Negative Valence Brain Targets and Predictors of Anxiety and Depression Treatment

Internalizing psychopathologies (IPs) involving depression and anxiety are among the most
prevalent, costly and disabling illnesses. Treatments for IPs are available but the extent to
which individual patients respond is quite heterogeneous. Little information exists,
particularly in the biological domain, which helps to explain individual differences in
treatment response. IPs share similar patterns of dysfunction within the Fronto-Limbic Affect
Regulation and Emotional Salience (FLARES) brain circuit, and two commonly used, 'gold
standard' treatments - selective serotonin reuptake inhibitors (SSRIs) and cognitive
behavioral therapies (CBTs) - are equally effective for both anxiety and depressive
disorders, and appear to change brain activity in the same areas within the FLARES circuit.
The overarching goal of the project is delineate what are common versus specific FLARE brain
targets for SSRI and CBT and identify specific aspects of FLARE dysfunction that might better
predict response to both and to a specific modality of treatment. This experiment integrates
emotion and its interaction with cognition across several stages of emotional experience,
encompassing studies that probe sensitivity to acute and potential threat and automatic and
volitional forms of affect regulation in relation to the FLARES brain network.

We will enroll 200 patients presenting to our Mood and Anxiety Disorders Program seeking
treatment for disabling 'anxiety, worry, depressed mood' (IPs, including those characterized
as Not Otherwise Specified) and randomize them to a 12-week course of SSRI or CBT.
Dimensional, transdiagnostic negative valence systems (NVS) constructs, including FLARES
function, will be measured before and after each treatment. Specifically, the project will
examine 2 Specific Aims: 1) Where and how do SSRI and CBT treatments exert their effects on
NVS constructs?; and 2) Which NVS construct can predict the likelihood of success from SSRI
and CBT treatment? Such findings can be used to guide the right patients to the right
treatments with the highest likelihood of success. They also elucidate a
pathophysiologically-driven mechanistic model of where and how treatments work in the brain
and thus hasten the development of new treatments that target the underlying pathophysiology
across internalizing conditions.