Cognitive Dysfunction in Depression

Dr Declan Lyons, Dr Roisin McCafferty and Dr Sadaf Khan look at cognitive dysfunction in depression — one of the most common residual symptoms of depression, despite treatment

This article appeared on the Irish Medical Times on 04/04/18.

Depression is now the leading cause of disability worldwide, affecting more than 300 million people at any one time (World Health Organization, 2017). The disability associated with depression is greater and more prolonged than can be accounted for by mood symptoms alone. Cognitive dysfunction is an important and often overlooked aspect of depression, particularly in regard to long-term recovery and quality of life.

Cognitive dysfunction occurs in 94 per cent of depressive episodes and can have an effect for many years after the original depressive episode has resolved.

Despite this, only 50 per cent of people who experience depression are asked about cognitive dysfunction by a clinician, and only now is cognition becoming a recognised treatment target in depression.

Traditionally major depressive disorder was looked at as an episodic illness, with treatment focused on attaining symptom remission. However, increasingly it has become evident that even in remission, patients who experience depression often have residual disability and poorer quality of life. Cognitive deficits remain even after the other depressive symptoms have been effectively treated, in 40 per cent of adults and 60 per cent of elderly.

Cognitive dysfunction in depression appears to be less severe than that which occurs in schizophrenia or bipolar affective disorder.

However, cognition may be the central mediator of functional outcomes in depression. Indeed, cognitive measures have been shown to be a more important factor in workplace functioning than overall severity of depressive symptoms.

The word cognition can be used in two senses: one is ‘hot’ (emotional) processing and the other is ‘cold’ processing. Clinicians are very familiar and at ease with assessing ‘hot’ cognitions, such as guilt, hopelessness and suicidal ideation. However, we tend to place much less emphasis on changes in ‘cold cognitions’ — changes in attention, executive function and memory. When a patient achieves remission, we can expect the emotional cognitions to return to normal.

Meanwhile, ‘cold’ cognitive impairments often endure following resolution of the depressive episode.

Regaining normal function-planning, organising and returning to work can all be impaired by residual impairments in ‘cold cognitions’. Therefore, ‘cold cognitions’ may contribute to poor long-term outcomes in a way that ‘hot’ processing does not.

Mechanisms

There are a variety of different cognitive deficits that occur in major depressive disorder. These include attention, processing speed, psychomotor skills, verbal learning and memory, as well as executive functioning such as planning and organising. Implicit memory appears to be spared. While attention and psychomotor processing often improve with treatment of depressed mood, the impairments in other areas are more likely to persist.

However, patients who have recovered from a depressive episode continue to show varying levels of impairment in all the above domains.

Depression is associated with deficits in learning and episodic memory. This has been hypothesised to be related to the reduction in hippocampal volume that occurs in depression. Depression also causes impaired engagement in the dorsolateral prefrontal cortex of the brain, the area associated with executive functioning.

Contrary to what was previously believed, cognitive difficulties in depression do not result from reduced effort by the patient. When assessed, cognitive dysfunction in depression is associated with more severe depressive symptoms, and has a particular association with psychomotor retardation.

Moreover, cognitive dysfunction in depression is both more common and more severe in older patient groups.

Presentation

Cognitive dysfunction often manifests itself as the increased difficulty to think, concentrate, learn and make decisions. It acts as another burden on the patient, along with the emotional effects of depression, and can lead to occupation loss and other functional impairments.

The effects of cognitive dysfunction vary depending on the person. For working age populations, cognitive impairment and the effect on their occupation is a major concern.

Depression often causes poor work attendance and performance and cognitive dysfunction further exacerbates this problem. For those aged older than 65, it is important to distinguish between cognitive dysfunction in depression and in an early neurodegenerative disorder.

Cognitive dysfunction is frequently the presenting symptom of a depressive episode in the elderly; as a ‘pseudo-dementia’. Conversely, depression and cognitive dysfunction can be an early
sign of dementia onset, where the depression can be a reaction to the loss of cognitive abilities.

Assessment

Currently, no best practice has been developed to assess and evaluate cognitive dysfunction when a patient is assessed for depression. Clinicians are frequently focused on mood and somatic symptoms. Equally, the emotional aspects of depression will often be more immediate to the patient and they may not perceive or articulate the cognitive dysfunction that also affects them. For this reason, it is important to take the time and care to assess for cognitive difficulties.

A thorough history and mental state exam should be supplemented by a collateral history, if available. Physical investigations and imaging (MRI, PET CT, DAT) should be used to rule out an organic cause for cognitive dysfunction, if suspected.

A neuropsychological battery is the most thorough option for assessing cognitive dysfunction in depression, and is the gold standard. The MMSE and MOCA, although very useful tests, are not sensitive enough to determine the level of cognitive dysfunction arising in depressive disorder.

The familiar depressive symptom assessment scales, such as the Patient Health Questionnaire, HAM-D and MADRS, all have one or two items that assess cognition. However, this is not sufficient to assess the level of cognitive dysfunction present, or to determine treatment response.

Self-reported measures are practical and useful tools for assessing cognitive dysfunction. These include the Perceived Deficits Questionnaire, the Cognitive and Physical Functioning Questionnaire and the British Columbia Cognitive Complaint Inventory. However, it should be noted that subjective measures of cognition correlate poorly with objective measures.

Objective tests such as the MATRICS Consensus Cognitive Battery can be carried out, but often they are not widely available.

Management:

Medication

There is a complex relationship between the pharmacotherapy of depression and cognitive dysfunction. Depressed patients treated with antidepressants do better on neuropsychological tests of cognitive functioning than untreated patients. However, they still do not tend to fully ‘normalise’, and perform comparatively worse than healthy cohorts. Additionally, more severe cognitive deficits predict worse response to pharmacotherapy.

Cognitive dysfunction is one of the most common residual symptoms of depression in spite of treatment. This reflects the likelihood that currently available pharmacological approaches do not sufficiently improve cognitive impairment in depression.

The role of serotonergic dysfunction has been suggested as a possible contributory factor in cognitive impairment in major depression. In line with this, treatment with SSRIs, such as Sertraline leads to improvement in certain cognitive domains. However, serotonin–norepinephrine reuptake inhibitors (SNRIs) are associated with a greater improvement on neuro­cognitive functions than selective serotonin reuptake inhibitors (SSRIs).

Duloxetine has been shown to be superior in comparison to placebo in improving scores of verbal learning, memory, selective attention and executive functioning.

In a study involving depressed outpatients, those treated with bupropion had similar scores compared to healthy cohorts in neurocognitive tests. Venlafaxine, an SNRI, performed less well than bupropion but better than SSRIs. It has been suggested that cognitive enhancement in depression may occur relative to anti-depressants’ noradrenergic activity.

Vortioxetine is a novel antidepressant that has been shown to improve cognitive function in adults with major depressive disorder.

It works in a multimodal fashion, as an SSRI and also through direct effects on a number of serotonin receptors, where it acts as an antagonist (5HT3, 5HT1D, 5HT7), a partial agonist (5HT1B) or full agonist.

This is thought to improve cognitive function via increased activity in the prefrontal cortex and long-term potentiation in the hippocampus.

In elderly depressed patients, Vortioxetine was shown to improve performance in processing speed, executive functioning and attention, in comparison to treatment with duloxetine. Path analyses indicated that this is a direct effect, not due to an improvement in mood symptoms of depression.

Modafinil, a psychostimulant, has a well-established safety profile which makes it an attractive candidate for improving cognitive function. It has shown benefit in improving episodic memory in depressed individuals; however, it did not improve performance on tests of planning, accuracy or sustained attention.

Some treatments such as benzodiazepines, mirtazapine and tricyclic antidepressants negatively impact cognitive functioning. This should be taken into account if they are being used.

Similarly, patients should be made aware that opioid-based painkillers, alcohol and illicit drug use can all impair cognitive functioning.

Non pharmacological

Psychotherapy and brain-training approaches draw on the concept of neuroplasticity; the brain’s inherent ability to change in response to environmental stimuli. In line with this, several computerised exercises have been designed to provide a progressive challenge to participants’ cognitive abilities.

Specifically, computerised cognitive training results in improved perceptions of memory and memory functioning and improvements in sustained attention and performance among a range of tasks.
While cognitive behavioural therapy (CBT) has a good evidence base in alleviating depressive symptoms, it has also been shown to be effective in improving psychosocial functioning. It has been suggested that this may be mediated via its effects on cognition.

Similarly, newer forms of CBT such as cognitive rehabilitation therapy (CRT) have been shown to restore normal occupational and social functioning by compensating for the newly formed cognitive deficits.

Aspects of cognitive dysfunction have been shown to improve with exercise, an effect separate from its beneficial effect on mood.

An important aspect of depression treatment, especially if cognitive dysfunction is prominent, is supporting the patient’s return to work. It is common for a patient to have had a period of sick leave, and their return must be handled intelligently and sensitively, possibly including disclosure to the employer and a phased return.

Conclusion

Cognitive dysfunction in major depressive disorder effects risk of relapse as well as long-term functioning and quality of life. To improve these outcomes we must assess and treat the cognitive aspects of the illness.

Despite current treatments, the level of residual disability experienced by patients with major depressive disorder remains intolerably high. Hopefully, this will improve with the development of new pharmacological agents as well as psychological and cognitive training interventions that specifically target cognitive dysfunction.

References on request

• Dr Roisin McCafferty and Dr Sadaf Khan are Psychiatry Registrars at St Patrick’s University Hospital.
• Dr Declan Lyons, Consultant Psychiatrist, St Patrick’s University Hospital.