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

Recent work shows that deep white matter hyperintensities in geriatric patients with MDD were located in brain regions associated with emotion regulation and executive function. Greater lesion volumes correlated with impairment in executive function.²³ Reduced hippocampal volume in elderly patients with MDD is also associated with greater cognitive dysfunction, especially impairment in executive function and memory.

While some evidence suggests that reduced hippocampal volume is related to illness duration, other studies find that patients with an onset of MDD after age 50 have more pronounced hippocampal volume reductions than MDD patients with earlier onset. In addition, both hypercortisolemia and a genetic profile that includes certain alleles of the serotonin transporter promoter gene have been associated with reduced hippocampal volume.²⁷

Patients with an onset of MDD after age 50 and MRI scan evidence of extensive deep white matter hyperintensities may represent a distinct subset of MDD patients whose illness results from generalized vascular disease.²⁴ The vascular depression subset of patients has a much higher rate of co-occurring general medical conditions, such as cardiovascular disease and diabetes, and patients in this subset are more likely to develop dementia.^10,28 While many believe that a vascular disease may play a causal role in a subset of the elderly with MDD, there is a lack of consensus about the specific criteria that define vascular depression. More recent work has de-emphasized the age of onset, since vascular disease clearly occurs in younger adults as well as in older adults. Alexopoulos¹⁴ emphasizes executive dysfunction as the cardinal feature, and Taylor and colleagues²⁹ focus on MRI evidence of vascular pathology. More work is needed to establish valid and reliable criteria for vascular depression.

It is also known that MDD predisposes to Alzheimer disease, and some forms of MDD may be a prodromal symptom of Alzheimer disease.³⁰ A provocative recent study found that a high ratio of plasma amyloid-b peptide 40 (Ab40) to Ab42 in elderly patients with depression was associated with a high rate of cognitive dysfunction. Since the Ab40 to Ab42 ratio is associated with the risk of Alzheimer disease, these investigators propose that amyloid-associated MDD may be a precursor to Alzheimer disease and a distinct form of MDD.³¹ Follow-up studies are needed to confirm or reject this hypothesis.

In general terms, moderate to severe cognitive dysfunction in geriatric patients falls into 3 groups:

• Vascular depression characterized by disproportionately impaired executive function and apathy
• Alzheimer depression characterized by profound recent memory impairments and disinhibition
•“Pseudodementia” characterized by profound but reversible recent and remote memory impairments and generally preserved attention and concentration in the setting of a poorly motivated demeanor

Whether these groups truly represent distinct and narrower disorders or diseases remains to be determined.

Clinical significance of cognitive dysfunction for treatment of MDD
Most antidepressant treatment studies find that cognitive function improves with treatment in younger adults, although processing speed may improve to a greater extent with treatment response while memory impairments may be more likely to persist.¹⁹ Fluoxetine(Drug information on fluoxetine) and paroxetine improved memory and attention in a large study of 242 elderly patients with MDD.³² Imipramine and fluvoxamine(Drug information on fluvoxamine) also improved measures of attention and processing speed.³³ However, neither nortriptyline(Drug information on nortriptyline) nor paroxetine(Drug information on paroxetine) improved cognition in a study by Nebes and colleagues³⁴ of elderly patients with depression: patients showed substantial residual posttreatment cognitive impairment.