Abstract
Comorbid posttraumatic stress disorder and major depressive disorder (PTSD + MDD) is the most common pathological response to trauma, yet despite their synergistic detriment to health, knowledge regarding the neurobiological mechanism underlying PTSD + MDD is extremely limited. This study proposes a novel model of PTSD + MDD that is built on biological systems shown to underlay PTSD + MDD and takes advantage of ketamine’s unique suitability to probe PTSD + MDD due to its rescue of stress-related neuroplasticity deficits. The central hypothesis is that changes in PTSD + MDD clinical symptoms are associated with functional connectivity changes and cognitive dysfunction and that ketamine infusions improve clinical symptoms by correction of functional connectivity changes and improvement in cognition. Participants with PTSD + MDD (n = 42) will be randomized to receive a series of six ketamine infusions or saline-placebo over three weeks. Pre/post-measures will include: (1) neuroimaging; (2) cognitive functioning task performance; and (3) PTSD, MDD, and rumination self-report measures. These measures will also be collected once in a trauma-exposed group including PTSD-only (n = 10), trauma-exposed-MDD (TE-MDD; n = 10), and healthy controls (HC, n = 21). Successful completion of the study will strongly support the concept of a biologically-based model of PTSD + MDD. The results will (1) identify functional imaging signatures of the mechanisms underpinning pathological responses to trauma, (2) shift focus from mono-diagnostic silos to unified biological and behavioral disease processes and, thus, (3) inform interventions to correct dysregulation of PTSD + MDD symptom clusters thereby supporting more precise treatments and better outcomes.
Highlights
Comorbid posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) represents a major public health burden as it is associated with poor clinical outcomes and substantial human disability
Aberrant connections between the left dorsolateral PFC (dlPFC), right ventromedial PFC (vmPFC) and hippocampus are thought to be involved with incomplete regulation of threat-related cues and heightened stress responsivity in individuals with PTSD+MDD
Upon successful completion of this research study, we expect to establish a model of PTSD + MDD based on neurocognitive, neuroimaging, and behavioral measures that will characterize the pathology at baseline in a heterogeneous group of trauma-exposed individuals and following treatment response to ketamine in a more narrow group of participants with PTSD + MDD
Summary
Comorbid posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) represents a major public health burden as it is associated with poor clinical outcomes and substantial human disability. Our proposal suggests a “vicious cycle” model of PTSD + MDD that incorporates dysfunctional glutamatergic signaling, functional dysconnectivity, cognitive deficits, and behavioral symptoms to perpetuate a state of chronic stress (see Figure 1). This model unifies a diverse literature and highlights the biological mechanisms underlying this common but complex clinical presentation. Aberrant connections between the left dlPFC, right vmPFC and hippocampus are thought to be involved with incomplete regulation of threat-related cues and heightened stress responsivity in individuals with PTSD+MDD Taken together, it appears that frontal asymmetry in PTSD + MDD accounts for the inability of the PFC and hippocampus to effectively regulate the amygdala in a memory-guided and context-dependent manner. The proposed research provides a strategy to characterize pathological responses to trauma and will permit determination of the validity of our hypotheses
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