When we fall down, can we get back up again?


Major depressive episodes often leave patients functionally incapacitated even after depressive symptoms have been lifted. The underlying cause of this residual impairment is thought to be cognitive dysfunction. During a Lundbeck-sponsored satellite symposium investigating the functional consequences of MDD, ways of assessing, monitoring, explaining and overcoming cognitive dysfunction were presented.


With the gratifying re-awakening of awareness of cognitive dysfunction as a core feature of major depressive disorders (MDD), Professor Judith Jaeger, New York, NY, USA, advocated that it should be monitored as a part of standard clinical practice. But how to go about it is not always straightforward, as she explained.

Not objective OR subjective…

Identify and evaluating cognitive dysfunction involves asking the patient questions using subjective rating scales, and by administering objective cognitive tests. The advantage of assessing performance using standardized cognitive tests is that these objective measures are relatively free from affective biases. However, the ‘norms’ for such objective testing are based on the assessment of whole populations and don’t reflect individual pre-morbid performance levels. For example, someone with very high pre-morbid cognitive functioning may experience objective cognitive decline but remain within the bounds of objective ‘normalcy’ for the cognitive measure. Thus, the objective test would suggest one thing while the patient ‘knows’ another.  

While objective measures are relatively free from affective biases, subjective measures cannot be ignored

…but objective AND subjective

Subjective measures cannot, therefore, be ignored although these, too, have limitations. For example, subjective cognitive dysfunction occurring in the absence of objective evidence of dysfunction could reflect a negative bias from mood disorder.

Many tools are now available to clinicians for measuring subjective and objective cognition function. Increasingly, these tools are delivered on computer platforms (e.g. tablets) with automated scoring and reporting functions which increases efficiency for clinicians. Two such tools, COGNIGRAM™ and THINC-it®, are available as free downloads. Their use should not only enable measurement of cognition status but also monitor individual changes in any cognitive impairment over time. In future, such devices will facilitate benchmarking of therapeutic efficacy and allow clinicians to determine whether any changes are clinically meaningful.

Functional impairment persists after symptom alleviation

The functional consequences of MDD were described by Dr Lene Hammer-Helmich, Valby, Denmark. In a series of real-world studies, people with remitted MDD had functional impairment at baseline (prior to receipt of antidepressant, be it first or second-line). This feature is seen across different cultures and is worse when switching than when initiating treatment for depression. Importantly, even after alleviation of the depressive symptoms, some functional impairment frequently remains.

Even after alleviation of the depressive symptoms, some functional impairment frequently remains

Cognitive impairment mediates functional impairment

A growing body of evidence supports cognitive symptom mediation of functional impairment. PERFORM-EU, a large, European observational cohort study, confirmed that cognitive symptoms are independently-associated with functional impairment and that residual cognitive symptoms measured at 2 months after initiation of treatment are associated with functional impairment up to 2 years later. Similar outcomes are apparent from PERFORM-K (Korea); other PERFORM studies are being conducted in Asia and Canada, the results of which are due soon.

A growing body of evidence supports cognitive symptom mediation of functional impairment

Structural equation modelling was undertaken to determine whether any one factor – cognitive impairment, functional impairment or depression severity – was predictive of any other over time. The model suggests that it is cognitive dysfunction that predicts both level of depression and functional disability over time. Thus, a therapy that targets cognition will likely also alleviate depressive symptoms and aid in functional recovery.

Remission needs to feel like remission

Not only is cognitive dysfunction a core feature of MDD, as Professor Christopher R Bowie, Toronto, Canada, explained, it’s also a key driver of sustained disability. What clinicians see as achieved remission does not always feel like remission to many patients with MDD. Professor Bowie outlined a feedback model of cognition and functioning in MDD that might explain why patients feel this way.

Cognitive dysfunction in MDD is a key driver of sustained disability

Catastrophic response to failure feeds cognitive dysfunction

Starting from the recognition that cognitive dysfunction occurs during a depressive episode, what follows in a substantial proportion of patients thereafter is a catastrophic response to failure when attempting problem solving tasks. That is, when patients fail to solve a problem, they believe that subsequent failures are increasingly likely. The odd feature of this is that when comparing responses to an objective test of cognitive function in normal and depressed patients, the level of successful problem solving in both groups is similar. What appears different is that MDD patients, even before attempting the test, believe more strongly than controls that they’ll do badly. And inevitably, they do!

Cognitive under-stimulation feeds cognitive dysfunction and functional impairment

This ‘negative’ thinking then brings about patients’ disengagement from the challenge of the tasks, decreased confidence in their problem solving ability, and withdrawal into themselves. Such decreased functioning creates a cognitively-understimulating daily life-style which feeds back into and likely exacerbates any persistent cognitive dysfunction. Clearly, targeted intervention at any part of this vicious cycle may improve outcomes in MDD.

Cognitive understimulation feeds back into and likely exacerbates any persistent cognitive dysfunction

ABCR breaks the cycle of cognitive understimulation

Professor Bowie described action-based cognitive remediation (ABCR), a new program that combines traditional cognitive remediation (tCR) training techniques with simulated workplace situations and goal setting for engaging with cognitively demanding activities. In a comparative study of tCR and ABCR, significantly more ABCR participants (83%) were retained in the intervention compared with tCR (57%) and reported greater increases in perceived competence with cognitively challenging tasks. ABCR participants were marginally more likely to be competitively employed (68.4% vs. 40%) and, among those employed, ABCR participants experienced less job-related stress. There is a caveat: ABCR durability likely requires a minimum of 12 weeks training and functional skill acquisition is limited without some therapist support or supplementary engagement in skills training.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

Symposium references
  1. Kraepelin, E. 1899. Psychiatry: a textbook for students and physicians. Amerind Publishing Co. New Delhi.
  2. Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res. 2006 Nov 29;145(1):39-48. Epub 2006 Oct 11.
  3. Maruff P, Jaeger J. 2016. Understanding the importance of cognitive dysfunction and cognitive change in major depressive disorder. In: McIntyre RS. Cognitive Impairment in Major Depressive Disorder. Clinical Relevance, Biological Substrates, and Treatment Opportunities. Cambridge University Press, Cambridge, pp. 15-29.
  4. Fava M, Iosifescu DV, Pedrelli P, Baer L. Reliability and validity of the Massachusetts general hospital cognitive and physical functioning questionnaire. Psychother Psychosom. 2009;78(2):91-7.
  5. McIntyre RS, Cha DS, Soczynska JK, Woldeyohannes HO, Gallaugher LA, Kudlow P, Alsuwaidan M, Baskaran A. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013 Jun;30(6):515-27.
  6. Saragoussi D., Haro J.M., Boulenger J.P., Jönsson B., Knapp M., Caillou H., Chalem Y., Milea D., François C. Patient-Reported Cognitive Dysfunction Negatively Impacts Functioning in Patients with Major Depressive Disorder – Preliminary Findings from the Perform Study. Poster PMH14 presented at the 16th ISPOR European Congress, Dublin, Ireland 2-6 November.
  7. Kim JM, Chalem Y, di Nicola S, Hong JP, Won SH, Milea D. A cross-sectional study of functional disabilities and perceived cognitive dysfunction in patients with major depressive disorder in South Korea: The PERFORM-K study. Psychiatry Res. 2016 May 30;239:353-61.
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