Teen Vulnerability to Irritability: Brain and Estrogen Changes

NCT07544966 | Not Yet Recruiting Phase 4 FDA Drug

• 1 other identifier: 25-2243
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 2

Brief Summary

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).

Conditions

Depression - Major Depressive Disorder; Irritability

Outcome Measures

Primary Outcomes (1)

• 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.

  Average Brief Irritability Test (BITe) will be collected daily across the complete study duration (week 1 -24).

Secondary Outcomes (3)

• Irritable behavior (point subtraction aggression paradigm (PSAP)

  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

  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).

  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)

Study Arms (2)

Kurvelo®, then Placebo COC

ACTIVE COMPARATOR

Participants will receive 8-weeks of continuous combined oral contraceptive (COC; Kurvelo®: 30mcg ethinyl estradiol (EE) and 0.15mg levonorgestrel (LNG), a synthetic estrogen and progestin, respectively). A 4-week washout period will then occur after which participants will receive 8-weeks of continuous placebo combined oral contraceptive (COC) pills.

Drug: Kurvelo; Drug: Placebo COC

Placebo COC, then Kurvelo®

PLACEBO COMPARATOR

Participants will receive 8-weeks of continuous placebo combined oral contraceptive (COC) pills. A 4-week washout period will then occur after which participants will receive 8-weeks of continuous combined oral contraceptive (COC; Kurvelo®: 30mcg ethinyl estradiol (EE) and 0.15mg levonorgestrel (LNG), a synthetic estrogen and progestin, respectively).

Drug: Kurvelo; Drug: Placebo COC

Interventions

Kurvelo DRUG

Kurvelo®: 30mcg ethinyl estradiol (EE) and 0.15mg levonorgestrel (LNG), a synthetic estrogen and progestin, respectively.

Kurvelo®, then Placebo COC; Placebo COC, then Kurvelo®

Placebo COC DRUG

Placebo pills from the Kurvelo® packages (cut from package to maintain blinding).

Kurvelo®, then Placebo COC; Placebo COC, then Kurvelo®

Eligibility Criteria

• Age: 12 Years - 16 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• Assigned female sex at birth
• Between the ages of 12 and 16
• Be eligible to receive a low-dose oral contraceptive (COC)
• Post-menarche. Participants will be post-menarche to avoid potential OC-related effects on bone growth prior to menarche
• At risk of suicide. To be considered "at suicide risk" participants must meet the following-Mood and Feelings Questionnaire score of ≥ 27

You may not qualify if:

• Personal history of metabolic or autoimmune disease
• Epilepsy
• Endometriosis
• Cardiovascular, gastrointestinal, hepatic, renal, or pulmonary disease Diabetes mellitus with vascular disease
• Uncontrolled hypertension
• Liver tumors (benign or malignant) or liver disease
• Undiagnosed abnormal uterine bleeding
• Headaches with focal neurological symptoms or migraine with aura
• Known or suspected pregnancy
• Current or past deep vein thrombosis or pulmonary embolism
• Cerebrovascular disease Coronary artery disease
• Thrombogenic valvular or rhythm disease (e.g., subacute bacterial endocarditis with valvular disease, atrial fibrillation)
• Inherited or acquired hypercoagulopathies
• Current or history of breast cancer or other hormone-sensitive malignancy
• Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Foundation of Hope for the Research and Treatment of Mental Illness: collaborator

Study Sites (2)

Biomedical Research Imaging Center (BRIC) at UNC

Chapel Hill, North Carolina, 27517, United States

Location

Carolina Crossing

Chapel Hill, North Carolina, 27517, United States

Location

Study Officials

• Elizabeth Andersen, PhD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elizabeth Andersen, PhD

CONTACT

(919) 843-8084; Elizabeth_Andersen@med.unc.edu

Natalie Deeb

CONTACT

nmdeeb@email.unc.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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 hormone 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 STBs) 3. a neuroimaging session.

Study Record Dates

• First Submitted: February 2, 2026
• First Posted: April 22, 2026
• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2029
• Last Updated: April 22, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)