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 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.

At the screening evaluation, informed consent for the screening evaluation is obtained. Participants subsequently undergo a psychiatric clinical interview using the Structured Clinical Interview Diagnostic for DSM-V (SCID-V), 24- item Hamilton Rating Scale for Depression (HRSD), Clinical Global Impressions Scale - Severity (CGI-Severity), Cumulative Illness Rating Scale for Geriatrics (CIRS-G) and Antidepressant Treatment History Form (ATHF) to document depression diagnosis, severity, and medical comorbidity. WAIS-IV Digit Symbol Coding will be completed to determine whether the patient meets inclusion criteria for PS (\>1 SD on age adjusted norms). If the patient is eligible for study entry, participation in the research protocol will be discussed and informed consent will be obtained. After consent is obtained, patients will receive a comprehensive baseline neuropsychological assessment and MRI (structural, resting state, and DTI). Neuropsychological assessments include MMSE, WAIS-IV Coding, NIH Toolbox Cognition Battery, NIH Supplement Auditory Verbal Learning Test (Rey), Trail Making Test (Part A and B), Stroop Color-Word Test, and The Letter and Animal Naming Test. These measures will capture global cognitive functioning, processing speed, attention, and response inhibition, and verbal fluency. After testing, patients will be randomized to either CCT or active control for 4 weeks (25'/day, 7 days/week). Patients randomized to CCT will complete seven 25-minute sessions per week for 4 weeks using BrainHQ's Double Decision in the experimental condition (a processing speed exercise) and BrainHQ solitaire in the control condition. At the conclusion of this four-week period, patients will complete a second neuropsychological assessment and a second fMRI (to determine change in resting-state BOLD signal in the CCN). Patients will then 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 escitalopram when in fact they will receive escitalopram for eight weeks. Patient assigned to the high expectancy condition will be told and they will receive escitalopram for eight weeks. Expectancy is measured at baseline and after informing patients of their randomization status. The difference between their pre and post randomization expectancy regarding treatment improvement is the expectancy effect. At the conclusion of the eight-week clinical trial, the difference in antidepressant response observed between the open and placebo-controlled medication treatments is a measure of the expectancy contribution to outcome. Neuropsychological assessment will occur again at the conclusion of the escitalopram trial (week 12). Clinical assessments will be conducted biweekly throughout the study.

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 21st 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.