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

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(Drug information on 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