PROJECT SUMMARY: Major Depressive Disorder (MDD) is a leading cause of disability, morbidity, and
mortality across the lifespan and poses a particularly severe public health problem in late life. Late-life depression
(LLD) is highly recurrent, can become chronic, and is often difficult to treat. Antidepressant treatment is often
ineffective in this population because of the presence of neurocognitive factors including slow processing speed
(PS), executive dysfunction (ED), and cerebrovascular disease (CVD) that interfere with treatment. It is crucial,
therefore, that we develop interventions that address antidepressant non-response and dramatically improve the
quality of life of millions of vulnerable older adults. We recently determined that an important cause of non-
response in this population is impaired expectancy effects, which in turn are compromised by slow speed of
processing. We propose, therefore, that antidepressant non-response in older adults with PS deficits is caused
by expectancy failure and that targeting PS deficits prior to antidepressant treatment will restore the capacity to
form expectations thereby improving antidepressant treatment response. An excellent candidate for improving
PS is computerized cognitive training (CCT), i.e., exercises that target, train, and strengthen specific cognitive
processes with the use of structured drills and repeated practice. To test our expectancy-processing speed
model, 100 depressed adults age 60 and over with PS deficits will be recruited. Participants will be randomized
to either CCT or control (Solitaire) for 4 weeks. Both conditions will train for 25 minutes per day, 7 days per week.
At the conclusion of this four-week period, patients will be randomly assigned to high versus low expectancy
treatment conditions. Patients assigned to the low expectancy condition will be told they will receive either
placebo or escitalopram when in fact they will receive escitalopram for eight weeks. Patients assigned to the
high expectancy condition will be told they will receive escitalopram for eight weeks. Neuropsychological
assessment will occur at baseline and weeks 4 and 12 whereas MRI scans will be conducted at baseline and
week 4. Clinical assessments will be conducted biweekly throughout the study. The goals of this study are to 1)
To determine whether PS mediates the relationship between CCT and expectancy, and 2) To compare endpoint
depression scores as a function of CCT and expectancy conditions. The novel experimental therapeutics
approach taken in this proposal cuts across several research themes (prevention and translation) and addresses
many of the challenges (digital technology and neural circuits) elaborated in NIMH’s Strategic Plan for mental
health research in the 22st century. Consistent with NIMH goals, it also develops strategies for tailoring existing
interventions to optimize outcomes and elucidates the mechanism by which antidepressant treatment in LLD can
be restored.
