Antidepressant Response in Older Adults With Comorbid PTSD and MDD

In the Investigator's ongoing studies of Posttraumatic Stress Disorder (PTSD) in older adults, it has been found that older adults with PTSD frequently meet the criteria for comorbid Major Depressive Disorder (MDD). Moreover, relative to trauma-exposed healthy controls (TEHCs), elders with PTSD manifest executive function deficits, fatigability, and mobility and physical function deficits that are consistent with what the investigator has observed in depressed older adults. Yet, the investigator has found that very few older adults with combined PTSD/MDD have received appropriate antidepressant treatment for their condition. These findings give rise to the questions of (1) how effective is antidepressant treatment for depressive symptoms in the context of PTSD/MDD and (2) are cognitive and physical function deficits in PTSD/MDD patients reversible with effective antidepressant treatment?

Chronic PTSD in older adults leads to increased risk of mortality from cardiovascular disease, metabolic syndrome, diabetes mellitus, and ulcerative gastrointestinal disease. PTSD appears to promote aging-associated syndromes such as frailty, and older patients with PTSD exhibit faster cognitive decline and have twice the risk of dementia compared to individuals without PTSD. In addition, laboratory studies report accelerated biological signatures of aging in PTSD patients, including shortened leukocyte telomere length, increases in pro-inflammatory cytokines, and increased oxidative stress. PTSD is associated with similar anatomical brain changes to those occurring with cognitive aging, including bilateral hippocampal volume reductions, specifically affecting the dentate gyrus (DG) and CA3 subregion, and increased microvascular lesions (white matter hyperintensities \[WMH\]). These observations suggest that the adverse health and functional outcomes associated with chronic PTSD in older patients may be explained by a deleterious interaction between pathophysiologic changes underlying PTSD and the biology of aging, the end result of which is to accelerate senescence throughout the body and particularly in the brain. However, no prior study has explicitly tested this hypothesis by examining indices of aging in older adults with and without PTSD. In our ongoing IRB #7489, The investigator hypothesize that chronic PTSD, over and above other contributing factors, accelerates biological aging in the brain and body, leading to adverse behavioral consequences such as frailty and cognitive decline. To test these hypotheses, 150 individuals are being recruited who are aged≥50and diagnosed with PTSD. A control group of 150 age-, sex-, and trauma exposure-matched subjects without PTSD are being recruited and assessed. Included subjects undergo comprehensive neuropsychological assessment and cerebral blood volume functional magnetic resonance imaging (CBV-fMRI) to assess regional hippocampal metabolic activity and function. Structural MRI is performed to quantify WMH, regional brain volume, and cortical thickness while resting-state fMRI measures functional connectivity within hippocampal networks. PTSD subjects and controls are compared on measures of aging within the following domains: neural (DG CBV, WMH, morphology), cognitive (processing speed, memory, executive function, pattern separation), somatic (peripheral inflammatory markers, leukocyte telomere length, and measures of oxidative stress), and behavioral (grip strength, gait speed, fatigue levels). By elucidating the interaction of chronic PTSD with aging processes, data from this project may contribute to the development of rationally designed, personalized, and age-appropriate novel treatments. Interim analyses of PTSD subjects in this study demonstrate a high degree of comorbidity with MDD. Among participants with PTSD enrolled to date, 67.1% meet the criteria for MDD and the mean Hamilton Rating Scale for Depression (HRSD) is 18.1. The most prominent cognitive differences observed to date in our study between PTSD and TEHC subjects is executive dysfunction, which is common in late-life depression. PTSD subjects have dramatically increased fatigability and prevalence of frailty criteria compared to TEHCs, abnormalities which are also frequently seen in our older MDD samples. Yet, the investigator has found that less than 25% of these individuals are currently receiving an adequate dose and duration of first-line pharmacotherapy for MDD, while only one-third report any past medication treatment. These data raise the question of whether patients with combined PTSD/MDD could benefit from adequate antidepressant medication treatment and to what degree their cognitive and physical function deficits would be reversible with this therapy.