2/2 Harnessing Hormonal Variation to Probe Neural Mechanisms and Optimize CBT Outcomes for OCD

Cognitive behavioral therapy involving exposure and ritual prevention (EX/RP) is a first-line treatment for
obsessive compulsive disorder (OCD). Despite its efficacy, it remains unclear how EX/RP influences the neural
mechanisms of the fear and anxiety brain networks to yield clinical improvement. Moreover, data indicate that
EX/RP outcomes may be more variable in women. Studies in rodents and healthy humans show that estrogen
(E) affects the brain regions involved in fear learning, extinction, and extinction retention (the fear extinction
network); E also has been shown to enhance extinction memory retention. In addition, the structure and
connectivity of these same brain regions predict OCD treatment outcomes, including EX/RP. These and other
data lead to the hypothesis that this Collaborative R01 will begin to test: that delivering EX/RP to women with
OCD during high E states improves extinction memory retention via enhanced engagement of the fear
extinction brain network, resulting in better clinical outcomes. We will also explore whether EX/RP-induced
extinction processes differ between women and men. Our specific aims are to examine: 1) the impact of
menstrual-cycle phase and sex on extinction-induced neural responses pre and post EX/RP; 2) the impact of
menstrual-cycle phase and sex on EX/RP outcome; and 3) the relationship between OCD symptom change
and EX/RP-induced neuronal changes. Our long-term goal is to understand how sex as a biological variable
affects specific neural processes and hence EX/RP treatment outcomes. To achieve our aims, 120 adults with
OCD – 80 natural cycling women and 40 men--will be recruited across two sites: The University of
Pennsylvania (UPenn) and the New York State Psychiatric Institute/Columbia University (NYSPI). Through a
subcontract, New York University (NYU) will provide expertise in the fMRI imaging paradigm that will be used
as an experimental tool to probe the fear extinction brain network. Study participants will complete fMRI
scanning before and after receiving manualized EX/RP. The EX/RP protocol will consist of 8 (90 minute) daily
sessions comprised of two introductory and six exposure sessions. Women will be randomly assigned to
complete EX/RP during either: a) the first 10 days after the start of menstruation (early follicular phase), when
E levels are low; or b) days 12-22 of the menstrual cycle (late follicular, early luteal phase), when E levels are
elevated. OCD symptoms and E levels will be measured at multiple time points. This design will allow us to
study the effects of hormonal variation during the menstrual cycle and sex on the fear extinction network and
on EX/RP outcome. The results will elucidate treatment mechanisms and could lead to personalized treatment
recommendations for women with OCD.

Grant Number: 5R01MH121608-05
NIH Institute/Center: NIH
Principal Investigator: Lily Brown