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NCT Number: NCT07544966

Teen Vulnerability to Irritability: Brain and Estrogen Changes

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).

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Key information

Conditions

Depression - Major Depressive Disorder Irritability

Age range

12 year–16 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 4

Primary location

Biomedical Research Imaging Center (BRIC) at UNC, Chapel Hill, North Carolina, United States

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Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Exclusion criteria

  • 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
  • Personal or first-degree relative with breast cancer or thromboembolic events

Treatment and study plan

Kurvelo

Drug

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

Placebo COC

Drug

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

Primary outcomes

  1. Irritability Symptoms (average Brief Irritability Test (BITe) across each 8-week condition)

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

    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.

Secondary outcomes

  1. Irritable behavior (point subtraction aggression paradigm (PSAP)

    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)

    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.

  2. medial prefrontal cortex GABAergic activity

    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)

    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).

  3. Functional connectivity between 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)

    Connectivity strength (-1 to +1) between the amygdala and frontal network (medial, ventrolateral, ventromedial prefrontal cortex).

Study contacts

Contact information is provided by the study sponsor or research team.

Elizabeth Andersen, PhD

CONTACT

[email protected]

(919) 843-8084

Natalie Deeb

CONTACT

[email protected]

Sponsors and collaborators

Lead sponsor

University of North Carolina, Chapel Hill

Other

Collaborators

  • Foundation of Hope, North Carolina

Registry information

Official study title

Neurobiological Mechanisms of Susceptibility to Estradiol Fluctuation in Female Adolescents at Risk of Suicide: An Experimental Approach.

Acronym: TeenVIBE

Important dates

Study start
2026
Primary completion
2028
Study completion
2029
First posted
Apr 22, 2026
Registry last updated
Apr 22, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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