Neurobiological Mechanisms of Susceptibility to Estradiol Fluctuation in Female Adolescents at Risk of Suicide: An Experimental Approach
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 50
- 试验地点
- 2
- 主要终点
- Irritability Symptoms (average Brief Irritability Test (BITe) across each 8-week condition)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 12 Years 至 16 Years（Child）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •Personal history of metabolic or autoimmune disease
- •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
研究组 & 干预措施
Kurvelo®, then Placebo COC
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.
干预措施: Kurvelo (Drug)
Kurvelo®, then Placebo COC
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.
干预措施: Placebo COC (Drug)
Placebo COC, then Kurvelo®
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).
干预措施: Kurvelo (Drug)
Placebo COC, then Kurvelo®
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).
干预措施: Placebo COC (Drug)
结局指标
主要结局
Irritability Symptoms (average Brief Irritability Test (BITe) across each 8-week condition)
时间窗: 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.
次要结局
- 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))