Cognitive Dysfunction in Depression: Is the immune system responsible?

When I was a clinical psychology trainee at Temple University in the United States, one of the most common complaints I heard from people battling depression was how much they struggled to think clearly, and how much these cognitive difficulties interfered with their ability to live their life. I am now in the final stage of my clinical psychology training at Massachusetts General Hospital and, unfortunately, our understanding of cognitive difficulties in depression is still quite limited. I will soon start as a postdoc at Massachusetts General Hospital’s Depression Clinical & Research Program and my goal is to advance our understanding of why cognitive difficulties emerge in depression so that we can develop effective treatments for this debilitating symptom of depression.

When people think about what depression entails, they usually think of states of ‘profound sadness’, ‘disengagement’ or ‘despondency’. Most people believe that they can, at least somewhat, understand how depression might feel — either because they happen to be one of the ‘one-in-five’ people with lived experience of depression or because they have had moments in their lives filled with sadness, disengagement, or despondency (albeit potentially without the severity and/or duration needed to meet formal criteria for depression). This focus on affect, such as sadness and despondency, as the defining features of depression, is, however, a relatively modern trend and prior to the 1850s, depression was considered “primarily a disorder of intellect, often — but not always — accompanied by sadness.” It is only in the last 20 years that researchers have, once again, seriously begun to consider why depressed people experience cognitive problems.

Is cognitive functioning really disrupted in depression?

That depressed people experience cognitive difficulties is well known. In fact, two of the nine diagnostic criteria that are used to establish a depression diagnosis are reflective of cognitive difficulties (diminished ability to think or concentrate, indecisiveness; psychomotor agitation/retardation) and between 30% and 80% of depressed individuals report cognitive problems, depending on the strictness of the criteria used. When evaluated, depressed individuals tend to display a broad range of cognitive problems, particularly on tests assessing: the capacity to rapidly process information; sustain attention; retain and recall information from memory; and executive functions (e.g., holding information in mind, impulse control, flexibly switching between different ways of responding).

And yet, throughout the twentieth century, these cognitive deficits were considered to be ‘epiphenomena’ of depressed mood that simply waxed and waned with the severity of depressed mood. During the last 20 years, researchers have started to focus on cognition in depression — not simply because of growing reason to believe that individuals who experience cognitive problems are more likely to experience impairment in their professional and interpersonal functioning — but because of mounting evidence those cognitive problems persist when depression is in remission.

A landmark 2019 review paper that pooled data from 11,882 individuals with remitted depression and 8,533 healthy controls found that individuals with remitted depression performed worse than their non-depressed peers across a wide range of tasks assessing processing speed, memory, attention, and executive function.

Of even greater concern, there is growing reason to suspect that depression may increase the risk for neurodegenerative disorders. A review in this area found that, in a majority of studies, a history of depression is associated with a two- to five-fold increased risk of developing dementia. This mounting body of evidence underscores the clinical importance of understanding why cognitive problems persist in remitted depression and the reason why depression increases the risk for dementia.

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Is inflammation the link between depression and cognitive difficulties?'

One plausible reason for why depressed individuals may experience persistent difficulties in cognitive function and increased risk for dementia is that their immune system is dysregulated.

The immune system acts — mobilizing immune and non-immune cells — to protect the body from threats from pathogens, like bacteria and viruses, and to promote healing when we are injured. In the process of destroying the invading pathogen, the immune response can sometimes cause a lot of collateral damage to nearby healthy tissue and so, it is critically important that the immune response is time-limited. However, some individuals experience chronic, low-grade inflammation (where parts of the immune system become persistently overly activated) in the absence of a pathogenic threat. This type of chronic, low-grade inflammation is associated with worse immune function and greater susceptibility to disease. Not only is chronic inflammation linked with cancer, cardiovascular disease, and neurodegenerative disorders, but 50% of all deaths are attributable to inflammation-related diseases.

Beyond the direct impact of chronic inflammation on human health, low-grade inflammation is known to affect brain regions and disrupt neurotransmission in ways that could explain why cognition is disrupted in depression. When the blood of depressed individuals is compared with non-depressed individuals, researchers consistently find that a sizeable minority — approximately 27% — of depressed individuals exhibit elevated levels of immune biomarkers (e.g., increased C reactive protein) that are indicative of chronic, low-grade inflammation (an important topic that has been discussed previously in Inspire the Mind before, here and here).

Some of my own research has sought to shine a light on how inflammation could be linked with cognitive problems in depression. In a population-representative sample of almost 44,000 Dutch adults, we found that it was depressed individuals who also exhibited inflammation (based on blood levels of C reactive protein) who performed worse on a test of executive function. Of concern, a similar pattern of results was also evident in two independent studies of U.S. and Dutch adolescents, suggesting that a deleterious effect of inflammation on cognitive abilities can even be detected early in life.

A limitation of this research is that it is associational in nature, meaning that it is difficult to know whether inflammation is causally related to cognitive problems in depression. For instance, there are multiple risk factors for depression — dysregulated sleep, poor diet, stress, physical inactivity, increased weight, and substance abuse — that are also risk factors for inflammation and cognitive difficulties.

And so, is it inflammation that causes cognitive problems in depression, or is it simply a risk marker for poor diet, which is the true cause? Or are all of the above caused by poor sleep? More research, especially research using experimental designs that are better equipped to make causal claims, is needed to identify the true cause(s) underlying cognitive problems in depression.

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What can we do to treat these cognitive difficulties?

Treatment options for depressed individuals seeking relief from cognitive problems, such as poor concentration, are extremely limited, although a range of treatments are currently being explored.

Physical exercise, brain training exercises, and repetitive transcranial magnetic stimulation are non-pharmacological treatments that have some initial support for their pro-cognitive effects. There is currently one pharmacological treatment (vortioxetine) that has been approved by the United States Food and Drug Administration for the treatment of cognitive problems in depression and initial results suggest that it may help deliver pro-cognitive effects for depressed individuals.

However, mixed results so far have been observed and the capacity of vortioxetine to exert persistent benefits beyond the short windows of clinical trials (the majority of which lasted 8 weeks) is unknown. Novel pharmacological treatments are currently being developed and trialled (excellent review available here) but the speed by which new efficacious treatments are discovered may be limited by a lack of mechanistic insight as to treatment targets.

In conclusion, there has been considerable progress over the last 20 years in recognizing the cognitive difficulties depressed individuals experience. We now have a better understanding of how they disrupt all dimensions of people’s social and professional life and there is mounting evidence that not only do these difficulties persist when depression is in remission, but depression is linked with an increased risk for neurodegenerative disorders. Now that we recognize that these cognitive problems exist in depression, we must work to understand why they emerge so that we can develop tools to treat them. There is strong reason to believe that a dysregulated immune system could be responsible for these cognitive difficulties in depression and experimental research is now needed to offer mechanistic insight as to the origins of cognitive dysfunction in depression so that they can be used as potential targets for treatment development.