Depression: cognitive function the next frontier

Do patients who ‘feel better’ necessarily ‘do better’? Recognising the role of cognitive impairment in the assessment and management of depression

In February 2015, Sidney Kennedy gave a presentation at the Lundbeck Institute on the topic ‘Neurocognition and Function - The Next Frontier in Treating Major Depressive Disorder?’. Kennedy, Professor of Psychiatry at St Michael’s Hospital and University of Toronto, Canada, has treated depression for over three decades and over this period has observed a shift in treatment goals. This article highlights key points from his presentation.

Objectives​

  • Identify specific cognitive difficulties in MDD patients​

  • Consider symptoms + cognition  +   function in your assessment and management plans​

Change thinking to improve thinking

There has been a shift from the treatment goal of symptom reduction to achieving functional remission. The aim is for a patient to resume a high quality life. When asked about the outcomes they most value, patients with depression give priority to positive mental health - which includes optimism, vigour and self-confidence, feeling like their usual selves, and a return to normal levels of functioning at home and work. According to the survey by Zimmerman et al1, these features - from the patient’s perspective - rank above reduction in symptoms of depression per se.

Patients' treatment objectives

Cognition is central to the positive mental health and functioning treasured by patients, and it is an aspect of depression that we have neglected. In treating depression, we generally do a reasonably good job: by classical criteria based on symptom reduction, the response rate to first line treatment is around 50%. But we can always do better. Homogeneous treatments are being used to tackle a heterogeneous disorder, and there are currently no objective biological measures on which to base diagnosis, prognosis or treatment selection.

One way to improve patient outcomes is to hold cognition in mind - as well as core depressive symptoms - when assessing patients, designing management plans and evaluating response.

Changing aims focus on function

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Depression: cognitive function the next frontier

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Evolving Goals for MDD Treatment​
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References

The past two decades have seen the aims of treatment broaden from a focus on the relief of depression symptoms to include functional and cognitive remission and quality of life

QOL = quality of life

McIntyre RS. J Clin Psychiatry 2013; 74 Supl 2:14-8

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What Patients Want!​
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References

When asked about outcomes they value, patients with depression cite positive mental health and a return to normal feelings and functioning - at home and work. Absence of the symptoms of depression in themselves was given a lower priority

 

Zimmerman M. et al. Am J Psychiatry. 2006; (1):148-50.

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MDD: Homogeneous Treatments for a Heterogeneous Disorder ​
  • Response rate to first line treatment is 50%​

  • Many patients are treatment resistant​​

  • There are no objective biological measures on which to base diagnosis, prognosis, or treatment selection​

Hold cognition in mind

For years, we have focused on depression as a mood disorder, and on features such as anhedonia. We have tended to believe that any cognitive deficits are secondary to the depression, and that they will go away once the depressed mood lifts. In addition, at a practical level, cognitive problems have been seen as difficult to assess, since neuropsychological testing is regarded as time consuming. We can now challenge all of these views.

Why has cognition in depression been ignored in the past?​

  • Belief that cognitive dysfunction is not a core feature of depression​

  • Schizophrenia and dementia are disorders of cognition - depression and bipolar disorder are mood disorders​

  • Neuropsychology testing takes so long and how is it relevant?​

  • Can it be treated?​

  • Doesn’t “pseudodementia” remit?​

Why cognition in depression should be explored, not ignored

  • Recognition of employment and health costs tied to depression​

  • Neurocognition is directly associated with functional outcomes​

  • Cognitive deficits

    • may predate onset of major depression

    • contribute to impairment during the depressive episode

    • predict poorer functional outcomes even after symptom response and remission

  • Depression-associated “pseudodementia” does not simply go away when mood improve

  • Costs of depression include cognitive impairment 

Costs of depression include cognitive impairment

Advances in neuroimaging are revealing the detailed neurocircuitry involved

  • Antidepressants differ in their impact on cognition

  • New non-pharmacological treatments may improve cognitive outcomes, and therefore, functional outcomes

A recent review by Rock et al2 posed the question of whether cognitive impairment should be considered a core feature of depression that may be a valuable target for treatment. It was concluded that both low mood and cognitive impairment are associated with poor psychosocial functioning, and that cognitive impairment represents a core feature of depression that should not be considered secondary to symptoms of low mood.

Cognitive deficits and resulting loss of function are a big deal - to an individual and to society as a whole. Significant employment and health costs are tied to depression. The impact on work performance is highlighted in an observational study by Koopmans et al.3 Between 2002 and 2005, they evaluated 15% of the Dutch working population and identified 9,910 new absence episodes due to depression. The mean duration of sickness absence due to depressive symptoms was 200 and 213 days in men and women, respectively. The rate of chronicity (1 year of absence) was 24%.

Evidence for cognitive deficits in depression

There is accumulating evidence on the nature and extent of cognitive impairment in depression, and of its correlates in neuro-anatomy and function.

Depressive symptoms may be associated with increased risk of developing dementia.4 In a 5-7 year follow-up of depressed individuals, the relative risk for developing dementia was 3.93.5

Depression is associated with several cognitive deficits including working memory, executive function, episodic memory and processing speed.6A study of more than eight thousand outpatients suggests that capacity for delayed recall declines steadily with the number of previous depressive episodes.7

 

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Depression: cognitive function the next frontier

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Sickness Absence due to MDD​
  • Evaluation of the 15% of the Dutch working population with absence episodes (n=9,910) due to depression between April 2002 and November 2005​

  • Mean duration of sickness absence was 200 days in men and 213 days in women​

  • Older employees had longer absence durations​

  • Depressive symptoms had an estimated rate of chronicity (1 year of absence) of 24%​

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Evidence for Neuropsychological Dysfunction in Depression
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References

There is evidence for neuropsychological dysfunction spanning many cognitive domains

Effects on eg social cognition may also be important

  • Well documented for
    • memory
    • processing speed
    • executive function

Effects on eg social cognition may also be important

  • depressed patients have altered perception of emotional cues such as facial expressiona dn body movement

 

0, essentially absent; 0/+, poorly documented, ambiguous, mild and/or variable; +, consistently present but not pronounced; ++, a common, marked characteristic; ?, not clearly evaluated

Millan ML, et al. Nat Rev Drug Discov. 2012;11(2):141-68

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Memory Function Declines with Increasing Number of Major Depressive Episodes
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References

A study in outpatients with MDD (n=8229) suggests the capacity for delayed recall declines steadily with the number of previous depressive episodes

  • among 1800 depressed patients in remission, who had responed withing 6 weeks, the number of recalled words was related to the number of previous episodes
  • delayed recall capacities fell by 2-3% for each prior episode

Gorwood P. et al. Am J Psychiatry 2008; 165(6): 731-9

Heritability of Cognitive Deficits in MDD

Investigators have also worked with data from Danish twin registries.8

  • Danish twin registry linked to Psychiatric Central Research Register
  • 94 identical and fraternal high risk vs. 88 low risk twins
  • Completed Trials A+B and Stroop
  • Psychologically healthy members of a twin pair in which the other member had depression showed lower performance on several measures of cognitive function.
  • In the case of executive function, the effect in monozygotic pairs was greater than that in dizygotic pairs.
  • Results suggest the heritability of cognitive deficits in MDD, and support the hypothesis that cognitive impairment is present before the onset of the affective disorder.

Cortical Thining and Neurocognitive Deficits in MDD

A three-generation cohort study of 131 participants who had either high- or low-familial risk for developing MDD and had structural MRI,9 identified a brain-based endophenotype for MDD that includes cortical thinning on lateral right hemisphere and medial left hemisphere in MDD and high risk groups. The magnitude of cortical thinning correlates with inattention and poor visual memory for social stimuli

Abnormal hippocampal activation in MDD

Abnormal hippocampal activation has also been observed in MDD.10 Milne and colleagues compared patients who experienced 3 or more previously treated depressive episodes (n=22) with age- and sex-matched controls (n=18). Functional MRI data were collected while participants performed a recollection memory process dissociation task. Activation of the right hippocampal and left parahippocampal gyrus was increased in controls compared with patients with MDD, suggesting that the brain of depressed patients has to ‘work harder’ to achieve the same result.

 

Improved mood and improved cognition don’t go hand in hand

Crucially, we should no longer accept the view that cognitive impairments will invariably disappear with successful treatment. Rock et al assessed whether cognitive is a core feature of depression that may be a treatment target.2 The meta-analysis used the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess cognitive function in patients with depression during symptomatic and remitted states.

  • All Subjects (700 MDD, 700 healthy controls)
    Executive function, memory and attention
  • Un-Medicated (270 MDD, 270 healthy controls)
    Executive function and attention
  • Remitted MDD (170 MDD, 170 healthy controls)
    Significant deficits in executive function and attention​​

Cognitive deficits in executive function, memory and attention were observed in MDD relative to controls. In addition, moderate deficits in executive function, attention and memory persisted in remitted patients. This indicates that cognitive impairment occurs separately from low mood. Compared with 170 healthy controls, significant deficits in executive function and attention remained, despite the resolution of mood symptoms. Cognitive problems do not necessarily resolve in synchrony with other core elements of depression. The authors conclude that cognitive impairment cannot be considered entirely secondary to symptoms of low mood, and that it may be a valuable target for future interventions.

Identifying a problem is the first step towards managing it. It is indeed true that neuropsychological testing used to be time-consuming, but new cognitive test batteries can now be completed in 10‑15 minutes, and some can be self-administered.

Measuring Cognitive Deficits

In terms of treatment, Christopher Bowie and colleagues are showing benefits using a computerised system that engages patients in game-type tasks lasting ninety minutes that relate to areas of cognitive function previously identified as requiring attention.11

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Depression: cognitive function the next frontier

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Measuring Cognitive Deficits​
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Cognitive deficits can be assessed by patient self-report. But given the nature of depression, including the tendency to negative bias, these may not be as useful as objective neuropsychological tests.

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Neuropsych Tests to Measure Performance on Cognitive Domains Affected in MDD
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References

DSST = Digit Symbol Substitution Test
RAVLT = Rey Auditory Verbal Learning Test

McIntyre RS, et al, 2014,. J Neuropsychopharmacol

Targeting Cognitive Deficits in MDD

Our choice of antidepressant can also have a positive or a negative impact on cognitive symptoms in depression, depending on their mechanism of action.

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Depression: cognitive function the next frontier

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Targeting Cognitive Deficits in MDD: Cognitive Remediation​
  • Potential aim to exercise specific pathways with the goal of remediating specific areas of cognitive function.​

  • Methods: Using behavioral strategies to improve a range of neuropsychological domains such as memory and executive functioning ​

  • Techniques: cognitive control training sessions,  computer games, group discussion, homework, application to real life situations​

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Evolving Goals for MDD Treatment​
Slide information
References

Cognition is central to the positive mental health and functioning treasured by patients. One way to improve outcomes is to hold cognition in mind when assessing and managing patients and evaluating response. This is increasingly reflected in the evolving goals of treatment.

QOL = quality of life

 

 

McIntyre RS. J Clin Psychiatry. 201; 74 Suppl 2: 14-18

Examples of tests relevant to cognitive domains affected by MDD

  • Digit Symbol Substitution Test: executive function, speed of processing and attention

  • Rey Auditory Verbal Learning Test: learning and memory

  • British Columbia Cognitive Complaints Inventory: memory, concentration, thinking speed, problem solving

References
  1.   Zimmerman M et al. How should remission from depression be defined? The depressed patient's perspective. Am J Psychiatry. 2006;163(1):148-50.

  2. Rock PL et al. Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med. 2014;44(10):2029-40.
    The authors assessed whether cognitive impairment is a core feature of depression that may be a treatment target. This meta-analysis used the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess cognitive function in patients with depression during symptomatic and remitted states. Cognitive deficits in executive function, memory and attention were observed in MDD relative to controls. In addition, moderate deficits in executive function, attention and memory persisted in remitted patients. This indicates that cognitive impairment occurs separately from low mood. The authors conclude that cognitive impairment cannot be considered entirely secondary to symptoms of low mood, and that it may be a valuable target for future interventions.

  3. Koopmans PC et al. Sickness absence due to depressive symptoms. Int Arch Occup Environ Health. 2008;81(6):711-9.

  4. Barnes DE et al. Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study. Arch Gen Psychiatry. 2006;63(3):273-9.

  5. Sáez-Fonseca JA et al. Long-term outcome of depressive pseudodementia in the elderly. J Affect Disord. 2007;101(1-3):123-9.

  6. Millan MJ, et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nat Rev Drug Discov. 2012;11(2):141-68.
    This review critically discusses the issue of cognitive dysfunction in psychiatric disorders, including MDD, and highlights the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders. Evidence is presented that depression is associated with several cognitive deficits including working memory, executive function, episodic memory and processing speed.

  7. Gorwood P et al. 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(6):731-9.
    This study assessed the impact of depression on hippocampal function. More than 8,000 MDD outpatients were tested for delayed recall. This memory function is particularly related to hippocampal integrity. Capacity for delayed recall decreased steadily with the number of previous depressive episodes. This suggests neurotoxicity may link depression to cognitive impairment.

  8. Christensen MV et al. Cognitive function in unaffected twins discordant for affective disorder. Psychol Med. 2006;36(8):1119-29.

  9. Peterson BS et al. A brain-based endophenotype for major depressive disorder. Annu Rev Med. 2011;62:461-74.
    Peterson and Weissman identified a brain-based endophenotype for MDD that includes cortical thinning on the lateral right hemisphere and medial left hemisphere, as well as bilateral hypoplasia of frontal and parietal white matter. These abnormalities were observed by structural MRI in a multi-generational cohort of 131 participants who themselves did not have MDD but who were at increased familial risk for developing the illness. Participants with this abnormality also had substantial problems with attention and memory for visual social stimuli.

  10. Milne AM et al. Abnormal hippocampal activation in patients with extensive history of major depression: an fMRI study. J Psychiatry Neurosci. 2012;37(1):28-36.
    The authors hypothesized that, compared to controls, patients with a protracted course of MDD (3 or more previously treated episodes) would show diminished hippocampal activation on functional magnetic resonance imaging (fMRI) during a recollection memory task. Controls showed increased activation of the right hippocampal and left parahippocampal gyrus compared with MDD patients during recollection memory trials. This finding suggests that these regions may be sensitive to the impact of disease burden and repeated episodes of MDD. These results also associate recollection performance impairment in patients with MDD with diminished engagement of the hippocampus.

  11. Bowie CR et al. Cognitive remediation for treatment-resistant depression: effects on cognition and functioning and the role of online homework. J Nerv Ment Dis. 2013;201(8):680-5.

  12. McIntyre RS et al. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-67.

  13. Iverson GL et al. Rapid screening for perceived cognitive impairment in major depressive disorder. Ann Clin Psychiatry. 2013;25(2):135-40.

 

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