The Pill Project - Oral Contraceptive and Serotonergic Brain Signaling

NCT05212389 | Unknown DMC

• 1 other identifier: 2021-003366-13
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Major Depressive Disorder; Sexual Behavior; Mood Disturbance; Mood Change; Affect Altered; Affect Blunted; Drug Mechanism

Keywords

Oral Contraceptive; Hormone sensitivity; Positron Emission Tomography; Magnetic Resonance Imaging; Functional Magnetic Resonance Imaging; serotonin 4 receptor; 5-HT4 receptor; (11C)SB207145

Outcome Measures

Primary Outcomes (1)

• 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

  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.

  3 months

Secondary Outcomes (21)

• 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

Other Outcomes (16)

• Change in serial Negative Affect (NA) score derived from daily ratings of the Positive and Negative Affect Schedule (PANAS) questionnaire

  3 months

• Change in Positive Affect (PA) score derived from the Positive and Negative Affect Schedule (PANAS) questionnaire (regarding "last few weeks")

  2 and 3 months

• Change in Negative Affect (NA) score derived from the Positive and Negative Affect Schedule (PANAS) questionnaire (regarding "last few weeks")

  2 and 3 months

Study Arms (2)

Femicept

ACTIVE COMPARATOR

3x28 days of treatment with Femicept. Each cycle consists of 21 days of active pill (Femicept) and 7 days of placebo pill.

Drug: Femicept

Placebo

PLACEBO COMPARATOR

3x28 days of treatment with placebo

Drug: Placebo

Interventions

Femicept DRUG

150 μg levonorgestrel +30 μg ethinylestradiol

Also known as: Combined oral contraceptive

Femicept

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 18 Years - 22 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead

Study Sites (1)

Neurobiology Research Unit

Copenhagen, 2100, Denmark

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Major; Sexual Behavior

Interventions

Contraceptives, Oral, Combined

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavior

Intervention Hierarchy (Ancestors)

Drug Combinations; Pharmaceutical Preparations; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptive Agents; Reproductive Control Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses

Study Officials

• Vibe Frokjaer, MD, PhD

  Neurobiology Research Unit, Copenhagen University hospital, Rigshospitalet, Denmark

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Vibe Frokjaer, MD, PhD

CONTACT

+453545 6714; vibe@nru.dk

Søren Larsen, MD

CONTACT

+453545 6708; soren.vinther@nru.dk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, Adjunct Professor

Model Details: Single-blinded placebo-controlled trial

Study Record Dates

• First Submitted: December 20, 2021
• First Posted: January 28, 2022
• Study Start: December 22, 2021
• Primary Completion: August 31, 2024
• Study Completion: August 31, 2025
• Last Updated: February 28, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Data are expected to become available from December 2026.
• Access Criteria: Data will be available on reasonable request via an application to the Cimbi database of molecular brain PET in healthy humans. Access can be requested through the procedures outlined here: https://cimbi.dk/index.php/documents/category/3-cimbi-database.

Locations

DK (1)