Hormonal Sensitivity and Brain Function: Do Oral Contraceptives Distort Serotonergic Brain Signaling?
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Change in neostriatal, neocortical, and hippocampal 5-HT4R brain binding from baseline to follow-up measured with Positron Emission Tomography (PET) in active vs. placebo group
研究概览
简要总结
Large register based work has shown that starting on oral contraceptives (OCs) is associated with an increased risk of developing depressive episodes. It is not known why this is, but changes in the serotonergic brain system might play a role. Intriguingly, in cross-sectional work, the investigators have demonstrated a lower level of the serotonin 4 receptor globally in the brain of healthy women using oral contraceptives compared to non-users. The order of magnitude of this difference is comparable to what has been observed in depressed individuals relative to healthy controls. In this study, the investigators will apply a longitudinal design to determine if starting on oral contraceptives induces a reduction in the serotonin 4 receptor in healthy women and whether such changes are related to potential changes in measures of cognition as well as mood/affect and sexual desire.
The study is a single-blind randomized placebo-controlled trial with a 3-month intervention paradigm of either Femicept (2nd generation combined oral contraceptive) or placebo. The investigators will include participants until 20 women have completed the study in each arm. Participants will go through an investigational program, including PET and MR brain scans and neuropsychological testing, before starting on the treatment and again during the third pill cycle. To capture changes in mood/ and sexual desire, the participants will complete daily questionnaires during the baseline menstrual cycle and during third pill cycle.
A linear latent variable model will be used to evaluate if OC use induces changes in the serotonin 4 receptor level and such changes will be correlated to changes in secondary outcomes (i.e., cognitive and psychometric measures).
详细描述
Background:
More than 100 million women worldwide use combined oral contraceptives (OCs), i.e. the most common types that combine estrogen and gestagen. Register-based epidemiological work has recently shown that starting on hormonal contraceptives is associated with an increased risk of developing a depressive episode, and apparently this includes the most severe cases that involve suicide. In addition, the use of OCs has also been linked to reduced sexual desire and interest, one of the common symptoms in depressive disorder. It is unknown why OCs can trigger a depressive episode, at least in a subgroup of women, or how this subgroup at high-risk may be identified in advance.
OCs act by suppressing the hypothalamic-pituitary-gonadal hormonal axis, which drives the reproductive system, resulting in downregulated sex hormones. Such changes in sex-steroid milieu shape human brain biology and function including serotonergic neurotransmission, which is key in maintaining mental health, including regulation of sexual desire. Preliminary and independent data from the Center for Integrated Molecular Brain Imaging (Cimbi) database, strongly suggest that healthy women who use OCs differ in terms of serotonergic brain architecture. In particular when using a potential marker of brain serotonergic function, the investigators have in a cross-sectional study shown, that OC users display lower serotonin 4 receptor (5-HT4R) brain binding relative to non-users. This difference is remarkably large and comparable to what is seen in depressed individuals compared to in healthy controls and to the effects provoked by pharmacological tools as traditional antidepressant drugs (SSRI). The 5-HT4R is relevant in the context of depression, since rodent work points to a fast-acting antidepressant- and anxiolytic-like effect of 5-HT4R stimulation and also, notably, 5-HT4R activation is implicated in behavioral and neurogenic effects of SSRIs. Therefore, a lowered 5HT4R agonism capacity in OC users would offer a plausible explanation for why OC use may provoke depressive symptoms.
The initial cross-sectional observation of a difference in 5-HT4R binding between OC users and non-users warrants replication and validation in an independent dataset and in a study design where causality can be inferred. With this study, the investigators apply longitudinal study design to determine if OC use versus placebo cause changes in 5-HT4R brain binding and if such changes map onto relevant signatures of brain functions and mental states, including sexual desire. The investigators anticipate that this work will substantially advance the understanding of how changes in sex-hormone milieu increase susceptibility for manifest depressive episodes and ideally provide novel preventive and therapeutic opportunities.
Study design:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 22 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Healthy women at 18-22 years of age
- •No use of hormonal contraception within the last year
- •Having a regular menstrual cycle of approximately 28 days, i.e., approximately 28 days between first day of menstrual bleedings.
排除标准
- •Current or previous neurological or psychiatric disease, severe somatic disease, or consumption of medical drugs likely to influence the test results
- •Non-fluent in Danish or pronounced visual or auditory impairments
- •Current or past learning disability
- •Current or previous pregnancy
- •A wish to become pregnant within the following 6 months
- •Participation in experiments with exposure to radioactivity (> 10 mSv) within the last year or significant occupational exposure to radioactivity
- •Contraindications for MRI (pacemaker, metal implants, claustrophobia)
- •Allergy to the ingredients in the administered drug
- •A diagnosis of hypo- or hypertension
- •A history of head injury or concussion resulting in loss of consciousness for more than 2 min
- •Alcohol abuse
- •Drug use other than tobacco and alcohol within the last 30 days
- •Cannabis > 50 x lifetime
- •Recreational drugs > 10 x lifetime (for each substance)
- •Nicotine addiction
- •Current psychoactive medication
- •Any risk factors for thromboembolic events
- •Other contraindications for use of Femicept
研究组 & 干预措施
Femicept
3x28 days of treatment with Femicept. Each cycle consists of 21 days of active pill (Femicept) and 7 days of placebo pill.
干预措施: Femicept (Drug)
Placebo
3x28 days of treatment with placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Change in neostriatal, neocortical, and hippocampal 5-HT4R brain binding from baseline to follow-up measured with Positron Emission Tomography (PET) in active vs. placebo group
时间窗: 3 months
Difference in latent variable construct of 5-HT4R level based on a quantification of 5-HT4R binding in primary regions of interest; neocortex, neostriatum, and hippocampus. Change is compared between the OC- and the placebo group.
次要结局
- Plasma testosterone(At baseline and after 3 months)
- Change in BOLD signal in resting state functional connectivity brain networks measured with fMRI(3 months)
- Change in white matter microstructure(3 months)
- Change in CAR(3 months)
- Change in serial Positive Affect (PA) score derived from daily ratings of the Positive and Negative Affects Schedule (PANAS) questionnaire.(3 months)
- Change in serial Total Mood Disturbance (TMD) scores derived from daily ratings of the Profile of Mood States - Short Form (POMS-SF) questionnaire(3 months)
- Change in serial sexual desire scores derived from daily ratings of the Element of Desire Questionnaire (EDQ)(3 months)
- Change in the Female Sexual Function Index (FSFI) score(2 and 3 months)
- Change in reward stimulated BOLD signal in ventral striatum measured with fMRI(3 months)
- Change in hippocampal volume(3 months)
- Change in total Verbal Affective Memory Test-24 (VAMT-24) performance(3 months)
- Change in affective bias for emotional detection(3 months)
- Plasma progesterone(At baseline and after 3 months)
- Gene transcription and methylation profiles(At baseline and after 3 months)
- Change in affective bias for emotion recognition(3 months)
- Change in Letter-Number Sequencing task score(3 months)
- Change in mean daily sleep quality(3 months)
- Change in Pittsburgh Sleep Quality Index (PSQI)(3 months)
- Plasma estradiol(At baseline and after 3 months)
- Serum allopregnanolone(At baseline and after 3 months)
- Change in General Anxiety Disorder 10 (GAD-10) score(2 and 3 months)
研究者
Vibe G Frøkjær, MD, PhD
MD, Adjunct Professor
Rigshospitalet, Denmark