Teen Vulnerability to Irritability: Brain and Estrogen Changes

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

Interventions

DRUG

Kurvelo

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

DRUG

Placebo COC

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

Sponsors & Collaborators

• Foundation of Hope for the Research and Treatment of Mental Illness

  collaborator UNKNOWN

• University of North Carolina, Chapel Hill

  lead OTHER

Principal Investigators

• Elizabeth Andersen, PhD · University of North Carolina, Chapel Hill

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

12 Years

Max Age

16 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2026-06-01

Primary Completion

2028-04-30

Completion

2029-04-30

FDA Drug

Yes

Countries

• United States

Study Locations