PROJECT SUMMARY
Nearly half of individuals with Major Depressive Disorder (MDD) have a comorbid anxiety disorder (AD), which
is associated with treatment resistance, morbidity, and mortality. Yet, the underlying process dysfunctions that
characterize comorbid AD and MDD (AD-MDD) are poorly understood. The premise of this proposal is that
exaggerated threat sensitivity in general, and potential threat vs acute threat in particular differentiates AD-
MDD from MDD. This project builds on our pilot data showing that people with AD-MDD have exaggerated
threat sensitivity compared to those with MDD across several levels (self-report, startle electromyogram
[EMG], functional magnetic resonance imaging [fMRI] and behavioral), and aims to delineate and quantify the
neural circuit dysfunctions underlying threat sensitivity (potential and acute threat) in AD-MDD relative to MDD
and AD. If confirmed, the proposed studies would provide behavioral, neural, and electrophysiological
processes that can be used for both quantitative severity assessment and as a treatment target for AD-MDD.
Whereas both AD-MDD and MDD individuals show blunted reward and interoceptive/salience processing, only
AD-MDD show exaggerated threat sensitivity. However, the neural basis for threat sensitivity is complex and
consists of both potential threat (PT; “anxiety”) and acute threat (AT; “fear”) related processes, which involve
different circuits, that have not been examined in AD-MDD. This proposal focuses on this crucial gap to better
delineate the neural circuitry. Benzodiazepines are common anxiolytics which are GABAergic agonists and
reduce PT rather than AT. We propose to use the benzodiazepine Lorazepam, as an acute pharmacological
probe to causally study threat circuitry and delineate neural mechanisms contributing to AD-MDD, MDD and
AD. This proposal's aims focus on: (1) probing differences in PT and AT at multiple levels of analysis between
AD-MDD, MDD and AD; and (2) determining how pharmacological manipulation targeting PT differs in its acute
neurological, electrophysiological and behavioral effects on AD-MDD vs MDD vs AD. We propose: (1) the
interaction of increased threat sensitivity and reward/salience blunting contributes to unique neural
and behavioral responses that are associated with greater disease burden for AD-MDD than MDD; and
(2) this sensitivity in AD-MDD is mechanistically related to specific neural activation changes in
targetable circuits associated with PT. This mechanistic R01 uses a benzodiazepine within an experimental
medicine model approach to causally modulate the threat processing system and associated circuits in AD-
MDD (N=55), MDD (N=55), and AD (N=55). In a crossover design, participants will receive a single 1mg dose
of Lorazepam and Placebo and complete threat tasks that delineate PT/AT during eyeblink startle EMG (Aim
1/3) and fMRI (Aim 2/3). The ultimate goal of this research is to establish treatment targets for AD-MDD for
novel interventions and provide evidence for the separation of MDD and AD-MDD in future clinical trials.
