermediate phenotypes or endophenotypes.9

It has been suggested that the onset of MDD after age 50 and/or MDD with visual signs of CNS injury associated with vascular disease (eg, deep white matter hyperinten­sities) might reflect symptoms that distinguish a narrower phenotype or subtype of MDD.10 In particular, the presence of more severe cognitive dysfunction in late-onset and vascular MDD is associated with a higher rate of regional deep white matter abnormalities, a greater likelihood of subsequent dementia, a reduced rate of antidepressant treatment response, and a higher rate of residual cognitive impairment after successful treatment of the depressive symptoms.11-16

Therefore, whether cognitive dys­function is associated with the overall syndrome of MDD may be less relevant than whether cognitive dysfunction identifies a more bio­log­ically homogeneous subset of people with the MDD syndrome.

Cognitive dysfunction in adult MDD
The definition of MDD includes subjective complaints of impaired ability to think or concentrate. It is common for people with MDD to perceive decreased ability to focus attention and to experience forgetfulness. When formal cognitive testing was undertaken in adult patients with MDD, modest degrees of abnormalities in explicit verbal and visual memory, attention, verbal learning, speed of task performance, and executive processes were found. The largest effect sizes across studies were seen in the domains of encoding and retrieval of episodic memory, although the magnitude of these abnormalities is less than in patients with dementia, bipolar disorder, or schizophrenia.17

The literature on cognitive deficits associated with MDD is extensive but somewhat inconsistent on many critical points. While the vast majority of studies have found cognitive abnormalities, some studies in adults younger than 50 years have found only mild abnormalities or normal cognitive function.18 In a large European study of 8229 younger (mean age, 48 years) outpatients with MDD, about 2.5% were classified as normal or better than normal on a delayed recall memory test; 15.5% were rated as mildly impaired, 41% as mildly to moderately impaired, 35% as moderately to severely impaired, and only 6% as severely impaired.4

Cognitive deficits are generally worse and more frequently present in patients who:

• Are older
• Have more severe MDD symptoms or psychotic or melancholic features
• Present with co-occurring fibro­myalgia, cardiovascular disease, or diabetes
• Have clinical features associated with a greater risk of bipolar disorder

Recent work suggests that hypercortisolemia may be associated with impaired memory and executive dysfunction in younger adults with MDD. Processing speed is more dependent on depression symptom severity.19

Many important questions remain. There continues to be some degree of uncertainty about whether cognitive symptoms are trait-related or state-related.20 While many studies have found cognitive dysfunction in patients with MDD who are in remission, many treatment studies show substantial improvement of cognitive measures in most patients. The question also remains as to how much reduced motivation, slowing, and inattention contribute to the broader set of cognitive abnormalities seen in patients with MDD.21

Furthermore, while some studies suggest that longer duration of illness or a greater number of prior episodes are associated with more severe cognitive dysfunction, other studies have failed to find these associations.

Cognitive dysfunction in geriatric MDD
The most robust and consistent abnormalities in cognition have been identified in older patients with MDD.5 This is perhaps not surprising in that most of the cognitive impairments seen in patients with MDD are remarkably similar to those that are found with normal aging, including slowed performance, attention problems, and short-term memory deficits.22 However, studies that have used same-age controls with similar degrees of risk factors for cardiovascular disease generally find that the MDD group has greater cognitive impairment.4,23

Within the geriatric MDD group, patients with a greater volume of deep white matter hyperintensities on MRI scans have the worst cognitive function.10,24 White matter hyperintensities are common in old age and occur in up to 60% of healthy older adults.25 However, older patients with MDD generally have a greater number of deep white matter hyperintensities than age-matched controls, and the presence of these lesions is associated with worse cognitive performance, particularly in domains of executive function.15,26

Recent work shows that deep white matter hyperintensities in geriatric patients with MDD were located in brain regions associated with emotion regulation and executive function. Greater lesion volumes correlated with impairment in executive function.23 Reduced hippocampal volume in elderly patients with MDD is also associated with greater cognitive dysfunction, especially impairment in executive function and memory.

While some evidence suggests that reduced hippocampal volume is related to illness duration, other studies find that patients with an onset of MDD after age 50 have more pronounced hippocampal volume reductions than MDD patients with earlier onset. In addition, both hypercortisolemia and a genetic profile that includes certain alleles of the serotonin transporter promoter gene have been associated with reduced hippocampal volume.27

Patients with an onset of MDD after age 50 and MRI scan evidence of extensive deep white matter hyperintensities may represent a distinct subset of MDD patients whose illness results from generalized vascular disease.24 The vascular depression subset of patients has a much higher rate of co-occurring general medical conditions, such as cardiovascular disease and diabetes, and patients in this subset are more likely to develop dementia.10,28 While many believe that a vascular disease may play a causal role in a subset of the elderly with MDD, there is a lack of consensus about the specific criteria that define vascular depression. More recent work has de-emphasized the age of onset, since vascular disease clearly occurs in younger adults as well as in older adults. Alexopoulos14 emphasizes executive dysfunction as the cardinal feature, and Taylor and colleagues29 focus on MRI evidence of vascular pathology. More work is needed to establish valid and reliable criteria for vascular depression.

It is also known that MDD predisposes to Alzheimer disease, and some forms of MDD may be a prodromal symptom of Alzheimer disease.30 A provocative recent study found that a high ratio of plasma amyloid-b peptide 40 (Ab40) to Ab42 in elderly patients with depression was associated with a high rate of cognitive dysfunction. Since the Ab40 to Ab42 ratio is associated with the risk of Alzheimer disease, these investigators propose that amyloid-associated MDD may be a precursor to Alzheimer disease and a distinct form of MDD.31 Follow-up studies are needed to confirm or reject this hypothesis.

In general terms, moderate to severe cognitive dysfunction in geriatric patients falls into 3 groups:

• Vascular depression characterized by disproportionately impaired executive function and apathy
• Alzheimer depression characterized by profound recent memory impairments and disinhibition
•“Pseudodementia” characterized by profound but reversible recent and remote memory impairments and generally preserved attention and concentration in the setting of a poorly motivated demeanor

Whether these groups truly represent distinct and narrower disorders or diseases remains to be determined.

Clinical significance of cognitive dysfunction for treatment of MDD
Most antidepressant treatment studies find that cognitive function improves with treatment in younger adults, although processing speed may improve to a greater extent with treatment response while memory impairments may be more likely to persist.19 Fluoxetine and paroxetine improved memory and attention in a large study of 242 elderly patients with MDD.32 Imipramine and fluvoxamine also improved measures of attention and processing speed.33 However, neither nortriptyline nor paroxetine improved cognition in a study by Nebes and colleagues34 of elderly patients with depression: patients showed substantial residual posttreatment cognitive impairment.

A recent study in geriatric patients with MDD showed that escitalopram therapy was associated with significant memory improvement.35 Similarly, a study with the serotonin-norepinephrine reuptake inhibitor duloxetine showed that memory and verbal learning significantly improved with treatment.36

The noradrenergic-dopaminergic antidepressant bupropion has also been reported to improve a variety of cognitive symptoms in a group of young (mean age, 24 years) adults with MDD.37 Bupropion led to robust improvements in visual memory and mental processing speed. Low pretreatment measures of visual memory and slow mental processing speed were predictors of good overall antidepressant response to bupropion.37

However, several studies have found that moderate cognitive dysfunction predicts failure to achieve antidepressant response in geriatric patients.38,39 Nonresponders to fluoxetine showed increased perseverative errors in one study.38 Another study showed that impairments in initiation/perseveration were associated with poor response in a group of geriatric patients with MDD who were treated with citalopram.15 In addition, fluoxetine was found to be less effective in MDD patients with psychomotor slowing.40 Finally, some investigators have proposed that SSRI response could be predicted in 85% of patients with MDD by using a battery of cognitive function tests.41

Conclusions
While many studies have noted significant cognitive abnormalities in persons with MDD, on average these disturbances tend to be mild to moderate in younger adults and of lesser frequency and severity than those found in people with bipolar disorder or schizophrenia. In younger adults, some data suggest that mental slowing and reduced motivation and attention may contribute to the apparent dysfunction in other cognitive domains. Cognitive dysfunction in younger adults tends to improve with treatment, although some patients continue to have residual mild impairment.2 Although a bupropion study showed that this drug was more likely to lead to an antidepressant response in patients who had evidence of cognitive dysfunction at baseline, no comparative data are available. Studies with SSRIs suggest that baseline cognitive impairment, reduced hippocampal volume, greater burden of white matter hyperintensities, and microstructural abnormalities in white matter may predict poor antidepressant response, especially in older patients.42

Cognitive dysfunction may be an endophenotype for a specific subset of MDD, and brain imaging abnormalities are possible biomarkers for this and other subsets of MDD. Whether these or other attempts will be successful in defining a more biologically homogeneous group of people within the syndrome of MDD is still unclear. Future research needs to focus on subsets of patients with MDD defined by a certain severity of cognitive dysfunction, a certain density of white matter abnormality, or markedly reduced hippocampal volume. To advance treatment, MDD studies need to more explicitly address the likelihood that this syndrome includes an exceptionally broad range of causal pathways and underlying mechanisms.

Based on what we currently know, patients with MDD should receive standard antidepressant treatment, regardless of cognitive dysfunction. Clinicians should be watchful for nonresponse in patients with more severe cognitive dysfunction at baseline and for progression to frank dementia in patients with significant residual cognitive dysfunction after successful antidepressant response.

While the fact that bupropion showed greater efficacy in younger adults with cognitive dysfunction in one study is interesting, no comparator was used and this has not been demonstrated in geriatric patients. Therefore, the available data do not favor the use of one antidepressant over another in patients with cognitive dysfunction. If dementia develops or co-occurs with MDD, combination treatment with antidepressants and drugs approved for treatment of dementia should be used in an integrated fashion.43

Drugs Mentioned in this Article
Bupropion (Wellbutrin, Zyban)
Citalopram (Celexa)
Duloxetine (Cymbalta)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Sarafem)
Fluvoxamine (Luvox)
Imipramine (Tofranil)
Nortriptyline (Aventyl, Pamelor)
Paroxetine (Paxil)

References:

1. Sheline YI. Neuroimaging studies of mood disorder effects on the brain. Biol Psychiatry. 2003;54:338-352.
2. Austin MP, Ross M, Murray C, et al. Cognitive function in major depression. J Affect Disord. 1992;25: 21-29.
3. Rothschild AJ, Benes F, Hebben N, et al. Relationships between brain CT scan findings and cortisol in psychotic and nonpsychotic depressed patients. Biol Psychiatry. 1989;26:565-575.
4. Gorwood P, Corruble E, Falissard B, Goodwin GM. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am J Psychiatry. 2008;165:731-739.
5. Herrmann LL, Goodwin GM, Ebmeier KP. The cognitive neuropsychology of depression in the elderly. Psychol Med. 2007;37:1693-1702.
6. Krishnan KR, Hays JC, Blazer DG. MRI-defined vascular depression. Am J Psychiatry. 1997;154:497-501.
7. Kendler KS. Reflections on the relationship between psychiatric genetics and psychiatric nosology. Am J Psychiatry. 2006;163:1138-1146.
8. Syndrome. Wikipedia, 2008. http://en.wikipedia.org/wiki/Syndrome. Accessed January 28, 2009.
9. Glahn DC, Thompson PM, Blangero J. Neuroimaging endophenotypes: strategies for finding genes influencing brain structure and function. Hum Brain Mapp. 2007;28:488-501.
10. Alexopoulos GS, Young RC, Meyers BS, et al. Late-onset depression. Psychiatr Clin North Am. 1988;11: 101-115. 11. Krishnan KR. Organic bases of depression in the elderly. Annu Rev Med. 1991;42:261-266.
12. Salloway S, Malloy P, Kohn R, et al. MRI and neuropsychological differences in early- and late-life-onset geriatric depression. Neurology. 1996;46:1567-1574.
13. 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.
14. Alexopoulos GS. The vascular depression hypothesis: 10 years later. Biol Psychiatry. 2006;60:1304-1305.
15. Alexopoulos GS, Kiosses DN, Heo M, et al. Executive dysfunction and the course of geriatric depression. Biol Psychiatry. 2005;58:204-210.
16. Bhalla RK, Butters MA, Mulsant BH, et al. Persistence of neuropsychologic deficits in the remitted state of late-life depression. Am J Geriatr Psychiatry. 2006;14:419-427.
17. Zakzanis KK, Leach L, Kaplan E. On the nature and pattern of neurocognitive function in major depressive disorder. Neuropsychiatry Neuropsychol Behav Neurol. 1998;11:111-119.
18. Grant MM, Thase ME, Sweeney JA. Cognitive disturbance in outpatient depressed younger adults: evidence of modest impairment. Biol Psychiatry. 2001; 50:35-43.
19. Reppermund S, Zihl J, Lucae S, et al. Persistent cognitive impairment in depression: the role of psychopathology and altered hypothalamic-pituitary-adrenocortical (HPA) system regulation. Biol Psychiatry. 2007;62:400-406.
20. Biringer E, Mykletun A, Sundet K, et al. A longitudinal analysis of neurocognitive function in unipolar depression. J Clin Exp Neuropsychol. 2007;29:879-891.
21. Scheurich A, Fellgiebel A, Schermuly I, et al. Experimental evidence for a motivational origin of cognitive impairment in major depression. Psychol Med. 2008;38:237-246.
22. Stewart R, Dufouil C, Godin O, et al. Neuroimaging correlates of subjective memory deficits in a community population. Neurology. 2008;70:1601-1607.
23. Sheline YI, Price JL, Vaishnavi SN, et al. Regional white matter hyperintensity burden in automated segmentation distinguishes late-life depressed subjects from comparison subjects matched for vascular risk factors. Am J Psychiatry. 2008;165:524-532.
24. Krishnan KR, Taylor WD, McQuoid DR, et al. Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression. Biol Psychiatry. 2004;55:390-397.
25. Guttmann CR, Jolesz FA, Kikinis R, et al. White matter changes with normal aging. Neurology. 1998; 50:972-978.
26. Kramer-Ginsberg E, Greenwald BS, Krishnan KR, et al. Neuropsychological functioning and MRI signal hyperintensities in geriatric depression. Am J Psychiatry. 1999;156:438-444.
27. O’Hara R, Schröder CM, Mahadevan R, et al. Serotonin transporter polymorphism, memory and hippocampal volume in the elderly: association and interaction with cortisol. Mol Psychiatry. 2007;12:544-555.
28. Gonzalez MB, Snyderman TB, Colket JT, et al. Depression in patients with coronary artery disease. Depression. 1996;4:57-62.
29. Taylor WD, Steffens DC, Krishnan KR. Psychiatric disease in the twenty-first century: the case for subcortical ischemic depression. Biol Psychiatry. 2006; 60:1299-1303.
30. Geerlings MI, den Heijer T, Koudstaal PJ, et al. History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology. 2008;70:1258-1264.
31. Sun X, Steffens DC, Au R, et al. Amyloid-associated depression: a prodromal depression of Alzheimer disease? Arch Gen Psychiatry. 2008;65:542-550.
32. Cassano GB, Puca F, Scapicchio PL, et al; Italian Study Group on Depression in Elderly Patients. Paroxetine and fluoxetine effects on mood and cognitive functions in depressed nondemented elderly patients. J Clin Psychiatry. 2002;63:396-402.
33. Koetsier GC, Volkers AC, Tulen JH, et al. CPT performance in major depressive disorder before and after treatment with imipramine or fluvoxamine. J Psychiatr Res. 2002;36:391-397.
34. Nebes RD, Pollock BG, Houck PR, et al. Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized, double- blind clinical trial with nortriptyline and paroxetine. J Psychiatr Res. 2003;37:99-108.
35. Savaskan E, Müller SE, Böhringer A, et al. Anti depressive therapy with escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients. Int J Neuropsychopharmacol. 2008;11:381-388.
36. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007;164:900-909.
37. Herrera-Guzmán I, Gudayol-Ferré E, Lira-Mandujano J, et al. Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder. Psychiatry Res. 2008;160:72-82.
38. Dunkin JJ, Leuchter AF, Cook IA, et al. Executive dysfunction predicts nonresponse to fluoxetine in major depression. J Affect Disord. 2000;60:13-23.
39. Bogner HR, Bruce ML, Reynolds CF 3rd, et al; PROSPECT Group. The effects of memory, attention, and executive dysfunction on outcomes of depression in a primary care intervention trial: the PROSPECT study. Int J Geriatr Psychiatry. 2007;22:922-929.
40. Taylor BP, Bruder GE, Stewart JW, et al. Psychomotor slowing as a predictor of fluoxetine nonresponse in depressed outpatients. Am J Psychiatry. 2006;163:73-78.
41. Kampf-Sherf O, Zlotogorski Z, Gilboa A, et al. Neuropsychological functioning in major depression and responsiveness to selective serotonin reuptake inhibitorsantidepressants. J Affect Disord. 2004;82:453-459.
42. Alexopoulos GS, Murphy CF, Gunning-Dixon FM, et al. Microstructural white matter abnormalities and remission of geriatric depression. Am J Psychiatry. 2008;165:238-244.
43. Bragin V, Chemodanova M, Dzhafarova N, et al. Integrated treatment approach improves cognitive function in demented and clinically depressed patients. Am J Alzheimers Dis Other Demen. 2005;20: 21-26.

Evidence-Based References
Biringer E, Mykletun A, Sundet K, et al. A longitudinal analysis of neurocognitive function in unipolar depression. J Clin Exp Neuropsychol. 2007;29:879-891
Grant MM, Thase ME, Sweeney JA. Cognitive disturbance in outpatient depressed younger adults: evidence of modest impairment. Biol Psychiatry. 2001; 50:35-43.

x