Purpose: Risk of severe psychopathology increases dramatically during adolescence, especially for females. Changes in ovarian steroids across the menstrual cycle produce windows of vulnerability to mood disturbances, particularly during the abrupt withdrawal of estradiol (E2) and progesterone (P4) prior to menses onset. Irrefutable evidence links stress with affective symptoms, potentially mediated by E2-related modifications of frontolimbic connectivity and prefrontal gamma-aminobutyric acid (GABA) inhibitory signaling. The primary objective of this project is to empirically test the impact of E2 and P4 change on vulnerable brain networks associated with irritability and other depressive symptoms in female adolescents at risk of suicide. Participants: The investigators will enroll 50 female adolescents ages 12-16 who are at risk of suicide (i.e., moderate depressive symptoms), and are eligible to receive oral contraceptives and undergo MRI imaging. Procedure: Using a randomized, placebo-controlled, cross-over design, participants will be studied under two conditions: 8 weeks of E2 and P4 stabilization (continuous combined oral contraceptive (COC) to prevent perimenstrual withdrawal) and 8 weeks of placebo, with a 1-month washout after each condition. Each condition will include: 1) daily samples of E2 and P4 urinary metabolites, 2) daily symptom ratings(e.g., irritability, negative affect and suicidal thoughts and behaviors (STBs)), and 3) a neuroimaging session with MRI and magnetic resonance spectroscopy (MRS).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
50
Kurvelo®: 30mcg ethinyl estradiol (EE) and 0.15mg levonorgestrel (LNG), a synthetic estrogen and progestin, respectively.
Placebo pills from the Kurvelo® packages (cut from package to maintain blinding).
Biomedical Research Imaging Center (BRIC) at UNC
Chapel Hill, North Carolina, United States
Carolina Crossing
Chapel Hill, North Carolina, United States
Irritability Symptoms (average Brief Irritability Test (BITe) across each 8-week condition)
The Brief Irritability Test (BITe) is a 5-item self-report instrument developed to measure irritability as a distinct emotional construct, defined by increased susceptibility to frustration, annoyance, and anger in response to minimal provocation. Participants rate each item (e.g., feeling grumpy, easily annoyed, on edge) using a 6-point Likert scale ranging from Never (1) to Always (6). Total scores range from 5 to 30, with higher scores indicating greater irritability. BITe total score is calculated as the sum of the five items.
Time frame: Average Brief Irritability Test (BITe) will be collected daily across the complete study duration (week 1 -24).
Irritable behavior (point subtraction aggression paradigm (PSAP)
The Point Subtraction Aggression Paradigm (PSAP) is a computerized task measuring reactive aggression in response to provocation. Participants believe they compete with an opponent to earn points. They may earn points, subtract a point from the opponent (aggressive response), or activate protection. Aggression is quantified as the number of point-subtraction responses, with higher values indicating greater aggressive behavior. Scores range from 0 to the total number of opportunities/response trials within the task session, depending on task duration and provocation frequency.
Time frame: During the neuroimaging session (inside the scanner) at week 8 (1 time point during the last week of condition 1) and week 20 (1 time point during the last week of condition 2)
medial prefrontal cortex GABAergic activity
Scanning will be conducted using a 7 Tesla Siemens MAGNETOM scanner (Siemens, Erlangen, Germany) with a Nova Medical 32-channel receive array head coil to obtain high-quality spectra from the medial prefrontal cortex (mPFCpref, 20 × 20 × 20 mm). The MRS voxels processed within the mPFC will be passed to the metabolite quantification process to quantify the level of gamma-aminobutyric acid (GABA).
Time frame: During the neuroimaging session (inside the scanner) at week 8 (1 time point during the last week of condition 1) and week 20 (1 time point during the last week of condition 2)
Functional connectivity between amygdala and frontal network (medial, ventrolateral, ventromedial prefrontal cortex).
Connectivity strength (-1 to +1) between the amygdala and frontal network (medial, ventrolateral, ventromedial prefrontal cortex).
Time frame: During the neuroimaging session (inside the scanner) at week 8 (1 time point during the last week of condition 1) and week 20 (1 time point during the last week of condition 2)
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